Somatostatin Analogs for Cancer Treatment and Diagnosis

Somatostatin 

Analogs in Cancer 

Management 

Editor 

C. Scarpignato, Parma/Nantes 

17 figures, 1 in color, and 16 tables, 2001 

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© 2001 S. Karger AG, Basel 

Vol. 46, Suppl. 2, 2000 

Contents 

Access to full text and tables of contents, 

including tentative ones for forthcoming issues: 

www.karger.com/journals/che/che_bk.htm 

V Foreword 

Lamberts, S.W.J. (Rotterdam) 

VIII Preface 

Scarpignato, C. (Parma/Nantes) 

1 Somatostatin Analogs for Cancer Treatment and Diagnosis: 

An Overview 

Scarpignato, C.; Pelosini, I. (Parma/Nantes) 

30 Antiproliferative Effect of Somatostatin and Analogs 

Bousquet, C.; Puente, E.; Buscail, L.; Vaysse, N.; Susini, C. (Toulouse) 

40 Established Clinical Use of Octreotide and Lanreotide in 

Oncology 

Öberg, K. (Uppsala) 

54 The Palliative Effects of Octreotide in Cancer Patients 

Dean, A. (Nedlands) 

62 Management of Breast Cancer: Is There a Role for 

Somatostatin and Its Analogs? 

Boccardo, F.; Amoroso, D. (Genoa) 

78 Somatostatin, Its Receptors and Analogs, in Lung Cancer 

O’Byrne, K.J. (Leicester); Schally, A.V. (New Orleans, La.); Thomas, A. 

(Leicester); Carney, D.N. (Dublin); Steward, W.P. (Leicester) 

109 Octreotide in the Management of Hormone-Refractory 

Prostate Cancer 

Vainas, I.G. (Thessaloniki)

127 Gastrointestinal Cancer Refractory to Chemotherapy: 

A Role for Octreotide? 

Cascinu, S.; Catalano, V.; Giordani, P.; Baldelli, A.M.; Agostinelli, R.; 

Catalano, G. (Pesaro) 

134 Pancreatic Cancer: Does Octreotide Offer Any Promise? 

Rosenberg, L. (Montreal) 

150 Octreotide for Cancer of the Liver and Biliary Tree 

Kouroumalis, E.A. (Heraklion) 

162 Somatostatin Analogs in Oncology: A Look to the Future 

Jenkins, S.A. (Swansea); Kynaston, H.G. (Cardiff); Davies, N. 

(London); Baxter, J.N. (Swansea); Nott, D.M. (London) 

197 Author Index 

198 Subject Index 

IV Contents

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Accessible online at: 

www.karger.com/journals/che 

Foreword 

Somatostatin plays an inhibitory role in 

the regulation of the function of a number of 

organs like the brain, the anterior pituitary 

gland, the gastrointestinal tract, the exocrine 

and endocrine pancreas, as well as lymphoid 

cells. It can be considered as an inhibitory 

(growth) factor in these organs, which mainly 

prevents local overreaction from a multitude 

of stimulatory factors. 

In addition to the negative role in controlling 

the physiological regulation of these organ 

systems, somatostatin also exerts inhibitory 

effects on the proliferation of normal and 

neoplastic cells. Somatostatin analogs inhibit 

tumor growth in a wide variety of experimental 

models in several species, like transplantable 

osteo- and chondrosarcomas, transplantable 

acinar and ductal pancreatic carcinomas, 

as well as different types of rat and mouse 

mammary and prostatic carcinomas. Also, a 

number of human pancreatic, colonic, gastric 

and small cell lung cancer lines xenografted in 

nude mice are inhibited in their growth during 

therapy with somatostatin analogs. 

While most of these experimental tumors 

and cell lines express a dense and homogeneous 

distribution of somatostatin receptors, 

some of these tumors seem to be inhibited in 

growth by somatostatin analog administra- 

tion via indirect mechanisms involving inhibitory 

effects on local or general growth factors 

(growth hormone, insulin-like growth factor 

1, epidermal growth factor, gastrointestinal 

hormones) and/or angiogenesis. 

One should realize, however, that in most 

of the experimental models the inhibitory effects 

of somatostatin analogs on growth are 

most potent early after tumor implantation as 

well as early after the start of drug administration, 

and that complete growth curves of the 

(transplanted) tumors with and without somatostatin 

analog treatment often indicate a 

delay in growth only, while an escape of tumor 

growth from the inhibitory effects of somatostatin 

analogs is observed eventually. This 

indicates a decreased sensitivity of these tumors 

during long-term somatostatin analog 

therapy, which involves somatostatin receptor 

downregulation and/or the selection of 

somatostatin receptor-negative tumor cell 

clones. 

In clinical oncology prostate, breast and 

endometrial carcinomas are known to be 

‘conditional’ cancers, which grow in certain 

specific hormonal environmental conditions. 

When these conditions are altered the tumors 

regress, but do not die. After a certain period 

of a persistent nonproliferating state, part of 

V

the tumor cells resume active growth. This is 

the simple basis for the success of androgen, 

estrogen and progesterone depletion in the 

treatment of these cancers. The symptomatic 

relief of patients with metastatic prostatic, 

breast and endometrial cancers during treatment 

with antiandrogens, antiestrogens and 

progesterone receptor-blocking agents is highly 

appreciated and looked for by oncologists 

that otherwise mainly use intensive chemotherapy. 

The promising data demonstrating that 

many experimental tumor models also seem 

to be ‘conditionally’ dependent on somatostatin, 

growth hormone, insulin-like growth factor 

1, prolactin and other hormones and 

growth factors has raised hopes that direct or 

indirect blockade of their activity and/or receptors 

on metastatic human cancers with 

well-tolerated drugs like somatostatin analogs, 

bromocriptine and retinoids would also 

induce a transient state of dormancy or even a 

slight temporary regression. Also, the somatostatin 

analog octreotide is widely and successfully 

used in patients with acromegaly, 

metastatic islet cell tumors and carcinoids. In 

these patients the quality of life improves and 

there is strong evidence for control of tumor 

growth as well as a clear prolongation of survival. 

Like most hormone-secreting tumors 

many human adenocarcinomas originating 

from the breast, colon, kidney, ovary as well 

as meningiomas and malignant lymphomas 

often express somatostatin receptors. Although 

somatostatin receptors are in many 

cases not distributed homogeneously over all 

tumor cells, and their numbers per tumor cell 

in general are lower than in hormone secreting 

tumors, most somatostatin receptor-bearing 

human cancers can be visualized by somatostatin 

receptor imaging. Only little evidence 

so far indicates that long-term therapy of patients 

with somatostatin receptor-positive tu- 

VI 

mors with somatostatin analogs induces a decrease 

or even control of tumor growth. More 

evidence points to a transient improvement 

in the quality of life in some of the patients 

treated. 

Human cancers differ in many respects 

from the experimental tumor models that respond 

so well to somatostatin analog therapy. 

(1) Most human cancers consist of a mixture 

of varying amounts of stromal tissue and different 

clones of epithelial tumor cells that do 

not uniformly express somatostatin receptors. 

This sharply contrasts with the monoclonal 

tumor models in animals, which in most instances 

express somatostatin receptors on all 

tumor cells. (2) Somatostatin receptor expression 

in human breast, prostate and colonic 

cancers often indicates loss of differentiation 

of the tumors, meaning that these undifferentiated 

tumors have a bad prognosis. (3) The 

nature of new clinical trials in oncology is 

often such that patients are mainly included 

‘late’ in their disease, when tumors have already 

progressed considerably. Also, it remains 

uncertain whether somatostatin receptor subtype 

2 (SSTR-2)-specific analogs like octreotide 

are the optimal compounds to be used in 

the treatment of human cancer. These analogs 

have little activity towards the SSTR-3 subtype, 

which is important in mediating apoptosis. 

In vitro studies have demonstrated that 

SSTR-2-expressing tumor cell lines as well 

as primary cultures of human tumors internalize 

radiolabeled somatostatin analogs like 

111 In-[DTPA 0 ]octreotide and [ 90 Y-DOTA 0 , 

Tyr 3 ]octreotide. Preclinical studies using experimental 

tumor models have now demonstrated 

that tumor growth can be inhibited by 

administration of these two radiopharmaceutical 

compounds. Clinical trials already demonstrated 

promising effects using these radiopharmaceuticals 

on tumor size in patients 

with advanced somatostatin receptor-positive 

neuroendocrine tumors. Also, the concept of 

Foreword

targeted chemotherapy to deliver chemotherapeutic 

compounds selectively to somatostatin 

receptor-positive tumor cells, thereby reducing 

their toxicity, has now been validated 

using newly developed cytotoxic somatostatin 

analogs in experimental mouse and rat models 

of human pancreatic, breast and prostate 

cancers. 

In this supplement to Chemotherapy Professor 

Scarpignato has succeeded in bringing 

together the most knowledgeable scientists in 

the field of oncology that have extensive personal 

experience with the use of somatostatin 

analogs in the treatment of cancer patients. 

Foreword 

They review the current status of their use in 

an admirable manner, while the perspectives 

of newer forms of therapy with the targeted 

somatostatin receptor-mediated approach are 

also discussed. 

I would like to congratulate the editor and 

the contributors on the exhaustive and balanced 

description of the current thoughts on 

the use of somatostatin analogs in patients 

with different forms of metastasized cancer. 

S.W.J. Lamberts, MD, PhD 

Professor of Medicine 

University Hospital Dijkzigt, Rotterdam 

VII

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Preface 

Despite the enormous advances in science 

and medical technology in recent times, our 

knowledge of the pathophysiology and treatment 

of neoplasia is far from complete and, 

for the patients at least, the myths that surround 

cancer remain intact. Cancer remains 

the ‘bogy man’ of medicine as we enter the 

new millennium, and the very mention of the 

word strikes mortal fear in patients and their 

families in a way not generally seen with any 

other disease. 

Although chemotherapy is very effective in 

the management of certain neoplasms such as 

testicular cancer, the efficacy of this therapeutic 

modality in the treatment of many 

common malignancies such as those of the 

lung, breast, prostate, bowel, pancreas and 

kidney is limited. Cure of macroscopic metastatic 

disease is exceedingly rare, and palliation 

of symptoms of metastatic neoplasms by 

chemotherapy can be problematic since the 

toxicity of the treatment often outweighs any 

improvement in quality of life resulting from 

a temporary decrease in tumor burden. This 

situation has not only motivated attempts to 

develop novel cytotoxic agents and targeted 

chemotherapy, but has also stimulated research 

on innovative noncytotoxic therapies 

for cancer. 

Amongst the various hormonal agents, currently 

being evaluated for the management of 

neoplasia, considerable attention is directed 

to somatostatin analogs. This is largely due to 

the demonstration of antineoplastic activity 

of these compounds in a variety of experimental 

models in vitro and in vivo and to the elucidation 

of some aspects of the molecular 

mechanisms whereby they exert their cytostatic 

and cytotoxic effects. Furthermore, 

clinical experience with somatostatin analogs 

in the treatment of conditions such as acromegaly 

and GEP tumors has shown that they 

are well tolerated compared to other antineoplastic 

therapies currently in use. As a consequence, 

there is much ongoing clinical research 

to determine whether or not results 

from experimental studies will translate into 

clinically useful antineoplastic activity. 

In the recent years there has been extensive 

international media coverage of the allegedly 

successful treatment of a number of malignant 

neoplasms with the Di Bella multitherapy 

(DBM). This is a multidrug, individually 

tailored medical treatment (comprising a 

mixture of melatonin, bromocriptine, somatostatin, 

a solution of retinoids, and, depending 

on the kind of cancer, either cyclophosphamide 

or hydroxyurea) developed by Luigi

Di Bella, an Italian physician. Over the past 

25 years Dr. Di Bella has consistently used it 

on an outpatient basis claiming its effectiveness 

in halting the progression or completely 

curing most cancers. Not surprisingly, in view 

of the public interest in cancer therapy, a 

number of associations have been formed to 

support this treatment. As a matter of fact, 

these associations mounted a campaign to 

request that DBM be included among those 

cancer treatments considered to be effective 

and that its cost be fully reimbursed by the 

Italian National Health Service. Despite some 

debate about the methodology of the different 

clinical trials [1–8], a phase II study, coordinated 

by the Italian National Institute of 

Health and the National Cancer Advisory 

Committee, did not show sufficient efficacy 

in patients with advanced cancer to warrant 

further clinical testing [9]. Furthermore, a follow-up 

of treated patients did not give any 

evidence that DBM improves the survival of 

cancer patients [10]. 

Since somatostatin or octreotide represent 

only one component of the DBM, the ineffectiveness 

of this approach does not necessarily 

translate into a lack of efficacy of peptide analogs 

in the management of neoplasia. A single 

component of a multidrug therapy could indeed 

be effective on its own [11]. However, as 

summarized by Jenkins et al. [12] in this 

issue, apart from some notable exceptions, 

somatostatin analog therapy has proven to be 

disappointing in the management of advanced 

malignancy. Should somatostatin analogs be 

abandoned? A thorough analysis of the available 

literature suggests that this is not the 

case. Indeed, besides being used in cancer 

treatment (alone or in combination with other 

cytotoxic or hormonal agents) and palliation, 

radiolabelled somatostatin analogs are employed 

for the localization of primary and 

metastatic tumors expressing somatostatin receptors. 

Indeed the so-called ‘somatostatin re- 

Preface 

ceptor scintigraphy’ is the most important 

clinical diagnostic investigation for patients 

with suspected neuroendocrine tumors. Targeted 

radiotherapy, which is being evaluated 

in clinical trials, represents an obvious extension 

of somatostatin scintigraphy. In addition, 

new receptor-selective and ‘universal’ 

analogs are being developed and new highdose 

regimens are being tested. Further, somatostatin 

receptor-targeted chemotherapy 

represents an appealing approach to treatment 

of SSTR-expressing tumors. Finally, the 

genetic transfer of hSSTR-2 and hSSTR-5 

genes together with the genes that encode 

their membrane proteins to those neoplasms 

that do not express these receptor subtypes 

will translate the benefits of gene therapy to 

somatostatin analogue treatment of cancer. 

The final chapter on somatostatin and cancer 

has, therefore, not yet been written. 

Taking all the above considerations into 

account, we felt it timely and worthwhile to 

attempt a critical review of the recent developments 

in the field. To this end, the present 

issue of Chemotherapy was planned with the 

aim of synthesizing the massive body of evidence 

available on somatostatin analog therapy 

of cancer and the scientific basis for their 

antineoplastic effects, to enable oncologists to 

rationalize the use of these compounds in 

their clinical practice and to stimulate research 

on new therapeutic approaches. 

Unlike some other publications in the 

field, this supplement is not the result of any 

national or international symposium. It represents 

the collection of 11 commissioned 

monographic reviews generously offered by 

30 international scientists, all of whom have 

significantly contributed to this new knowledge, 

in order to provide a glimpse of what 

may lie ahead. I am indebted to all the contributors 

for having accepted to share with us 

their experience of somatostatin analog therapy 

of cancer and for providing us with excel- 

IX

lent manuscripts despite their many daily 

commitments. 

I would like to thank Mr. Peter Roth and 

Mrs. Andrea Brauns of S. Karger AG for 

their excellent cooperation during the publication 

of this supplement. Moreover, I am 

grateful to Novartis Pharma AG who backed 

the publication costs and to Voluntary Association 

for Cancer Research in Parma 

(A.VO.PRO.RI.T.) for financial help and for 

spreading this volume to Italian physicians. 

My sincere gratitude goes also to Dr. Viktor 

Boerlin, Mr. Gary Cheng and Dr. Susanne 

Schaffert at the Strategic Marketing Depart- 

November 2000 

References 

1 Müllner M: Di Bella’s therapy: The 

last word? The evidence would be 

stronger if the researchers had randomised 

their studies. BMJ 1999; 

318:208–209. 

2 Reyes JL: Compared to what? eBMJ 

1999; 22 January. 

3 Liberati A, Magrini N, Patoia L, Pagliaro 

L: Randomised controlled 

trials may not always be absolutely 

needed. BMJ 1999;318:1073. 

4 Raschetti R, Bruzzi P: Methodological 

and ethical difficulties in clinical 

oncology trials. Di Bella Multitreatment 

Italian Trial Coordinating 

Group. Lancet 1999;353:153–154. 

5 Raschetti R, Greco D, Menniti-Ippolito 

F, Spila-Alegiani S, Traversa 

G, Benagiano G, Bruzzi P: The Di 

Bella multitherapy trial. Criticisms 

ignores standard methodology of 

cancer treatments. BMJ 1999;318: 

1074. 

6 Müllner M, Evans SJW: Reply. BMJ 

1999;318:1073. 

7 Tirelli U, Di Filippo F: Debate on 

Di Bella therapy. Lancet 1999;354: 

159. 

8 Laderoute MP: Debate on Di Bella 

therapy. Lancet 1999;354:159. 

9 Italian Study Group for the Di Bella 

Multitherapy Trials: Evaluation of 

an unconventional cancer treatment 

(the Di Bella multitherapy): Results 

of phase II trials in Italy. BMJ 1999; 

318:224–228. 

X Preface 

ment, Novartis, who rendered this publication 

possible. They have shown great interest in the 

project from the very beginning and made 

huge efforts to make these proceedings available 

to the medical community. Last but not 

least, I am indebted to Dr. Spencer A. Jenkins 

(Departments of General Surgery & Urology, 

University Hospital of Wales, Cardiff, UK) for 

his invaluable help during my editorial work. 

He made constructive criticism and gave useful 

suggestions for every paper published in 

this supplement. We have had many discussions 

from which some ideas and concepts 

expressed in our papers emerged. 

Carmelo Scarpignato 

MD, DSc (Hons), PharmD (h.c.), FCP, FACG 

Professor of Pharmacology and Therapeutics 

Associate Professor of Gastroenterology 

Universities of Parma and Nantes 

10 Buiatti E, Arniani S, Verdecchia A, 

Tomatis L: Results from a historical 

survey of the survival of cancer patients 

given Di Bella multitherapy. 

Cancer 1999;86:2143–2149. 

11 Calabresi P: Medical alternatives to 

alternative medicine. Cancer 1999; 

86:1887–1889. 

12 Jenkins SA, Kynaston HG, Davies 

N, Baxter JN, Nott DM: Somatostatin 

analogues in oncology: A look to 

the future. Chemotherapy 2001;47 

(suppl 2):162–196.

Chemotherapy 2001;47(suppl 2):1–29 

Somatostatin Analogs for 

Cancer Treatment and Diagnosis: 

An Overview 

Carmelo Scarpignato a, b Iva Pelosini a 

a Department of Internal Medicine, School of Medicine and Dentistry, University of Parma, 

Italy; b Department of Gastroenterology and Hepatology, Faculty of Medicine, University of 

Nantes, France 

Key Words 

Somatostatin W Octreotide W Lanreotide W 

Vapreotide W Cancer treatment W 

Somatostatin receptor scintigraphy W 

Somatostatin receptor-targeted 

radiotherapy 

Abstract 

Due to the limited efficacy and considerable 

toxicity of conventional chemotherapy, novel 

cytotoxic agents and innovative noncytotoxic 

approaches to cancer treatment are being 

developed. Amongst the various hormonal 

agents, increasing attention is being 

directed to somatostatin analogs. This is 

largely due to the demonstration of antineoplastic 

activity of these compounds in a variety 

of experimental models in vitro and in 

vivo and to the elucidation of some aspects 

of the molecular mechanisms underlying 

their antineoplastic activity. On the other 

hand, clinical experience with somatostatin 

analogs in the treatment of conditions like 

ABC 

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0009–3157/01/0478–0001$17.50/0 



acromegaly and GEP tumors has shown that 

they are well tolerated compared to other 

antineoplastic therapies currently in use. As 

a consequence, there is much ongoing clinical 

research to determine whether or not 

results from experimental studies will translate 

into clinically useful antineoplastic activity. 

Besides being used in cancer treatment 

and palliation, radiolabelled somatostatin 

analogs are employed for the localization of 

primary and metastatic tumors expressing 

somatostatin receptors. The so-called ‘somatostatin 

receptor scintigraphy’ is indeed the 

most important clinical diagnostic investigation 

for patients with suspected neuroendocrine 

tumors. Targeted radiotherapy, which 

is being evaluated in clinical trials, represents 

an obvious extension of somatostatin 

scintigraphy. Since the short half-life of native 

somatostatin makes continuous intravenous 

infusion mandatory, several long-acting 

analogs have been synthesized. Amongst 

the hundreds of peptides synthesized, octreotide 

(which binds mainly to SSTR-2 and 

Carmelo Scarpignato, MD, DSc, PharmD, FCP, FACG 

Laboratory of Clinical Pharmacology, Department of Internal Medicine 

Maggiore University Hospital, I–43100 Parma (Italy) 

Tel. +39 0521 903863, Fax +39 0521 292499, E-Mail scarpi@tin.it

SSTR-5 receptor subtypes) has been the 

most extensively investigated. A thorough 

analysis of the pharmacological activities 

and therapeutic efficacy of the native somatostatin 

and the synthetic analogs (octreotide, 

lanreotide and vapreotide) reveals that 

the biological actions of these peptides are 

not always identical. These differences appear 

to be related to the different affinities of 

the natural hormone and synthetic derivatives 

for the different receptor subtypes. For 

all the three peptides long-lasting formulations 

have been developed to provide patients 

with the convenience of once or twice a 

month administration and to ensure stable 

drug serum concentrations between injections. 

Radiolabelled derivatives of octreotide, 

lanreotide and vapreotide have been synthesized 

and used as radiopharmaceuticals for 

somatostatin receptor scintigraphy and somatostatin 

receptor-targeted radiotherapy. 

The safety profile of synthetic somatostatin 

analogs is well established. Most adverse 

reactions to these peptides are merely a consequence 

of their pharmacological activity 

and consist mainly of gastrointestinal complaints, 

cholelithiasis and effects on glucose 

metabolism. They are often of little clinical 

relevance, thus making somatostatin analogs 

safe drugs for long-term use. While immediate 

release preparations are the drugs 

of choice in the short term, long-acting formulations 

are better indicated, on an outpatient 

basis, for the long-term management of 

chronic conditions. New ‘receptor-selective’ 

and ‘universal’ somatostatin analogs are being 

developed and combinations of currently 

available derivatives with other (cytotoxic 

and/or hormonal) agents are being explored 

in the search for an efficacious and well-tolerated 

treatment of the various malignancies. 

Somatostatin receptor-targeted chemotherapy 

(with conjugates of somatostatin peptides 

with cytotoxic drugs) and gene therapy (e.g. 

transferring the SSTR-2 gene into neoplastic 

cells), which have been successfully tested in 

experimental studies, should be applied to 

human beings in a not too distant future. 

Introduction 

2 Chemotherapy 2001;47(suppl 2):1–29 Scarpignato/Pelosini 

Copyright © 2001 S. Karger AG, Basel 

Although cytotoxic chemotherapy is very 

effective in the management of certain neoplasms 

such as testicular cancer, the efficacy 

of this therapeutic modality in the treatment 

of many common neoplasms such as those of 

the lung, breast, prostate, bowel, pancreas and 

kidney is limited. Cure of macroscopic metastatic 

disease is exceedingly rare, and palliation 

of symptoms of metastatic neoplasms by 

chemotherapy can be problematic since the 

toxicity of the treatment often outweighs any 

improvement in quality of life resulting from 

the temporary decrease in tumor burden [1– 

4]. Moreover, postsurgical adjuvant chemotherapy 

is frequently without beneficial effect 

(as in the case of renal cancer), or is associated 

with only small improvements in diseasefree 

survival (as in the case of colon cancer, 

for instance). This situation has not only 

motivated attempts to develop novel cytotoxic 

agents, but also has stimulated the research 

regarding innovative noncytotoxic approaches 

to cancer treatment [1–4]. 

Amongst the various hormonal agents, increasing 

attention is being directed to somatostatin 

analogs [5–12]. This is largely due 

to the demonstration of antineoplastic activity 

of these compounds in a variety of experimental 

models in vitro and in vivo [5, 7] and 

to the elucidation of some aspects of the molecular 

mechanisms underlying their antineoplastic 

activity [13–16]. On the other hand, 

clinical experience with somatostatin analogs 

in the treatment of conditions like acromegaly 

and GEP tumors has shown that they are well

tolerated compared to other antineoplastic 

therapies currently in use [16, 17]. As a consequence, 

there is much ongoing clinical research 

to determine whether or not results 

from experimental studies will translate into 

clinically useful antineoplastic activity. 

Besides being used in cancer treatment and 

palliation, radiolabelled somatostatin analogs 

are employed for the localization of primary 

and metastatic tumors expressing somatostatin 

receptors [18–21]. The so-called ‘somatostatin 

receptor scintigraphy’ is indeed 

the most important clinical diagnostic investigation 


tumors [19]. Targeted radiotherapy, 

which is being evaluated in clinical trials [22, 

23], represents an obvious extension of somatostatin 

scintigraphy. This paper will review 

the chemistry and pharmacokinetics of 

currently used synthetic peptides and summarize 

the rationale for their use in cancer treatment 

and diagnosis. 

Somatostatin Analogs: 

Chemistry and Pharmacokinetics 

Due to its central role in the regulation of 

growth hormone secretion, somatostatin is often 

referred to as somatotropin release-inhibiting 

factor (SRIF) or growth hormone (GH) 

release-inhibiting factor [24]. This peptide 

displays a wide range of biological actions that 

can make it an appropriate drug for the treatment 

of a variety of human diseases. 

Shortly after the isolation of somatostatin, 

protein chemists began to synthesize peptide 

analogs with a similar spectrum of action but 

with much longer biological half-life [25]. The 

short half-life of the native peptide [26] makes 

indeed continuous intravenous infusion mandatory. 

To design a more stable peptide derivative 

one needs to strengthen the metabolic resis- 

Somatostatin Analogs for Cancer 

Treatment and Diagnosis 

Fig. 1. Sites of enzymatic degradation of natural somatostatin. 

tance of the cleavage sequences of the native 

peptide. In the case of somatostatin, at least 5 

sites of enzymatic degradation are known 

(fig. 1) [27]. The most dangerous cleavage can 

occur after Trp 8 because such a rupture leads to 

completely inactive fragments. Aminopeptidase 

attack at the N-terminal is less important 

since sequences which are 1 or 2 amino acids 

shorter are as potent as the native peptide. 

The usual trick to prevent or slow down 

enzymatic degradation of a peptide is the 

replacement of an L-amino acid by its D-isomer. 

Fortunately, the systematic replacement 

of L- by D-amino acids demonstrated that this 

exchange at position 8 is not only well tolerated 

but also leads to an enhanced GH-inhibitory 

potency [28]. 

Further important information on the active 

site can be deduced by systematic replacement 

of all amino acids in SRIF by a 

neutral amino acid such as Ala. The total 

inactivity of analogs with Ala in positions 6, 7, 

8 or 9 indicates that these residues are essential 

for its biological activity. Similarly, yet 

more information can be gained by systematically 

deleting single amino acids from the natural 

sequence. Such studies showed that the 

first two amino acids, Ala-Gly, are not necessary 

for full biological activity [28]. 

Chemotherapy 2001;47(suppl 2):1–29 3

Fig. 2. Primary structure of octreotide and derived peptides. 

Table 1. Synthetic analogs of somatostatin currently available 

Cyclic octapeptide analogsLinear peptide analogsHexapeptide analogs 

SMS 201-995 (octreotide) 

RC-160 (vapreotide) 

NC-8-12 

NC-4-28S 

DC 23-60 

BIM 23014 (lanreotide) 

BIM 23023 

BIM 23034 

BIM 23059 

BIM 23060 

D-Trp 8 somatostatin-14. 

Lcu 8 , D-Trp 22 , Tyr 25 somatostatin-28. 

Against this background, hundreds of somatostatin 

analogs have been synthesized in 

many research centers all over the world. 

Amongst the different peptides (table 1), the 

octapeptide SMS 201-995, called octreotide, 

has been the most extensively investigated 

[for reviews, see 29–32]. More recently, two 

BIM 23049 

BIM 23051 

BIM 23052 

BIM 23053 

BIM 23055 

BIM 23057 

BIM 23065 

BIM 23067 

BIM 23068 

BIM 23069 

4 Chemotherapy 2001;47(suppl 2):1–29 Scarpignato/Pelosini 

MK-678 

BIM 23050 

Linear octapeptide analogs 

EC5-21 

BIM 23042 

BIM 23056 

BIM 23058 

additional peptides [33], namely lanreotide 

(BIM 23014) [34] and vapreotide (RC-160) 

[35], have become available for clinical use. It 

is worthwhile to emphasize that all the three 

peptides share a common feature, namely 

the tetrapeptide X 7 -Trp 8 -Lys 9 -Y 10 (where X 

could be either Phe or Tyr and Y either Thr or

Fig. 3. Stability of octreotide (SMS 

201-995) and SIRF against degradation 

by rat kidney homogenates 

[from 25]. 

Fig. 4. Plasma levels of unchanged 

peptides in the rat: intravenous 

application of [ 3 H-Phe 6 ]SRIF (o) 

and [ 4 C-D-Trp 4 ]octreotide ()). 

SRIF was injected at 1.6 mg/kg 

(12–16 mCi/mmol), octreotide at 

1 mg/kg (35 ÌCi/mg). Unchanged 

peptides were recovered after highpressure 

liquid chromatography 

purification of plasma samples. 

Data are taken from Peters [42] for 

SRIF and from Lemaire et al. [38] 

for octreotide. Only the most relevant 

alpha phases of elimination 

are indicated. 

Val, fig. 2), thus suggesting that this amino 

acid sequence is essential for receptor binding 

[36]. And indeed conformational analysis of 

the bioactive analogs of somatostatin that 

have conformational constraints revealed that 

the peptide backbone is not directly involved 

in binding, but serves mainly as a scaffold 

allowing the side chains to adopt the necessary 

pharmacophore spatial arrangement necessary 

for receptor binding [37]. 

Compared with native somatostatin, the 

synthetic derivatives show a remarkable stability. 

Indeed, introduction of a D-amino acid (D- 

Phe or D-ßnal) at the N-terminus protects 

against exopeptidases, as does the amino-alcohol 

Thr(ol) at the C-terminus of octreotide and 



lanreotide. The disulfide bridge itself offers 

some protection, and the D-Trp protects a position 

which would otherwise be cleaved by a 

specific endopeptidase. For instance, when incubated 

with kidney homogenate, a system 

known to degrade natural peptides within a few 

minutes, more than 90% of the biological activity 

of octreotide was still present after 20 h, 

whereas the natural peptide was almost completely 

destroyed in less than 1 h (fig. 3) [25]. 

The pharmacokinetics of octreotide was 

investigated in rats after administration of 

unlabelled and labelled ( 3 H- and 14 C-) peptides 

[38], and data were compared with those 

from a study with 3 H-labelled SRIF [39] 

(fig. 4). The marked stability of octreotide 

Chemotherapy 2001;47(suppl 2):1–29 5 

3 

4

Fig. 5. Tissue levels of octreotide 

after subcutaneous administration 

of 1 mg/kg in the rat. Tissue levels 

were measured by means of 

a specific radioimmunoassay after 

extraction into a mixture of 

methanol-trifluoroacetic acid (80– 

0.1%) and subsequent lyophilization 

and reconstitution in buffer. 

For each organ the columns represent 

(from left to right) concentrations 

measured 0.5, 4, 7 and 24 h 

after administration [from 39]. 

against proteolytic degradation together with 

a reduced hepatic clearance is responsible for 

the dramatically improved elimination halflife 

in rats [39, 40]. In both rats and monkeys, 

the peptide is well absorbed after subcutaneous 

administration, the elimination rate 

(based on plasma levels) being slower in the 

latter species [41]. Significant levels of octreotide 

can also be detected in the rat after oral 

administration of the peptide [41]. 

While extensive degradation into small 

fragments and amino acids is evident in all 

tissues within the first minutes after intravenous 

injection of 3 H-SRIF in rats [42], octreotide 

proved to be quite stable in all the tissues 

examined [38]. Concentrations measured by 

quantitative whole body autoradiography, 

which determines total radioactivity, and by 

specific radioimmunoassay were quite comparable. 

Thirty minutes after intravenous administration 

the highest concentrations were 

detected in the kidney, skin and liver. By following 

the time course of organ distribution 

of total radioactivity and of unchanged octreotide 

(fig. 5) it became apparent that elimination 

from presumed target organs such as 

pituitary and pancreas was much slower when 

compared with nontarget tissues such as muscle, 

lung and heart. This indicates high-affini- 

ty binding to target receptors characterized by 

slow off-kinetics. 

Pharmacokinetic investigations have also 

been performed in healthy subjects and patients 

with pituitary tumors and the review by 

Chanson et al. [40], to which the reader is 

referred, thoroughly summarizes all the available 

data. Studies in healthy volunteers [43] 

demonstrated that octreotide plasma levels 

are proportional to the dose administered 

both after intravenous and subcutaneous administration. 

Plasma peak concentration values, 

which were reached after 30 min, were 

approximately half those obtained after intravenous 

injection of the same dose. Systemic 

bioavailability after subcutaneous octreotide 

was reported to be almost complete [44]. 

Plotting the areas under concentration-time 

curves (AUCs) against the dose administered, 

gives a linear relationship and this suggests 

that the pharmacokinetic of octreotide is linear 

– at least in the dose range studied – irrespective 

of the route of administration [43]. 

The disposition half-life ranged from 80 to 

100 min for both routes of administration, 

depending on the dose, that is more than 30 

times the half-life of the natural peptide. 

In blood, octreotide is mainly distributed 

in the plasma, 65% of the drug being bound to 

6 Chemotherapy 2001;47(suppl 2):1–29 Scarpignato/Pelosini

lipoprotein and, to a lesser extent, albumin, 

while negligible amounts are taken up by red 

cells [38]. No conclusive data are available 

concerning the tissue distribution of octreotide 

in humans [45], although it has been 

shown that the drug concentrates in many tissues 

in the rat [38]. 

Pharmacokinetic data on the metabolism 

and elimination of octreotide are similar in 

acromegalic and healthy individuals [46, 47]. 

When compared with healthy volunteers, total 

body clearance of octreotide was reduced 

to 75 ml/min (4.5 liters/h) in patients with 

chronic renal failure [48]. Although biliary 

excretion and proteolysis are also important 

elimination pathways in the rat and the dog, 

they have not been thoroughly studied in humans. 

The pharmacokinetics of lanreotide in 

healthy volunteers [49, 50] has shown a pattern 

similar to that observed with octreotide, 

i.e. a Tmax of about 30 min and an elimination 

half-life of 90 min after single subcutaneous 

injection of the peptide. The pharmacokinetics 

of lanreotide proved to be linear either 

after subcutaneous or intravenous route. The 

significant negative correlation between plasma 

GH and peptide concentrations observed 

in the study does suggest a dose-dependent 

biological effect [49]. Conversely from octreotide, 

lanreotide in blood is mainly bound to 

albumin [51]. 

Given the very short half-life of SRIF, distribution 

and elimination studies become almost 

obsolete, and application is restricted to 

continuous infusion to maintain therapeutically 

relevant plasma concentrations. With 

octreotide and lanreotide, however, the highly 

improved metabolic stability, small volume 

of distribution and low clearance result in a 

long duration of exposure; consequently, longlasting 

biological activity after a single subcutaneous 

injection of the analogs is obtained. 



Receptor Selectivity of Somatostatin 

Analogs 

The action of somatostatin is mediated 

through specific receptors that are functionally 

coupled to inhibition of adenylyl cyclase via 

pertussis toxin-sensitive GTP binding proteins 

[for reviews, see 15, 52–54]. Up to five 

cell-surface somatostatin receptors have been 

characterized. They have been termed SSTR- 

1 through SSTR-5 according to the chronology 

of their discovery and because they all display 

the structural hallmark of the seventransmembrane-domain 

receptor (SSTR is indeed 

the acronym for somatostatin seventransmembrane-domain 

receptor). Their tissue 

distribution is depicted in figure 6. Human 

SSTRs (hSSTRs) are encoded by a family 

of 5 genes which map to separate chromosomes 

and which, with one exception, are 

intronless. SSTR-2 gives rise to spliced variants, 

SSTR-2A and 2B. hSSTR-1 to hSSTR-4 

display weak selectivity for SST-14 binding 

whereas hSSTR-5 is SST-28-selective. Based 

on structural similarity and reactivity for octapeptide 

and hexapeptide SST analogs (table 

2), hSSTR-2, 3 and 5 belong to a similar 

SSTR subclass. hSSTR-1 and 4 react poorly 

with these analogs and belong to a separate 

subclass [55, 56]. 

Somatostatin receptors have also been detected 

in a number of tumors such as pituitary 

adenomas, neuroendocrine and nonendocrine 

tumors [57–60]. Pituitary and islet tumors 

express several SSTR genes suggesting 

that multiple SSTR subtypes are coexpressed 

in the same cell [56]. However, there is variability 

in both the number and the distribution 

of somatostatin receptors between tumors 

and from site to site in a given tumor 

[61, 62]. Since a variable suppression of GH 

plasma levels following administration of somatostatin 

or octreotide has been demonstrated 

in an acromegalic patient, it has been 


Fig. 6. Localization of human somatostatin receptors. GI = Gastrointestinal. 

Table 2. Agonist selectivity (Ki, nM) of cloned hSSTR 

Compound SSTR-1 SSTR-2 SSTR-3 SSTR-4 SSTR-5 

Somatostatin-14 

1.1 1.3 1.6 0.53 0.9 

Somatostatin-28 2.2 4.1 6.1 1.1 0.07 

Octreotide 11,000 2.1 4.4 11,000 5.6 

Lanreotide 11,000 1.8 43 66 0.62 

Vapreotide 11,000 5.4 31 45 0.7 

Seglitide 11,000 1.5 27 127 2 

From Patel and Srikant [55]. 

Table 3. Receptor selectivity of some synthetic somatostatin analogs 

Compound SSTR-1 SSTR-2 SSTR-3 SSTR-4 SSTR-5 

Somatostatin-14 

Synthetic analogs 

+++ +++ +++ +++ +++ 

Octreotide 0 ++ + 0 + 

Lanreotide 0 ++ 0 0 +++ 

Vapreotide 0 + 0 0 +++ 

Derived from data in table 2 by using a cut-off value for agonist selectivity (Ki) of 6 nM. 

hypothesized that the heterogeneity of both 

the number and distribution of somatostatin 

receptors might in part explain the individual 

variable sensitivity to treatment with somatostatin 

or its analogs [61, 62]. 

Although the actions of synthetic analogs 

are similar to those of native somatostatin, 

some differences have emerged that probably 

relate to the different ligand affinities for 

SSTR subtypes (table 3). This may have sev- 


eral clinical consequences and the spectrum 

of the therapeutic efficacy of octreotide and 

its derivatives (i.e. lanreotide and vapreotide) 

may not be the same as somatostatin. Indeed, 

cells expressing SSTR-1 or SSTR-4 will respond 

poorly or not at all to somatostatin analogs. 

Somatostatin Analogs: Mechanisms 

of the Antineoplastic Action 

Besides having an important role in the 

symptomatic treatment of endocrine tumors 

through peptide suppression, somatostatin 

may also exert an antiproliferative effect, 

which is not limited to endocrine tumors. 

Nonendocrine tumors may also be affected, 

although some somatostatin influence may in 

part be hormonally mediated. Some authors 

have actually reported – after treatment with 

somatostatin and synthetic analogs – tumor 

regression either in patients or animals with 

experimentally induced neoplasms. 

More recent research has provided information 

regarding mechanisms underlying the 

antiproliferative and apoptosis-inducing actions 

of somatostatin analogs. These include 

both direct mechanisms that are sequelae of 

binding of somatostatin analogs to somatostatin 

receptors present on neoplastic cells 

[57–60] and indirect mechanisms related to 

effects of somatostatin analogs on the host 

[for reviews, see 7, 14, 15]. 

The indirect mechanism would operate 

through a suppression of the GH release from 

the pituitary and the resulting inhibition of 

the hepatic production of insulin-like growth 

factor-1 (IGF-1) [14, 15]. The fall in IGF-1 

could inhibit the growth of various tumors 

since IGF-1 and IGF-2 as well as other growth 

factors, including EGF, appear to be involved 

in the proliferation of neoplastic cells. The 

potential importance of these mechanisms of 



action is emphasized by the in vivo antineoplastic 

activity of these compounds against 

somatostatin receptor-negative neoplasms. 

Another potential mechanism through 

which somatostatin may exert an antitumor 

effect is through its inhibition of tumor angiogenesis, 

which is essential for implantation 

and growth [63–65]. Several experimental 

pieces of evidence suggest that SSTR-2 preferring 

agonists such as octreotide do inhibit 

angiogenesis in vitro and in vivo [11]. Since 

peritumoral vessels express somatostatin receptors 

[66] and neovascularization is enhanced 

by IGF-1 [67], inhibition of angiogenesis 

itself might involve direct and/or indirect 

actions of somatostatin analogs on the nontransformed 

cells comprising the microvasculature 

of neoplastic tissue. 

Studies performed over the past 5 years 

have demonstrated that induction of apoptosis 

represents one of the mechanisms by 

which cytotoxic drugs exert their antineoplastic 

action [68]. Several lines of evidence suggest 

that somatostatin analogs can also induce 

apoptosis via interaction with SSTR-3 [14]. In 

this connection it is worth mentioning that 

IGF-1 is recognized as a potent antiapoptotic 

factor [69]. Thus, the inhibitory effects of 

somatostatin analogs on IGF-1 gene expression 

may enhance their direct apoptosis-inducing 

action and contribute to the apoptotic 

effect of these compounds. A recent investigation 

[70], performed in patients with gut neuroendocrine 

tumors, did show that treatment 

with high-dose somatostatin analogs induces 

apoptosis in tumor cells, which correlated 

with the biochemical response (i.e. decrease in 

tumor markers), while low-dose somatostatin 

analogs do not modify the apoptotic index. 

Finally, somatostatin analogs stimulate the 

activity of the reticuloendothelial and lymphopoietic 

systems in the rat [6]. Changes in 

natural killer cell activity were reported in 

man [6]. It is, therefore, possible that modula- 


Table 4. Possible mechanisms of the antineoplastic 

action of somatostatin analogs 

1 Direct antimitotic effects via somatostatin 

receptors on tumor cells 

2 Suppression of the release of trophic hormones 

(e.g. GH, insulin, prolactin and gut peptides) 

3 Direct or indirect inhibition of growth factors 

(e.g. IGF-1, EGF, PDGF) 

4 Inhibition of angiogenesis 

5 Induction of apoptosis 

6 Modulation of the immune response 

tion of immune defense mechanisms might 

contribute to the tumor growth inhibitory effects 

of these compounds. 

In summary, somatostatin and its analogs 

may have tumoricidal or antiproliferative effects 

mediated by suppressing promotor hormones, 

by inhibiting mitogens (directly suppressing 

cell division, protein synthesis, or 

translation), by inhibiting angiogenesis and 

inducing apoptosis or by stimulating the immune 

system (table 4). Although the clinical 

relevance of some experimental models is at 

present unknown, the prospects of such investigations 

are worthy of serious consideration. 

Octreotide and its derivatives may thus 

evolve towards an adjunctive, albeit limited 

role, in a direct chemotherapeutic management 

of endocrine and nonendocrine tumors. 

The key to this problem appears to be in the 

heterogeneity of somatostatin receptor subtype. 

There is no doubt that not all of the 

receptor subtypes are responsible for growth 

inhibition [58, 59]. Indeed, there is evidence 

that some may even promote cell growth. The 

future of somatostatin as a clinically useful 

anticancer drug thus lies in the characterization 

of the specific receptors that mediate 

growth inhibition and the synthesis of analogs 

that bind selectively to them. 

Long-Lasting Formulations of 

Somatostatin Analogs 

Several studies [71–75] showed that Sandostatin 

® administered by continuous subcutaneous 

pump infusion produced better suppression 

of GH and IGF-1 serum concentrations, 

rapid clinical improvement, and 

shrinkage of GH-secreting adenomas in comparison 

to intermittent subcutaneous injections. 

Data on the very good efficacy of Sandostatin 

administered by pump infusion stimulated 

research to develop a new galenical formulation 

that could ensure long-lasting, sustained 

and consistent drug delivery. Nasal administration 

provides a satisfactory control of 

GH hypersecretion, but because of poor local 

tolerability, its chronic use is not feasible at 

present [76]. An extended-release formulation 

mimicking the continuous subcutaneous infusion 

of octreotide to be injected monthly 

would be an obvious improvement in the 

treatment of acromegalic patients requiring 

long-term Sandostatin therapy by twice daily 

or 3 times daily dosing. Sandostatin LAR ® , 

obtained by incorporating octreotide into microspheres 

of a biodegradable polymer, poly(DL-lactide-co-glycolide 

glucose), was developed 

to provide patients with the convenience 

of a once-a-month administration and 

to ensure a stable serum octreotide concentration 

between injections, sustained GH and 

IGF-1 suppression, good clinical control of 

symptoms and signs of acromegaly, and improved 

acceptability and compliance for longterm 

treatment with Sandostatin [for a review, 

see 77]. 

The release characteristics and toxicology 

of Sandostatin LAR were studied in rats and 

rabbits [32, 78]. Single intramuscular injections 

of Sandostatin LAR resulted in an initial 

peak, attributed to drug adsorbed to the surface 

of microspheres, followed by low concentrations 

over 1–2 weeks and thereafter by sus- 


Fig. 7. Time course of serum octreotide 

concentrations after administration 

of single doses of 

10 mg (P, n = 16), 20 mg (d, n = 

39) or 30 mg ($, n = 37) of Sandostatin 

LAR to acromegalic patients. 

Each point is the mean of 12-hour 

mean concentrations per patient. 

Vertical bars are standard errors 

[from 78]. 

tained octreotide plasma levels over a period 

of 4–6 weeks. After repeated injections at 4week 

intervals, consistent and stable plasma 

concentrations of octreotide were recorded. 

Toxicological studies performed in rabbits 

and rats revealed only a very limited, reversible 

granulomatous myositis at the injection 

site. The biodegradation of the microspheres 

is completed within 10–12 weeks, and toxicological 

studies showed that Sandostatin LAR 

has low toxicity and good local tolerability 

[32, 78]. 

Three different preparations (i.e. 10, 20 or 

30 mg) are available for clinical use. Their 

pharmacokinetics has been studied in acromegalic 

patients [78]. A consistent pattern of 

octreotide release from the polymer matrix of 



Sandostatin LAR was documented in all studies 

and for all dose levels investigated. A rapid 

increase in octreotide serum concentrations 

was noted after intramuscular injection of 

Sandostatin LAR, with a peak occurring within 

1 h after the injection followed by a progressive 

decrease to low octreotide levels 

within 12 h. On days 2 through 7, after single 

doses of Sandostatin LAR, octreotide serum 

concentrations were at lowest levels. Thereafter, 

an increase in serum octreotide concentrations 

occurred, and dose-dependent plateau 

concentrations were observed between 

days 14 and 42 followed by a progressive 

decrease from day 42 on (fig. 7). In the plateau 

phase (days 14–42), the daily average plasma 

concentrations remained very stable over the 


Table 5. Mean pharmacokinetic parameters of octreotide assessed over a period of 60 days 

[from 78] 

Dose of Sandostatin LAR 

10 mg (n = 16) 20 mg (n = 39) 30 mg (n = 37) 

tmax, days 

28B10 28B11 34B17 

Cmax, ng/l 387B107 1,126B749 1,935B1,430 

Cmax/D, ng/l 39B11 56B38 66B48 

AUC0–60 days, ng/l 13,412B3,417 35,737B16,243 61,494B28,245 

AUC0–60 days/D, ng/l 1,341B342 1,787B812 2,050B942 

Plateau duration, days19.3B10.2 18.5B10.1 18.5B9.8 

Relative bioavailability1 , % 31 39 50 

tmax = Time to maximum concentration; Cmax = maximum concentration; Cmax/D = maximum 

concentration normalized on dose; AUC0–60 days = area under the curve from day 0 to 

day 60; AUC0–60 days/D = AUC normalized on dose. Plateau duration is the duration during 

which the concentrations were above 80% of Cmax. 

1 Relative bioavailability with respect to subcutaneous 3 times daily treatment; values are 

the geometric mean. 

12-hour observation period, similar to those 

seen after subcutaneous continuous infusion. 

The height of the octreotide peak on day 1 for 

all doses tested was lower than the plateau 

concentrations, and the area under the peak 

on the day of injection of Sandostatin LAR 

was not larger than 0.5% of the total AUC 

(0–60 days). 

A dose-dependent increase of the maximum 

concentration and AUC of octreotide 

was recorded in the dose range between 10 

and 30 mg. The computed key pharmacokinetic 

parameters are summarized in table 5. 

In agreement with animal data, human 

studies also showed good systemic and local 

tolerability as well as a lack of dose dumping 

(i.e. immediate release of significant quantities 

of drug). Preliminary results from studies 

performed in acromegalic subjects, responsive 

to subcutaneous octreotide, have shown 

that one single injection of 30 mg Sandostatin 

LAR is followed by 4- to 6-week GH suppression 

in 80% of patients [78–80]. It is likely, 

therefore, that this long-lasting formulation 

can replace 3 times daily subcutaneous injections 

by an intramuscular injection at 4-week 

intervals to improve the acceptability of longterm 

therapy in acromegalics. In addition, by 

releasing consistent concentrations of serum 

octreotide and by producing a consistent suppression 

of GH secretion, Sandostatin LAR 

appears to be as effective as subcutaneous 

infusions of Sandostatin and more effective 

than intermittent subcutaneous administration. 

Indeed, in the patients switched from 

subcutaneous treatment to Sandostatin LAR, 

suppression of GH secretion and serum 

IGF-1 concentrations and the clinical improvement 

have been either as good as or better 

than with Sandostatin administered subcutaneously 

[78]. Indeed, a larger number of 

patients showed a normalization of serum 

IGF-1 concentrations and a clinical improvement. 

Beyond the improvement/disappearance 

of symptoms/signs of acromegaly, some 

patients actually become asymptomatic. The 


Fig. 8. Pharmacokinetics of lanreotide 

and GH pattern in 21 patients 

at the first intramuscular injection 

of the drug (Somatuline SR, 

30 mg) [from 89]. 

usefulness of this octreotide formulation in 

the management of malignant carcinoid syndrome 

has been recently shown [81]. 

A slow-release formulation (Somatuline- 

SR ® ) is also available for the other somatostatin 

analog, lanreotide. This formulation 

has been studied in healthy volunteers [82] 

and acromegalic patients [83]. The maximum 

lanreotide concentration (Cmax) in plasma 

(38.3 B 4.1 ng/ml) was obtained 2 h following 

injection. The levels then progressively decreased, 

remaining above 1.5 ng/ml until day 

11 and reaching 0.92 B 0.28 ng/ml 2 weeks 

after injection. The apparent plasma half-life 

and mean residence time were 4.52 B 0.50 

and 5.48 B 0.51 days, respectively [81]. 

Studies with Somatuline-SR have been 

carried out by several European centers [83– 

88] on a few groups of acromegalic patients, 

often selected on the basis of their previous 

responsiveness to octreotide therapy. An Italian 

multicenter study [89] evaluated the tolerability 

and effectiveness of this formulation in 

a large number of acromegalic patients with 

active disease, unselected in terms of their 



previous responsiveness to octreotide, and 

found that 30 mg of the compound, administered 

every 14 days, provided an effective 

treatment in the majority. After drug administration, 

an inverse correlation was found 

between lanreotide and GH plasma levels 

(fig. 8). 

Both octreotide and lanreotide slow-release 

formulations, administered monthly 

and every 10–14 days, respectively, proved to 

be effective in controlling symptoms associated 

with neuroendocrine gut tumors, providing 

– in addition – a substantial improvement 

in patient compliance [90–95]. 

A slow-release formulation of vapreotide 

was developed more than 10 years ago [96] 

whereas a long-term delivery system has been 

produced only recently [97]. This injectable, 

biodegradable depot formulation ensures satisfactory 

peptide blood levels in rats for over 

250 days. No pharmacokinetic data with 

these formulations have yet been published in 

humans. 


Radiolabelled Somatostatin Analogs 

Radiopharmaceuticals for Somatostatin 

Receptor Scintigraphy 

The diagnosis and staging of neuroendocrine 

tumors is often difficult and time consuming. 

Blood levels of hormonal markers are 

frequently elevated and allow a presumptive 

diagnosis [98] but, since tumors are frequently 

small, standard imaging techniques such as 

ultrasonography or computed tomography 

cannot accurately localize the tumor [99]. Arteriography 

and selective venous sampling are 

more specific, but technically demanding and 

not always accurate [100]. Somatostatin receptor-expressing 

tumors and their respective 

metastases are attractive targets for diagnostic 

imaging with gamma emitter-labelled synthetic 

analogs. Indeed, somatostatin receptor 

detection can be accomplished by injecting a 

radiolabelled peptide analog and imaging tissue 

uptake of the compound via scintigraphy. 

Selective radioactive uptake will occur in proportion 

to the density and affinity of the 

receptor population. Octreotide binds with 

high affinity to the SSTR-2, while this analog 

has a relatively low affinity for SSTR-3 and 

SSTR-5 and shows no binding to SSTR-1 and 

SSTR-4 (see above). Octreotide scintigraphy 

(OctreoScan ® ) is, therefore, based on the visualization 

of (an) octreotide-binding somatostatin 

receptor(s), most probably SSTR- 

2 and SSTR-5 [18–21]. Visualization of 

SSTR-positive tumors is widely used in tumor 

staging and may also predict therapeutic response 

to octreotide. A number of studies 

[101, 102] have suggested that somatostatin 

receptor scintigraphy can be used to select 

patients with malignant carcinoid tumors 

suitable for somatostatin analog treatment 

and exclude those that will not benefit from 

such medication since most hormone-secreting 

tumors react in vitro to octreotide with an 

inhibition of hormone release and possibly 

inhibition of growth. It has been shown, for 

instance, that in patients with carcinoids, 

there was a complete agreement between the 

presence of mRNA for SSTR-2 detected by in 

situ hybridization and therapeutic response to 

octreotide [103]. In those patients with pathological 

tracer accumulation without expression 

of somatostatin SSTR-2 mRNA, other 

SSTRs may be present that can bind the 

somatostatin analog but not inhibit hormone 

secretion. However, octreotide scintigraphy 

alone may not be sufficient in determining the 

patients with neuroendocrine tumors who can 

benefit from chronic treatment with somatostatin 

analogs, because almost 20% of patients 

with pathological somatostatin scintigraphy 

fail to respond to such treatment and further, 

in rare cases, octreotide treatment results in 

clinical improvement in spite of octreotide 

scintigraphy failure to demonstrate any tumor 

localization [58, 59]. 

A radioiodinated analog of somatostatin, 

[ 123 I-Tyr 3 ]octreotide (fig. 9), was first used to 

detect somatostatin receptor-positive tumors 

[104]. However, despite the successful visualization 

with this radiopharmaceutical of a variety 

of somatostatin receptor-positive tumors 

in more than 100 patients, this method of in 

vivo imaging had several drawbacks, amongst 

which are the limited availability of chemically 

pure 123 I and the high abdominal background 

of radioactivity, caused by clearance 

of this analog via the liver [104]. Therefore, an 

111 In-labelled somatostatin analog was developed. 

[Diethylenetriamine pentaacetic acid 

(DTPA)-D-Phe 1 ]-octreotide was shown to 

bind 111 In efficiently in a single step procedure. 

The binding as well as the biological 

activity of this new labelled peptide were 

shown to be similar to that of octreotide, making 

it a good radiopharmaceutical for in vivo 

imaging of somatostatin receptor-positive tumors 

[105]. The 111 In-labelled octreotide is 

excreted mainly via the kidneys, 90% of the 


Fig. 9. Chemical structures of octreotide, 

[Tyr 3 ]-octreotide, DTPA 

and DOTA. 

dose being present in the urine 24 h after 

injection. Because of its relatively long effective 

half-life, [ 111 In-DTPA-D-Phe 1 ]-octreotide 

is a radiopharmaceutical which can be 

used to visualize somatostatin receptor-bearing 

tumors efficiently after 24 and 48 h, when 

interfering background radioactivity is minimized 

by renal clearance [104]. The synthesis 

and biological properties of 99m Tc-hydrazinonicotinyl-Tyr 

3 -octreotide (HYNIC-TOC) 

using different coligands for radiolabeling was 

reported quite recently by Decristoforo et al. 

[106]. HYNIC-TOC was radiolabelled at high 

specific activities using tricine, ethylenediaminediacetic 

acid, and tricine-nicotinic acid 

as coligand systems. All 99m Tc-labelled 

HYNIC peptides showed retained somatostatin 

receptor binding affinities (Kd !2.65 

nM). Protein binding and internalization 

rates were dependent on the coligand used. 

Specific tumor uptake between 5.8 and 9.6% 

of the injected dose/g was found for the 99m Tclabelled 

peptides compared with 4.3% injected 

dose/g for [ 111 In-DTPA-D-Phe 1 ]-octreotide 

[106]. The high specific tumor uptake, 

rapid blood clearance, and predomi- 



nantly renal excretion make [ 99m Tc-EDDA- 

HYNIC-TOC] a promising candidate as an 

alternative to [ 111 In-DTPA-D-Phe 1 ]-octreotide 

for tumor imaging. 

The major limitation of somatostatin receptor 

scintigraphy using radiolabelled ligands 

of octreotide is that the technique will 

only allow detection of those tumors expressing 

hSSTR-2 and hSSTR-5 and possibly those 

neoplasms expressing hSSTR-3 in sufficient 

density to allow visualization. Radioligands 

of lanreotide or vapreotide might be more 

useful than radiolabelled ligands of octreotide 

in visualizing those tumors that express 

hSSTR-4, but not hSSTR-2 and hSSTR-5. Visualization 

of tumors by lanreotide or vapreotide 

scintigraphy but not by octreotide scintigraphy 

may provide a rationale for the selection 

of patients that are likely to benefit from 

therapy with these analogs but this hypothesis 

requires confirmation in prospective controlled 

trials. 

Taking the above considerations into account, 

radiolabelled derivative of both lanreotide 

[ 111 In-DOTA-lanreotide] and vapreotide 

[ 111 In-DTPA-D-Phe 1 ]-RC-160 have been de- 


veloped [107–109]. However, while labelled 

lanreotide showed a high tumor uptake for a 

variety of different human tumor types and 

a favorable dosimetry over labelled octreotide 

[107], with [ 111 In-DTPA-D-Phe 1 ]-RC- 

160 blood radioactivity (background) was 

higher, resulting in a lower tumor to blood 

(background) ratio [108]. This radiopharmaceutical 

should, therefore, have no advantage 

over [ 111 In-DTPA-D-Phe 1 ]-octreotide for the 

visualization of somatostatin receptors which 

bind both analogs. However, recent reports 

suggest the existence of different somatostatin 

receptor subtypes on some human cancers, 

which differentially bind the synthetic somatostatin 

analogs [60]. These tumors include 

cancers of the breast, ovary, exocrine 

pancreas, prostate and colon. Radiolabelled 

lanreotide or vapreotide might be of interest 

for future use in such cancer patients as a 

radiopharmaceutical for imaging somatostatin 

receptor-positive tumors, which do not 

bind octreotide. Compared with the parent 

peptide (i.e. lanreotide), DOTA-lanreotide 

seems to display a distinct binding pattern, 

since it binds all transfected hSSTR subtypes 

as well as a large variety of primary human 

tumors [107]. As a consequence, the radiopharmaceutical 

is claimed to be a ‘universal’ 

SSRT ligand. A multicenter study (called 

Multicentre Analysis of a Universal Receptor 

Imaging and Treatment Initiative: a European 

Study) was recently started, for which 

the acronym MAURITIUS has been coined. 

[DOTA]-lanreotide was then renamed MAU- 

RITIUS. In a preliminary report 111 In-MAU- 

RITIUS was used in a series of 25 patients 

with advanced malignancies refractory to 

conventional antineoplastic treatment and in 

all of them at least one tumor site could be 

visualized at scintigraphy [110]. Interestingly 

enough, some neoplasms, which were repeatedly 

negative by the conventional OctreoScan, 

could be visualized by means of this 

new radiopharmaceutical, thus suggesting 

that somatostatin receptors other than 

hSSTR-2 and hSSTR-5 are responsible for 

binding. 

While single photon emission computed 

tomography seems to improve accuracy of 

somatostatin receptor scintigraphy [111], intraoperative 

gamma detection reveals abdominal 

endocrine turmors more efficiently 

than conventional OctreoScan [112–114] and 

may allow improvement in surgical management 

allowing radioimmunoguided surgery 

[115]. In vitro and in vivo studies [116] 

showed that a recently developed terbium- 

161-labelled derivative, i.e. [ 161 Tb-DTPA-D- 

Phe 1 ]-octreotide, represents a promising pharmaceutical 

for intraoperative scanning and 

radiotherapy. 

Octreotide has also been labelled with positron-emitting 

67 Ga [117], 64 Cu [118, 119] or 

18 F [120]. Some of these radiolabelled derivatives 

([2 - 18 F - fluoropropionyl - D - Phe 1 ]octreotide, 

[ 64 Cu-TETA-D-Phe 1 ]-octreotide 

and [ 67 Ga]-DFO-B-succinyl-D-Phe 1 ]-octreotide) 

have, therefore, been used for PET imaging 

[120]. However, the hepatobiliary excretion 

of these compounds complicates the interpretation 

of the images arising from abdominal 

tumors [120]. In contrast, [ 64 Cu- 

TETA-D-Phe 1 ]-octreotide binds to somatostatin 

receptor with five times the affinity of 

[ 111 In-DTPA-D-Phe 1 ]-octreotide, has desirable 

clearance properties (renal clearance with 

rapid excretion) and is a potential agent for 

PET imaging of somatostatin receptors. At 

present, however, other labelled compounds 

(e.g. 11 C-5-HTP or 11 C-labelled-L-DOPA) are 

preferred for PET scanning of neuroendocrine 

tumors [121]. 

The detection of heterogenous metastases 

(with regard to the expression of different 

peptide receptors or the accumulation of other 

radioligands) becomes possible if a combination 

of different radiolabelled peptides or 


of a radiolabelled peptide with other radioligands 

(all labelled with different radionuclides) 

can be used. Simultaneous use of 111 Inoctreotide 

and 131 I-MIBG (metaiodobenzylguanidine) 

scintigraphy in patients with metastasized 

pheochromocytoma [22] represents 

a successful example of such an approach. 

Radiopharmaceuticals for Somatostatin 

Receptor-Targeted Radiotherapy 

A new and fascinating application of radiolabelled 

peptides is represented by their use in 

the so-called peptide receptor radiotherapy 

[122]. The success of this therapeutic strategy 

relies upon the concentration of the radioligand 

within tumor cells which will depend on 

the rates of internalization, degradation and 

recycling of both ligand and receptor. 

Binding of several peptide hormones to 

specific surface receptors is generally followed 

by internalization of the ligand-receptor complex 

via invagination of the plasma membrane 

[123]. The resulting intracellular vesicles, 

termed endosomes, rapidly acidify, thus 

causing dissociation of the ligand from the 

receptor. The ligand may be delivered to lysosomes 

and the receptor recycles back to plasma 

membrane. The whole process takes approximately 

15 min and a single receptor can 

deliver numerous ligand molecules to the lysosomes 

[124]. 

Receptor-mediated endocytosis of somatostatin 

analogs is especially important 

when radiotherapy of somatostatin-positive 

tumors using radiolabelled analogs is considered. 

Human neuroendocrine tumor cells internalize 

the radioligand [ 111 In-DTPA-D- 

Phe 1 ]-octreotide. However, this radioligand 

may not be the most suitable compound to 

carry out radiotherapy because 111 In, which 

emits Auger (as well as conversion) electrons, 

is probably not the optimal radionuclide. 

Moreover, since a stable coupling of ·- and ßemitting 

isotopes to [DTPA-D-Phe 1 ]-octreo- 



tide has not been feasible, a novel compound 

[tetraazacyclododecane tetraacetic acid 

(DOTA), Tyr 3 ]-octreotide (compound coded 

as SDZ-SMT 487, fig. 9) in which the DTPA 

molecule is replaced by another chelator, 

DOTA, allowing a stable bind with the ßemitter 

yttrium-90, has been synthesized 

[125]. It was recently shown that iodinated 

[DOTA, Tyr 3 ]-octreotide is internalized in a 

large amount by mouse AtT20 pituitary tumor 

cells as well as by human insulinoma cells 

[126]. The high internalization rate of this 

ligand in vitro was also evident from the very 

high uptake of this radioligand in vivo by 

somatostatin receptor-positive organs in rats 

[126]. Along with the high internalization of 

the iodinated molecule, de Jong et al. [127] 

recently showed that the amount of [ 90 Y- 

DOTA, Tyr 3 ]-octreotide internalized by somatostatin 

receptor-positive pancreatic tumor 

cells was higher than that of [ 111 In- 

DOTA, Tyr 3 ]-octreotide and of [ 111 In-DTPA- 

D-Phe 1 ]-octreotide (1.8- and 3.5-fold, respectively). 

In vitro, SMT 487 binds selectively 

with nanomolar affinity to the somatostatin 

receptor subtype 2 (IC30 = 0.39 B 0.02 nM). 

In vivo, [ 90 Y-DOTA, Tyr 3 ]-octreotide shows a 

rapid blood clearance (t½· !5 min) and high 

accumulation in somatostatin subtype 2 receptor-expressing 

tumors [128]. The in vivo 

administration of this radiopharmaceutical 

induces a rapid tumor shrinkage in three different 

somatostatin receptor-positive tumor 

models, namely CA20948 rat pancreatic tumors 

grown in normal rats, AR42J rat pancreatic 

tumors and NCI-H69 human small 

cell lung cancer both grown in nude mice. The 

radiotherapeutic efficacy of 90 Y-SMT 487 was 

enhanced when used in combination with 

standard anticancer drugs, such as mitomycin 

C, and resulted in a tumor decrease of 70% of 

the initial volume. In the CA20948 syngeneic 

rat tumor model, a single treatment with 10 

ÌCi/kg [ 90 Y-DOTA, Tyr 3 ]-octreotide resulted 


in the disappearance of 5 out of 7 tumors. 

Thus the new radiotherapeutic agent showed 

its curative potential for the selective treatment 

of SRIF receptor-expression tumors 

[128]. According to these data, [ 90 Y-DOTA, 

Tyr 3 ]-octreotide would appear to be a suitable 

radiopharmaceutical for somatostatin receptor-targeted 

radiotherapy. 

To achieve an optimal radiotherapeutic effect, 

the radiopharmaceutical should also be 

retained within tumor cells to allow intracellular 

radioactivity exerting its antineoplastic 

activity. Therefore ‘trapping’ of radioligands 

into the tumor cells may be an additional 

important mechanism determining the 

amount of uptake of the radiopharmaceutical 

which is used for somatostatin receptor scintigraphy 

and/or targeted radiotherapy. While 

previous investigations [124] have shown that 

[ 111 In-DTPA-D-Phe 1 ]-octreotide is delivered 

in vivo to lysosomes of pancreatic tumor cells, 

the intracellular fate of [ 90 Y-DOTA, Tyr 3 ]octreotide 

is presently unknown. 

Although being not the ideal radioligand, 

[ 111 In-DTPA-D-Phe 1 ]-octreotide has been 

used for radionuclide therapy in patients with 

somatostatin receptor-positive tumors and 

proved the feasibility of the approach [129]. 

The trial did show a tendency towards better 

results in patients whose tumors had a higher 

accumulation of the radioligand. In a recent 

preliminary study, Otte et al. [130] reported 

encouraging results after treatment with [ 90 Y- 

DOTA, Tyr 3 ]-octreotide (OctreoTher ® ) in 10 

patients with different somatostatin receptorpositive 

tumors. In addition, a case report 

[131] described a favorable response of a metastatic 

gastrinoma to treatment with another 

90 Y-labelled somatostatin analog, namely 

[ 90 Y-DOTA]-lanreotide [132]. 

The concept of targeted radiotherapy of 

tumors using radioligands of somatostatin 

analogs remains a very attractive approach 

for the treatment of neoplasia. The very fact 

that it is over 12 years since the concept of 

octreotide targeted radiotherapy of neoplasia 

was first proposed and we are still awaiting 

good phase 2 clinical trials on the efficacy and 

tolerability of this appealing treatment highlights 

the practical difficulties involved in developing 

this technique. 

Safety and Tolerability of 


The safety profile of Sandostatin is well 

established [17]. Most adverse reactions to 

octreotide are merely a consequence of its 

pharmacological activity and consist mainly 

of gastrointestinal complaints, cholelithiasis 

and effects on glucose metabolism. The reported 

cases of toxicity unrelated to the drug’s 

pharmacological profile include reactions at 

the injection site, allergic reactions, and a few 

cases of reversible hepatic dysfunction. Although 

the kind of adverse events associated 

with Sandostatin is well known, their true frequency 

has not been accurately estimated. 

34.4% of patients reported one or more side 

effects, most of which (93.2%) were of little 

clinical relevance [17]. For this reason, adverse 

events are only seldom mentioned in 

published series and are rarely reported to the 

manufacturer. In contrast, most reports received 

by the Novartis Pharmacosurveillance 

Unit pertained to events occurring in patients 

with severe underlying diseases and multiple 

drug treatment; therefore, a cause-effect relationship 

with octreotide could only seldom be 

established. 

The tolerability of octreotide LAR appears 

to be comparable to that of the subcutaneous 

formulation [77]. Here again, gastrointestinal 

adverse events predominate: abdominal pain, 

flatulence, diarrhea, constipation, steatorrhea, 

nausea and vomiting occurred in up to 

50% of patients with acromegaly who re- 


Fig. 10. Adverse events observed 

in acromegalic patients (n = 93– 

101) after a single intramuscular 

injection of Sandostatin LAR (10– 

30 mg) or multiple injections (30 

injections at 4-week intervals) of 

the same formulation (20–40 mg) 

[from 77]. 

ceived 1–3 intramuscular doses of octreotide 

LAR (10–30 mg). Representative results from 

the largest clinical trial are depicted in figure 

10. Gastrointestinal symptoms tended to 

be mild to moderate and often disappeared 



within 1–4 days of the injection. Furthermore, 

the incidence of these events decreased 

with long-term (up to 7 months) treatments. 

In addition, there was no evidence that tolerability 

worsened with increasing dose. 


Injection site events (pain, burning, redness 

and swelling at injection site) occurred in 

some patients receiving intramuscular octreotide 

LAR, but were generally mild and of 

short duration [77]. These phenomena are 

thought to be caused by the acidic vehicle of 

Sandostatin formulations and can be minimized 

by simple precautions, i.e. to allow refrigerator-cold 

vials to reach room temperature 

before administration, and to rotate the 

sites of injections. 

Although the risk of cholelithiasis increases 

in patients receiving octreotide [17], simultaneous 

bile acid administration strongly reduces 

its incidence [77]. Although diabetes mellitus 

may occur as a result of reduced glucose tolerance, 

the net effect of drug-induced changes is 

usually mild and not clinically relevant [17, 

77]. Finally, few patients developed moderate 

to severe hair loss [77]. The spectrum and incidence 

of adverse events reported after lanreotide, 

either immediate and slow release formulations, 

are similar to those reported after 

octreotide [87, 88, 93, 94], the majority of poorly 

tolerant patients experiencing untoward 

reactions to both compounds [87]. 

Synthetic somatostatin analogs are, therefore, 

safe drugs for long-term use. While immediate 

release preparations are the drugs of 

choice in the short term, long-acting formulations 

are better indicated, on an outpatient 

basis, for the long-term management of 

chronic conditions. 


Diagnosis and Treatment: A Look 

into the Future 

New Somatostatin Analogs and Regimens 

The principal challenge in somatostatin research 

derives from the fact that the five basic 

somatostatin receptor subtypes have high 

structural similarities and different tissue dis- 

tributions. The strong functional similarity 

among the five receptor types is exhibited in 

their common inhibitory effect on adenylyl 

cyclase activity. Therefore, it is understandable 

that somatostatin, which binds with high 

affinity to each receptor type, has multiple 

physiological actions. To explore the specific 

biological function of each subtype, receptorspecific 

synthetic analogs, agonists (as well as 

antagonists) are being developed. New compounds 

in the early phase of development 

include receptor-selective and ‘universal’ analogs. 

The receptor-selective analogs bind to 

one, possibly two somatostatin receptor subtypes 

[133, 134] while the universal analogs 

bind to most or all of the five known SSTRs. 

The elucidation of the 3-dimensional structures 

of receptor subtype-selective somatostatin 

agonists has aided and will considerably 

enhance the rational design of novel analogs 

including non-peptide compounds [135–137]. 

Development of potent non-peptide somatostatin 

analogs is important because they may 

display a good bioavailabilty [138] following 

oral administration. Continuing research on 

somatostatin receptors and somatostatin analogs 

will help to characterize better the functional 

somatostatin receptor models. Recent 

availability of the five transfected cell lines has 

enabled the use of more rational research 

methods. This will help to develop novel drug 

candidates beyond the clinically used octreotide-type 

analogs. Newly developed analogs 

(BIM 23190 and BIM 23197) show higher 

plasma levels, greater distribution to target tissues 

and longer in vivo stability [139]. They 

may prove to be superior to the currently available 

compounds for the treatment of acromegaly 

and some types of cancer. 

Future investigations should also be aimed 

at further exploring the use of long-acting 

somatostatin analogs as antineoplastic agents, 

either alone or in combination with other 

drugs. In this respect, it will be important to 


etter define the dose-response relationship 

and to ascertain whether higher doses are 

associated with more disease stability or with 

greater response rate or survival [16]. 

Somatostatin Receptor-Targeted 

Chemotherapy 

It is now well established that chemotherapeutic 

compounds and toxins can be covalently 

attached to various carriers, including 

hormones, for which receptors are present on 

cancer cells or to antibodies that preferentially 

recognize tumor cells [140]. Such conjugates 

are designed to deliver cytotoxic agents 

more selectively to cancer cells. Ideally, tumor 

cells that bind these conjugates would be 

killed while normal cells that do not have the 

receptors would be spared [141]. 

Like targeted radiotherapy, somatostatin 

receptor-targeted chemotherapy represents 

an appealing approach to treatment of SSTR 

expressing tumors. By synthesizing conjugates 

of somatostatin analogs and cytotoxic 

drugs (such as methotrexate or doxirubicin) 

[142, 143], selective accumulation of cytotoxic 

radicals in somatosatin receptor-positive 

tumor cells would be possible. Obviously, 

with the currently available somatostatin analogs, 

targeted chemotherapy would be limited 

to the treatment of SSTR-2- and SSTR-5expressing 

tumors. Experimental studies 

[142, 143] have actually shown that these 

derivatives are less toxic and more effective 

than the parent cytotoxic drugs in inhibiting 

tumor growth in vivo. A recent study [144] 

demonstrated a high efficacy of SSTR-targeted 

chemotherapy in a model of disseminated 

human androgen-independent prostatic 

carcinoma. The use of cytotoxic somatostatin 

analog AN-238 (fig. 11) could provide an 

effective therapy for patients with advanced 

hormone-refractory prostatic carcinoma. 

Other studies in progress show that growth of 

various human pancreatic, colorectal and gas- 



Fig. 11. Molecular structure of the cytotoxic somatostatin 

analog AN-238. The somatostatin analog RC- 

121 is linked through the ·-aminogroup of it D-Phe 

moiety and a glutaric acid spacer to the 14-OH group 

of 2-pyrrolinodoxorubicin [from 142]. 

tric cancers in nude mice as well as glioblastomas 

and non-SCLC can be suppressed by 

cytotoxic somatostatin analogs [141]. Thus 

these somatostatin analogs might find applications 

for the therapy of different types of 

human malignancies. 

Gene Therapy 

Gene therapy is at an early phase, but 

represents an exciting opportunity to prolong 

life in some patients with advanced malignancies 

[145–149]. The key problems are getting 

the replacement gene to the appropriate cellular 

target and once there persuading it to 

make the normal gene product in sufficient 

quantities to correct the defect. With respect 

to somatostatin analog therapy there are a 

number of areas in which effective gene therapy 

may be used to potentiate the antineoplastic 

effects of these drugs. The most obvious 

application of gene therapy to somatostatin 

analog treatment of neoplasia is the delivery 


Fig. 12. Expression of the SSTR-2 

in pancreatic tumor cells suppresses 

clonigenicity in vitro and 

tumorigenicity in nude mice by a 

feedback mechanism. According to 

the findings in vitro and in vivo, 

the expression of this receptor subtype 

leads to an increase in somatostatin 

ligand production and hence 

a constitutive receptor activation. 

Experimental data also suggest that 

the SSTR-2 expression is associated 

with an increase in the endoproteolytic 

processing of prosomatostatin 

[from 7]. 

of hSSTR-2 and hSSTR-5 genes together with 

the genes that encode their membrane proteins 

to those cancers such as pancreatic, gastric 

and colorectal carcinomas that do not 

express these receptor subtypes. The somatostatin 

analogs currently available for clinical 

use (i.e. octreotide, lanreotide and vapreotide) 

all exert the majority of their antineoplastic 

effects via hSSTR-2 and hSSTR-5 and it follows, 

therefore, that effective transfer of genes 

encoding for hSSTR-2 and hSSTR-5 and their 

membrane proteins to cancers which do not 

express these receptor subtypes may render 

them responsive to the direct antineoplastic 

effects of the current generation of somatostatin 

analogs. 

Human pancreatic adenocarcinomas lose 

the ability to express SSTR-2, the somatostatin 

receptor, which mediates the antiproliferative 

effect of currently available somatostatin 

analogs. Reintroducing SSTR-2 into human 

pancreatic cancer cells by stable expression 

evokes an autocrine negative feedback loop 

leading to a constitutive activation of the 

SSTR-2 gene and an inhibition of cell proliferation 

and tumorigenicity. In vivo studies 

[150], performed in athymic mice, confirmed 

the antitumor bystander effects resulting from 

the transfer of the SSTR-2 gene into human 

pancreatic cancer cell line BxPC-3. Mice were 

separately xenografted with control cells on 

one flank and with SSTR-2-expressing cells 

on the other flank. A distant antitumor effect 

was induced: growth of control tumors was 

delayed by 33 days, the Ki67 index decreased 

significantly, and apoptosis increased when 

compared with control tumors that grew 

alone [150]. The distant bystander effect may 

be explained in part by a significant increase 

in serum somatostatin-like immunoreactivity 

levels resulting from the autocrine feedback 

loop produced by SSTR-2 expressing cells 

(fig. 12) [151] and inducing an upregulation of 

the type 1 somatostatin receptor, SSTR-1, 

which also mediates the antiproliferative effect 

of somatostatin [150]. 

Limitations to peptide receptor radiotherapy 

are principally due to poor tumor pene- 


tration of the radioligand and insufficient accumulation 

of radioactivity within the neoplastic 

cell. In addition, low or variable expression 

of tumor-associated receptors may 

lead to poor tumor localization of radiolabelled 

peptide agonists. An attempt to overcome 

these problems consists in the use of 

biological response modifiers to increase target 

receptor expression [152]. In this connection, 

replication-deficient adenoviral vectors 

were constructed encoding the cDNA for the 

somatostatin receptor subtype (SSTR-2). In 

vitro binding and in vivo tumor localization 

were observed with radiolabelled octreotide 

analogs to cells infected with adenoviral vectors 

encoding the corresponding gene [152]. 

Provided it is successful in humans, this 

method could be useful for increasing the 

therapeutic efficacy of targeted radiotherapy 

in cancer patients. 

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Antiproliferative Effect of 

Somatostatin and Analogs 

Corinne Bousquet Elena Puente Louis Buscail Nicole Vaysse 

Christiane Susini 

INSERM U 151, CHU Rangueil, IFR 31, Toulouse, France 

Key Words 

Somatostatin receptor W Proliferation W 

Receptor signaling 

Abstract 

Over the past decade, antiproliferative effects 

of somatostatin and analogs have been 

reported in many somatostatin receptor-positive 

normal and tumor cell types. Regarding 

the molecular mechanisms involved, somatostatin 

or analogs mediate their action 

through both indirect and direct effects. Somatostatin 

acts through five somatostatin receptors 

(SSTR1–5) which are variably expressed 

in normal and tumor cells. These 

receptors regulate a variety of signal transduction 

pathways including inhibition of adenylate 

cyclase, regulation of ion channels, 

regulation of serine/threonine and tyrosine 

kinases and phosphatases. This review focuses 

on recent advances in biological mechanisms 

involved in the antineoplastic activity 

of somatostatin and analogs. 

ABC 

Fax + 41 61 306 12 34 





0009–3157/01/0478–0030$17.50/0 



Introduction 

Somatostatin (somatotroph release-inhibiting 

factor) was originally discovered as a 

hypothalamic neurohormone that inhibited 

growth hormone secretion. It was subsequently 

demonstrated that somatostatin is a widely 

distributed peptide both in the central and 

peripheral nervous systems and in peripheral 

tissues including the endocrine pancreas, gut, 

adrenals, kidney and immune cells. In mammals, 

two forms of bioactive peptides, somatostatin 

14 and a C-terminally extended form, 

somatostatin 28 are produced by tissue-specific 

proteolytic processing of a common precursor. 

Somatostatin acts on various targets 

including the brain, pituitary, pancreas, gut, 

adrenals, thyroid, kidney and on the immune 

system to regulate a variety of physiological 

functions. Its actions include inhibition of endocrine 

and exocrine secretions, modulation 

of neurotransmission, motor and cognitive 

functions, inhibition of intestinal motility, absorption 

of nutrients and ions, vascular contractility 

and cell proliferation. 

Due to the short half-life of natural somatostatin 

peptides (F1 min), many somato- 

Dr. Christiane Susini 

INSERM U151, Institut Louis Bugnard, IFR 31 

CHU Rangueil, F–31403 Toulouse Cedex 4 (France) 

Tel. +33 5 61 32 24 07, Fax +33 5 61 32 24 03 

E-Mail susinich@rangueil.inserm.fr

statin peptide analogs have been synthesized. 

Among them, octreotide (SMS 201-995), lanreotide 

(BIM 23014) and vapreotide have 

been intensively investigated and are in clinical 

use for the medical treatment of acromegaly 

and neuroendocrine tumors. All of these 

cyclic octapeptides retain amino acid residues 

(or substitutes) within a cyclic peptide backbone 

involved in the biological effect of the 

peptide (Phe 7 or Tyr 7 , DTrp 8 , Lys 9 and Thr 10 

or Val 10 ) and display markedly increased stability 

(half-life 190 min). The biological effects 

of somatostatin are mediated via high 

affinity plasma membrane receptors which 

are coupled to various signal transduction 

pathways including inhibition of adenylate 

cyclase and Ca 2+ channels and stimulation of 

several K + channels and protein phosphatases. 

Somatostatin receptors are widely distributed 

throughout many tissues ranging 

from the central nervous system to the pancreas 

and gut, and also in pituitary, kidney, 

thyroid, lung and immune cells [for a review, 

see 1, 2]. 

Compelling evidence has implicated somatostatin 

in the inhibition of the growth and 

development of various normal and tumor 

cells. Thus, somatostatin analogs show antineoplastic 

activity in a variety of experimental 

models in vivo and in vitro [for a review, 

see 3, 4]. Somatostatin receptors are expressed 

in a large variety of human tumors. 

Octreotide treatment induces the shrinkage of 

the pituitary [5] and the stabilization of neuroendocrine 

tumor progression [6]. However, 

the clinical implications of the presence of 

somatostatin receptors in tumors for diagnostic 

and therapeutic purposes will need to define 

the physiological role of each receptor 

subtype expressed in the tumors with respect 

to its antisecretory and antiproliferative properties. 

Somatostatin or its analogs may influence 

tumor cell growth via indirect and 

direct mechanisms and this review focuses on 

Antiproliferative Effect of Somatostatin 

and Analogs 

recent advances in the molecular mechanisms 

involved in the antiproliferative effect of somatostatin 

and analogs. 

Somatostatin Receptor Family 

To date, five receptor subtypes, SSTR-1– 

SSTR-5, have been cloned. Human SSTRs are 

encoded by 5 genes localized on separate 

chromosomes. Four of these genes are intronless, 

the exception being SSTR-2 which is 

alternatively spliced in rodents to generate 

two isoforms named SSTR-2A and SSTR-2B 

which diverge in their C-terminal sequence. 

The SSTRs subtypes belong to the family of 

G-protein-coupled receptors with seven transmembrane 

spanning domains and present a 

high degree of sequence identity (39–57%). 

They all bind somatostatin 14 and somatostatin 

28 natural peptides with similar affinity 

(nM range) although with a slightly higher 

affinity for somatostatin 14. Only SSTR-5 displays 

a 10-fold higher affinity for somatostatin 

28. However, they show major differences 

in their affinities for analogs. Analogs 

exhibit a low affinity for SSTR-1 and SSTR-4 

(61 ÌM) whereas they bind SSTR-2, SSTR-5 

with a high affinity, comparable to that of 

somatostatin 14 (nM range) and bind SSTR-3 

with moderate affinity (65–10 nM) [7, 8]. 

Using recombinant SSTRs transiently or 

stably expressed in various eukaryote cells, 

the intracellular signaling pathways coupled 

to SSTRs have been extensively studied. Each 

receptor subtype is coupled to multiple intracellular 

transduction pathways via pertussis 

toxin-sensitive heterotrimeric GTP binding 

proteins. Inhibition of the adenylate cyclase 

system leading to reduction of intracellular 

cAMP was one of the first signaling pathways 

identified to be associated with the occupation 

of somatostatin receptors. All five SSTRs 

are functionnally coupled to inhibition of ade- 


nylate cyclase via a pertussis toxin-sensitive 

protein, G·i1 or G·i2, or G·i3 being involved in 

mediating this coupling [7, 8]. 

A second key plasma membrane signaling 

pathway involved in somatostatin action 

concerns K + and Ca 2+ channels. In neuronal 

and neuroendocrine cells, somatostatin and 

analogs regulate several subsets of K + channels 

including inward rectifying (GIRK1; via 

G protein G·i3), transient outward, delayed 

rectifying, voltage-dependent M current and 

ATP-sensitive K + channels as well as large 

conductance Ca 2+ -activated BK channels. 

Activation of K + channels by somatostatin 

causes hyperpolarization of the plasma 

membrane and leads to decreased Ca 2+ influx 

through voltage-gated Ca 2+ channels and 

consequently to reduction of intracellular 

Ca 2+ . Expression of GIRK1 channels together 

with each somatostatin receptor in Xenopus 

oocytes demonstrate that SSTR-2, 

SSTR-3, SSTR-4 and SSTR-5 can couple to 

inward rectifying K + channels, SSTR-2 being 

the most efficiently coupled [9]. The SSTR 

subtypes coupled to other K 2+ channels remain 

to be elucidated. Somatostatin can also 

decrease Ca 2+ influx by directly inhibiting 

high voltage-dependent Ca 2+ channels via 

G0·2. Somatostatin receptors couple to Ntype 

and L-type voltage-dependent calcium 

channels in several cell types including 

mouse pituitary AtT-20 cells and rat insulinoma 

RINm5F cells [7, 8]. Using receptor 

subtype-specific analogs, it has been demonstrated 

that SSTR-2 and SSTR-5 can negatively 

couple to voltage-dependent calcium 

channel (L-type) in mouse pituitary cells 

[10]. SSTR-1 is also implicated in the inhibition 

of Ca 2+ influx since it has been shown to 

mediate the inhibition of voltage-dependent 

Ca 2+ channels in rat insulinoma 1046-38 

cells [11]. Both of these two signal transduction 

pathways, inhibition of Ca 2+ and to a 

lesser extent inhibition of cAMP, mediate 

the negative regulation of hormone and neurotransmitter 

secretions induced by somatostatin. 

A third important membrane signaling 

a pathway linked to somatostatin receptors 

involves the regulation of protein phosphatases. 

Somatostatin and analogs activate a 

number of protein phosphatases including 

serine/threonine phosphatases, tyrosine phosphatases 

and Ca 2+ -dependent phosphatase 

[12–15]. SSTR-1, SSTR-2, SSTR-3 and 

SSTR-4 have been reported to stimulate tyrosine 

phosphatase activity when expressed in 

NIH 3T3 fibroblast or CHO cells [16–18]. 

Somatostatin receptor subtypes involved in 

the regulation of serine/threonine phosphatase 

have not yet been identified. 

Concerning the coupling of SSTRs with 

phospholipase C pathway, the results are controversial. 

In COS-7 cells expressing each receptor 

subtype, all five receptors are able to 

stimulate phospholipase C and increase Ca 2+ 

mobilization via a pertussis toxin-dependent 

G protein, albeit at agonist concentration higher 

than 1 nM. However, the coupling of SSTR- 

2, SSTR-5 and SSTR-3 to phospholipase C is 

more efficient. For SSTR-3, this coupling is 

involved in the stimulatory effect of somatostatin 

on guinea pig intestinal smooth muscle 

cell contraction and is mediated by phospholipase 

C-ß3 [19]. In contrast, in transfected 

CHO-K1 cells, SSTR-5 inhibits phospholipase 

C-mediated intracellular Ca 2+ mobilization 

whereas SSTR-4 is without effect [20]. 

The MAP kinase pathway is also involved 

in signal transduction coupled to SSTR but 

the modulation differs according to the receptor 

subtype. When expressed in CHOK1 cells, 

SSTR-4 activates MAP kinases Erk1/2 leading 

to phosphorylation and activation of 

phospholipase A2 and release of arachidonic 

acid whereas SSTR-5 inhibits MAP kinases 

ERK1/2 by a mechanism involving a dephosphorylation 

cascade including inhibition of 

guanylate cyclase and thus decreasing cGMP 

32 Chemotherapy 2001;47(suppl 2):30–39 Bousquet/Puente/Buscail/Vaysse/Susini

formation and inhibition of cGMP-dependent 

protein kinase G [21]. 

Finally, another signal transduction pathway 

coupled to SSTR-1 has also been reported. 

Indeed, in transfected mouse fibroblast 

Ltk– cells, SSTR-1 has been reported to 

be negatively coupled to Na + /H + exchanger by 

a mechanism independent of G protein. In 

the same cells, transfected SSTR-2 has no 

effect [22]. 

Indirect Effects of Somatostatin on 

Cell Growth 

Indirect effects of somatostatin on tumor 

growth may be the result of inhibition of 

secretion of growth-promoting hormones and 

growth factors which stimulate the growth of 

various types of cancer. It is known that 

tumors depend on specific growth factors for 

their growth. For example, insulin-like growth 

factor-1 (IGF-1) which is produced by hepatocytes 

through GH-dependent and GH-independent 

mechanisms is an important modulator 

of many neoplasms that express IGF-1 

receptors and respond to this mitogenic factor 

[23]. Octreotide has been demonstrated to 

negatively control the serum IGF-1 level as a 

result of an effect on GH secretion and SSTR- 

2 and SSTR-5 have been demonstrated to be 

implicated in this effect [24]. In addition, a 

direct effect on IGF gene expression has also 

been reported [25]. The suppressive action of 

somatostatin analogs on the GH-IGF-1 axis 

has been proven effective in the treatment of 

GH-secreting pituitary adenomas [26]. Clinical 

studies have demonstrated a reduction of 

IGF-1 gene expression and serum levels of 

IGF-1 after treatment of breast cancers with 

octreotide and these effects are increased 

when combined with the antiestrogen tamoxifen 

[27]. Somatostatin and analogs also increase 

the expression and the secretion of 



IGF-binding protein-1, which specifically 

binds IGF-1 and negatively regulates plasma 

IGF-1 [28]. Somatostatin and analogs may 

also inhibit the secretion of gastrointestinal 

and pancreatic hormones involved in the regulation 

of tumor growth such as cholecystokinin, 

gastrin, insulin and glucagon and growth 

factors such as the epidermal growth factortransforming 

growth factor · family. In somatostatin 

SSTR-2 knockout mice, the use of 

new selective subtype analogs has enabled 

investigators to demonstrate the role of 

SSTR-2 in inhibiting glucagon and gastrin 

release from mouse pancreatic · and gastric 

cells, respectively, and the role of SSTR-5 as a 

mediator of insulin secretion from mouse 

pancreatic ß cells has recently been reported 

[24, 29]. In addition, the detection of SSTR-2 

receptors with specific anti-SSTR-2 antibodies 

in human A and B pancreatic islet cells 

suggests that this receptor subtype is involved 

in the regulation of human pancreatic hormones 

[30]. The role of other receptor subtypes 

in the regulation of hormone secretion 

remains to be defined. 

Somatostatin or its analogs can also indirectly 

control tumor development and metastasis 

by inhibition of angiogenesis. Somatostatin 

analogs inhibit angiogenesis in vitro and 

in vivo [31]. Overexpression of peritumoral 

vascular somatostatin receptors with a highaffinity 

for somatostatin 14, somatostatin 28 

and octreotide (suggesting a preferential expression 

of SSTR-2 subtype) has been reported 

in human primary colorectal carcinomas, 

small cell lung carcinoma of the lung, 

breast cancer, renal cell carcinoma and malignant 

lymphoma. Furthermore, the expression 

of somatostatin receptors in tumor vessels appears 

to be independent of receptor expression 

in the tumor [32]. This suggests that somatostatin 

and its receptors may play a regulatory 

role in hemodynamic tumor-host interactions, 

angiogenesis and vascular drainage. 


Evidence suggests that somatostatin may 

influence the immune system. Somatostatin 

and receptors are expressed in human lymphoid 

organs and can regulate various immune 

functions including lymphocyte proliferation, 

immunoglobulin synthesis, and cytokine 

production [33]. It has recently been 

reported that SSTR-2, SSTR-3, SSTR-4 and 

SSTR-5 are expressed in human lymphoid 

cell lines and expression of SSTR-2 is upregulated 

following lymphocyte activation [34]. It 

has been well demonstrated that somatostatin 

and octreotide inhibit the proliferation of human 

and rat T lymphocytes in vitro [33, 35] 

and that somatostatin inhibits IFN-Á release 

from T lymphocytes probably via the SSTR-2 

subtype leading to a decrease of Ig2a levels 

[36]. However, no information is available on 

the effect of somatostatin in vivo on the immune 

system. 

Direct Effect of Somatostatin on 

Tumor Cells 

Somatostatin may also directly inhibit tumor 

cell growth by interacting with specific 

somatostatin receptors located on tumor cells. 

Using either radiolabeled somatostatin or its 

analogs, somatostatin receptors have been described 

in a large variety of human cancer 

cells (including pituitary adenomas, islet tumors, 

carcinoids, adenocarcinomas of breast, 

prostate, ovary, kidney and colon origin, lymphomas 

as well as astrocytomas and neuroblastomas 

and medulloblastomas). Most tumors 

express the SRIF1 subtype characterized 

by a high affinity for natural peptides and 

hexapeptide-stable analogs but a number of 

tumors express the SRIF2 subtype characterized 

by a low affinity for analogs. More recent 

analyses of SSTR mRNAs demonstrate that 

various human tumors from neuroendocrine 

and gastroenteropancreatic origin, brain tu- 

mors (gliomas and meningiomas), prostate, 

lung and breast tumors express various SSTR 

mRNA, each tumor expressing more than one 

subtype, SSTR-2 being the most frequently 

expressed [for a review, see 37, 38]. Indeed, in 

carcinoid tumors, of 87 tumors examined, approximately 

85% are positive for SSTR-2. 

The majority of these tumors also express 

SSTR-5, with SSTR-1, SSTR-3 and SSTR-4 

being less abundant. The high frequency of 

SSTR-2 mRNA (and probably also the presence 

of SSTR-5 mRNA) found in neuroendocrine 

tumors allows the localization of various 

human tumors and metastases by somatostatin 

receptor scintigraphy following injection 

of indium-111-labeled octreotide. However, 

the detection of specific SSTR mRNA in 

tumors does not necessarily reflect the presence 

of the protein. The recent availability of 

polyclonal antibodies has enabled different 

groups to identify the SSTR proteins. Indeed, 

using SSTR-2 antibodies, Dutour et al. [39] 

report the expression of SSTR-2 in human 

gliomas and meningiomas with a rich expression 

in both human brain tumor and peritumoral 

tissue, and a prominent expression 

in blood vessels. Immunohistochemical detection 

of somatostatin receptors SSTR-1, 

SSTR-2 and SSTR-3 using specific antibodies 

in 33 breast tumors allows the detection of the 

receptors on tumor cells but the level and the 

pattern of the expression of SSTR vary greatly 

between individual carcinomas: SSTR-2 detected 

at a high level in 28 tumors (85%), 

SSTR-1 in 17 tumors (52%) and SSTR-3 in 16 

tumors (48%) [40]. Of 35 patients with carcinoid 

tumors, the presence of SSTR-2 protein 

has been detected in 25 patients and there was 

a correlation with the presence of SSTR-2 

mRNA, the tracer uptake using somatostatin 

receptor autoradiography and the therapeutic 

response to somatostatin analog treatment 

[41]. In contrast to that observed in neuroendocrine 

tumors, in advanced pancreatic and 


prostatic as well as colorectal adenocarcinoma, 

SSTR-2 expression is lost. This may have 

a growth advantage in these tumors and provide 

one explanation for the lack of therapeutic 

effect of somatostatin analogs in such tumors 

[42, 43]. 

The presence of somatostatin receptors in 

tumors argues in favor of a direct role for 

somatostatin in the regulation of tumor 

growth. A direct inhibitory effect of somatostatin 

or analogs on cell growth has been demonstrated 

on various cancer cell lines which 

express endogenous somatostatin receptors 

(cells of mammary, pancreatic, gastric, lung, 

colorectal or thyroid origin) [for a review, see 

4]. However, the mechanisms of cell growth 

arrest induced by somatostatin are still poorly 

understood. The fact that these tumor cells 

express multiple somatostatin receptors raises 

the questions of whether different somatostatin 

receptor(s) may account for these effects 

and which mechanisms are involved. 

The direct inhibitory action of somatostatin 

on cell growth may result from the blockade 

of mitogenic growth factor signal. In NIH 

3T3 or CHO cells expressing SSTR-1 or 

SSTR-2, octreotide and vapreotide inhibit 

cell proliferation induced by serum or insulin 

with an affinity which correlates with the 

binding affinity of analogs to each receptor 

subtype. This effect involves the stimulation 

of a tyrosine phosphatase [16, 19]. The somatostatin-sensitive 

tyrosine phosphatase has recently 

been identified as SHP-1. This tyrosine 

phosphatase contains two SH2 domains 

which are involved in protein-protein interactions. 

SHP-1 associates in vivo with various 

activated tyrosylated growth factor tyrosine 

kinase receptors and cytokine receptors. Recent 

studies have suggested a role of SHP-1 in 

terminating growth factor and cytokine mitogenic 

signals by dephosphorylating critical 

molecules [44]. In CHO cells expressing 

SSTR-2, SHP-1 is weakly associated with the 



SSTR-2 receptor via the protein Gi·3 at the 

resting level and occupation of SSTR-2 by 

analogs transiently increases the formation of 

SSTR-2-SHP-1-Gi·3 complexes leading to the 

activation of the enzyme. The activated enzyme 

rapidly dissociates from the SSTR-2 

subtype, associates with the activated and tyrosylated 

insulin receptor, dephosphorylates 

it and its substrates, thus leading to a negative 

regulation of the insulin mitogenic signaling 

[45] due to G1 cell cycle arrest and 

inhibition of insulin-induced S phase entry 

[Pages, pers. results]. A somatostatin-induced 

increase of SHP-1 translocation to the membrane 

is also observed in MCF-7 mammary 

cancer cells [46]. The use of dominant negative 

SHP-1 reveals that SHP-1 is required 

for the antiproliferative signal initiated by 

SSTR-2 [47]. In addition, SSTR-4 could also 

mediate the antiproliferative effect of somatostatin 

via a tyrosine phosphatase since in 

the rat thyroid PC13 cell line which only 

expresses SSTR-4 mRNA, somatostatin inhibits 

insulin- and insulin-plus-TSH-dependent 

proliferation through the stimulation of 

a tyrosine phosphatase and induces a block 

in the G1/S progression in the cell cycle [48]. 

Concerning SSTR-5, its expression in CHO- 

K1 cells leads to somatostatin analog-induced 

inhibition of cell proliferation stimulated 

by serum or cholecystokinin via a pertussis 

toxin-dependent Gi/0 protein [20]. The 

signaling pathway coupled to SSTR-5 and 

leading to inhibition of proliferation is selective 

for SSTR-5 and has been recently 

identified. It involves the inhibition of guanylate 

cyclase leading to a decrease of cGMP 

formation, inhibition of cGMP-dependent 

protein kinase G and inhibition of MAP kinase 

ERK1/2 [21]. 

The antiproliferative effect of somatostatin 

can also result from apoptosis. Apoptosis 

has been reported to be induced by the SSTR- 

3 subtype via a G protein-dependent signaling 


and to be associated with an intracellular 

acidification and activation of endonuclease 

and induction of p53 and Bax [49, 50]. In 

human pancreatic cancer cells expressing mutated 

p53 and devoid of endogenous SSTR-2, 

expression of SSTR-2 does not result in a G1 

cell cycle arrest but induces an increase in cell 

death [Rochaix, pers. results]. This indicates 

that apoptosis can be signaled by other SSTR 

than SSTR-3 and somatostatin can induce 

apoptosis by p53-dependent and p53-independent 

mechanisms. 

Besides the antiproliferative effect of somatostatin 

due to cell growth arrest and/or 

apoptosis, somatostatin may directly control 

cell growth by inhibiting the synthesis and/or 

the secretion of autocrine growth factors, cytokines 

and hormones involved in the proliferation 

of tumor cells. It is well known that 

the aberrant expression of growth factors, cytokines 

or hormones and their receptors represent 

fundamental circuits that may spur 

and sustain uncontrolled growth and metastatic 

behavior of cancer cells. For example, 

EGF-related growth factors such as transforming 

growth factor-· and amphiregulin 

and/or their specific receptor, the EGF receptor 

as well as IGF-1 receptor and its ligand, 

have been detected in several types of human 

cancers, including breast, lung, pancreatic 

and colorectal cancers [51, 52]. Gastrin and 

CCK-B receptor isoforms are coexpressed 

in gastrointestinal cancer cells [53]. These 

growth factors may act by paracrine and autocrine 

mechanisms to exert growth promoting 

and metabolic effects. Somatostatin may influence 

the synthesis and/or the secretion of 

these factors and/or downregulate the expression 

of their receptors leading to disruption of 

proliferative autocrine loops. At the cellular 

level, blockade of secretion by somatostatin is 

mediated through inhibition of Ca 2+ and 

cAMP production. Additionally, somatostatin 

can directly interfere with the exocytotic 

machinery by inhibiting the protein phosphatase 

calcineurin [14]. The specific SSTR subtypes 

involved in these processes and the 

mechanisms involved remain to be determined. 

Recent results using the patch-clamp 

technique indicate that in human neuroendocrine 

gut tumor cells, somatostatin and octreotide 

inhibit L-type voltage-dependent calcium 

channels with the same amplitude suggesting 

that at least SSTR-2 and SSTR-5 may 

be involved in the inhibition of Ca 2+ influx 

and thereby inhibition of tumor-produced 

neurotransmitters and hormone [54]. 

The antiproliferative effects of somatostatin 

result from its actions via the endocrine 

pathway but evidence exists that somatostatin 

can also act via an autocrine/paracrine pathway. 

Indeed, immunoreactive somatostatin 

has been found in somatostatin receptor-positive 

normal and tumor cell types such as 

endocrine and lymphoid cells, breast cancer 

cells, colonic tumor cells and, additionally, 

somatostatin mRNA is detected in a wide 

variety of neuroendocrine tumors known to 

express somatostatin receptors [55–58]. Correction 

of the SSTR-2 deficit in human pancreatic 

cancer cells by SSTR-2 expression induces 

a negative autocrine loop in the absence 

of exogenous ligand, which is due to the 

SSTR-2-induced expression and secretion of 

endogenous SSTR-2 ligand (somatostatin 14 

and somatostatin 28). This results in inhibition 

of cancer cell proliferation and reversion 

of cell tumorigenicity in vitro and in vivo 

after xenografts in nude mice [59]. SSTR-2 

may function as a determinant factor in the 

negative control of cell growth and a loss of 

such an autocrine loop by the loss of expression 

of one component such as SSTR-2 or 

endogenous ligand contributes to the malignancy 

of cancers. 

As observed for other receptors coupled to 

G protein, somatostatin receptors are sensitive 

to agonist-induced desensitization and/or 


internalization and/or up- or down-regulation. 

Indeed, agonist-dependent internalization 

and upregulation of somatostatin receptors 

have been demonstrated in various cell 

lines expressing multiple SSTRs or transfected 

cells expressing individual subtype after 

prolonged agonist exposure. Although the 

molecular mechanisms involved in these effects 

are poorly understood, it appears that 

the response of somatostatin receptors to agonist 

application is agonist-, receptor- and cell 

type-specific. Indeed, a different pattern of 

internalization has been reported for the five 

SSTRs, in CHO-K1 cells and in human embryonic 

kidney (HEK) cells expressing individual 

subtypes. In CHO-K1 cells, SSTR-2–5 

undergo rapid internalization following agonist 

activation but SSTR-1 is not internalized. 

In contrast, in HEK cells, SSTR-1, SSTR-2 

and SSTR-3 are internalized in response to 

somatostatin 14 or somatostatin 28 whereas 

SSTR-5 is only internalized in response to 

somatostatin 28 and SSTR-4 is not internalized 

[for a review, see 8, 37]. In addition, 

somatostatin upregulates SSTRs in a receptor 

subtype-specific manner. Long-term exposure 

of CHO-K1 cells to somatostatin upregulates 

SSTR-1, SSTR-2 and SSTR-4 by 110, 26 and 

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22%, respectively, whereas the levels of SSTR- 

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Established Clinical Use of Octreotide 

and Lanreotide in Oncology 

Kjell Öberg 

Department of Medical Sciences, Uppsala University, Uppsala, Sweden 

Key Words 

Neuroendocrine tumors W Octreoscan W 

Octreotide W Lanreotide W Octastatin 

Abstract 

The diagnosis and treatment of neuroendocrine 

tumors have been significantly improved 

during the last decades. Localization 

and staging of the disease by somatostatin 

receptor scintigraphy (Octreoscan) are now 

the ‘gold standard’ for the management of 

these tumors. Treatment with somatostatin 

analogs has improved quality of life and 

possibly also survival for patients with neuroendocrine 

tumors. New long-acting formulations 

of the somatostatin analogs are as 

effective as the old regular formulations 

but will further improve quality of life for 

the patients. Tumor-targeted therapy with 

111 In and 90 Y coupled to somatostatin analogs 

show promising results but await further 

studies. 

ABC 

Fax + 41 61 306 12 34 





0009–3157/01/0478–0040$17.50/0 



Introduction 

Octreotide and lanreotide are registered in 

most countries for the control of symptoms 

associated with metastatic carcinoid and VIPsecreting 

tumors. The clinical efficacy of somatostatin 

analogs has been established for 

many neuroendocrine tumors including acromegaly, 

although the latter will not be discussed 

in this paper. 

Neuroendocrine gut and pancreatic tumors 

constitute about 2% of all malignant 

gastrointestinal tumors. Carcinoids are the 

most common type of neuroendocrine tumors 

and may be classified according to the region 

in which they arise into foregut, midgut and 

hindgut carcinoids [1, 2]. Foregut tumors 

originate in the thymus, lung and gastroduodenal 

mucosa and represent about 15% of all 

carcinoids. Midgut carcinoids with the primary 

located in the jejunum, ileum and the proximal 

colon including the appendix comprise 

the most common (40–50%) of all clinically 

relevant carcinoids. Hindgut tumors lo- 

Prof. Kjell Öberg 

Department of Medical Sciences, Uppsala University 

Uppsala (Sweden) 

Tel. +46 18 66 49 17, Fax +46 18 51 01 33 

E-Mail Kjell.Oberg@medicin.uu.se

cated in the rectum, sigmoid and the distal 

colon comprise approximately 20–25% of all 

carcinoids and are normally hormonally inactive 

(nonfunctioning). The hormones secreted 

by foregut carcinoids are varied giving rise to 

many clinical syndromes such as acromegaly, 

Cushing’s disease, SIADH, Zollinger-Ellison 

syndrome as well as the carcinoid syndrome 

per se. 

The above classification of carcinoid tumors 

has been questioned since it causes considerable 

confusion. Consequently the term 

carcinoid might in the future be reserved 

only for classical midgut carcinoids. Other 

neuroendocrine tumors in the gut should be 

assigned the term ‘neuroendocrine tumors’ 

followed by their primary location, e.g. neuroendocrine, 

lung, gastric, duodenal, pancreatic, 

colonic and rectal tumors. The dominant 

hormone produced by the tumors may 

also be included in the classification, e.g. gastrin-producing 

neuroendocrine tumor. Such a 

classification would certainly be helpful in 

communicating information about these tumors 

and also in evaluating potential therapies 

[1]. 

The carcinoid syndrome is a well-defined 

clinical syndrome which includes flushes, diarrhea, 

carcinoid heart disease with right 

heart failure and bronchial constriction accompanied 

by elevated levels of plasma serotonin 

and/or urinary 5-HIAA. The tumors 

also release tachykinins, bradykinins and 

prostaglandins. For some patients the syndrome 

is severe enough to be potentially lifethreatening 

with extensive flushing combined 

with hypotension or very frequent diarrhea, 

the so-called ‘carcinoid crisis’ [2, 3]. Another 

group of neuroendocrine tumors are the endocrine 

pancreatic tumors which are classified 

as funtioning if they are associated with a clinical 

syndrome related to the hormone they 

produce or which are considered nonfunctioning 

if they do not present with clinical 



symptoms of excessive hormone release. The 

latter category constitutes around 30% of all 

endocrine pancreatic tumors and includes 

those which secrete pancreatic polypeptide, 

chromogranin A, peptide YY and neurotensin 

[4, 5]. 

The two most common clinical syndromes 

related to endocrine pancreatic tumors are the 

Zollinger-Ellison syndrome resulting from 

gastrin overproduction [6] and the hypoglycemic 

syndrome which is related to high insulin/proinsulin 

release [7]. The Zollinger-Ellison 

syndrome (gastrinoma) may also arise 

from hypersecretion of gastrin production by 

duodenal carcinoids (around 40%). More 

than 70% of the gastrin-producing tumors are 

malignant with early lymph node involvement. 

Most neuroendocrine pancreatic tumors 

are malignant except for insulin-producing 

tumors where 80% are benign solitary 

tumors in the pancreas [7]. 

Other functioning endocrine pancreatic 

tumors are the VIP-producing syndrome or 

WDHA syndrome which is characterized by 

extensive diarrhea, hypokalemia and achlorhydria 

[8]. In such patients the diarrhea volume 

might exceed more than 10 liters per 

day and they often require intensive care. 

Such tumors are mostly confined to the pancreas 

but sometimes may be located to the 

lung or sympathetic ganglia. Another rare tumor 

is the glucagonoma. The glucagonoma 

syndrome [9] is characterized by a typical 

necrolytic migratory erythema, diabetic glucose 

tolerance, anemia, weight loss and 

thromboembolism which may be related because 

of glucagon production and its endorgan 

effects. Both these rare tumors have 

been treated successfully with somatostatin 

analogs. 

Multiple endocrine neoplasia type 1 

(MEN-1) is a familial disorder inherited as an 

autosomal dominant trait with variable penetrance 

patterns. In MEN-1 the pituitary, para- 


thyroids and endocrine pancreas are the most 

commonly affected organs but the adrenal 

cortex and the thyroid can also be involved 

[10]. A specific genetic deletion has been described 

for MEN-1, i.e. a loss of heterozygosity 

of the MEN-1 locus on chromosome 11q13 

where the MEN-1 gene is deleted or mutated. 

About 80% of MEN-1 patients develop endocrine 

pancreatic tumors. Furthermore, 

about 30% of all gastrin-producing neuroendocrine 

gastrointestinal tumors are related to 

the MEN-1 syndrome. Some of these patients 

also develop lung, duodenal or gastric carcinoids. 

In fact, gastrinoma in MEN-1 patients 

is more often located in the duodenum than 

the pancreas itself and sometimes you can 

find the gastrinomas in both locations. 

The diagnosis of neuroendocrine tumors is 

based on histopathology, the cells showing the 

typical features of amine precursor uptakes 

and decarboxylation including positive silver 

staining (argyrophil, argentaffin) and positive 

staining for antibodies to chromogranin A, 

synaptophysin and NSE. The more sophisticated 

histopathology takes the tumor biology 

into account such as the proliferation markers 

(Ki-67, PCNA), angiogenetic factors (VEGF, 

b-FGF), adhesion molecules (CD-44, exon 

V6–V9) and finally deletions and mutations 

of the MEN-1 gene (menin). 

An essential component in the diagnosis of 

neuroendocrine tumors is the biochemical determination 

of the different peptide hormones 

they secrete. For example, determination 

of chromogranin A is the most important 

screening marker for the diagnosis of neuroendocrine 

tumors. Urinary 5-HIAA is important 

in diagnosing the carcinoid syndrome 

[1]. The localization and staging of neuroendocrine 

tumors may be significantly improved 

by somatostatin receptor scintigraphy 

(octreoscan), which will be discussed below in 

relation to treatment with somatostatin analogs. 

Somatostatin receptor scintigraphy is 

42 Chemotherapy 2001;47(suppl 2):40–53 Öberg 

nowadays the procedure of choice for localizing 

neuroendocrine tumors and supported by 

computed tomography and ultrasonography 

to determine the tumor size follow-up during 

therapy. Endoscopic ultrasonography has recently 

come into clinical use and has been particularly 

useful for localizing endocrine pancreatic 

tumors located particularly in the head 

of the pancreas. 

The prognosis of neuroendocrine tumors, 

particularly carcinoids, has normally been assumed 

to be relatively good without treatment. 

Therefore, many physicians have been 

reluctant to administer medical treatment in 

the early stages of the disease. However, a 

critical analysis of the 5-year survival rates of 

patients with neuroendocrine tumors suggests 

that the prognosis of such patients is not as 

good as many physicians believe. Thus, the 5year 

survival rates of patients with neuroendocrine 

tumors is less than 20% when liver 

metastases are present. Furthermore, the median 

survival for patients with malignant carcinoid 

tumors with the carcinoid syndrome is 

less than 2 years from the time of diagnosis 

[1, 2]. 

The therapy for neuroendocrine tumors is 

aimed at providing symptomatic relief by 

suppression of hypersecreting hormones, inhibition 

of tumor growth and at improving 

and maintain a good quality of life. Surgery is 

the treatment of choice for malignant neuroendocrine 

tumors, and even if surgical resection 

is not possible, debulking and bypassing 

procedures should be considered [11]. To 

further reduce the tumor burden, embolization, 

with and without cytotoxic agents has 

been demonstrated to have beneficial effects 

[12]. External irradiation has been of limited 

value in most neuroendocrine tumors but 

may relieve pain in some patients [13]. Hitherto 

tumor-targeted treatment has been attempted 

using 131 I-MIBG [14] but the technique 

has now been replaced by 111 In-DTPA-

octreotide. More recently 90 Y label compounds 

have also been evaluated [15]. The 

medical treatment for neuroendocrine tumors 

include chemotherapy, somatostatin analogs 

and interferon-· [1, 16, 17]. Chemotherapy, 

particularly streptozotocin plus 5-fluorouracil, 

has demonstrated to be a valuable therapeutic 

regimen for endocrine pancreatic tumors 

with response rates of 50–70% being 

reported [1, 16, 17]; however, classical midgut 

carcinoids do not respond to chemotherapy, 

its response rates being less than 10% [1, 16, 

18]. The therapeutic idea of somatostatin analogs 

in the management of neuroendocrine 

tumors will be discussed in detail below. Interferon-· 

has been shown to be of beneficial 

value, particularly in patients with midgut 

carcinoids with a reported subjective improvement 

in about 50% of the patients, a 

reduction in tumor size in 14% and biochemical 

responses in 40–50% of the patients [1, 

19]. Patients who tolerate interferon-· therapy 

frequently exhibit significant long-term responses 

with a median survival from the diagnosis 

of the carcinoid syndrome of more than 

60 months [20]. 

Somatostatin Receptors 

Somatostatin receptors are expressed in somatostatin 

target tissues such as brain, pituitary, 

pancreas, gastrointestinal tract, blood 

vessels as well as in various types of tumors. 

At present five somatostatin receptor subtypes 

(SSTR-1–5) have been cloned and pharmacologically 

characterized [21–23]. All the 

somatostatin receptors are coupled to G proteins 

and belong to the seven-transmembranespanning 

receptor family. All the somatostatin 

receptor subtypes bind to their native hormones 

(SRIF-28 and SRIF-14) with high affinity. 

In contrast, short synthetic somatostatin 

(SRIF) analogs used clinically such as 



octreotide, lanreotide and octreostatin display 

high affinity binding only for SSTR-2 and 

SSTR-5 receptors, intermediate binding affinity 

for SSTR-3 subtype and very low or no affinity 

for SSTR-1 and SSTR-4 subtypes. The five 

somatostatin receptor subtypes cloned to date 

show very poor homology (40–50%) which 

may account, at least in part for the different 

binding affinities [23]. Although a number of 

studies have been performed over the past 

years to determine the distribution of the five 

somatostatin receptor subtypes, their physiological 

role is still poorly understood. This is 

partly due to the fact that there is no set of agonists 

and antagonists available with sufficient 

receptor selectivity for a single receptor subtype 

and because of coexpression of two or 

more SRIF receptor subtypes in a particular 

organ. All five somatostatin receptors are functionally 

coupled to inhibition of adenylyl cyclase. 

Likewise, the five subtypes induce phosphotyrosine 

phosphatase-1c in each case via 

pertussis toxin-sensitive GTP binding proteins. 

Some of the receptor subtypes are also 

coupled to K + and Ca 2+ channels, the Na 2+ /K + 

hydrogen exchanges and to phospholipase C 

and MAP kinases. Neuroendocrine tumors express 

a variety of somatostatin receptors but 

particularly receptor subtype 2 [22, 24, 25]. 

Thus the SSTR-2 receptor subtype is expressed 

in 90% of carcinoid tumors and in 80% of 

endocrine pancreatic tumors. An exception are 

insulin-producing pancreatic tumors where 

less than 50% express the somatostatin receptor 

2 subtype. However, neuroendocrine tumors 

also express SSTR-5, SSTR-3 and SSTR- 

1 subtypes. Further, it is demonstrated that different 

somatostatin receptor subtypes are expressed 

in various patterns on different tumors 

[22]. This demonstration may explain the conflicting 

results of the therapeutic efficacy of 

reported somatostatin analogs in the management 

of neuroendocrine tumors. Activation of 

somatostatin receptor subtypes 1 and 2 results 


in the activation of tyrosine phosphatase, the 

activity of which has been correlated with the 

antimitotic effect of somatostatin and its analogs 

in some types of cells [26]. In addition, 

inhibition of cell proliferation is mediated by 

the somatostatin receptor subtype 5, but via a 

different mechanism, which probably involves 

changes in the intracellular calcium 

fluxes [23, 27]. Somatostatin receptor type 3 

(SSTR-3) has been reported to mediate apoptosis. 

Thus, high dose treatment with octreotide, 

which only has a low binding affinity for 

the SSTR-3 subtype induces apoptosis both in 

carcinoid tumors and BON-1 cells xenotransplanted 

to nude mice [28]. Octreotide and 

other somatostatin analogs significantly inhibit 

the growth of the neuroendocrine-differentiated 

cell line BON-1, the pancreatic cancer 

cell line AR42J and the human breast cancer 

line MCF-7 in experimental animals [28, 

29]. Tumors treated with somatostatin analogs 

are less vascular than those in untreated 

mice suggesting that the peptide inhibits angiogenesis. 

This suggestion is supported in a 

chorioalantoic membrane model of the chick 

embryo where octreotide inhibits angiogenesis 

in a dose-related manner [26]. Furthermore, 

octreotide in combination with endothelial 

growth factor inhibits blood vessel 

growth. Reubi et al. [30] demonstrated a high 

concentration of somatostatin receptors in the 

veins draining some human tumors. However, 

the expression of somatostatin receptors 

in the veins was not different from that in the 

tumour per se. 

Weckbecker et al. [29] studied the effects 

of octreotide in combination with doxorubicin, 

mitomycin C and Taxol or 5-FU on the 

growth of the pancreatic cancer cell line 

AR42J in vitro. Octreotide potentiated the 

antiproliferative effect of three of four cytotoxic 

agents (mitomycin C, doxorubicin and 

taxol) and was additive to 5-FU. The authors 

also investigated the temporal effects of a 


combination of octreotide and doxorubicin. 

They observed that the antiproliferative effect 

was greater if the doxorubicin therapy was 

administered initially with the octreotide 

therapy added 24 h later. The in vitro data 

was further confirmed in vivo using nude 

mice bearing AR42J tumors. 

Somatostatin Receptor Scintigraphy 

Somatostatin receptor scintigraphy is the 

most important clinical diagnostic investigation 


tumors [31, 32]. Dynamic scintigraphy 

detected more than 90% of all patients with 

carcinoid tumors, particularly liver metastases, 

regional lymph node metastases, bone 

metastases and sometimes also the primary 

tumor. In patients with endocrine pancreatic 

tumors, the clinical use of scintigraphy in the 

detection of such tumors has not been as fruitful 

as in carcinoid tumors. However, in a 

recent study 122 patients with a diagnosis of 

the Zollinger-Ellison syndrome were evaluated 

with upper gastrointestinal endoscopy, 

computerized tomography (CT), magnetic 

resonance imaging (MRI), angiography and 

bone scanning, to attempt to design a treatment 

plan [33]. Patients then underwent somatostatin 

receptor scintigraphy with 111 In- 

DTPA-D-Phe-octreotide. The somatostatin 

scintigraphy (62%) was superior to both CT 

(39%) and MRI (50%) in localizing primary 

tumors and was equal to all conventional 

imaging studies in combination. For metastatic 

disease scintigraphy (100%) was again 

superior to CT and MRI (64 and 80%, respectively) 

and equal to all conventional studies 

combined (96%). In 14% of the tumors, scintigraphy 

was the only technique which was 

positive. The scintigraphic results changed 

the clinical management in 47% of patients 

with gastrinoma. Therefore in patients with

Table 1. Meta-analysis of 

symptomatic (subjective), 

biochemical and radiological 

responses to different treatments 

with somatostatin analogs in 

studies conducted over the last 10 

years in patients with metastatic 

neuroendocrine tumors 

the Zollinger-Ellison syndrome the investigators 

suggested that somatostatin receptor scintigraphy 

should be regarded as the imaging 

modality of choice. In a prospective study 

evaluating somatostatin receptor imaging in 

160 patients with confirmed gastroenteropancreatic 

tumors, somatostatin receptor scintigraphy 

was positive in 68% of patients. More 

interesting was the observation that in 46 patients, 

negative by conventional imaging, somatostatin 

receptor scintigraphy detected 47 

previously undiagnosed lesions in 36 patients. 

Furthermore, somatostatin receptor scintigraphy 

modified the tumor staging in 38 patients 

and changed the surgical strategy in 40 patients 

[34]. On the basis of these findings, 

somatostatin receptor scintigraphy should be 

performed routinely in patients with neuroendocrine 

tumors both for the staging and for 

therapeutic decisions. Small tumors, less than 

1 cm in diameter, such as in patients with 

MEN-1 still represent a diagnostic problem. 

Furthermore, in all primary tumors or metastases, 

even in the same patient, the ex- 



Response Standard doses 

of octreotide 

(100–1,500 Ìg/day) 

Slow release 

lanreotide 

(30 mg/14 day i.m.) 

High dose 

lanreotide 

(9–15 mg/day) 

Symptomatic 

Biochemical 

146/228 (64)34/66 (52) 11/26 (42) 

CR 6/54 (11)2/80 (2.5)1/33 (3) 

PR 116/211 (55)35/80 (44) 24/33 (72) 

SD NS 32/80 (40)7/33 (21) 

PD 

Radiological 

NS 11/80 (13.5)1/33 (3) 

CR – – 1/53 (2) 

PR 7/131 (5)2/42 (5) 6/53 (11) 

SD 50/131 (38)32/42 (76) 25/53 (47) 

PD 74/131 (56)8/42 (19) 21/53 (39) 

Figures represent numbers with the percentage in parentheses. CR = 

Complete response; PR = partial response; SD = stable disease; PD = progressive 

disease; NS = not indicated. 

pression of somatostatin receptor subtypes is 

not identical and they may not express the 

SSTR-2 or SSTR-5 subtypes. Since octreoscans 

are dependent as the expression of the 

SSTR-2 and SSTR-5 subtypes, positive somatostatin 

receptor scintigraphy has a predictive 

value for treatment with somatostatin analogs 

[35, 36]. Conversely, tumors not expressing 

the SSTR-2 and SSTR-5 subtypes will not be 

detectable by scintigraphy and are unlikely to 

respond to somatostatin analog therapy. 

Treatment with Somatostatin 

Analogs (table 1) 

Somatostatin analogs, octreotide being the 

first available for clinical use [37], have become 

increasingly important in the management 

of patients with neuroendocrine tumors 

of the gut and pancreas. The rationale for the 

clinical efficacy of somatostatin analogs in 

the management of neuroendocrine tumors 

is related to the expression of somatostatin 


eceptors in 80–90% of all such cases. All of 

the somatostatin analogs presently available 

for clinical use (octreotide, lanreotide, octastatin) 

bind with high affinity to the SSTR-2 

and SSTR-5 subtypes and with lower affinity 

to SSTR-3 subtype. Although somatostatin 

analogs have been available for more than 15 

years, we are still lacking randomized controlled 

trials, probably because neuroendocrine 

tumors represent rare diseases. Furthermore, 

the inclusion of different types of neuroendocrine 

tumors in multicenter trials is 

not appropriate for studying the efficacy of 

somatostatin analogs on these indications 

since there are large differences between ‘classical’ 

midgut carcinoids with a low proliferative 

capacity and several forms of endocrine 

pancreatic tumors or other foregut tumors 

which progress rapidly and show a high proliferative 

capacity. 

The efficacy of somatostatin analog therapy 

could be divided into subjective, biochemical 

and tumor responses (tumor size reduction). 

A complete remission is rarely obtained 

but partial remission is more than 50% reduction 

of clinical symptoms, biochemical markers 

or tumor size; stable disease is less than 

50% reduction of these parameters but also 

less than 25% increase of the same parameters. 

Progressive disease is more than 25% 

increase of clinical symptoms, biochemical 

markers or tumor size. 

In the first trial reported by Kvols et al. 

[37], octreotide subcutaneously (150 Ìg t.i.d.) 

was observed to present symptomatic responses 

in 88% and biochemical responses in 

72% of patients with carcinoid tumors. The 

median duration of the biochemical response 

was 12 months. In 1989 Gorden et al. [38] 

performed a meta-analysis of all reported 

cases of neuroendocrine tumors treated with 

somatostatin analogs. The meta-analysis indicated 

symptomatic improvement in 92% 

and a biochemical response in 66% of the 


patients. A reduction of the tumor size was, 

however, only noted in 8% of octreotidetreated 

patients, whereas tumor size was unchanged 

in 85%. In that study tachyphylaxis 

was observed in 40% of the patients but a proportion 

did respond to increased doses of 

octreotide. The median dose of octreotide 

used in these studies was 300 Ìg/day s.c. Low 

dose octreotide therapy (50 Ìg b.i.d.) resulted 

in significantly lower biochemical response 

rates (30%) compared to the regular dose analog 

therapy [39]. 

More than 50 patients with gastrinomas 

have been treated with doses of 100–1,500 Ìg 

octreotide/day, most of them in the short term 

[40, 41]. A clinical response defined as control 

of gastric hypersecretion, pain and diarrhea 

was observed in 90% of the patients and was 

accompanied by a significant reduction in 

serum gastrin and basal acid secretion. In a 

long-term study by Ruszniewski et al. [42], the 

maximal acid output decreased during 9–12 

months of octreotide treatment suggesting an 

antitrophic effect of the analog (i.e. reduction 

of parietal cell mass). Such an effect has also 

been reported by an Italian group who demonstrated 

that octreotide, 500 Ìg once a day, 

elicited a significant decrease in its ECL cell 

population, which was paralleled by progressive 

reduction in serum gastrin levels in patients 

with chronic atrophic gastritis [43]. 

However, although somatostatin analog therapy 

is not the primary treatment for gastrinomas, 

many patients being initially treated 

with H2 receptor blockers or proton pump 

inhibitors combined with surgery, long-acting 

somatostatin analogs (Sandostatin-LAR ® , 

Lanreotide PR ® ) may be beneficial for a subgroup 

of patients with malignant gastrinomas. 

Patients with insulin-producing tumors 

treated with somatostatin analogs should be 

very carefully monitored for escalation of 

their hypoglycemia. In some patients counterregulatory 

mechanisms, such as the growth

hormone, IGF-1 and glucagon may be more 

suppressed than the insulin secretion by the 

tumor [41, 44, 45]. About 50% of insulin-producing 

tumors do not express somatostatin 

receptor 2 and 5 subtypes. However, there is a 

subgroup of insulin-producing tumors that 

might benefit from somatostatin analog therapy 

and these are the predominantly malignant 

insulinomas which concomitantly hypersecrete 

gastrin and/or glucagon. In patients with 

the WDHA syndrome and VIP-producing tumors 

which are unoperable and in whom chemotherapy 

has only been transiently effective, 

octreotide has been suggested to be the treatment 

of choice [41, 45, 46]. Symptomatic 

improvement has been reported in more than 

80% of such patients treated with octreotide 

at doses of 100–400 Ìg/day. However, in 

some patients the beneficial effect of octreotide 

lasted only a few days requiring progressive 

increases in doses. Biochemical responses 

have been reported in about 80% of VIPoma 

patients. Symptomatic relief was not always 

related to a reduction of plasma concentration 

of VIP suggesting that octreotide may have a 

direct effect on the gut. In some patients 

octreotide has also been shown to change the 

molecular forms of circulating VIP, possibly 

into less bioactive forms. In approximately 

90% of patients with glucagonomas who 

present with a rash it disappears rapidly after 

octreotide therapy [41, 47]. Other symptoms 

characteristic of the syndrome such as weight 

loss and diarrhea may improve during octreotide 

therapy but the analog has a variable 

effect on diabetes. Plasma glucagon is reduced 

in approximately 60% of patients during octreotide 

therapy. The symptomatic response 

observed during octreotide therapy was independent 

of the plasma glucagon, the concentration 

suggesting a direct effect of the analog 

on the skin. Furthermore, in patients with glucagonomas, 

octreotide can change the circulating 

molecular forms of glucagon, indicating 



that the analogs inhibit the posttranslational 

processing of preproglucagon, thereby reducing 

the circulating levels of bioactive glucagon. 

Somatostatin-producing tumors, the socalled 

somatostatinomas, have been regarded 

as resistant to treatment with somatostatin 

analogs. However, a symptomatic and biochemical 

response has been reported in a 

small number of patients during octreotide 

therapy which correlated with the presence of 

somatostatin receptor subtypes in the tumors 

[48]. 

The inhibition of tumor growth in patients 

with carcinoid and endocrine pancreatic tumors 

has been reported to be low in most 

studies (0–17%) [40, 41, 49]. In a study by 

Saltz et al. [50] in patients with neuroendocrine 

tumors treated with octreotide (150– 

250 Ìg t.i.d.), no regression was documented. 

However, octreotide stabilized the size assessed 

by CT in 50% of the patients for a 

median duration of 5 months. In a German 

multicenter trial, 52 patients with different 

forms of neuroendocrine malignancies and 

CT-documented tumor progression were 

treated with octreotide 200 Ìg t.i.d. [51]. Stabilization 

of tumor growth was achieved in 19 

of 52 patients (36%) for a median duration of 

18 months. Even though a reduction in tumor 

size is rarely seen with standard octreotide 

treatment, stabilization of further tumor 

growth suggests that octreotide has an antiproliferative 

effect. 

Harris and Redfern [49] performed a 

meta-analysis of data compiled from 62 published 

studies on patients with carcinoids to 

examine the relationship between the dose of 

octreotide and the clinical efficacy evaluated 

by analyzing urinary 5-HIAA, flushing and 

diarrhea in patients. Six dose ranges of octreotide 

were assessed and ranged from 100 

to 3,000 Ìg/day. The maximum clinical response 

to octreotide occurred in patients 

treated with 300–375 Ìg/day with some fur- 


ther improvement in doses up to 1,000 Ìg/ 

day. Doses of octreotide above 10,000 Ìg 

showed no additional clinical benefit. The authors’ 

conclusion from this study is that there 

was a significant patient-to-patient variation 

in the sensitivity to octreotide treatment and 

that it is important to titrate the dose of 

the analog in each patient until adequate 

symptoms and/or biochemical control are 

achieved. 

High-Dose Somatostatin Analog 

Therapy 

A few studies have addressed the potential 

value of high-dose somatostatin analog treatment 

in neuroendocrine gastrointestinal tumors 

[52–56]. A dose-related tumor response 

has been demonstrated in a variety of tumor 

models with increasing somatostatin analog 

treatment. In a trial of our group [53], 19 

patients with advanced neuroendocrine gastrointestinal 

tumors (13 carcinoids and 6 

EPT) were included in the study. The mean 

duration of disease prior to entry into the trial 

was 56 months and all except 4 patients had 

received a variety of treatments. Finally patients 

had failing standard dose octreotide 

therapy. Somatostatin receptor scintigraphy 

was positive in 17 of 18 patients before initiation 

of lanreotide administered in increasing 

doses up to 12 mg/day s.c., a dose which was 

maintained for 1 year or until tumor progression. 

High-dose lanreotide resulted in biochemical 

responses in 58% of the patients, 

stabilization of the disease was observed in 

70% and 1 patient (5%) showed a partial 

tumor response. Furthermore, patients with 

both a biochemical response and stabilization 

of their disease exhibited a progressive increase 

in the number of apoptotic cells in the 

tumor, maximal apoptosis occurring 12 

months following commencement of lanreo- 


tide therapy [28, 53]. Apoptosis may have 

been mediated via the binding of lanreotide to 

somatostatin receptor type 3, as suggested by 

Patel and Srikant [23]. Moreover, in this trial 

positron emission tomography using the tracer 

11 C-L-DOPA lanreotide inhibited exocytosis 

more strongly than the inhibition of its 

synthesis of the peptide [57]. Anthony et al. 

[54] treated 13 patients with neuroendocrine 

tumors, refractory to standard doses of octreotide, 

with a high dose of the analog 

(6 mg/day) and reported a partial tumor response 

in 4 patients (31%) and stabilization of 

the disease in 2 (15%). The same group reported 

on high-dose lanreotide (9 mg/day) in 

13 patients with various neuroendocrine tumors 

finding a partial remission in 4 patients 

(31%) and stabilization of the disease in 2 

(15%). Faiss and Wiedenmann [55] treated 30 

patients with metastatic neuroendocrine gastrointestinal 

tumors with 15 mg/day of lanreotide 

for 1 year and reported one complete 

and one partial tumor response. These studies 

suggest that a high-dose therapy of octreotide/ 

lanreotide can produce additional antiproliferative 

effects in patients deteriorating on 

regular dose analog therapy. These observations 

form the basis for a currently ongoing 

study with ultrahigh doses (160 mg/month) of 

octreotide (Onco-LAR ® ). 

Continuous Infusion of Somatostatin 


Several studies of patients with acromegaly 

have indicated that a continuous infusion of 

octreotide has advantages over intermittent 

subcutaneous injections of the analog [58]. A 

more pronounced clinical and biochemical 

control can be achieved at lower intravenous 

doses of somatostatin analogs and the adverse 

effects may be less than with higher subcutaneous 

doses. To test this hypothesis we

performed a European multicenter trial in 35 

patients with carcinoid syndrome (19 of them 

had failed standard doses of octreotide) with 

octastatin (RC-160) at a dose of 1.5 mg/day 

given as a continuous subcutaneous infusion 

via micropump for 3–6 months [56]. This was 

the first clinical trial of octastatin of particular 

interest since in vitro studies have suggested 

that octastatin has a stronger antiproliferative 

effect than both octreotide and lanreotide [58, 

59]. In this trial subjective improvement and 

disease stabilization were observed in 60% of 

the patients. However, the biochemical response 

rate was rather low (23%) and there 

was no tumor response. 

Slow Release Formulations of 


One of the most important improvements 

in somatostatin analog treatment is the development 

of a slow release formulation. Sandostatin-LAR 

and Lanreotide-PR in which octreotide 

and lanreotide have been incorporated 

into microspheres of a biodegradable 

polymer were available for clinical use. Sandostatin-LAR 

can be administered once every 

4 weeks and Lanreotide-PR every 2 weeks 

[60]. Ruszniewski et al. [61] treated 39 patients 

with carcinoids with Lanreotide-PR (30 

mg i.m. every 2 weeks) and reported subjective 

responses in approximately 55% of patients, 

biochemical responses in 42%. However, 

no tumor response was observed after 

6 months of lanreotide treatment. We conducted 

a European multicenter trial and included 

55 patients (48 carcinoids and 7 EPT) 

with Lanreotide-PR (30 mg i.m.) every 2 

weeks for 6 months [62]. Symptomatic improvement 

was observed in 38% of carcinoids, 

66% of gastrinomas and one VIPoma. 

Biochemical responses were obtained in 47% 

and tumor responses in 2 patients (7%). Sta- 



bilization of tumor growth was achieved in 

80% of patients. In this trial quality of life was 

studied using a validated instrument (QLC 

30) and assessment after 1 month showed a 

significant improvement of emotional and 

cognitive function, overall health as well as 

sleeping disorders and diarrhea. This was the 

first trial to demonstrate that long-acting somatostatin 

analog therapy improves the quality 

of life of patients with neuroendocrine 

tumors. 

Combination Trial with Somatostatin 


The combination of somatostatin analogs 

with other agents is an interesting area for 

future studies. We have previously reported 

that a combination of octreotide and interferon-· 

produced biochemical responses in 75% 

of patients resistant to either interferon-· 

alone or conventional doses of octreotide [63]. 

In vitro and in vivo studies of BON-1 tumors 

indicate that a combination of these two compounds 

has a stronger antiproliferative effect 

than interferon or octreotide alone [28]. An 

Italian trial reported on 58 patients with metastatic 

neuroendocrine tumors who were initially 

treated with octreotide at a dose of 

500 Ìg t.i.d. [52]. The dose was increased to 

1,000 Ìg t.i.d. and this regimen was continued 

until disease progression. Twenty-five patients 

with progressive disease during octreotide 

treatment received concomitant chemotherapy 

(dacarbazine 200 mg/m 2 , 5-FU 250 

mg/m 2 , epidoxorubicin 25 mg/m 2 ) administered 

intravenously daily for 3 days every 3 

weeks. For the whole group of 58 patients the 

median duration of octreotide treatment was 

5 months. In 27 patients the disease stabilized 

for at least 6 months. A partial remission was 

achieved in 2 patients which lasted 10 and 14 

months, respectively. The median survival of 


the entire group was 22 months. In this trial 

no additive or synergistic effect was obtained 

by adding chemotherapy. Therefore, the interesting 

observation by Weckbecker et al. 

[29] that doxorubicin in combination with 

octreotide showed a significant synergistic effect 

in in vitro and in vivo studies remains to 

be proven in forthcoming randomized clinical 

trials. 

Tumor-Targeted Radioactive 

Somatostatin Analog Treatment 

Peptide receptor scintigraphy with a radioactive 

somatostatin analogue ( 111 In- 

DTPA-octreotide) is a sensitive and specific 

technique to identify in vivo the presence and 

abundance of somatostatin receptors in various 

tumors. The method has now been accepted 

as an important tool for the staging 

and localization of neuroendocrine tumors. 

However, the technique is currently being 

evaluated as a possible means of targeting 

neuroendocrine tumors with ‘tumor-targeted’ 

radiotherapy using a repeated administration 

of high doses of 111 In-DTPA-octreotide. 111 In 

emits Auger electrons having a tissue penetration 

of 0.02–10 Ìm. In a recent trial 30 endstage 

patients with progressive neuroendocrine 

tumors were treated with 111 In-DTPAoctreotide 

up to a maximal cumulative dose 

of 74 GBq in a phase 1 trial. No major clinical 

side effects were observed after up to 2 years’ 

treatment, except that in a few patients there 

was a transient decline in platelets and lymphocytes. 

Of the 21 patients who received a 

cumulative dose of more than 20 GBq, 8 

patients showed stabilization of disease and 

there was a reduction in tumor size in a further 

6. Furthermore, there was a tendency 

towards better results in patients whose 

tumor cells showed higher accumulation of 

the radioligand. We treated 16 patients, also 


end-stage neuroendocrine tumor patients, at 

doses up to 60 GBq and observed 30% response 

rates and also a tendency towards better 

results with higher tracer accumulation of 

the radioligand. Theoretically depending on 

the homogeneity of the distribution of tumor 

cells expressing somatostatin receptor subtypes 

and the size of tumors, ß-emitting radionucleids, 

e.g. 90 Y labelled to DOTA octreotide, 

may be more effective than 111 In targeting 

radionuclear therapy. Such trials are now 

in progress. Recently a study of 10 patients 

treated with 90 Y DOTA TOC has been reported 

[15]. Two patients showed a significant 

antitumor response and another 2 developed 

stable disease. In 9 of the 10 patients 

treated renal and bone marrow toxicity did 

not exceed grade 1. One patient developed a 

persisting grade 2 thrombocytopenia at a total 

dose of 180 mCi. Tumor-targeted radioactive 

somatostatin analog therapy awaits further 

evaluation in patients with less advanced disease. 

Adverse Reaction to Somatostatin 

Analog Therapy 

The most common side effects of somatostatin 

analog are generally mild and include 

nausea, transient abdominal cramps, flatulence, 

diarrhea and local reaction at the injection 

site [58]. Most of these minor side effects 

resolve with time. In 20–50% of patients gall 

stones are formed de novo, but these remain 

virtually always asymptomatic [64]. Rare, 

more severe adverse events of octreotide therapy 

include hypocalcemia, bradycardia, acute 

pancreatitis, hepatitis, jaundice, transitory, 

ischemic attacks, and a negative inotropic 

effect of the analogs.

Future Aspects 

Somatostatin analogs can relieve symptoms, 

reduce circulating hormone levels and 

stabilize tumor growth in more than 50% of 

patients, which makes them a good therapy 

for patients with neuroendocrine tumors. 

There is, however, as yet no published study 

that shows that therapy with somatostatin 

analogs improves survival. However, the majority 

of centers working with patients with 

neuroendocrine tumors use a multimodal 

therapeutic approach. Thus, it is very unlikely 

that a patient with a neuroendocrine tumor 

will receive a somatostatin analog as the 

only treatment during the clinical course of 

the disease. There is no doubt that somatostatin 

analog therapy has significantly improved 

the quality of life in patients with 

malignant neuroendocrine tumors and is 

very important for palliative treatment. The 

most promising future areas are the clinical 

usefulness of slow release formulations, possibly 

also high-dose, slow release formulations 

(Onco-LAR) and the ‘tumor targeted’ 

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The Palliative Effects of Octreotide in 

Cancer Patients 

Andrew Dean 

Palliative Care Service, Sir Charles Gairdner Hospital, Nedlands, Australia 

Key Words 

Palliative care W Somatostatin W Opioids 

Abstract 

Octreotide is an extremely useful compound 

for palliative care physicians. It appears to be 

active in a number of different pain states 

and may be given by the spinal and intraventricular 

route. Its actions in reducing gut motility 

and secretions make it a valuable adjunct 

in the management of inoperable bowel 

obstruction. The same actions make it a 

potent antidiarrheal agent. Octreotide will often 

succeed where other antidiarrheal agents 

fail. Its ability to reduce gut secretions has led 

to its use in the treatment of fistulae. It has 

also been proposed as a useful drug in the 

management of cachexia and ascites. Most 

of the existing evidence is based on small 

numbers of case reports and further larger 

trials are necessary. 

ABC 

Fax + 41 61 306 12 34 





0009–3157/01/0478–0054$17.50/0 



Introduction 

Octreotide, a synthetic analog of somatostatin, 

is an interesting compound to many 

specialities. It has a number of properties 

which make it potentially useful in many different 

palliative care situations. This paper 

serves to address some of its applications. 

When considering the palliative uses of octreotide, 

the most pertinent quote to consider 

is ‘in most situations where the drug has been 

found to be useful, no controlled clinical trials 

have been performed. At least in part this has 

been due to the rarity of the conditions 

treated. It does make it difficult, however, to 

assess just how effective octreotide is in many 

circumstances’ [1]. 

Pain 

The past 5 years have seen tremendous 

improvements in the understanding of pain 

and analgesic neurophysiology. A distinction 

is made between opioid-sensitive pain and the 

Dr. Andrew Dean 

Palliative Care Service, Sir Charles Gairdner Hospital 

Nedlands, WA 6009 (Australia) 

Tel. +61 8 9346 2551, Fax +61 8 9346 1848 

E-Mail andrew.dean@health.wa.gov.au

pain that exhibits partial or no response to 

narcotic analgesics. There are now a vast 

array of opioids to choose from including 

morphine, hydromorphone, methadone, oxycodone, 

and fentanyl, each having a place 

in mainstream analgesic pharmacotherapy. 

Opioids, however, are not perfect analgesics. 

Pain from nerve damage (neuropathic pain, 

neurogenic pain) exhibits a variable degree of 

opioid resistance. There has been substantial 

work done in identifying some of the mechanisms 

of opioid resistance. Drugs with actions 

on sodium channels, NMDA receptors, calcium 

channels and inflammatory mediators 

are now abundant. Many new and old drugs 

are thus used by the pain practitioner. 

Innovative routes of drug delivery are now 

also more common. The use of epidural and 

intrathecal analgesia for acute, chronic and 

cancer pain is commonplace. The number of 

patients who fail these now standard analgesic 

approaches are becoming fewer. The controversy 

regarding the value of octreotide in pain 

medicine should be viewed in this context of a 

drug with potential therapeutic benefit for a 

relatively small number of patients, i.e. those 

who fail the traditional approach. 

In understanding the actions of octreotide 

in pain, it is first necessary to note that somatostatin 

receptors are found in dorsal horn 

afferent neurones, spinal interneurones, and 

ascending and descending pathways. Native 

somatostatin is found in the periaqueductal 

grey matter, substantia gelatinosa, the spinal 

cord and in descending pathways [2–7]. Somatostatin 

is produced in the hypothalamus, 

cortex, cerebellum and spinal cord as well as 

in multiple organs of the gastrointestinal tract 

(stomach, small bowel, colon and pancreas) 

[2, 8–11]. 

The effects of octreotide on pain can be 

considered to be a summation of its actions as 

a neurotransmitter and as an autocrine/paracrine 

regulator. These effects are mediated via 



a family of (as yet) 5 identified somatostatin 

receptors [12]. 

Given the distribution of somatostatin receptors 

in those parts of the nervous system 

concerned with pain transmission and inhibition, 

somatostatin and its analogs would be 

expected to have an effect on pain. The cellular 

and molecular effects of somatostatin and 

its analogs are also interesting. The somatostatin 

receptors are G-coupled protein receptors 

which exhibit many different actions. 

The various somatostatin analogs also exhibit 

differential receptor binding. Some receptors 

cause hyperpolarization of the cell 

membrane [13] and also block calcium channels 

[14]. Binding to some receptors regulates 

glutamate currents at the AMPA receptor 

[15]. Interestingly, opposing effects are seen 

on the glutamate current depending on which 

receptor subtype is activated [15]. 

Further indirect evidence of a potential 

analgesic action is found in examining the 

effects of other drugs on somatostatin secretion. 

Opioids and GABA agonists inhibit somatostatin 

secretion, as do high dose steroids. 

Low dose steroids, however, encourage somatostatin 

release. These are essentially observational 

phenomena which do not in themselves 

prove that somatostatin or its analogs 

are directly analgesic but certainly provide 

circumstantial evidence that somatostatin 

may be involved in the pain process. 

What clinical evidence is there for analgesic 

activity? In 1990 and 1991 [16, 17] subcutaneous 

octreotide was reported to relieve 

headache in acromegaly which was not related 

to tumor size. Naloxone did not reverse 

analgesia, suggesting that the analgesic effect 

was not mediated by standard opioid mechanisms. 

The limitations of imaging techniques 

in assessing minute changes in intracranial 

tumor size should, however, be noted. 

No randomized controlled trials have 

proven subcutaneous octreotide to have a spe- 


Table 1. Analgesic requirements before and after epidural or intrathecal somatostatin treatment 

for the 8 patients in the study of Mollenholt et al. [20, p. 537] 

Patient 

number 

1 

Daily analgesic dose 

before somatostatin 

treatment 

Ketobemidone, 60 mg orally 

Ketobemidone, 20 mg i.m. 

Paracetamol, 3 g orally 

Daily concomitant 

analgesic dose during 

somatostatin treatment 

56 Chemotherapy 2001;47(suppl 2):54–61 Dean 

Response to 

treatment 

None Excellent 

2 Morphine, 500 mg i.v. Morphine, 20 mg s.c. a Good 

3 Ketobemidone, 80 mg i.v. 

Methadone, 30 mg orally 

None Excellent 

4 Morphine, 300 mg i.v. Morphine, 20 mg s.c. b Good 

5 Morphine, 40–60 mg s.c. 

Morphine, 160 mg orally 


6 Morphine, 60 mg orally 


7 Morphine, 10–30 mg s.c. 



8 Morphine, 1,500 mg orally 

Ketobemidone, 100 mg rectally 

Unaltered Poor 

Morphine, 0–20 mg orally 

Paracetamol, 1 g rectally 



Good 

Good 

Morphine, 60 mg i.v. c Fair 

Ketobemidone is a synthetic opioid that is equipotent with morphine. 

a This dose of morphine was used to treat withdrawal symptoms and not for pain relief. 

b Intravenous morphine, 300 mg daily after removal of dislodged intrathecal catheter. 

c Intravenous morphine, 200–1,200 mg daily after the unintentional removal of the epidural 

catheter. 

cific analgesic action. De Conno et al. [18] 

found pain relief in 1 of 10 patients treated 

with subcutaneous octreotide for pain from 

cancer. Although a chemical action was proposed 

by the authors, it should be noted that 

the only patient with analgesic effect received 

relief from severe postprandial pain complicating 

pancreatic carcinoma. Pancreatic carcinoma 

can produce mesenteric ischemia because 

of its proximity to the celiac axis. We 

have treated several patients with mesenteric 

ischemia complicating pancreatic cancer with 

subcutaneous octreotide. This appeared to be 

an effective analgesic in these circumstances. 

The most likely mechanism of action is a 

reduction in bowel motility and secretion, 

with consequent reduction in ischemic pain. 

Spinal octreotide and somatostatin have 

been used for analgesia. Epidural somatostatin 

was shown to be an effective analgesic 

in upper abdominal surgery [19]. Mollenholt 

et al. [20] reported in 1994 that of 8 patients 

with intractable cancer pain treated with spinal 

somatostatin, 6 patients reported excellent 

or good pain relief (table 1). Five of these were 

patients who were probably suffering from

neurogenic pain. Penn et al. [21] reported the 

results of a 6-patient pilot study on intrathecal 

octreotide infusion for cancer pain. The patients 

were suffering from a variety of different 

pain types but it would appear a significant 

component of them had neurogenic pain. 

Good analgesia was generally obtained. Interestingly, 

analgesia was achieved in patients 

who had demonstrated significant opioid resistance. 

There has been much controversy 

regarding the use of spinal somatostatin and 

octreotide because of reports of neurotoxicity 

in some animal species [22–24]. 

Intraventricular octreotide has also been 

used to provide effective analgesia [25]. This 

should potentially be useful in patients with 

head and neck cancer exhibiting local nonopioid-sensitive 

pain. 

Interestingly the study of Mollenholt et al. 

[20] in 1994 was able to perform autopsies on 

5 patients who received spinal somatostatin. 

Three patients of the 5 studied showed some 

demyelination either of dorsal roots or dorsal 

columns. These effects could also be explained 

as being part of a paraneoplastic process. 

No patients had neurological deficits 

which could be correlated with this finding. 

The debate continues whether octreotide 

should be used by these routes but it is encouraging 

to read the report of Paice et al. [26] of 

octreotide being used for 5 years via the intrathecal 

route to successfully manage chronic 

pain. This occurred without neurotoxicity. 

Although there are no large randomized 

double-blinded controlled trials of octreotide 

in these situations, the large numbers of case 

reports indicating that octreotide has potent 

analgesic activity (especially in non-opioidsensitive 

pain) is encouraging. My own practice 

is to use octreotide via these routes as an 

adjunct to other analgesics when conventional 

approaches fail but ultimately the decision on 

whether or not to use octreotide in difficult pain 

scenarios is down to the individual clinician. 



Bowel Obstruction 

Since Khoo et al. [27] reported the use of 

octreotide in bowel obstruction in 1992, there 

have been many publications about this subject. 

The effects of octreotide on the gut are to 

reduce gut motility and secretion. Native somatostatin 

has been shown to inhibit fluid 

secretion into the rat jejunum [28] and stimulate 

sodium and chloride absorption in the 

rabbit ileum [29]. Octreotide has been shown 

to prolong small intestinal transit time in humans 

[30]. As both gastric and pancreatic 

secretions are significantly decreased, there is 

less total fluid turnover in the gut. 

A consequence of reduction in gut distension 

is to delay the onset of edema and ischemia 

in the antimesenteric border of the intestine. 

The subsequent delay in necrosis and 

perforation in mice with proximal small bowel 

obstruction treated with octreotide was 

noted in 1992 [31]. If this effect is mirrored in 

humans, as might be expected, it raises interesting 

questions relating to potential improvement 

and survival of patients receiving octreotide 

for bowel obstruction. In one controlled 

study of jejunal ligation in rats, octreotide 

significantly reduced the diameter of obstructed 

bowel and reduced sodium and potassium 

losses. The histopathological ischemic 

changes were more prominent in the 

control group and anastomotic bursting pressures 

were higher in the treated group. 

In a palliative care perspective, the main 

benefit of octreotide use in this setting is a 

reduction in distressing symptoms. The original 

report of Khoo et al. [27] was of 5 patients 

with vomiting unresponsive to conventional 

antiemetics but who responded rapidly 

to octreotide 300 mg/24 h subcutaneously. A 

marked reduction in nasogastric tube aspirate 

was noted in 2 of these patients. In our own 

experience and that of others this observation 


has been consistent [32–35]. One patient of 

ours with inoperable bowel obstruction survived 

for 3 months being treated at home with 

subcutaneous octreotide and nightly subcutaneous 

fluid. The use of octreotide in palliative 

care in the home setting has also been reported 

by Mercadante [36]. 

Diarrhea 

The actions of octreotide in reducing intestinal 

motility and water secretion plus the 

effects on sodium and potassium absorption 

[1] make octreotide an important agent in the 

treatment of diarrhea. 

Profuse diarrhea is an accompaniment of 

many illnesses. In the cancer field it complicates 

hormonally active intestinal tumors and 

is a feature of short bowel syndrome after 

multiple resections [37]. Diarrhea also complicates 

celiac plexus block, a technique used 

in cancer pain treatment [38]. Subcutaneous 

octreotide has successfully treated this symptom 

in these conditions where other treatments 

have failed. The diarrhea associated 

with AIDS can be particularly severe and 

when seemingly intractable, octreotide offers 

an excellent therapeutic solution [39]. 

Octreotide also has a role in supportive 

care of patients undergoing chemotherapy. 

Agents such as 5-fluorouracil can cause severe 

diarrhea unresponsive to conventional treatment. 

Octreotide may often work in this situation 

[40–42] but it does not seem to have a 

preventive action [43]. As with all diarrheas 

the etiology should be clearly established and 

treated specifically as appropriate. 

Long-term subcutaneous administration of 

octreotide is not a cost-effective means of 

symptom management. If conventional measures 

such as use of opioids and drugs such as 

loperamide fail, then it is my view that octreotide 

is certainly worth a trial. Some sources 


suggest that loperamide is at least as effective 

as low dose octreotide (150 Ìg/day) [44]. In 

my experience doses from 300–600 Ìg daily 

are usually effective in controlling difficult 

diarrheal states. Although 600 Ìg is the usual 

ceiling dose we have used doses of up to 

1,200 Ìg daily with good effect and without 

adverse consequence. 

Fistulae 

Many patients develop fistulae after abdominal 

surgery for recurrent malignancy. 

The intensity of fistula output can be particularly 

distressing as both a constant reminder 

of the unremitting nature of malignant disease 

and from practical aspects such as requirements 

for multiple stoma bags. Octreotide 

can certainly reduce the fistula output 

[45] in these situations with consequent improvement 

in quality of life. Although randomized 

control trials of octreotide on fistula 

closure have not demonstrated significant 

benefit, there has been some debate as to the 

reason for this [46–48]. 

In an interesting report by Jenkins et al. 

[49] the authors measured pancreatic enzyme 

concentration in fistula secretion and found 

that enzyme concentration increases between 

intermittent subcutaneous injections of octreotide; 

they postulate that a low-volume 

high-enzyme concentration fistula output 

may be detrimental to fistula closure. It is not 

known whether subcutaneous infusion of octreotide 

would prevent this observation. 

Hernandez-Aranda et al. [50] showed an 

improvement in fistula closure rate in a 

mixed group of patients with enterocutaneous 

fistulae. Interestingly the total parenteral nutritional 

time required in the treated group 

was shorter in the octreotide group than in the 

placebo group.

Other Uses – Cachexia, Ascites and 

Carcinoid Syndrome 

Some interesting laboratory data has appeared 

on the use of octreotide with insulin 

and with insulin plus growth hormone for the 

treatment of cancer cachexia. As increased 

glucagon levels are found in some situations 

of cancer cachexia, the experimental rationale 

was to reverse the low insulin/glucagon ratio. 

A study was carried out in rats and the combination 

of somatostatin plus insulin was shown 

to increase weight and muscle protein [51]. 

Combination of octreotide, insulin and 

growth was also investigated and found to 

have similar effects. Whether the growth hormone 

added anything to the regimen was not 

clear. 

Although seemingly physiologically effective, 

it remains to be seen whether this translates 

into a useful quality of life measure in 

human cancer-associated cachexia. 

Cairns and Malone [52] have recently published 

a report of 3 cases of patients with 

ascites who were treated with octreotide. For 

2 of these patients, the quantity of ascites 

appeared to decrease significantly and the 

need for paracentesis ceased. One of these 

patients was suffering from adenocarcinoma 

of the colon and the other adenocarcinoma of 

the breast. The exact reason for these observations 

is unclear but an effect on somatostatin 

receptors on tumors has been postulated. 

Octreotide is exceptionally useful in the 

palliation of symptoms due to the carcinoid 

syndrome. It can succesfully control flushing 

as well as diarrhea. Patients with the metastatic 

carcinoid syndrome who experience bone 

pain also reported alleviation of this symptom 

when treated with octreotide [53]. 

One concern in long-term administration 

is dose tachyphylaxis. In a prospective study 

of octreotide’s effect on gastric function some 

of the physiological effects were noted to di- 



minish on day 6 and 7 of treatment [54]. Certainly 

it is not known whether this is of clinical 

importance in palliative care patients 

whose prognosis is often short. In our own 

experience, dose tachyphylaxis does not appear 

to be an important issue. As octreotide 

use in palliative situations becomes more 

commonplace, the literature may well answer 

some of these questions. 

Although the physiology and pharmacology 

of octreotide is well understood, there remains 

a shortage of randomized controlled 

trials which prospectively study its use in 

many conditions. Case reports and anecdotal 

evidence abound. For the palliative care practitioner 

I believe octreotide is an important 

compound with many potential uses. The recent 

development of a long-acting slow-release 

depot preparation of octreotide and other 

somatostatin analogs is certainly exciting. 

The potential uses of this preparation would 

not necessitate subcutaneous infusion pumps, 

which is clearly a great convenience to the palliative 

care patient. I look forward to more 

randomized control trials in the forthcoming 

years. 

Acknowledgments 

I am indebted to Karen Mattioli and Joanne Blight 

for their assistance in the preparation of the manuscript 

and to Professor Carmelo Scarpignato (University 

of Parma, Italy) for his encouragement, constructive 

criticism and assistance with the bibliography. 


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Dramatic improvement 

with the somatostatin analogue SMS 

201-995. Clin J Pain 1990;6/3:243– 

245. 

17 Pascal J, Freijanes J, Berciano J, 

Pesquerac C: Analgesic effect of octreotide 

in headache associated with 

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opioid mechanisms. Case report. 

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18 De Conno F, Saita L, Ripamonti C, 

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in the treatment of pain in 

advanced cancer patients. J Pain 

Symptom Manage 1994;9:34–38. 

19 Taura P, Planella V, Balust J, Anglada 

T, Carrero E, Brugues S: Epidural 

somatostatin as an analgesic in 

upper body surgery: A double blind 

study. Pain 1994;59/1:135–140. 

20 Mollenholt P, Rawal N, Gordh T, 

Olsson Y: Intrathecal and epidural 

somatostatin for patients with cancer. 

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neuropathologic investigations 

of spinal cord and nerve roots. Anesthesiology 

1994;81:534–542. 


21 Penn RD, Paice JA, Kroin JS: Octreotide: 

A potent new non-opiate 

analgesic for intrathecal infusion. 

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22 Gaumann DM, Yaksh TL: Intrathecal 

somatostatin in rats: Antinociception 

only in the presence of toxic 

effects. Anesthesiology 1988;69: 

733–742. 

23 Asai T: Use of epidural somatostatin 

for postoperative analgesia is not 

justifiable. Pain 1995;62:388. 

24 Yaksh TL: Spinal somatostatin for 

patients with cancer: Risk-benefits 

assessment of an analgesic. Anesthesiology 

1994;81:531–533. 

25 Candrina R, Gallli G: Intraventricular 

octreotide for cancer pain. J Neurosurg 

1992;76:336–337. 

26 Paice JA, Penn RD, Croin JS: Intrathecal 

octreotide for relief of intractable 

nonmalignant pain: 5-year experience 

with two cases. Neurosurgery 

1996;38/1:203–207. 

27 Khoo D, Riley J, Waxman J: Control 

of emesis in bowel obstruction 

in terminally ill patients. Lancet 

1992;339:375–376. 

28 Dharmsathaphorn K, Sherwin RS, 

Dobbins JW: Somatostatin inhibits 

fluid secretion in the rat jejunum. 

Gastroenterology 1980;78:1554– 

1558. 

29 Dharmsathaphorn K, Binder HJ, 

Dobbins JW: Somatostatin stimulates 

sodium and chloride absorption 

in the rat ileum. Gastroenterology 

1980;78:1559–1565. 

30 Dueno MI, Bai JC, Santangelo WD, 

Krejs GJ: Effect of somatostatin analogue 

on water and electrolyte 

transport and transit time in human 

small bowel. Dig Dis Sci 1987;32: 

1092–1096. 

31 Gittes GK, Nelson MT, Debas HT, 

Mulvihill SJ: Improvement in survival 

of mice with proximal small 

bowel obstruction treated with octreotide. 

Am J Surg 1992;163:231– 

233. 

32 Mercadante S, Maddaloni S: Octreotide 

in the management of inoperable 

gastrointestinal obstruction 

in terminal cancer patients. J Pain 

Symptom Manage 1992;7:496–498.

33 Mercandate S, Spoldi E, Caraceni A, 

Maddaloni S, Simonetti MT: Octreotide 

in relieving gastrointestinal 

symptoms due to bowel obstruction. 

Palliat Med 1993;7/4:295–299. 

34 Mangili G, Franchi M, Mariani A, 

Zanaboni F, Rabaiotti E, Rigerio L, 

Bolis PF, Ferrari A: Octreotide in 

the management of bowel obstruction 

in terminal ovarian cancer. Gynecol 

Oncol 1996;61:345–348. 

35 Fainsinger RL, Pisani A, Bruera E: 

Use of somatostatin analogues in 

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36 Mercadante S: Bowel obstruction in 

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experience. Support Care Cancer 

1995;3/3:190–193. 

37 Sharkey MF, Kadden ML, Stabile 

BE: Severe posthemicolectomy diarrhoea: 

Evaluation and treatment 

with SMS 201-995. Gastroenterology 

1990;99:1144–1148. 

38 Dean AP, Reed WD: Diarrhoea – 

An unrecognised hazard of coeliac 

plexus block. Aust NZ J Med 1991; 

1:47–48. 

39 Cello JP, Grendell JH, Basuk P, Simon 

P, Weiss L, Wittner M, Rood 

RP, Wilcox CM, Forsmark CE, 

Read AE, et al: Effect of octreotide 

on refractory AIDS associated with 

diarrhoea. A prospective multicentre 

clinical trial. Ann Intern Med 

1991;155:705–710. 

40 Cascinu S, Fedeli A, Fedeli SL, 

Catalano G: Control of chemotherapy 

induce diarrhoea with octreotide 

in patients receiving 5-fluorouracil. 

Eur J Cancer 1992;28:482–483. 

41 Cascinu S, Fedeli A, Fedeli SL, Catalano 

G: Control of chemotherapyinduced 

diarrhoea with octreotide. 

A randomised trial with placebo in 

patients receiving cisplatin. Oncology 

1994;51/1:70–73. 




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in the treatment of fluorouracil 

induced diarrhoea: A randomised 

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148–151. 

43 Meropol NJ, Blumenoson LE, 

Creaven PJ: Octreotide does not 

prevent diarrhoea in patients 

treated with weekly 5-fluorouracil 

plus high dose leucovorin. Am J 

Clin Oncol 1998;21/2:135–138. 

44 Geller RB, Gilmore CE, Dix SP, Lin 

LS, Topping DL, Davidson TG, 

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patients. Am J Hematol 

1995;50/3:167–172. 

45 Nubiola P, Badia JM, Martinex- 

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Surg 1989;210/1:56–58. 

46 Nubiola-Calonge P, Badia JM, Sancho 

J, Gil MJ, Segura M, Sitges-Serra 

A: Blind evaluation of the effect 

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small bowel fistulae output. Lancet 

1987;ii:672–674. 

47 Scott NA, Finnegan S, Irving MH: 

Octreotide and postoperative enterocutaneous 

fistulae: A controlled 

prospective study. Acta Gastroenterol 

Belg 1993;53/3–4:266–270. 

48 Sancho JJ, di Costanzo J, Nubiola P, 

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F, Franch G, Oliva A, Gubern JM, 

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octreotide in patients with postoperative 

enterocutaneous fistula. Br J 

Surg 1995;82:638–641. 

49 Jenkins SA, Nott DM, Baxter JN: 

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enzymes between consecutive 

doses of octreotide: Implications 

for the management of fistulae. 

Eur J Gastroenterol Hepatol 1995;7/ 

3:255–258. 

50 Hernandez-Aranda JC, Gallo-Chico 

B, Fores-Ramirez LA, Avalos- 

Huante R, Magos-Vazquez FJ, 

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fistula with or without 

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Nutr Hosp 1996;11/4:226– 

229. 

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MH: Reversal of tumor-associated 

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1:87–97. 

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53 Smith S, Anthony L, Roberts LJ, 

Oates JA, Pincus T: Resolution of 

musculoskeletal symptoms in the 

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with the somatostatin analogue octreotide. 

Ann Intern Med 1990;112: 

66–68. 

54 Londong W, Angerer M, Kutz K, 

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1989;96:713–722. 



Management of Breast Cancer: 

Is There a Role for Somatostatin and 

Its Analogs? 

Francesco Boccardo Domenico Amoroso 

Academic Unit of Medical Oncology, National Cancer Institute, Genoa, Italy 

Key Words 

Somatostatin W Somatostatin analogs W 

Breast cancer 

Abstract 

Somatostatin and related peptides are a 

family of peptides which are ubiquitous and 

function as endogenous growth inhibitors. 

Analogs have been developed through the 

introduction of a D-amino acid in the position 

8 of somatostatin moiety which is more resistant 

to the action of endogenous peptidases 

than the parental moiety. Both somatostatin 

and its analogs interact with specific receptors 

on the cell surface. The five receptor subtypes, 

SSTR-1 to SSTR-5, which have been 

characterized so far, have a different affinity 

for somatostatin and its analogs. This and 

the fact that receptors are not homogeneously 

expressed in tissues account for 

the different activity of these compounds, all 

of which have demonstrated tumoristatic 

ABC 

Fax + 41 61 306 12 34 




0009–3157/01/0478–0062$17.50/0 



properties both in vitro and in vivo. The interaction 

of somatostatin and of somatostatin 

analogs with specific SSTR receptors is crucial 

to the antiproliferative mechanisms exerted 

by these compounds in vitro and in 

some animal models and the various pathways 

have been reviewed in detail. However, 

inhibition of angiogenesis and suppression 

of lactogenic hormones might represent alternative 

mechanisms, in particular in breast 

cancer. The rationale for the use of somatostatin 

and its analogs in breast cancer patients 

and to combine these peptides with 

antihormones, like antiestrogens or prolactin-lowering 

drugs, or cytotoxics has been 

reviewed together with the results obtained 

in phase II and comparative trials. The reasons 

for the limited efficacy shown by these 

compounds either when used alone or when 

used in combination with other drugs have 

also been critically reviewed in the perspective 

of new trials. 


Prof. F. Boccardo, Cattedra e UO Universitaria di Oncologia Medica 

Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi, 10 

I–16132 Genova (Italy) 

Tel. +39 010 5600503, Fax +39 010 352753 

E-Mail boccardo@hp380.ist.unige.it

Introduction 

Breast cancer is still a leading health issue 

in women. In fact, this disease is the most 

common cancer affecting women in developed 

countries and a major cause of cancer 

death [1, 2]. The incidence of breast cancer 

has gradually increased during the past decades 

in parallel with an increase in the ageing 

of the population. It was estimated that in 

1997 about 180,000 new cases of breast cancer 

were diagnosed in the USA and that about 

44,000 women died of this disease [3]. However, 

in many countries incidence and mortality 

have recently levelled off or even decreased 

[4–7], as a consequence of both early 

diagnosis and the introduction of more effective 

treatments. 

Strategies to control breast cancer include: 

(1) primary prevention, to decrease the incidence 

of this disease, (2) early diagnosis, to 

ensure that more patients might be diagnosed 

with curable disease, and (3) improvement of 

treatment, to increase cure rates. Primary prevention 

is not possible at present due to the 

multifactorial etiopathogenesis of this disease. 

However, increasing knowledge of the 

genetic alterations which can trigger the neoplastic 

transformation of breast cells and the 

recognition of the molecular events which 

control the growth of transformed cells have 

provided new targets for therapeutic and chemopreventive 

approaches [8–10]. Tamoxifen 

has recently been proven to be effective in 

decreasing the incidence of breast cancer in 

one study [11]. However, the lack of effectiveness 

in two other studies [12, 13] and the side 

effects produced by the long-term administration 

of this antiestrogen, including endometrial 

cancer and thromboembolic events, still 

question its role as a chemopreventive agent 

in healthy women. It is now recognized that 

mammographic screening results in a 25– 

30% decrease in the risk of women aged 50 

years or over dying of breast cancer [14]. 

However, the role of mammographic screening 

in women between the ages of 40 and 50 

years is still unclear. Treatment of patients 

with primary breast cancer involves multiple 

treatment modalities, including surgery, radiotherapy 

and systemic therapy with combination 

chemotherapy, hormonal agents or 

both. Based on the assumption that primary 

breast cancer is a systemic disease in which 

subclinical metastases are already present at 

diagnosis in most patients [15], systemic adjuvant 

therapy has been extensively studied in 

several individual randomized trials. To assess 

a reliable fallout from these trials, partially 

avoiding the biases intrinsic to each study, 

the statistical technique of metanalysis was 

employed to add value to observed or expected 

events from each trial and to provide 

an estimate of the overall effect of treatment 

[16]. Over the past decade there have been 

four metanalyses of data from prospective 

randomized trials, involving more than 

75,000 women treated with different adjuvant 

therapies. Current knowledge comes 

from the results of these metanalyses and, in 

particular, from the most recent of them. 

These metanalyses showed: that combination 

chemotherapy is able to reduce the annual 

risk of death by about 20%, especially in 

women younger than 50 [17], that prolonged 

treatment with tamoxifen is able to reduce to 

a similar extent the annual risk of death in all 

age groups, especially in women with estrogen-receptor-positive 

tumors [18], and that 

ovarian ablation appears to produce results 

comparable to those obtained by tamoxifen or 

chemotherapy in younger women [19]. Because 

there was enough evidence to suggest 

that the combination of chemotherapy with 

tamoxifen (or ovarian ablation in premenopausal 

women) might be even more effective 

than either treatment modality alone, this 

treatment option was included among the rec- 

Somatostatin and Breast Cancer Chemotherapy 2001;47(suppl 2):62–77 63

ommendations for women with a higher risk 

of relapse generated by a panel of experts at a 

conference on breast cancer held in St. Gallen 

in 1998 [20]. In spite of more recent results of 

adjuvant therapy, at least 50% of women with 

primary breast cancer ultimately develop distant 

metastases and die of their disease, the 

risk being strictly correlated with the pathological 

status of axillary lymph nodes [21]. 

Once metastatic disease becomes overt, 

treatment strategy should be realistically addressed 

to achieve the best palliative results, 

through a wise use of chemotherapy and endocrine 

therapy. Endocrine manipulations represent 

the oldest form of systemic therapy 

for advanced breast cancer. Overall, approximately 

one third of unselected patients with 

metastatic breast cancer respond to these manipulations 

[22]. However, the discovery of 

steroid receptors contributed a lot to the selection 

of patients most likely to benefit from 

endocrine maneuvers and 50–75% objective 

response rates are usually reported in estrogen- 

or progesterone receptor-positive patients 

[23]. Tamoxifen has become the most 

widely used hormone therapy for advanced 

breast cancer, particularly after the menopause. 

However, other types of endocrine 

therapies, such as gonadal ablation in premenopausal 

women and progestins and aromatase 

inhibitors in postmenopausal women, 

may also provide considerable disease remission 

[22], especially in patients who progress 

after first-line treatment with tamoxifen [24]. 

New hormonal compounds, including second 

generation steroidal and nonsteroidal aromatase 

inhibitors which are now the treatment of 

choice for patients who relapse following 

front-line or adjuvant treatment with antiestrogens, 

are now being evaluated as an alternative 

to tamoxifen and are candidates for 

becoming an alternative to this agent even in 

the adjuvant setting [24]. Finally, new steroidal 

antiestrogens are now being evaluated 

either in patients failing first-line tamoxifen 

treatment or as a first-line treatment option, 

in view of their non-cross-resistance with triphenylethylene 

derivatives and lack of the 

pure agonistic effects exerted by these compounds 

[25]. 

In spite of the availability of so many therapeutic 

choices, the search for new compounds 

is still crucial and is encouraged by the 

new insight into the molecular biology of the 

neoplastic cell, with special regard to the different 

types of receptors, which are expressed 

on the surface of breast cancer cells and which 

interact with many signalling pathways. Since 

most breast cancers express a variety of somatostatin 

receptors, the therapeutic potential 

of somatostatin and its analogs has been 

investigated in breast cancer patients. Preclinical 

and clinical findings accumulated so far 

are the objective of this review. 

Structure and Function of 

Somatostatin and Its Analogs 

Somatostatin and somatostatin-related 

peptides are a family of peptides that include 

two important products, somatostatin-14 

(SS14) and somatostatin-28 (SS28), a number 

of species-specific variants and even more numerous 

prehormone forms. SS14 and SS28 

are mainly found in the gut and in various 

exocrine and endocrine glands throughout the 

body. However, they are ubiquitous and can 

be found also in the nervous system, specifically 

in the hypothalamus, limbic system, 

brain stem and spinal cord [26]. Somatostatin 

has a broad spectrum of biological actions and 

exerts suppressive effects on a large variety of 

cells, functioning as an endogenous growth 

inhibitor [26]. 

Naturally occurring peptides have a plasma 

half-life of less than 3 min, since they are 

rapidly inactivated by endogenous peptidases 

64 Chemotherapy 2001;47(suppl 2):62–77 Boccardo/Amoroso

[27]. Therapeutic application of the native 

peptide has, therefore, been limited to those 

conditions where the use through intravenous 

continuous infusion is appropriate. Therefore, 

many efforts have been made to develop 

more stable peptides. Incorporation of D-amino 

acids into the somatostatin backbone succeeded 

in slowing down enzymatic degradation 

[28]. In particular, the introduction of 

a D-amino acid after tryptophan in the position 

8 of the moiety led to the development of 

analogs with an enhanced GH inhibitory potency 

[29]. Therefore, the three more extensively 

tested analogs, i.e. SMS 201–995 (octreotide), 

BIM 23014 (lanreotide) and RC- 

160 (vapreotide), are octapeptides [29]. 

Octreotide is 45 times more potent in vitro 

than naive somatostatin in inhibiting the release 

of GH and 11 times more potent in 

inhibiting the release of glucagon. This analog 

is also more potent in inhibiting insulin secretion 

[30]. 

Attempts to develop an analog with minimal 

effects on insulin and glucagon secretion, 

but a more profound effect on the release of 

GH and of GH-dependent growth factors, 

such as insulin-like growth factors (IGF), resulted 

in the development of lanreotide. Both 

octreotide and lanreotide are available as 

slow-release formulations obtained through 

the microencapsulation of the active drug 

in a matrix of polylactide-glycolide microspheres. 

These polymers are completely biodegradable 

and are commonly administered 

at 2- to 4-week intervals [26]. 

Mode of Action of Somatostatin 

and Its Analogs: Overview of 

Receptor Functions 

Critical to somatostatin action is the presence 

of somatostatin receptors, which principally 

have two distinct functions: (1) to bind 

the ligand with high affinity and (2) to produce 

a transmembrane signal evoking a biological 

response. Up to five somatostatin receptor 

subtypes, SSTR-1 to SSTR-5, have 

been cloned and functionally characterized 

[31–35]. They all bind SS14 and SS28 with 

similar affinity but show major differences in 

the affinity for different somatostatin analogs 

[31, 34, 35]. Octreotide and vapreotide have a 

low affinity for SSTR-1, but have a high affinity 

for SSTR-2. Both of them can inhibit the 

proliferation of cells expressing SSTR-2 [32, 

34, 35]. Vapreotide and octreotide have also a 

moderate to high affinity for SSTR-3 and 

SSTR-5 [32, 34]. In addition, vapreotide has a 

moderate affinity for SSTR-4 [35]. Noteworthy, 

the specificity of these analogs depends 

on their different affinity for receptor subtypes 

and on receptor heterogeneity on the 

surface of target cells. Indeed, there is a considerable 

heterogeneity between tumors and 

within the same tumor with respect to the 

density of somatostatin binding sites, higher 

receptor levels having been found in more differentiated 

tumors [36]. This implies the possibility 

for somatostatin receptors to represent 

differentiation markers, at least in certain 

neoplastic lineages and for their loss to 

be implicated in tumor progression. After 

the chronic administration of somatostatin, 

downregulation of receptors can occur, as 

shown by studies performed in pituitary cell 

lines [37]. However, this effect is not the rule. 

In vivo studies indicate that continuous treatment 

of acromegalic patients with octreotide 

does not desensitize the cellular responsiveness. 

Moreover, there is evidence that changes 

in gene expression or mRNA stability, rather 

than in receptor affinity, can be involved in 

both up- and downregulation of somatostatin 

receptors [39]. This mechanism is common 

with other peptides, i.e. LHRH analogs, and 

results in the occupation of a high proportion 

of somatostatin receptors which are inter- 


nalized into the cell and maintained so until 

treatment with somatostatin is continued. 

However, an immediate rebound effect has 

been observed on somatostatin discontinuation, 

which is associated with a rapid rise in 

target hormones [40]. Slow release somatostatin 

analogs can also be ineffective in maintaining 

the tissue levels necessary to downregulate 

the receptors and GH escape can occur 

in some patients if dosages are not appropriate 

[26]. 

After binding with somatostatin, receptor 

activation occurs. This in turn is associated 

with several transmembrane signalling pathways 

via pertussis toxin-sensitive guanine nucleotide-binding 

proteins [41]. In particular, 

the activation of the receptors is associated 

with a prompt reduction in the intracellular 

level of mediators, like cAMP and Ca 2+ , due 

to the effects on membrane adenylyl cyclase 

and ion (K + , Ca 2+ ) channels [42, 43]. However, 

this proximal effect can explain only in 

part the inhibitory action of somatostatin on 

hormone secretion and more distal effects of 

the peptide in this respect have also been documented 

[44–46]. Another effector system, 

i.e. tyrosine phosphatase, has recently been 

shown to be stimulated by somatostatin receptor 

activation, leading to dephosphorylation 

and inactivation of the EGF receptor 

[47]. Emerging information regarding signal 

transduction pathways related to somatostatin 

receptor activation is crucial to understanding 

the possible mechanisms of action of 

somatostatin and of its analogs as antiproliferative 

agents. The transfection of the five 

cloned human somatostatin receptors into 

somatostatin receptor-negative cell lines was 

shown to induce specific signal transduction 

pathways associated with individual somatostatin 

receptor subtypes. For instance, it has 

been demonstrated that SSTR-3-transfected 

CHO cells respond to octreotide with the 

upregulation of p53 and the subsequent in- 

duction of apoptosis [48]. However, the presence 

of a particular receptor subtype on the 

tumor cell does not guarantee that its binding 

with the ligand is followed by the activation of 

antiproliferative or apoptotic pathways. For 

instance, octreotide can be ineffective in inducing 

apoptosis through its binding with 

SSTR-3 in tumors with a mutation in the p53 

gene [48]. In other experimental systems, a 

signal transduction pathway associated with 

SSTR-2 implying the upregulation of phosphoprotein 

phosphatase activity has been 

demonstrated [34, 47, 49]. The activation of 

this pathway is supposed to represent one of 

the possible mechanisms through which somatostatin 

analogs exert their antineoplastic 

effects. In fact, the blockade of phosphoprotein 

phosphatase stimulates cellular proliferation 

[50], enhancing the consequences of the 

binding of growth factors, like EGF or IGF-1, 

to their receptors. 

Mechanisms of Antitumor Action in 

Breast Cancer of Somatostatin 

and Its Analogs 

While estradiol is recognized as the predominant 

hormone stimulating the growth of 

human breast cancer, there is also evidence 

that lactotrophic hormones (GH and prolactin) 

are involved in the growth of breast 

tumors, particularly in murine models [51]. 

Indeed, prolactin receptors can be demonstrated 

in 20–50% of human breast cancer 

cells and at least some MCF-7 cell clones have 

been shown to be prolactin-dependent [52, 

53]. Inhibition of the release of lactotrophic 

hormones may, therefore, be one of the mechanisms 

through which somatostatin and its 

analogs could inhibit breast cancer growth. 

There is a substantial literature demonstrating 

considerable antineoplastic activity 

of somatostatin and its analogs in many in 


vitro and in vivo experimental systems [54, 

55] and increasing information concerning 

the antiproliferative effects of these compounds 

has emerged over the past decade. 

Several mechanisms have been proposed, 

and it is important to note that they are not 

mutually exclusive. The direct mechanisms 

refer to the inhibition of proliferation and/or 

the induction of apoptosis, as a consequence 

of the binding of somatostatin and of its analogs 

to specific receptors on the target neoplastic 

cell, as reported above. The presence 

of somatostatin receptors seems to be the 

major determinant of the antiproliferative 

activity of somatostatin analogs in animal 

models [34, 47–49, 56]. Thus, a strong antiproliferative 

effect of these analogs has been 

demonstrated in mice bearing both estrogendependent 

and estrogen-insensitive MXT 

transplantable tumors that express somatostatin 

receptors [27]. Conversely, no activity 

was shown on DMBA-induced mammary 

carcinoma of the rat that does not express 

somatostatin receptors [27]. It is worth noting 

that up to 60% of human breast cancers 

were found to express somatostatin receptors, 

although they may not always be homogeneously 

distributed in the whole tissue 

sample. The specificity of action of various 

analogs through their binding with specific 

type of receptor is a subject of ongoing investigation, 

although recent data suggest that 

the antiproliferative effects of somatostatin 

against breast cancer are mostly mediated by 

receptor subtypes 2 and 5 [58]. 

Somatostatin receptors are frequently expressed 

in tumors with a high estrogen and 

progesterone receptor content [59], while in 

contrast a negative relationship was found 

between their expression and EGF receptors 

[60], which are regarded as poor prognostic 

indicators [60]. 

The indirect mechanisms of action of somatostatin 

and of its analogs are a direct 

consequence of the systemic effects of these 

compounds and even somatostatin receptornegative 

tumors might be inhibited through 

these mechanisms. The indirect mechanism 

that has received the greatest attention to date 

concerns the inhibitory effect of somatostatin 

analogs on the IGF family (IGF-1 and 

IGF-2). 

IGF-1 and IGF-2 are peptides with structural 

similarities to insulin. IGF-1 is involved 

in normal growth and development processes, 

while the physiological function of IGF-2 remains 

unclear, although it appears to be essential 

for normal fetal growth. IGFs induce 

mitogenesis in cultured fibroblasts, chondroblasts, 

osteoblasts, neuroglial cells and erythroid 

progenitor cells. These peptides also 

appear to be involved in the control of cell 

proliferation in various malignant phenotypes 

[61–64], including breast cancer. The proliferative 

effects of IGF-1 and IGF-2 are mediated 

by IGF-1 receptors, which have been detected 

in 67–93% of human breast tumors [65–68]. 

Modulation of IGF-1 and IGF-2 activity occurs 

through the interaction with circulating 

IGF-binding proteins. However, also the GH- 

IGF-1 axis appears to have an important 

influence on the biological behavior of many 

common neoplasms. The suppressive effect of 

somatostatin analogs on serum IGF-1 levels 

might be related either to the direct inhibition 

of IGF-1 gene expression or to the suppression 

of GH-dependent IGF-1 synthesis in the 

liver [69, 70]. The direct suppressive action 

on IGF-1 gene expression remains incompletely 

characterized and it is possible that 

both mechanisms (i.e. the suppression of IGF- 

1 gene expression and the suppression of IGF- 

1 synthesis in the liver) might contribute to 

somatostatin antiproliferative activity. Moreover, 

somatostatin analogs have been found 

to stimulate the secretion of certain IGFbinding 

proteins, an action which has been 

proposed to attenuate IGF-1 bioactivity 


independently of the suppressive effect on 

IGF-1 levels [71, 72]. Since IGF-1 is recognized 

as a potent antiapoptotic factor [73, 74], 


analogs could also be mediated by the suppressive 

effects on IGF-1 gene expression, 

which in turn could enhance the antiapoptotic 

effects exerted by these compounds in experimental 

models [75, 76]. 

The interference with blood flow and nutritional 

support to the tumor could be a third 

mechanism through which somatostatin and 

its analogs could exert their antitumor properties. 

In fact, somatostatin receptors, namely 

the SSTR-2 subtype, have been demonstrated 

in the peritumoral veins of various human 

cancers, including breast tumors [77] and it 

appears that the increased expression of somatostatin 

receptors in peritumoral vessels in 

comparison to normal, nontumoral, tissue, 

might be related to the neoplastic process 

itself [77]. 

Somatostatin and Its Analogs: 

In vitro and in vivo Studies 

Inhibition of Tumor Growth with 


in Combination with Antiestrogens 

Based on the data mentioned above, it can 

be argued that somatostatin and its analogs 

might have some effect on the proliferation of 

breast cancer. However, unopposed estrogen 

action can be greater than the growth inhibitory 

effects of somatostatin and its analogs [78]. 

The molecular basis for the attenuation of this 

antiproliferative effect has not been elucidated. 

However, consistent with this effect is 

the observation that antitumor activity of octreotide 

in the MXT breast tumor model was 

enhanced by the coadministration of an 

LHRH analog, which lowers estradiol levels 

[79]. Moreover, the activity of octreotide 

was maximized in the absence of estrogens 

[78]. Such considerations provided the rationale 

for the concomitant administration of 

somatostatin or of its analogs with other hormonal 

agents, namely antiestrogens. The capability 

of tamoxifen to suppress the GH-IGF 

axis through the suppression of IGF-1 gene 

expression and of serum IGF-1 levels [80–82] 

provided a further rationale for this combination 

therapy. 

Several preclinical and clinical observations 

have suggested an additive biological 

and antitumor effect by combining somatostatin 

analogs and tamoxifen. In short-term 

experiments in rats, the concomitant administration 

of octreotide with tamoxifen suppresses 

serum IGF-1 levels and IGF-1 gene 

expression more potently than either agent 

alone [83]. This combination has also been 

evaluated in the DMBA-induced rat mammary 

tumor model [84]. These experiments 

showed that the development and the volume 

of DMBA-induced tumors were significantly 

reduced in the animals treated with both 

agents as compared to the animals treated 

with either agent alone. In clinical studies, an 

enhanced suppression of serum IGF-1 levels 

in patients receiving a combination of octreotide 

or lanreotide with tamoxifen has also 

been demonstrated [85]. 

It is noteworthy that in all experimental 

systems, tumor response to the combination 

of octreotide and tamoxifen was greater in 

smaller than in larger tumors, i.e. at an earlier 

stage of the disease, when the angiogenetic 

response to specific peptides released by the 

cancer cells is higher [86–88]. Since it has 

been suggested that part of the antitumor 

activity of somatostatin might be related to its 

inhibition of angiogenesis, these experiments 

have anticipated that somatostatin and its 

analogs would be more effective at an earlier 

stage of the disease in humans as well, for 

instance by preventing the growth of micro- 


metastases following surgery, and that the 

therapeutic effect might be much more limited 

in patients with overt metastatic disease. 


Somatostatin and Its Analogs in 

Combination with Chemotherapeutic 

Agents 

In order to augment the effects of chemotherapy, 

a combination of hormonal therapy 

and cytotoxics has been proposed. Such combination 

therapies are aimed at achieving additive 

or synergistic antitumor effects while 

reducing the incidence and the severity of side 

effects. The biological rationale for this form 

of treatment is tumor cell heterogeneity, since 

breast cancer consists of various populations 

of cells with different sensitivities to cytotoxic 

and hormonal agents. The modulatory effect 

of somatostatin analogs in combination with 

different chemotherapeutic agents has been 

studied in different preclinical studies [89]. 

Among the agents tested, combinations of mitomycin 

C, doxorubicin, Taxol and 5-fluorouracil 

have been investigated more extensively 

than other cytotoxics in a number of models. 

Thus, in AR42J cells, which express the 

somatostatin receptor subtype 2 and whose 

growth has been shown to be inhibited by 

octreotide [90], both mitomycin C and Taxol 

exerted antiproliferative effects that appeared 

to be synergistically enhanced by octreotide 

[89]. Both additive and synergistic interactions 

between octreotide and 5-fluorouracil 

were shown, depending on the 5-fluorouracil 

concentration used. This type of interaction 

was also observed with other combinations of 

octreotide and cytotoxics [91]. 

The combination of doxorubicin and octreotide 

resulted in a clear dose-dependent 

synergistic interaction on AR42J cells [89]. 

Moreover, it has been demonstrated in vitro 

that doxorubicin accumulation in MCF-7 

cells treated with octreotide was increased 3- 

to 4-fold [92]. This observation suggests that 

octreotide modulates the uptake of doxorubicin 

and/or interferes with the activity of P-170 

glycoprotein responsible for multidrug resistance. 

The combination of chemotherapy with 

somatostatin analogs also received attention 

because of the demonstrated ability of octreotide 

to reduce gastrointestinal toxicity associated 

with some cytotoxic agents [93]. 

However, the evidence concerning the biological 

and clinical effects of combining somatostatin 

analogs and chemotherapeutic 

agents is still limited and does not make it 

possible to draw any conclusion about the 

potential role of such combinations in anticancer 

therapy. 

Clinical Studies 

The clinical experience with somatostatin 

or its analogs in advanced breast cancer is still 

limited, despite the promising findings observed 

in experimental studies which clearly 

indicate inhibition of tumor growth. 

The majority of clinical studies have been 

carried out in patients pretreated with a variety 

of therapies and combining somatostatin 

or somatostatin analogs with tamoxifen or 

with prolactin-lowering drugs such as bromocriptine 

(table 1). 

Vennin et al. [94] treated 16 postmenopausal 

patients with 200 Ìg octreotide daily 

for at least 30 days and observed a disease stabilization 

in 3, and a decrease of IGF-1 levels 

by 33% in 8. Manni et al. [95] treated 10 postmenopausal 

breast cancer patients with a 

combination of octreotide (200–400 Ìg daily) 

and bromocriptine (5 mg/day) and observed 

disease stabilization in 1 patient. Interestingly, 

the baseline levels of IGF-1 declined in 6 

out of 9 women. Moreover, following provocative 

tests, GH levels were suppressed in 7 


Table 1. Phase II studies with somatostatin and its analogs alone or in combination with 

other hormonal agents 

Authors Treatment Dose/schedule Patients OR 

Vennin et al. [94] Octreotide 200 Ìg/day 16 3 SD 

Manni et al. [95] Octreotide and 200–400 Ìg/day 

1 0 1 SD 

bromocriptine 5 mg/day 

Stolfi et al. [96] Octreotide 750 Ìg for 10 days, 1 

then 500 Ìg for 5 days 

0 3 PR 

Anderson et al. [97] Octreotide and 200–400 Ìg/day 

6 4 SD 

bromocriptine 2.5–5 mg/day 

Canobbio et al. [98] Lanreotide and 20–30 mg/2 weeks 36 4 CR 

tamoxifen 30 mg/day 

12PR 

Di Leo et al. [99] Lanreotide 30 mg/2 weeks 10 None 

O’Byrne et al. [100] Vapreotide 3 mg/day, then 

1 

4.5 mg/day, then 6 mg/day 

4 None 

OR = Objective response; SD = stable disease; PR = partial response; CR = complete 

response. 

and prolactin levels in 8 of 9 patients in whom 

these assessments were possible. Three patients 

experienced nausea and 1 of them had 

to discontinue treatment. Stolfi et al. [96] 

treated 10 patients with octreotide given by 

intravenous infusion for 10 days at a dose of 

750 Ìg t.i.d. and then intramuscularly for a 

further 5 days at the dose of 500 Ìg b.i.d. They 

obtained a partial response in 3 patients. 

Moreover, a marked reduction in edema, cyanosis 

and bleeding from ulcerated tumor lesions 

was noted in most of the treated patients. 

Anderson et al. [97] treated 6 patients with 

octreotide (200–400 Ìg daily) and bromocriptine 

(2.5–5 mg/day), and observed a disease 

stabilization in 4. Suppression of both prolactin 

and IGF-1 levels were observed in all 

patients during the entire treatment period. 

Canobbio et al. [98] treated 36 postmenopausal 

patients with locally advanced or metastatic 

breast cancer with lanreotide (one 20to 

30-mg slow-release vial i.m. every 2 weeks) 

and tamoxifen (30 mg/day). None of them 

had received prior treatment with hormone or 

chemotherapy. In 4 patients a complete response 

was observed and a partial response in 

12, with an overall response rate of 52% (95% 

confidence interval: 35–69%). Toxicity was 

generally mild and treatment was well tolerated, 

mild diarrhea being the most common 

side effect. No patient, however, had to discontinue 

the treatment because of toxicity. A 

significant decrease in IGF-1 levels was observed 

at 3 and 6 months in the majority of 

patients. 

Di Leo et al. [99] evaluated the activity of 

lanreotide (BIM 23014) in 10 women with 

advanced breast cancer. The drug was administered 

at a dose of 30 mg i.m. fortnightly. No 

objective response was observed, and GH and 

IGF-1 serum levels were not adequately suppressed 

over time. 

O’Byrne et al. [100] treated 14 women with 

advanced breast cancer with the somatostatin 

analog vapreotide (RC-160) at a dose of 

3 mg/day in week 1 increasing to 4.5 mg/day 

during weeks 2– 4 and then to 6 mg/day thereafter 

by continuous subcutaneous infusion. 


Table 2. Phase III studies with 

somatostatin analogs 

No objective tumor response was observed. 

However, a significant reduction in serum 

IGF-1 and prolactin levels was observed. 

In 1998 in Italy, the Health Minister promoted 

the evaluation of the antitumor effects 

of a therapeutic regimen containing somatostatin 

or octreotide, melatonin, bromocriptine 

and a retinoid mixture in eleven phase II 

trials, involving 386 patients with various tumors, 

including breast cancer. Cyclophosphamide 

was added for the treatment of certain 

types of cancer. The conclusions were quite 

discouraging since no evidence of efficacy was 

observed in any the studies performed [101]. 

In particular, no substantial therapeutic activity 

was observed in breast cancer patients. 

The promising findings achieved by somatostatin 

analogs alone or in combination 

with tamoxifen or bromocriptine in experimental 

models have not been confirmed as 

yet even in controlled trials (table 2). One 

hundred and thirty-five postmenopausal patients 

with metastatic breast cancer were randomized 

to tamoxifen (20 mg/day) alone or 

combined with octreotide (150 Ìg s.c. twice 

daily) [102]. About 30% of the patients enrolled 

in this study were pretreated with chemotherapy 

and 7% of them had received prior 

Authors Treatment Patients OR 

% 

Ingle et al. [102] Tamoxifen (20 mg/day) 

Tamoxifen (20 mg/day plus 

135 49 

octreotide (150 Ìg twice/day) 43 

Bajetta et al. [103] Tamoxifen plus placebo 103 21 

Tamoxifen plus octreotide 20 

Bontenbal et al. [104] Tamoxifen 

Tamoxifen (40 mg/day) plus 

22 36 

octreotide (0.6 mg/day) and CV 

205-502 (75 Ìg/day) 

55 

OR = Objective response. 

treatment with tamoxifen. Although a significantly 

greater decline in serum IGF-1 levels 

was observed in the group of patients treated 

with the combination therapy, no differences 

were observed with respect to either progression-free 

survival or overall survival. The objective 

response rate was 49% in patients 

treated with tamoxifen alone and 43% in 

patients treated with tamoxifen and octreotide. 

Most patients treated with octreotide 

and tamoxifen experienced side effects, such 

as nausea, diarrhea and steatorrhea. 

Bajetta et al. [103] carried out a randomized 

double-blind phase III trial in previously 

untreated metastatic breast cancer patients 

who were randomly allocated to tamoxifen 

combined either with placebo or with octreotide. 

Unfortunately, drugs dosages were not 

reported. Two hundred and three patients 

were included. An overall tumor response rate 

of 20% was observed in the octreotide and 

tamoxifen arm compared to 21% in the placebo 

and tamoxifen arm. No difference was 

observed between groups in median time to 

progression, while more patients in the octreotide 

group experienced adverse effects 

such as diarrhea and abdominal pain. 


Table 3. Toxicity of somatostatin and its analogs 

[105] 

Local (at the site of injection) 

Pain 

Redness 

Abscess 

Systemic 

Gastrointestinal 

Nausea 

Abdominal cramps 

Diarrhea 

Steatorrhea 

Malabsorption of fat 

Flatulence 

Cholesterol gallstones 

Glucose metabolism 

Reduced glucose tolerance 

Hyperglycemia 

Hypoglycemia 

The feasibility and the endocrine and antitumor 

effects of a combination of octreotide 

(3 ! 0.2 mg s.c.) with tamoxifen (40 mg/day) 

and an antiprolactin drug (CV 205–502: 

75 Ìg/day) was studied by Bontenbal et al. 

[104]. They randomized 22 metastatic breast 

cancer patients who were given either 40 mg/ 

day of tamoxifen or the above-mentioned 

combination. An objective response was observed 

in 36% of the patients treated with 

tamoxifen alone and in 55% of the patients 

treated with the combination therapy. A significant 

decrease of plasma IGF-1 levels was 

observed in both treatment arms. However, 

the authors reported a more uniform suppression 

of IGF-1 in the combined treatment. 

Toxicity 

Treatment with somatostatin or with its 

analogs is usually well tolerated, the most 

commonly encountered side effects being 

listed in table 3 [105]. When the subcutaneous 

route of administration is used, slight pain 

and redness at the site of injection have been 

reported. Mild diarrhea, abdominal cramps 

and malabsorption of fat have also been observed 

in 5–10% of patients. The severity of 

these symptoms appears to be dose-dependent 

and they usually decrease spontaneously. 

In insulin-dependent diabetics a 10–20% reduction 

of the daily dose of insulin may be 

required. However, severe hypoglycemia is 

not usually observed. Cholesterol gallstone 

formation has been observed in 20–30% of 

patients after prolonged treatment, but fortunately 

they remain asymptomatic in most 

cases. 

Conclusions 

Somatostatin analogs are a novel class of 

compounds that have an established role in 

the management of patients with neuroendocrine 

tumors but only a potential role in the 

treatment of other solid tumors, including 

breast cancer. In this tumor type in particular, 

somatostatin analogs showed a limited activity 

either when used alone or when given in 

combination with tamoxifen or bromocriptine. 

Moreover, none of the randomized trials 

that compared the therapeutic value of the 

combination of octreotide and tamoxifen versus 

tamoxifen alone showed any advantage in 

favor of combined treatment. Therefore, although 

the great majority of trials failed to 

show major side effects attributable to somatostatin 

analogs, there is no place as yet for 

the use of these compounds outside of controlled 

trials. However, further studies need to 

be done in humans on the preclinical evidence 

of improved efficacy of somatostatin 

analogs, either when used alone or when 

given in combination with both tamoxifen 

and chemotherapeutic agents. Moreover, the 

fact that an adequate suppression of the GH- 


IGF-1 axis and of lactogenic hormone secretion 

was also demonstrated in clinical studies, 

but was not associated with a substantial antitumor 

activity, suggests that a more appropriate 

setting, dosing and scheduling should 

be established for further trials. 

The limited tumor response observed in 

clinical studies may have several explanations. 

The somatostatin receptors, when 

present in advanced breast tumors, are not 

homogeneously distributed. Therefore, it can 

be speculated that only receptor-positive cells 

could be inhibited in their growth by somatostatin 

analogs. The majority of patients included 

in clinical trials with somatostatin analogs 

had far advanced disease in which somatostatin 

receptors might be lacking or might 

be defective in their affinity for somatostatin 

analogs. In other cases it is possible that the 

tumors affecting the patients treated with 

such compounds did not express the receptor 

specifically capable of binding the analog 

used. This mechanism is suggested by the lack 

of a complete cross-resistance among the 

different analogs in neuroendocrine tumors. 

Another possible reason for the limited clinical 

efficacy observed in breast cancer patients 

treated with somatostatin or somatostatin 

analogs could be inadequate dosing or scheduling. 

In fact, the doses employed in animal 

models were usually higher than those employed 

in clinical trials. Again the possibility 

of achieving better symptom control with 

higher doses or more appropriate scheduling 

of the same somatostatin analog has been 

observed in patients affected by neuroendocrine 

tumors. While an adequate suppression 

of GH, prolactin and IGF-1 levels has been 

observed in most of the studies conducted in 

humans, there is no proof yet that circulating 

levels of lactogenic hormones and of insulinlike 

peptides can influence breast cancer 

growth. Rather the direct inhibitory effect on 

tumor growth mediated by the binding of 

somatostatin analogs to their specific receptors 

might be more crucial, as suggested by the 

experiments in vitro using human breast cancer 

cell lines. There is evidence that the concentrations 

which are needed at the target cell 

level can largely exceed those that can be produced 

by a dose which otherwise can adequately 

suppress lactogenic hormones and 

IGF-1-circulating levels. Therefore, although 

results of clinical trials have been quite discouraging 

so far, further testing of somatostatin 

analogs alone or in combination with other 

antiproliferative drugs, including cytotoxics, 

is warranted. Patients with tumors displaying 

neuroendocrine features or those with tumors 

positive on OctreoScan ® might be those best 

suitable for such new trials, provided that 

higher doses and more appropriate regimens 

of somatostatin or its analogs be used within 

the frame of well-designed and controlled 

trials. 


The authors thank Mrs. A. Fossati for her skilful 

assistance. 


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246–254. 



Somatostatin, Its Receptors and 

Analogs, in Lung Cancer 

Kenneth J. O’Byrne a Andrew V. Schally b Ann Thomas a 

Desmond N. Carney c William P. Steward a 

a University Department of Oncology, Leicester Royal Infirmary, UK; b Endocrine, Polypeptide 

and Cancer Institute, Tulane University Medical School and Veterans Affairs Medical Centre, 

New Orleans, La., USA; c Department of Medical Oncology, Mater Misericordiae Hospital, 

Dublin, Ireland 

Key Words 

Somatostatin W Receptor W Lung cancer W 

[ 111 In]pentetreotide W Chemotherapy 

Abstract 

Despite developments in diagnosis and treatment, 

lung cancer is the commonest cause of 

cancer death in Europe and North America. 

Due to increasing cigarette consumption, the 

incidence of the disease and resultant mortality 

is rising dramatically in women. Novel 

approaches to the management of lung cancer 

are urgently required. Somatostatin is a 

tetradecapeptide first identified in the pituitary 

and subsequently throughout the body 

particularly in neuroendocrine cells of the 

pancreas and gastrointestinal tract and the 

nervous system. The peptide has numerous 

functions including inhibition of hormone release, 

immunomodulation and neurotransmission 

and is an endogenous inhibitor of 

cell proliferation and angiogenesis. Somatostatin 

and its analogs, including octreotide 

ABC 

Fax + 41 61 306 12 34 




0009–3157/01/0478–0078$17.50/0 



(SMS 201–995), somatuline (BIM 23014) and 

vapreotide (RC-160), act by binding to specific 

somatostatin receptors (SSTR) of which 

there are 5 principal subtypes, SSTR-1–5. Although 

elevated plasma somatostatin levels 

may be detected in 14–15% of patients, tumor 

cell expression appears rare. SSTR may 

be expressed by lung tumors, particularly 

small cell lung cancer and bronchial carcinoid 

disease. [ 111 In]pentetreotide scintigraphy 

may have a role to play in the localization 

and staging of lung cancers both before and 

following treatment, and in detecting relapsed 

disease. The potential role of radiolabelled 

somatostatin analogs as radiotherapeutic 

agents in the management of lung 

cancer is currently being explored. Somatostatin 

analog therapy results in significant 

growth inhibition of both SSTR-positive and 

SSTR-negative lung tumors in vivo. Recent 

work indicates that these agents may enhance 

the efficacy of chemotherapeutic 

agents in the treatment of solid tumors including 

lung cancer. 


K.J. O’Byrne 

University Department of Oncology, Leicester Royal Infirmary 

Leicester LE1 5WW (UK) 

Tel. +44 116 258 7602 

E-Mail Kobyrne@Lri.org.uk

Introduction 

At the turn of the century lung cancer was 

an extremely rare tumor. Since then its incidence 

has increased to such an extent that it is 

now the commonest cause of cancer death in 

Europe and North America. This dramatic 

change is largely attributable to cigarette 

smoking which is responsible for over 80% of 

all cases. A reduction in cigarette smoking in 

developed countries is beginning to produce 

an age-adjusted decrease in the incidence of 

lung cancer in men. However, smoking rates 

and the incidence of lung cancer are rising rapidly 

in women. The disease has now surpassed 

breast cancer as the commonest cause of cancer 

death in women. Of great concern is the 

fact that the peak of the lung cancer epidemic 

in women has not yet been reached [1, 2]. 

Despite improvements in the diagnostic, 

surgical, chemotherapeutic and radiotherapy 

management of lung cancer the overall results 

of treatment are poor. The 5-year survival 

rate for small cell lung cancer is approximately 

3%, and for non-small cell lung cancer 8– 

14%. Novel approaches to management are 

urgently required. The growth in our understanding 

of the molecular biology of lung cancer 

is leading to the development of new 

approaches to the treatment of this group of 

diseases including the use of growth factor 

antagonists, growth factor receptor antibodies 

and antiangiogenic agents [3–7]. 

Somatostatin 

Somatostatin is a tetradecapeptide hormone 

first identified in the hypothalamus as 

an inhibitor of growth hormone release. The 

peptide has subsequently been found throughout 

the body, particularly in the pancreas, gastrointestinal 

tract and nervous system. Somatostatin 

inhibits the release of growth hor- 



mone and thyroid-stimulating hormone from 

the anterior pituitary and hormone release 

from the pancreas and gastrointestinal tract. 

Somatostatin also functions as a neurotransmitter, 

immunomodulator and suppressor of 

angiogenesis and cell proliferation [8–14]. It 

acts by binding to specific receptors (SSTR) of 

which 5 principal subtypes have been identified: 

SSTR-1, SSTR-2, SSTR-3, SSTR-4 and 

SSTR-5 [15]. 

Growth Inhibitory Effects of 

Somatostatin and Somatostatin 


Through the activation of SSTR, somatostatin 

and its analogs exert a number of direct 

growth inhibitory effects on normal and malignant 

cells. All 5 SSTR are functionally coupled 

to adenylyl cyclase. Activation of SSTR results 

in inhibition of the intracellular accumulation 

of cyclic adenosine monophosphate (cAMP). 

This may result in direct inhibition of the 

growth of cells in which accumulation of 

cAMP, and subsequent activation of the protein 

kinase A pathway, results in proliferation 

[14–16]. This is supported by observations in 

the SSTR-2-positive human pancreatic cancer 

cell line CFPAC-1 where in vitro growth inhibition 

by the octapeptide somatostatin analog 

RC-160 is associated with inhibition of cAMP 

accumulation [17]. Acting through SSTR-5, 

the somatostatin analog RC-160 has been 

demonstrated to suppress the proliferative effects 

of cholecystokinin on CHO cells by inhibiting 

the accumulation of cyclic guanosine 

monophosphate (cGMP) [18]. 

On binding to their extracellular receptor 

domains, many growth factors induce intracellular 

receptor tyrosine kinase activity. 

Likewise a number of oncogene products are 

truncated growth factor receptors, lacking an 

extracellular domain but having permanent 


Table 1. Antiproliferative activity of somatostatin 

Direct effects 

Activation of phosphatase activity 

Inhibition of cAMP accumulation 

Inhibition of cGMP accumulation 

Inhibition of the mobilization of intracellular calcium 

through 

1 Inhibition of cell membrane calcium channels 

2 Interaction with phospholipase C and inositol/ 

phospholipid growth pathways 

Induction of programmed cell death (apoptosis) 

Indirect effects 

Inhibition of the release of trophic factors from elsewhere, 

e.g. EGF and IGF-1 

Inhibition of angiogenesis 

Inhibition of cancer cell adhesion 

endogenous intracellular tyrosine kinase activity. 

This activity results in phosphorylation 

of a number of tyrosine residues on the intracellular 

portion of the receptor. The phosphorylated 

tyrosine residues interact with 

guanine nucleotide-binding proteins and subsequently 

ras, inducing a phosphorylation 

cascade which activates transcription factors 

and ultimately results in cell proliferation 

[19]. Somatostatin stimulates the activity of 

phosphatases including phosphotyrosine 

phosphatases which have been demonstrated 

to dephosphorylate the tyrosine residues of 

activated type 1 growth factor receptors, such 

as the epidermal growth factor receptor 

(EGFR) [10, 11, 14, 20, 21]. Further evidence 

for activation of intracellular phosphatases 

comes from studies which have demonstrated 

that somatostatin analogs can inhibit insulinlike 

growth factor-1 (IGF-1) and serum-stimulated 

MAP kinase activation in vitro [22]. 

Activation of phosphatases is associated with 

inhibition of the proliferation of SSTR-positive 

normal and cancer cells in vitro [6, 10, 14, 

20–22]. The activation of phosphotyrosine 

phosphatases is mediated through SSTR-1 

and SSTR-2 [10]. Somatostatin and somatostatin 

analogs also inhibit the accumulation of 

intracellular calcium from both extracellular 

and intracellular sources [11, 23]. 

Somatostatin analogs have been shown to 

inhibit the growth of SSTR-negative tumors 

in vivo demonstrating important indirect antiproliferative 

effects. Many tumors express 

IGF-1 receptors (R) and proliferate in response 

to exposure to IGF-1 [24, 25]. Therefore 

blocking the release of growth factors 

from normal and malignant tissues may inhibit 

autocrine-, paracrine- and endocrineinduced 

cancer cell proliferation [14]. 

Through the inhibition of the protein kinase 

A pathway, somatostatin and its analogs may 

not only modulate cell growth but also suppress 

the synthesis and release of hormones 

and trophic growth factors, including growth 

hormone and IGF-, from normal tissues [13, 

14]. In keeping with these findings the growth 

inhibitory effects of RC-160 in SSTR-negative 

tumors are associated with a decrease in 

serum growth hormone (GH) and IGF-1 levels. 

Furthermore, the growth inhibition is associated 

with suppression of tumor cell IGF- 

1R expression [14, 26–28]. 

Somatostatin analogs are also potent antiangiogenic 

agents having direct growth inhibitory 

effects on proliferating endothelial 

cells [12]. As angiogenesis is essential for the 

growth of a tumor greater than 1–2 mm in 

diameter, interference with this process may 

result in the inhibition of cancer growth [29]. 

Somatostatin also reduces the capacity of malignant 

cells to adhere to blood vessel walls 

thereby reducing the metastatic potential of 

malignant tumors [30]. 

In keeping with both the direct and indirect 

antiproliferative growth inhibitory effects 

described, somatostatin and its analogs have 

been shown to induce tumor cell apoptosis 

both in vitro and in vivo (table 1) [13, 14]. 

80 Chemotherapy 2001;47(suppl 2):78–108 O’Byrne/Schally/Thomas/Carney/ 

Steward

Somatostatin Expression in Lung 

Cancer 

Small cell lung cancer (SCLC) accounts for 

approximately 20% of all lung tumors. SCLC 

is a neuroendocrine tumor characterized by 

the expression of pan-neuroendocrine markers 

including neuron-specific enolase (NSE), 

creatine kinase BB and chromogranin, and 

specific hormones and their receptors including 

bombesin (GRP) and IGF-1 [5, 13, 25, 

31]. Many of these substances may be elevated 

in the serum and/or plasma of patients 

with SCLC at presentation and, particularly 

in the case of NSE, may be of value as tumor 

markers, the levels falling if the disease responds 

to chemotherapy and rising if the disease 

progresses or relapses [13, 32, 33]. 

A number of studies have suggested that 

SCLC may synthesize and secrete somatostatin. 

The detection of elevated serum 

somatostatin-like immunoreactivity in lung 

cancer patients was first reported in 1980 

[34]. Subsequent investigations revealed elevated 

somatostatin serum levels in 4 of 26 

(15%) [35] and 3 of 21 (14%) patients [36] 

with SCLC compared to controls. Immunoreactive 

tissue somatostatin has been detected 

in 5 of 9 [35] and 2 of 6 SCLC tumor sample 

extracts [37]. Somatostatin has also been detected 

in 1 of 13 culture media of SCLC cell 

lines [38] and extracted from 5 of 13 cell lines 

[39]. Finally Chretien and coworkers [40] 

reported immunohistochemically detectable 

somatostatin in 75% of cytology-positive 

bronchial brushing smear samples obtained 

from 24 SCLC patients. They concluded that 

the presence of somatostatin immunoreactivity, 

along with other features, was highly suggestive 

of SCLC. However, some studies either 

failed to detect, or have shown a very low 

incidence of somatostatin-like immunoreactivity 

in SCLC tumor samples. In 2 studies 

employing indirect immunoperoxidase tech- 



niques only 1 of 94 [41] and 1 of 10 [42] paraffin-embedded 

SCLC samples were found to 

express somatostatin. Furthermore, in a recent 

study of cryostat sections from 4 SCLC 

tumors, in situ hybridization failed to detect 

evidence of somatostatin mRNA expression 

[43]. The significance of somatostatin expression 

in SCLC has not been addressed in these 

studies. 

We evaluated somatostatin immunoreactivity 

in plasma samples and tissue sections of 

biopsy and surgically resected paraffin-embedded 

tumor specimens of patients with 

SCLC. Elevated fasting plasma somatostatin 

levels were seen in 6/44 (13.6%) of the patients 

studied. Elevated somatostatin levels 

were also seen in 2 SCLC patients who had 

associated diabetes mellitus, 1 insulin-dependent 

and the other non-insulin-dependent. 

Diabetes mellitus is associated with elevated 

fasting somatostatin levels [44, 45]. The degree 

of elevation in the serum levels was similar 

in both the diabetic and nondiabetic SCLC 

patients. This observation raises the possibility 

that elevated somatostatin levels in SCLC 

patients may be secondary to the release of 

other hormones/peptides released by, or because 

of, the tumor rather than being ectopic 

in nature. This contention is supported by the 

fact that we were unable to detect definite 

somatostatin immunoreactivity in tissue sections 

from paraffin-embedded tumor samples 

from 163 patients with SCLC using streptavidin-biotin 

immunohistochemistry (unpubl. 

data). 

Further evidence to support the argument 

that the elevated somatostatin plasma levels 

are often not ectopic in nature comes from the 

finding of a close association between somatostatin 

and calcitonin gene-related peptide 

(CGRP) expression in the SCLC patients 

in our study (p = 0.019; unpubl. data). Recent 

work has shown that CGRP and somatostatin 

modulate chronic hypoxic pulmonary hyper- 


tension. In in vivo experiments evaluating the 

role of CGRP in the regulation of pulmonary 

arterial pressure, infusion of this peptide into 

the pulmonary circulation of hypobaric hypoxic 

rats not only prevents pulmonary hypertension 

but also results in an increase in lung 

plasma somatostatin. Under these circumstances 

somatostatin has been shown to inhibit 

CGRP release [46]. Chronic hypoxic pulmonary 

hypertension may occur in patients 

with lung cancer and may explain, in part, the 

elevated CGRP and, as a result, somatostatin 

plasma levels observed in the SCLC patients 

[47]. 

Recent work has shown that a proportion 

of non-SCLC (NSCLC) tumors may also express 

pan-neuroendocrine markers including 

NSE and chromogranin and specific peptide 

hormones including calcitonin, CGRP and 

GRP [48–50]. The immunohistochemical expression 

of 2 or more neuroendocrine markers 

within a tumor and elevated serum NSE 

levels are observed in approximately 20% of 

patients with NSCLC and appear to define a 

subgroup of patients whose disease is more 

responsive to cytotoxic chemotherapy than 

neuroendocrine marker-negative disease [48, 

51, 52]. The immunohistochemical detection 

or extraction of somatostatin from NSCLC 

tumor tissue samples has been described in a 

number of small studies [42, 53, 54]. In their 

study of NSCLC tumors which had been 

found to contain dense-core granules (a marker 

of neuroendocrine differentiation) by electron 

microscopy, Wilson et al. [42] detected 

somatostatin immunoreactivity in all 7 cases. 

All had associated expression of NSE, human 

chorionic gonadotropin, serotonin and keratin. 

Somatostatin expression has also been 

described in a range of atypical pulmonary 

tumors including an adenocarcinoma with endometrioid 

features [55], an adenocarcinoma 

resembling fetal lung [56], a chondroma [57] 

and a blastoma [58]. We have evaluated a 

number of endocrine markers in serum and 

plasma and paraffin-embedded tissue sections 

of patients with NSCLC. Although elevated 

serum NSE levels were seen in 7/25 

(28%) patients, somatostatin immunoreactivity 

was absent in all plasma and paraffinembedded 

tissue sections examined (unpubl. 

data). 

Bronchial carcinoids are likewise neuroendocrine 

tumors and express both pan-neuroendocrine 

markers and specific hormones, 

including GRP, gastrin, glucagon, calcitonin 

and adrenocorticotropin (ACTH) [59, 60]. In 

a recent study of 57 carcinoid tumors, somatostatin 

immunoreactivity was detectable 

in 43% of 30 typical and 22% of 27 atypical 

tumors [59]. 

The balance of evidence of the aforementioned 

findings suggests that somatostatin expression 

in SCLC and NSCLC is rare. Elevated 

plasma/serum levels may, in many instances, 

be a secondary response to the disease 

and other ectopic hormones produced by 

these tumors rather than as a result of ectopic 

production of the hormone from the tumor 

itself. This suggestion is supported by the 

close correlation between elevated somatostatin 

and CGRP levels observed in 

SCLC patients. 

Somatostatin Receptor (SSTR) 

Expression in Lung Cancer 

The presence of SSTR on normal and malignant 

tumor cells has been the subject of 

considerable research since the early part of 

the last decade. SSTR are expressed by tumors 

derived from tissues known to be targets 

for somatostatin including somatotroph, thyrotroph 

and endocrine-inactive pituitary adenomas, 

central nervous system tumors including 

meningiomas, astrocytomas, oligodendrogliomas 

and medulloblastomas, gastrointesti- 


Steward

nal tract and pancreatic neuroendocrine 

(GEP) tumors, medullary thyroid carcinoma, 

and malignancies of the reticuloendothelial 

system including both Hodgkin’s and non- 

Hodgkin’s lymphomas. SSTR have also been 

detected on a proportion of breast, renal, 

prostatic, ovarian, exocrine pancreatic and 

colorectal carcinomas and osteosarcomas [13, 

14, 61, 62]. 

SCLC SSTR Expression 

The presence of SSTR on lung tumors was 

first demonstrated by Taylor et al. [63] in 

1988 when they characterized the in vitro 

binding of [ 125 I-Tyr 11 ]somatostatin-14 to 

membranes prepared from cultured human 

SCLC tumor cells derived from the classical 

SCLC cell line NCI-H69. Binding was monophasic 

and of high affinity with an equilibrium 

dissociation constant (Kd) = 0.59 B 

0.02 nM. The estimated maximum binding 

capacity (Bmax) was 173 B 2.4 fmol/mg protein. 

Specific binding sites were also detected 

on membrane preparations from solid NCI- 

H69 xenografts grown in athymic nude mice. 

However, while the calculated equilibrium Kd 

was similar, the Bmax was only about 10% of 

that observed in cell culture. The binding was 

specific in that biologically active analogs of 

somatostatin were potent inhibitors of [ 125 I- 

Tyr 11 ]somatostatin-14 binding whilst biologically 

inactive somatostatin analogs and unrelated 

compounds such as bombesin and gastrin-17 

were not. 

In subsequent experiments crude membrane 

preparations from xenografts of 2 other 

classic SCLC cell lines NCI-H345 and NCI- 

H209 were reported to express high-affinity 

SSTR. However, SSTR expression was not 

observed in the variant SCLC cell line NCI- 

H417 or the poorly differentiated solid SCLC 

tumor LX-1 [64, 65]. In vitro autoradiographic 

techniques have also been employed to study 

SSTR expression in SCLC tumor speci- 



mens derived from cell lines and patients. 

SSTR have been demonstrated on fresh tumor 

specimens in 2 of 4 and 2 of 3 SCLC samples 

[66, 67]. The binding characteristics for 

somatostatin were characterized in 1 of the 2 

SSTR-positive SCLC specimens in the study of 

Reubi et al. [66]. Specific high-affinity (Kd = 

0.53 nM), low-capacity (Bmax = 189 fmol/mg 

protein) binding sites were detected, results 

consistent with the previous studies in cell 

lines. Macaulay et al. [68] demonstrated specific 

SSTR on 3 of 4 SCLC cell line xenografts. 

Strong expression was detected in SCLC tumors 

derived from the SCLC cell line NCI-H69 

while weak, patchy expression was observed on 

tumors from the classic cell line HXI49 and the 

variant cell line ICR-SC17. Xenografts from 

the classic cell line HC12 were SSTR-negative. 

We evaluated the specific binding of radiolabelled 

RC-160 on membrane preparations 

from 9 SCLC cell lines. Specific binding sites 

for the octapeptide somatostatin analog were 

demonstrated on 6 of the 9 cell lines investigated 

(67%). Scatchard analysis of the displacement 

curve of the cell line NCI-H69 

revealed evidence of 2 specific binding sites, 1 

of high affinity and low capacity and the other 

of low affinity and high capacity [69]. The 

high-affinity binding site was in keeping with 

previous studies. The precise nature of the second 

binding site in our study was uncertain. As 

RC-160 binds with high affinity to SSTR-2 

and SSTR-5, moderate affinity to SSTR-3 and 

low affinity to SSTR-1 and SSTR-4 [15], the 

results suggested that the high-affinity binding 

site represented SSTR-2 or SSTR-5 while the 

low-affinity site represented SSTR-1 or SSTR- 

4 or, indeed, nonspecific protein binding. 

Evaluation of SSTR subtype expression by 

RT-PCR has confirmed that SCLC tumors 

may express more than one SSTR subtype. In 

the first reported study, the classic SCLC cell 

lines NCI-H69 and NCI-H345 were found to 

express SSTR-1 and SSTR-2 mRNA [70]. 


This is entirely in keeping with the RC-160 

results presented here. A further study analyzed 

the binding activity of [ 125 I]somatuline 

and [ 125 I-Tyr 11 ]somatostatin-14 to crude homogenates 

of tumor xenografts from 3 SCLC 

cell lines, SCLC-6, SCLC-10 and SCLC-75. 

Employing cross-linking techniques 3 receptor 

proteins were identified. One major complex 

of 57 kD was bound by both radioligands in all 

3 tumors. Two other minor complexes were 

only identified by the natural ligand [ 125 I- 

Tyr 11 ]somatostatin-14, 90 kD in all 3 tumors 

and 70 kD in 2 tumors. Subsequent analysis 

revealed the presence of SSTR-1 mRNA in all 3 

tumors while SSTR-2 mRNA expression was 

observed in only 2. No SSTR-3 transcript was 

detected [71]. Finally RT-PCR analysis of the 

cell line COR-L103 revealed mRNA transcripts 

for SSTR-2, SSTR-3 and SSTR-4. Extra 

bands were obtained by PCR-single strand 

conformation polymorphism analysis of the 

SSTR-2 gene. Sequence analysis of the SSTR-2 

gene demonstrated a point mutation in codon 

188 of TGG for tryptophan to TGA for a stop 

codon causing loss of 182 C-terminal amino 

residues of the receptor. The nucleotide sequences 

of SSTR-3 and SSTR-4 were normal. 

Using the radiolabelled somatostatin analog 

[ 125 I-Tyr 11 ]somatostatin-14, affinity crosslinking 

studies revealed a lack of expression of 

a 72-kD protein compared to the pituitary cell 

line AtT-20, indicating that SSTR-2 is not 

expressed on cell membranes of COR-L103 

cells due to this point mutation [72]. 

Regarding SSTR-2 expression in SCLC, 

Taylor et al. [73] also detected an mRNA transcript 

in NCI-H69 corresponding to a truncated 

isoform of SSTR-2. This was felt likely to represent 

a human homolog of the rodent receptor 

SSTR-2B. Immunoblotting analysis using the 

SSTR-2-specific antibody, 2e3, detected multiple 

immunoreactive protein species, including 

a predominant 150-kD molecule. The SSTR-2 

identity was confirmed by blocking detection 

of the predominant 150-kD band by addition 

of the SSTR-2-derived 2e3 peptide. SSTR-2 

mRNA expression has also been identified in 

resected, snap-frozen, SCLC tumor specimens 

through in situ hybridization [74]. 

In an RT-PCR study Fujita et al. [75] analyzed 

SSTR-1 and SSTR-2 expression in 9 

SCLC cell lines, including 5 classic and 4 morphologically 

variant cell lines. Both receptor 

subtypes were detectable in all SCLC cell 

lines. Collectively these results indicate that 

SSTR are present in between 50 and 100%, 

and specific high-affinity binding sites for radiolabelled 

somatostatin analogs in 50–75% 

of SCLC tumor samples studied. 

NSCLC SSTR Expression 

In contrast to SCLC, initial studies suggested 

that NSCLC tumors do not express SSTR. 

Using autoradiography, no specific binding 

of the radiolabelled somatostatin analogs 

[ 125 I-Tyr 3 ]octreotide or [ 125 I-Leu 8 , D-Trp 22 , 

Tyr 125 ]somatostatin-28 was observed on cell 

pellets of the NSCLC tumors NCI-H23 or 

NCI-H226 [68], while only barely detectable 

levels of specific [ 125 I-Tyr 11 ]somatostatin-14 

binding were detected in membrane preparations 

of the NSCLC cell line H-165 [64]. Similarly 

in 2 studies in 1990, SSTR were not 

detected in 17 NSCLC fresh-frozen tumor 

samples using autoradiography [66, 67]. 

Using the radiolabelled somatostatin analog 

[ 125 I-Tyr 11 ]somatostatin-14, we were unable 

to detect specific somatostatin binding 

sites on membrane preparations from xenografts 

of the adenocarcinoma NSCLC cell line 

NCI-H157 [26]. The results were in accord 

with the findings of previous NSCLC tumor 

sample studies [64–67]. However, we did detect 

a single class of specific binding sites for 

[ 125 I]RC-160 in each of 3 NSCLC tumor samples 

[69]. All 3 were squamous cell tumors. 

The tissues examined were composed of 

a number of cell types including tumor 


Steward

cells, stroma, inflammatory cells and necrotic 

tissue. This observation raised the possibility 

that the NSCLC cells themselves were not 

expressing SSTR and that [ 125 I]RC-160 was 

binding specifically to inflammatory cells 

within the tumor which are known to express 

SSTR [62]. 

Two recent studies support the suggestion 

that the [ 125 I]RC-160 may bind specifically to 

NSCLC cancer cells. Employing RT-PCR, 

Fujita et al. [75] demonstrated SSTR-1 and 

SSTR-2 expression in a panel of squamous 

cell and adenocarcinoma NSCLC cell lines. 

The relative levels of SSTR-1 expression in 

the squamous cell tumors were similar to 

those seen in SCLC cell lines and were higher 

than those in adenocarcinomas. Indeed, in 2 

of the 5 adenocarcinomas examined, expression 

of SSTR-1 mRNA was very weak. Unlike 

SCLC, there was a positive correlation between 

SSTR-1 and SSTR-2 subtypes in the 

NSCLC tumor cell lines. In another study specific 

somatostatin binding sites for the radiolabelled 

hexapeptide somatostatin analog 

[ 125 I]MK-678 were found in 2 NSCLC cell 

lines, A 549 and H-165 [73]. This finding is of 

particular interest as previous studies with H- 

165 had shown this cell line to have only barely 

detectable levels of specific [ 125 I-Tyr 11 ]somatostatin-14 

binding [64]. As with the octapeptide 

somatostatin analog RC-160, MK- 

678 binds with high affinity to SSTR-2. Subsequent 

RT-PCR confirmed SSTR-2 mRNA 

expression within both NSCLC tumors [73]. 

We have also evaluated somatostatin analog 

binding to bronchial carcinoid tissue [69]. 

A single class of high-affinity binding site for 

[ 125 1]RC-160 was detected in the membrane 

preparations of both tumors assessed. These 

findings were not unexpected given that 

SSTR expression is common to similar tumors 

in the gastrointestinal tract [61, 76]. 

In summary, the available evidence indicates 

that the majority of SCLC tumors and 



bronchial carcinoids express specific SSTR 

with high affinity for both hexa- and octapeptide 

somatostatin analogs. Although some 

controversy remains, recent results also indicate 

that a significant proportion of NSCLC 

tumors are SSTR-positive, SSTR-1 and 

SSTR-2 mRNA having been detected in both 

squamous and adenocarcinomas. 

Radiolabelled Somatostatin 

Analog Imaging in Lung Cancer: 

Therapeutic Implications 

In 1989, Krenning et al. [77] reported the 

use of the radiolabelled somatostatin analog 

[ 123 I-Tyr 3 ]octreotide for the detection and 

localization of SSTR-positive tumors through 

scintigraphic imaging techniques. This agent 

was successfully applied in patients to visualize 

neuroendocrine GEP tumors, meningiomas 

and paragangliomas. Subsequent work 

led to the development of [ 111 In]pentreotide 

which is easier to make up, remains longer in 

the circulation and has a longer imaging halflife 

and reduced hepatobiliary metabolism 

than the former agent improving the quality 

of the images obtained, particularly in the liver. 

The effectiveness of [ 111 In]pentreotide has 

been established in the management of GEP 

tumors including carcinoid. The radiolabel 

often localizes primary GEP tumors that are 

undetectable by other methods including 

abdominal ultrasonography, computed tomography 

(CT) and magnetic resonance 

imaging (MRI), arteriography and venous 

sampling. [ 111 In]pentreotide may also detect 

otherwise unsuspected metastatic deposits. 

The localization of both the primary and metastatic 

deposits using a single technique contributes 

to the patient’s comfort and convenience 

and may lead to changes in patient 

management in a significant proportion of 

cases [61]. [ 111 In]pentreotide scintigraphy 


is of proven value in predicting the responsiveness 

of hormone-associated conditions, 

arising as a result of GEP tumors, to octreotide 

therapy [78]. 

SCLC [ 111 In]Pentetreotide Imaging 

SCLC remains a disease with a poor prognosis 

despite being sensitive to both chemotherapy 

and radiotherapy. SCLC patients are 

staged as having either limited or extensive 

disease. Limited disease, corresponding to 

stage I to IIIB disease in the TNM classification, 

is confined to a hemithorax including 

the mediastinum and the ipsilateral and contralateral 

hilar and scalene lymph nodes. Consolidation 

radiotherapy to the primary tumor 

site and mediastinum may improve long-term 

survival in patients with limited stage disease 

who have a good partial or complete response 

to chemotherapy. The median survival for 

patients with limited disease is approximately 

15 months and 7–20% survive for 5 years or 

more. Extensive stage SCLC refers to the 

spread of the tumor beyond these boundaries 

and includes patients with IIIB disease with 

an associated malignant pleural effusion. In 

patients with extensive disease the median 

survival is approximately 9–12 months with 

few long-term survivors. Therefore, stage has 

a significant impact on prognosis and, in 

some cases, on the management of patients [3, 

79]. 

In keeping with the demonstration of 

SSTR in SCLC tumors, disease sites were 

visualized in 5 of 8 patients using [ 123 I- 

Tyr 3 ]octreotide [80]. On the basis of these 

observations we carried out a study to evaluate 

the efficacy of [ 111 In]pentetreotide scintigraphy 

as a staging modality in SCLC patients 

prior to chemotherapy and in the assessment 

of disease response after treatment. 

Thirteen patients with newly diagnosed 

SCLC were studied prior to receiving chemotherapy. 

Following standard staging investiga- 

tions, 6 patients were found to have limited 

disease, and 7 extensive disease. Of the 7 

patients with extensive disease, liver metastases 

were seen in 4, bony metastases in 4, a 

single large brain metastasis in 1 and an adrenal 

metastasis in 1. Scintigraphic imaging 

with [ 111 In]pentetreotide led to the detection 

of all primary sites of disease. This included a 

patient whose primary tumor, detected at 

bronchoscopy, was not visualized with chest 

x-ray (CXR) or CT of the thorax. In the 7 

patients with extensive disease metastatic disease 

was detected in 3 out of 4, and skeletal 

disease in 2 out of 4 patients. In 1 patient a 

previously undetected cerebellar metastasis 

was found, not suspected following routine 

staging. This was later confirmed with a CT 

brain scan. Therefore the imaging procedure 

correctly staged 9 out of 13 patients (69%), 

detecting 5 out of 10 known metastases and 

1 previously unknown disease site (56%). Disease 

was downstaged in 4 out of 7 patients 

with extensive disease and upstaged in 1 patient 

with limited disease. In summary, 

[ 111 In]pentetreotide detected secondaries in 4 

or 50% of the 8 patients found to have metastases 

at the completion of all investigations 

[81]. 

We subsequently assessed a further 10 patients 

with SCLC. Eight of these were evaluated 

during chemotherapy. [ 111 In]pentetreotide 

failed to localize the primary tumor in 1 

patient and detected metastases in only 1 of 6 

patients with extensive disease. Of the remaining 

2 patients 1 was imaged at the time 

of disease relapse. The patient had extensive 

disease. All known tumor sites were localized. 

The other patient was imaged for what was 

thought to be NSCLC. Both standard and 

[ 111 In]pentetreotide imaging indicated resectable 

disease. Histological evaluation of the 

resected specimen following surgery revealed 

a limited stage SCLC tumor (table 2) [82]. 


Steward

Four patients imaged prior to treatment, 2 

with limited disease and 2 with extensive disease, 

were reevaluated with [ 111 In]pentetreotide. 

A further patient with extensive disease 

who was imaged with [ 111 In]pentetreotide after 

completion of his first cycle of chemotherapy 

was also assessed after completion of 

treatment. Pathological uptake of the radiolabel 

was detected in the region of the original 

disease in 2 patients thought to be in complete 

remission following standard staging procedures. 

In 1 of these patients a subsequent 

MRI study demonstrated an abnormality 

away from the bronchus suggestive of residual 

disease. The patient subsequently relapsed at 

this site. Therefore the technique may allow a 

more accurate assessment of prognosis for the 

individual patient following completion of 

chemotherapy and aid subsequent management 

decisions [81]. 

Single photon emission computed tomography 

(SPET) imaging was performed in 9 

patients and improved the anatomical localisation 

of disease in the thorax but contributed 

little to the overall assessment. 

The failure of [ 111 In]pentreotide scintigraphy 

to visualize all disease sites in 9 of the 15 

patients (60%) with metastases outside the 

thorax, despite detecting the primary tumor 

in 14 of these cases, is unclear. Nonspecific 

uptake of the radiolabel seen in the spleen, 

kidneys and urinary tract, liver and gastrointestinal 

tract, pituitary and thyroid gland may 

obscure visualization of metastases to these 

areas. However, the lack of uptake of radiolabel 

by bone and brain deposits cannot be 

explained in this way. This raises a number of 

possibilities. In a proportion of cases the metastatic 

disease may represent a dedifferentiated 

clone of the primary SCLC tumor not 

expressing SSTR. In individual cases local 

factors may downregulate SSTR expression. 

Furthermore, binding of the radioligand to 

the receptor may be blocked if high local lev- 



Table 2. Summary of results of SCLC patient imaging 

studies (n = 23) 

Sites of 

disease 

Number of disease sites detected 

standard 

staging 

Primary 

22 22a Liver 10 5 

Adrenal 1 0 

Bone 6 3 

Brain 1 1b [ 111 In]pentetreotide 

imaging 

a [ 111 In]pentetreotide imaging detected an intrathoracic 

primary SCLC not seen on CXR or CT scan of 

the thorax. 

b An otherwise unsuspected cerebellar metastasis. 

On completion of the study metastases were not 

visualized in 9 out of 15 patients with proven metastatic 

disease. [ 111 In]pentetreotide imaging failed to detect 

any site of disease in one patient with extensive 

SCLC. 

els of endogenous somatostatin are being produced. 

Furthermore, in those patients imaged 

while receiving chemotherapy the primary tumor 

was seen in 7 of 8 patients but metastases 

were detected in only 1 of 6 patients with metastatic 

disease. This observation suggests that 

the chemotherapy itself may affect uptake of 

the radiolabel. This suggestion is supported 

by the results of a recent study in which the 

uptake of [ 111 In]pentetreotide by primary 

SCLC tumors was significantly lower in patients 

imaged during chemotherapy compared 

to those evaluated before treatment (tumor 

to background ratios = 1.94 B 0.79 vs. 

2.35 B 0.9; p ! 0.005) [83]. 

In image-negative metastatic disease the 

SCLC cells themselves may not be expressing 

SSTR-2 or SSTR-5, the subtypes known to 

bind octreotide with high affinity. Rather it 

may be that the primary tumor is being visualized 

due to uptake of the radiolabel by the local 


inflammatory response, as activated immune 

cells are known to express SSTR [62] and/or 

by SSTR expressed in high concentrations on 

peritumoral blood vessels [12, 84]. If this is 

so, then those tumors where the metastases 

are seen may represent the true proportion of 

metastatic SCLC tumors which express highaffinity 

binding sites for radiolabelled somatostatin 

analogs – 6 of 15 (40%) patients with 

extensive disease evaluated in this study. 

This would be in keeping with the proportion 

of SCLC tumors known to express specific 

high-affinity binding sites for radiolabelled 

somatostatin analogs in vitro as discussed 

earlier. 

The effectiveness of [ 111 In]pentetreotide 

scintigraphy in the detection and localization 

of disease sites in SCLC patients has been 

evaluated and verified in a number of studies 

[83, 85–94]. Pretreatment of SCLC patients 

with cold somatostatin prior to administration 

of [ 111 In]pentetreotide may enhance the 

visualization of metastases through increased 

uptake of the radiolabel by the tumor [91, 95]. 

However, the lack of visualization of all sites 

of disease indicates that the imaging technique 

has limited value as a single modality in 

the staging of SCLC prior to commencing chemotherapy. 

Nonetheless a recent cost-effectiveness 

analysis indicated that [ 111 In]pentetreotide 

scintigraphy should be performed 

in patients with SCLC as it may alter 

the staging of the disease and localize otherwise 

undetected brain metastases. Under 

these circumstances the cost increase is outweighed 

by changes in patient management 

and the possibility of irradiating brain metastases 

at an early stage which may ultimately 

lead to improvements in symptom control 

[94]. 

Novel approaches to therapy in SCLC are 

currently being assessed and include inhibiting 

the action of autocrine growth factors 

such as GRP with GRP antagonists and GRP 

receptor antibodies [5]. Somatostatin analogs 

are currently being evaluated as possible therapeutic 

agents in SCLC with encouraging results 

in vitro and in vivo. In acromegaly and 

GEP tumors, the presence of SSTR has been 

shown to predict responsiveness to somatostatin 

analog therapy [78, 96, 97]. Imaging of 

SCLC tumors with [ 111 In]pentetreotide may 

have a role to play in identifying those patients 

most likely to respond to somatostatin 

analog treatment. Of great significance in this 

respect is the efficacy of the radiolabel in 

detecting residual SCLC disease following 

chemotherapy, and relapsing disease, observations 

which suggest that treated SCLC tumors 

continue to express SSTR. This lays the 

groundwork for evaluation of somatostatin 

analogs as therapeutic agents in the treatment 

of chemotherapeutically debulked or relapsing 

SCLC in the future. 

NSCLC [ 111 In]Pentetreotide Imaging 

In NSCLC the most important decisions to 

reach are whether the patient has resectable 

disease and, if so, is fit for surgery. If a patient 

is being considered for surgery extensive investigations 

are recommended including a 

full blood count, biochemistry profile, CXR 

and CT thorax, liver and adrenals. If mediastinal 

lymph nodes greater than 1.5 cm in the 

shortest transverse diameter are seen on the 

CT scan, mediastinoscopy and/or mediastinotomy 

should be performed to exclude inoperable 

disease prior to definitive surgery. Any 

symptoms the patient has which may be attributable 

to metastatic disease should be 

thoroughly investigated, e.g. an isotope bone 

scan for bone pain and a CT brain scan to 

assess headaches. Recent evidence suggests 

that stage III disease in patients with an Eastern 

Cooperative Oncology Group (ECOG) 

performance status of 0, 1 and possibly 2 may 

benefit from chemotherapy followed by radical 

radiotherapy. Furthermore, while still 


Steward



Fig. 1. Anterior and posterior views of the thorax and upper abdomen of 2 patients with 

NSCLC. A A stage IIIB tumor with abnormal uptake of [ 111 In]pentetreotide throughout the 

right lung and mediastinum confirmed both radiologically and at surgery is clearly demonstrated. 

B Increased uptake in the right upper lobe consistent with a Pancoast tumor confirmed 

with CT imaging is shown. 

largely investigational, there is accumulating 

evidence that preoperative, neoadjuvant chemotherapy 

may downstage the disease in a 

proportion of patients with stage IIIA, N2 disease 

making resection possible. These patients 

likewise require intensive staging to exclude 

disseminated disease. If the disease is 

inoperable due to the patient’s health and 

radical radiotherapy is not deemed appro- 

priate, or if stage IV disease is established, 

then staging investigations may be kept to a 

minimum [4, 98]. 

We studied [ 111 In]pentetreotide scintigraphy 

in 23 patients with NSCLC prior to treatment. 

The primary tumor was detected in all 

cases (fig. 1). Furthermore, the resectibility of 

the disease was correctly established in 20 

cases. The value of the technique was best 


exemplified in 2 patients. In the first disease 

spread was seen with [ 111 In]pentetreotide 

imaging which was not initially suspected. In 

the second patient a small primary squamous 

cell cancer found at bronchoscopy, but not 

visualized on CXR or CT thorax and upper 

abdomen, was localized. Of the 3 patients 

incorrectly staged, 2 were as the result of falsepositive 

uptake in benign lesions in the mediastinum, 

in a thyroid colloid cyst associated 

with intense lymphocytic infiltration in one 

case and in granulomatous lymph nodes in the 

other. These findings are readily explained by 

the fact that specific high-affinity SSTR may 

be expressed by immune cells, including those 

present in granulomas [61, 62]. In a third 

patient, mediastinal involvement and a malignant 

pleural effusion were missed. In a further 

patient the tumor, thought to be T2, N0/N1 

disease, turned out on CT of the thorax and 

upper abdomen and at surgery to extend to 

and involve the chest wall pleura indicating T3 

disease. As with CT scanning, it is difficult to 

distinguish between tumor and postobstructive 

atelectasis or consolidation as inflammatory 

cells may express high-affinity SSTR. 

Nonetheless, this did not affect staging of disease 

in our patient series (unpubl. data). 

[ 111 In]pentetreotide SPET imaging was 

performed in 16 of the 23 NSCLC patients. 

Unlike SCLC, SPET imaging significantly affected 

staging in a number of cases by improving 

anatomical localization of the disease, indicating, 

in particular, spread of disease to the 

pleura/chest wall (unpubl. data). 

Although these results are encouraging, 

they also demonstrate some of the potential 

limitations of the technique. While the radiolabel 

is specific for SSTR-expressing tissues, it 

is not specific for individual pathological processes 

as demonstrated by the detection of 

benign disease in the mediastinum in 2 patients 

in this series. Likewise it is well established 

that not all tumors of a particular 

pathological subtype necessarily express highaffinity 

binding sites for radiolabelled somatostatin 

analogs [61, 99]. Furthermore, it is 

likely that in some cases individual tumors 

may not express SSTR in sufficient density to 

be visualized by [ 111 In]pentetreotide scintigraphy. 

Therefore, false-negative results may 

occur. While the primary tumor may be localized, 

metastases may not necessarily contain 

SSTR-expressing cells. Also, although not a 

problem in the NSCLC studies reported here, 

nonspecific uptake of the radiolabel seen in 

the spleen, kidneys and urinary tract, liver 

and gastrointestinal tract, pituitary and thyroid 

gland may obscure visualization of metastases 

to these areas. 

Two further studies have confirmed that 

[ 111 In]pentetreotide scintigraphy is effective 

in the localization of NSCLC tumors, detecting 

the primary tumor in 40 of 40 [86] and 10 

of 13 patients, respectively [87]. However, 

metastatic sites of disease were not as frequently 

detected, thereby demonstrating the 

limitations of the technique. Of 15 patients 

with known metastases in the study of Kwekkeboom 

et al. [86], disease spread was detected 

in only 6, including 1 patient with a 

previously undetected brain metastasis – this 

was subsequently confirmed on CT brain 

scan. Spread to the mediastinum was detected 

in 5 of 15 cases and to the opposite lung in 1 of 

3 cases. Hepatic, adrenal and bone metastases 

were also missed. In the second study, while 

metastatic disease was detected in 9 of 10 

patients, spread to the liver was not detected 

in any of the 5 patients with known hepatic 

metastases [87]. 

The finding of uptake in NSCLC tumors 

was, to some extent, unexpected as the in 

vitro experimental data available prior to 

commencing the [ 111 In]pentetreotide studies 

had failed to reveal specific binding sites for 

a number of radiolabelled somatostatin 

analogs [64, 66, 67]. As discussed earlier we 


Steward

demonstrated the presence of high-affinity 

binding sites for the radiolabelled somatostatin 

analog [ 125 I]RC-160 in 3 squamous cell 

lung cancers. Two of these tumors had been 

localized with [ 111 In]pentreotide prior to surgical 

resection. Histological assessment of the 

resected specimens carried out before conducting 

the binding assays showed them to 

be comprised of tumor cells, necrotic tissue, 

connective tissue and/or inflammatory cells. 

Therefore, the SSTR may have been expressed 

by activated immune cells [62] and/ 

or the cancer cells themselves. The imaging 

study of Kwekkeboom et al. [86] is of interest 

in this regard. They argued that the detection 

and localization of NSCLC tumors was due to 

uptake of the radiolabel in tissues surrounding 

the tumor rather than to uptake by the 

tumor cells. This suggestion was based on 

observations that in a number of cases in 

their series (1) a halo effect was seen around 

the tumor on planar imaging, (2) SPET imaging 

showed increased radioactivity at the periphery 

of the tumor and (3) the region of 

accumulation of radioactivity during scintigraphy 

was greater than the tumor as measured 

on CT. Following [ 111 In]pentetreotide 

scintigraphy a number of these patients underwent 

surgery. Subsequent autoradiographic 

evaluation of the resected tumors using the 

radiolabelled octapeptide somatostatin analog 

[ 125 I-Tyr 3 ]octreotide failed to reveal SSTR 

on tumor cells. 

However, subsequent work demonstrated 

the presence of SSTR in NSCLC tumor cells 

[73, 75, 100]. As discussed earlier, in one of 

these studies moderate concentrations of specific 

binding sites for the radiolabelled hexapeptide 

somatostatin analog [ 125 I]MK-678, 

which binds SSTR-2 with high affinity, were 

found in 2 NSCLC cell lines. Subsequent RT- 

PCR confirmed SSTR-2 mRNA expression 

within both NSCLC tumors [73]. Therefore, it 

would appear likely that the localization of 



some NSCLC tumors is due, at least in part, 

to specific uptake of [ 111 In]pentetreotide by 

the malignant cells. 

The results of the present study suggest 

that [ 111 In]pentetreotide imaging may have a 

role to play as an adjunct in the diagnostic 

evaluation of patients with NSCLC. The 

imaging studies in SCLC and those reported 

for other tumors [61, 81, 101, 102] demonstrate 

that [ 111 In]pentetreotide scintigraphy 

may be of value in monitoring the response of 

SSTR-positive lung tumors to chemotherapy. 

As cytotoxic chemotherapy now plays an increasingly 

important role in the management 

of patients with NSCLC, [ 111 In]pentetreotide 

scintigraphy may prove to be an effective 

radiological technique for assessing the response 

of image-positive NSCLC tumors to 

such therapy. Furthermore, [ 111 In]pentetreotide 

scintigraphy may be of particular importance 

in the evaluation of the response of 

NSCLC tumors to novel treatments, including 

somatostatin analog treatment. 

Bronchial Carcinoid [ 111 In]Pentetreotide 

Imaging Studies 

We have reported the localization of bronchial 

carcinoid in 2 of the 3 patients studied 

with [ 111 In]pentetreotide scintigraphy [103]. 

As in the NSCLC patients SPET not only 

improved anatomical localization of the 

disease but also was necessary to detect 

the tumor in one case. In the patient where 

the primary tumor was not localized with 

[ 111 In]pentetreotide scintigraphy, diffuse, low 

intensity uptake of the radioligand was noted 

in the opposite lung, an area of known bronchiectasis. 

This false-positive localization is in 

keeping with the findings in the NSCLC patients 

described earlier where 2 false-positive 

results were recorded. Following resection of 

the carcinoid tumor in one of the imagepositive 

cases, membrane-binding assays revealed 

the presence of a single class of high- 


affinity binding site for the radiolabelled somatostatin 

analog [ 125 I]RC-160 [103]. 

Apart from presenting with respiratory 

symptoms, symptoms of metastatic disease, 

physical signs and associated abnormalities 

on CXR or CT scan, and, rarely, the carcinoid 

syndrome, patients with bronchial carcinoid 

tumors may present with ectopic hormone 

syndromes including Cushing’s syndrome 

and acromegaly. In many cases the tumor 

producing the ectopic-hormone-related syndrome 

cannot be localized on physical examination 

or with standard biochemical and radiological 

techniques. [ 111 In]pentetreotide 

scintigraphy has now been evaluated in a 

series of patients with Cushing’s syndrome 

secondary to ectopic ACTH or corticotropinreleasing 

factor. In keeping with the results 

reported for neuroendocrine tumors in general, 

the primary tumor or its metastases were 

localized in 8 of 10 patients. The failure of 

[ 111 In]pentetreotide scintigraphy to detect 

ACTH-secreting pituitary adenomas and an 

adrenal tumor in 9 patients is in accord with 

the ineffectiveness of somatostatin analog 

therapy in the management of Cushing’s disease 

[104]. 

Subsequent studies have confirmed these 

results and indicate that SSTR-2 is expressed 

by bronchial carcinoid tumors [104–113]. The 

results suggest SSTR imaging may be an important 

diagnostic investigation in the workup 

of patients with suspected ectopic hormonesecreting 

tumors and their metastases. 

Radiotherapeutics 

The possibility of employing a radiolabelled 

chelated somatostatin analog as a radiotherapeutic 

agent in treating SSTR-positive 

tumors, including those of the lung, is an 

exciting prospect for the future. Since somatostatin 

analogs are based on sequences of 

the native hormone, they rarely induce immunization. 

The accumulation of [ 111 In]pentetreotide 

in gastrointestinal neuroendocrine tumors is 

between 0.0123 and 0.2% of the administered 

dose per gram of tumor tissue. The rapid 

clearance of the radiolabel from the blood, the 

relatively low accumulation in the liver (1.9 

and 2.2% of the administered dose at 4 and 

24 h, respectively) with resultant relatively 

low excretion into the gastrointestinal tract 

and the predominant renal clearance are advantageous 

in this regard. However, the 

amount of renal accumulation and the relatively 

long renal effective half-life may limit 

the maximally applicable radiation dose [61, 

99]. Recent studies suggest that there are a 

number of approaches which may be useful in 

reducing the uptake of [ 111 In]pentetreotide by 

normal tissues. 

Pretreatment of patients with SCLC and 

carcinoid disease with cold octreotide increases 

tumor uptake of [ 111 In]pentetreotide, 

whereas uptake into the liver, spleen and kidneys 

is reduced [91, 109]. This in vivo observation 

has been supported in vitro in mouse 

AtT20/Dl6V pituitary tumor cells and primary 

cultures of human GH-secreting pituitary tumor 

cells. After 4 h of incubation up to 8% of 

the added [ 125 I-Tyr 3 ]octreotide had accumulated 

in AtT20/Dl6V cells and between 0.24 

and 4.98% in 6 of the 7 human tumor cultures. 

This accumulation was specific and time-, temperature- 

and pertussis-toxin-sensitive G protein-dependent. 

Displacement of binding and 

internalization of [ 125 I-Tyr 3 ]octreotide in 

AtT20/Dl6V cells by the addition of unlabelled 

octreotide showed a bell-shaped curve. At low 

concentrations (0.1–1 nM) unlabelled octreotide 

enhanced the binding and internalization 

of [ 125 I-Tyr 3 ]octreotide whereas at higher concentrations 

saturation occurred. Furthermore, 

after 4 h of incubation, 88% of the radioactivity 

present in the cells was still peptide-bound 

suggesting slow intracellular breakdown of the 

radioligand [95]. 


Steward

Infusion of amino acids, known to block 

renal tubular peptide reabsorption, significantly 

reduces renal parenchymal uptake of 

[ 111 In]pentetreotide 4 h after administration 

when compared to controls. In this there was 

a nonsignificant increase in urinary clearance 

of the isotope over the 4 h consistent with 

reduced re-uptake of the radiolabel, and a lack 

of effect of the amino acids or radiolabelled 

peptide on glomerular filtration rate [114]. 

A number of new potential radiotherapeutic 

agents are currently under investigation. 

188 Re, a potential radiotherapeutic isotope, 

has been coupled to octreotide. [ 188 Re]octreotide 

has been assessed for the in vivo localization 

of NCI-H69 SCLC tumor xenografts in 

athymic nude mice and proved as efficient as 

[ 111 In]pentetreotide in this regard [115]. Likewise, 

l6l Tb has been coupled to octreotide. In 

studies in the rat, l6l Tb-DTPA-octreotide has 

similar distribution characteristics to [ 111 In]pentetreotide 

but with less uptake in the liver 

and other SSTR-expressing tissues such as the 

pancreas and adrenals, and negligible excretion 

into the bile. The uptake of l6l Tb-DTPAoctreotide 

by the renal tubules after glomerular 

filtration can be reduced by administration 

of lysine or sodium maleate [116]. The 

radiotherapeutic isotope 64 Cu, a reactor-produced 

radionuclide, has been coupled to octreotide. 

Apart from its radiotherapeutic potential, 

64 Cu is also a suitable radioisotope for 

PET scanning. The resulting product, 64 Cu- 

TETA-octreotide, binds to SSTR with 5 times 

the affinity of [ 111 In]pentetreotide and, like 

[ 111 In]pentetreotide, is excreted principally 

through the renal system [117]. Finally, [ 90 Y] 

has been linked to DTPA-benzyl-acetamido- 

D-Phe 1 , Tyr 3 -octreotide and has proved effective 

in the treatment of SSTR-positive tumors 

in a nude mouse model [118]. Other somatostatin 

analogs are being linked to therapeutic 

radioisotopes with encouraging results. 

[ 188 Re]RC-160 has been evaluated in vivo in 



nude mice bearing xenografts of the SSTRpositive 

prostate cancer cell lines DU-145 and 

PC-3. In PC-3 xenografts, [ 188 Re]RC-160 induced 

a dose-dependent therapeutic response, 

with disease stabilization or shrinkage, even 

in animals with relatively large tumor masses 

[119]. 

These results demonstrate that, in selected 

cases, radiolabelled somatostatin analogs may 

be employed as adjuncts to standard radiological 

techniques for the scintigraphic localization 

of primary lung tumors and their metastases. 

Radiotherapeutic somatostatin analogs 

may have a role to play in the treatment of 

lung tumors, in particular chemotherapeutically 

debulked SCLC, in the future. 

Somatostatin Analogs in the 

Treatment of Lung Cancer 

Given the mode of action of somatostatin 

and the fact that between 50 and 100% of 

SCLC cell lines and fresh frozen tissue specimens 

express SSTR, the role of somatostatin 

and somatostatin analogs as possible therapeutic 

agents in SCLC has been investigated 

in a number of studies. Initial experiments 

with somatostatin-14 were not encouraging 

[120]. In 1988 Kee et al. [121] demonstrated 

that somatostatin could inhibit the secretion 

of bombesin-like peptides from SCLC cell 

lines. Subsequently in 1988 Taylor et al. [122] 

evaluated the somatostatin analog somatuline 

in the treatment of NCI-H69 in vitro. Significant 

inhibition of cell proliferation was demonstrated. 

The average cell concentration of 

treated samples was 59% of that observed 

in tumor controls after 72 h. Further work 

with NCI-H345 revealed that somatuline 

could not only inhibit the clonal growth of 

SCLC cell lines but could also inhibit VIPinduced 

cAMP formation within the tumor 


cells [123]. Somatuline inhibits serum-induced 

MAP kinase activation in SCLC cells at 

a dose range similar to that required to inhibit 

cell proliferation. This observation suggests 

that phosphatase activation is important for 


analogs in SCLC as discussed earlier [10, 11, 

14, 20, 21]. These results suggest that the 

SSTR on SCLC tumors are functional and 

interact with growth pathways within the 

cell. 

Following the promising results of the in 

vitro work, in vivo experiments in athymic 

nude mice were performed. Suspensions of 

NCI-H69 cells, containing 5 ! l0 6 cells, were 

injected into the flanks of athymic nude mice. 

These tumors were treated with somatuline 

500 Ìg i.p. b.i.d. in one group and s.c. around 

the tumor in another. Both regimens resulted 

in delay of the mean tumor lag time compared 

to controls. Inhibition of tumor growth was 

dramatic with subcutaneous injection around 

the tumor site, with virtually no growth being 

seen at 48 days. Discontinuing treatment by 

any route resulted in an acceleration of tumor 

growth. The effects of somatuline treatment 

on NCI-H69 xenografts were also studied. 

The experiment was repeated as before but 

with a third group receiving subcutaneous 

somatostatin analog treatment at a site distant 

from the tumor. Again significant growth inhibition 

was seen in all treated groups [122]. 

Subsequent work with somatuline in SSTRpositive 

cell lines has confirmed the earlier 

findings [64, 124]. Furthermore, significant 

growth inhibition of the SSTR-negative variant 

SCLC cell line NCI-H417 and poorly differentiated 

SCLC cell line LX-1 by somatostatin 

analogs was seen suggesting that they may 

inhibit SCLC tumor growth by indirect as 

well as direct means [64]. The hexapeptide 

somatostatin analog, MK-678, has also been 

demonstrated to affect NCI-H69 tumor 

growth in vivo. Treatment with 300 Ìg/kg s.c. 

t.i.d. for 46 days resulted in a 51% decrease in 

tumor area, a 64% decrease in tumor DNA 

content and a 55% decrease in RNA content. 

Tumor protein and weight were not affected 

[125]. 

The effect of octreotide in the treatment of 

SCLC has also been assessed in vitro and in 

vivo. The SCLC lines NCI-H69, HX149, 

ICR-SC17 and HC12 were evaluated. The 

growth of the SCLC cell line HX149, found to 

have weak and patchy specific somatostatin 

binding sites at autoradiography, was significantly 

inhibited but that of the other cell lines, 

two of which were SSTR-positive, was unaltered 

[68]. 

We evaluated the efficacy of RC-160 in the 

treatment of SCLC. In NCI-H69 SCLC xenografts 

significant inhibition of tumor growth 

accrued from day 7 (p ! 0.05) through to the 

end of the experiment (p ! 0.01). The mean 

tumor weight was reduced significantly (p ! 

0.01) by RC-160 compared to the control 

group. Tumor volume doubling time in mice 

receiving RC-160 was extended from 7.5 to 

12.7 days. Histologically, the number of mitotic 

and apoptotic cells in treated tumors did 

not differ significantly from control. However, 

the ratio of apoptotic to mitotic indices 

was significantly higher in the group receiving 

RC-160 (p ! 0.05; table 3) [26]. 

Somatostatin analogs have also been evaluated 

in the treatment of NSCLC. Somatuline 

has been demonstrated to inhibit the in vivo 

growth of the SSTR-poor NSCLC cell line H- 

165 supporting the contention that indirect 

growth inhibitory effects may be important in 

the antitumor activity of somatostatin analogs 

in solid tumors [64]. Regarding this study it is 

important to keep in mind the results of subsequent 

work which, using the radiolabelled 

somatostatin analog [ 125 I]MK-678 as radioligand 

and RT-PCR techniques, demonstrated 

that H-165 is SSTR-positive [73]. 


Steward

Table 3. Summary of RC-160 in vivo growth inhibition study data 

Tumor volume, mm3 Initial 

Final 



SCLC NCI-H69 

control RC-160 

10.5B1.6 

249.7B182.3 

9.8B1.8 

66.0B26.5* 

NSCLC NCI-H157 

control RC-160 

10.0B2.0 

1,580.3B455.7 

11.1B2.6 

291.0B207.8* 

Body weight, g 26.3B2.3 26.5B1.0 26.5B1.0 24.2B4.7 

Tumor weight, g 0.27B0.19 0.058B0.04* 1.9B0.3 0.64B0.3* 

Tumor doubling time, days 7.512.7 3.88 6.06 

Mitotic and apoptotic indices 

Mitotic index 37.9B2.9 23.0B4.6 17.3B4.0 12.9B1.2 

Apoptotic index 35.4B2.6 42.3B3.2 2.87B0.54.00B0.7 

Ratio of apoptotic to mitotic indices 0.96B0.1 2.27B0.5* 0.19B0.04 0.35B0.08 

GH assay 

GH, ng/ml 3.8B0.52.0B0.5* 6.8B0.8 3.5B0.3* 

Receptors 

EGF Kd, nM 1.3 1.6 0.7 0.5 

EGF Bmax, fmol/mg protein 278 174 249 100 

IGF-1 Kd, nM 1.0 0.9 0.50.7 

IGF-1 Bmax, fmol/mg protein 294 176 257 129 

Bombesin/GRP Kd, nM 1.1 1.3 ND ND 

Bombesin/GRP Bmax, fmol/mg protein 420 435ND ND 

Somatostatin Kd, nM 3.55.5 ND ND 

Somatostatin Bmax, fmol/mg protein 450 570 ND ND 

There were 10 animals in each group. GRP = Gastrin-releasing peptide; ND = not detected. Tumor and body 

weight values are means B standard deviation of the mean. Mitotic and apoptotic indices and GH values are 

means B standard error of the mean. * p ! 0.05 [26]. 

Nonetheless, our work supports the contention 

that indirect antiproliferative effects 

are important in the growth inhibition of 

lung tumors by somatostatin analogs. RC- 

160, 100 Ìg s.c. once daily, significantly inhibited 

the growth of NCI-H157 tumors from 

day 14 of treatment (p ! 0.01). The final 

tumor volume and tumor weight were significantly 

reduced in animals receiving RC-160 

compared with controls (table 3). Tumor volume 

doubling time was prolonged from 3.88 

to 6.06 days. No significant difference in the 

extent of necrosis, mitoses or apoptosis or in 

the ratio of apoptotic to mitotic indices between 

control and the RC-160-treated group 

was seen. No specific SSTR-binding sites 

were found on membranes prepared from the 

NSCLC tumor xenografts [26]. Similar in 

vivo growth inhibition has been observed in 

other SSTR-negative tumors [27]. 

In our studies GH levels in animals treated 

with RC-160 were significantly decreased 

[26], compared with controls (table 3), a finding 

confirmed in subsequent work [27]. GH 

induces the synthesis of IGF-1, an important 

growth factor for solid tumors including lung 


cancer [25]. In breast cancer patients RC-160 

has been demonstrated to significantly reduce 

serum IGF-1 levels [28]. This may result in a 

reduced proliferative stimulus for tumors sensitive 

to the growth stimulatory effects of 

IGF-1 including lung cancers [5, 14, 28]. 

RC-160 also reduces elevated prolactin 

levels to within the normal range in patients 

with breast cancer. Prolactin is an autocrine 

growth factor for breast cancer. Somatostatin 

analogs have little or no effect on primary 

pituitary hyperprolactinemia. These findings 

suggest that the normalization of serum prolactin 

levels in breast cancer patients is due to 

a direct effect on hormone synthesis and release 

by the breast cancer cells themselves 

[28]. Somatostatin analogs inhibit the release 

of bombesin-like peptides from SCLC tumor 

cells [122] and gastrin from cultured human 

endocrine cells [126]. The results suggest that 

somatostatin analogs may downregulate autocrine 

feedback loops in SSTR-positive malignancies 

including lung tumors, in particular 

SCLC [5, 26]. 

Impact of Somatostatin Analogs on SCLC 

and NSCLC SSTR and Growth Factor 

Receptor Expression 

In accord with previous studies [5, 14, 61, 

69, 127], and those mentioned above, we 

demonstrated specific binding sites for radiolabelled 

somatostatin, bombesin/GRP, IGF-1 

and epidermal growth factor (EGF) on membrane 

preparations from treated and control 

xenografts of the SCLC cell line NCI-H69 

[26]. Likewise, EGF [128] and IGF-1 [129] 

binding sites were found on the NSCLC xenografts, 

but no specific binding sites for radiolabelled 

somatostatin and bombesin/GRP receptors 

were detected [26]. 

The effects of RC-160 on SSTR, EGFR, 

luteinizing hormone-releasing hormone-R 

and IGF-1R expression have been evaluated 

in a number of tumors. RC-160 appears to 

upregulate SSTR [130, 131] while downregulating 

EGFR [130, 132–136], LHRH-R [130, 

137] and IGF-1R [131, 137] expression. Although 

only performed on one occasion, the 

results of the membrane binding assays from 

our study are consistent with the previous 

findings. The EGF and IGF-1 Bmax were 

both reduced in RC-160-treated SCLC and 

NSCLC xenografts as compared to controls 

(table 3). EGFR levels in the RC-160-treated 

samples were 63 and 40%, and IGF-1R levels 

60 and 50% of control in SCLC and 

NSCLC membranes, respectively. No change 

was observed in the Kd and Bmax values for 

bombesin/GRP in the SCLC tumor xenografts 

[26]. 

Both the Kd and Bmax for somatostatin 

increased with RC-160 treatment indicating 

reduced binding affinity but increased binding 

capacity. The Kd and Bmax values for 

[ 125 I-Tyr 11 ]somatostatin-14 were higher in 

membranes prepared from NCI-H69 xenografts 

than the Kd and Bmax for [ 125 I]RC-160 

high-affinity binding site in membranes prepared 

from NCI-H69 cell pellets grown in 

vitro [26, 69]. No low-affinity binding sites 

were detected [26]. 

Taken together these findings indicate that 

RC-160 therapy may affect the expression of a 

number of growth-stimulatory and potentially 

growth-inhibitory receptors as well as growth 

factors in lung cancer. These changes may 

result in a downregulation of autocrine, paracrine 

and endocrine proliferative stimuli in 

SCLC and NSCLC. 

Angiogenesis 

Angiogenesis is necessary for the growth 

of a primary tumor beyond 1–2 mm in diameter 

and plays an important role in tumor 

metastasis [29]. Recent work has demonstrated 

that in patients with resectable 

NSCLC, one of the most important prognostic 

factors is the degree of angiogenesis in the 


Steward

esected tumors as assessed by microvessel 

counts. Tumors with high microvessel 

counts are associated with spread of the tumor 

to locoregional lymph nodes and a significantly 

worse prognosis [138]. The potent 

antiangiogenic activity of somatostatin analogs 

[12] may be one of the principal mechanisms 

by which these agents inhibit lung cancer 

growth in vivo. This may be particularly 

so in tumors with negative or low levels of 

specific binding sites for radiolabelled somatostatin 

analogs as is the case for the 

NSCLC cell line NCI-H157. 

Patient Studies 

Treatment of SCLC 

A number of small studies have now been 

conducted in patients with SCLC. The first 

involved 20 patients including 6 newly diagnosed 

patients and 14 presenting with relapsed 

disease following first line treatment. 

Octreotide 250 Ìg s.c. t.i.d. resulted in a significant 

reduction of serum IGF-1 levels. The 

overall change in IGF-1 levels, with the lowest 

level while on treatment expressed as a percentage 

of the pretreatment baseline value, 

was median 53% and mean 62 B 7% (range 

23–150%). Despite the reduction in IGF-1 

levels, there was no evidence of antitumor 

activity as measured by tumor bulk or NSE 

levels. However, 2 of the 14 patients with 

relapsed SCLC had stabilization of their disease 

accompanied by improvements in respiratory 

symptoms for 8 and 15 weeks [68]. In a 

subsequent study, in which 13 patients with 

SCLC were treated with octreotide 200 Ìg s.c. 

t.i.d. for 1 week, a significant decrease in 

mean serum NSE levels from baseline values 

of 44.4 B 57.7 to 32.6 B 42 ng/ml was seen 

[139]. 

In a phase I dose-escalating study of octreotide 

and somatuline in the management 



of neuroendocrine tumors, 2 patients with 

SCLC were recruited to the somatuline arm. 

An objective tumor response was seen in 1 of 

these patients [140]. This was followed by a 

phase I dose escalation study in 18 patients 

with relapsing or resistant SCLC following 

treatment with standard cytotoxic chemotherapy. 

Patients received between 2 and 10.5 mg/ 

day of somatuline by continuous subcutaneous 

infusion. The agent was well tolerated 

with grade 1 or 2 diarrhea occurring in 8 

patients and pain at the site of injection 

requiring a change in infusion site in 3 patients. 

A mean reduction of 17% in IGF-1 levels 

was seen. The relationship between the 

dose of somatuline administered and the reduction 

in IGF-1 levels was statistically significant, 

higher doses being more potent in this 

regard (p ! 0.01). By day 28 disease progression 

was seen in all 15 patients evaluable for 

tumor response and therefore treatment was 

discontinued [141]. 

Finally, the efficacy of octreotide has been 

studied in a number of SCLC patients with 

syndromes related to ectopic hormone secretion. 

Octreotide 100 Ìg s.c. was evaluated in 

2 patients with SCLC tumors and Cushing’s 

syndrome secondary to ectopic ACTH release. 

In both cases a paradoxical increase in 

plasma ACTH and cortisol levels was seen. 

One patient went on to have treatment with 

a slow release preparation of somatuline. 

Following intramuscular depot injection of 

30 mg of somatuline a rise in ACTH and cortisol 

levels similar to that seen with the octreotide 

challenge was found [142]. The 

cause for this remains unknown but raises 

the possibility that, in certain cases, somatostatin 

analogs may have a stimulatory rather 

than inhibitory effect on the tumor as suspected 

in one study in patients with prostate 

cancer [143]. 

Finally, as is the case for patients with neuroendocrine 

GEP and medullary thyroid tu- 


mors, somatostatin analogs may have a role to 

play in the management of SCLC-related paraneoplastic 

diarrhea [144]. 

Management of Bronchial Carcinoid 

As outlined earlier, [ 111 In]pentetreotide 

imaging has an important role in the detection 

and staging of patients with bronchial carcinoid 

tumors including those presenting with 

ectopic hormone syndromes including Cushing’s 

syndrome and acromegaly [103–112]. In 

1988, 2 patients with bronchial carcinoidassociated 

Cushing’s syndrome were treated 

with octreotide to see if this could induce a 

reduction in circulating ACTH levels and an 

improvement in symptoms. Octreotide 50 Ìg 

s.c. stat produced a 50% reduction of ACTH 

in 1 patient whilst the other was maintained 

in a clinical and biochemical remission for 10 

weeks with octreotide 100 Ìg s.c. t.i.d. [145]. 

Subsequent reports indicate that, in the majority 

of cases, octreotide is an effective agent 

in the management of bronchial carcinoidrelated 

ectopic hormone syndromes providing 

palliation not only in Cushing’s syndrome 

but also for ectopic GHRH-related acromegaly 

[111, 113, 146, 147]. 

A recent case study reported the evaluation 

of octreotide in the treatment of a patient with 

multiple cerebral metastases from a bronchial 

carcinoid. Neurologically, the principal symptom 

was expressive dysphasia. Treatment 

with octreotide, initially in combination with 

a corticosteroid, resulted in disease stabilization 

for 6 months. During that time the patient’s 

symptoms resolved [148]. 

However, ACTH does not fall in response 

to octreotide in all cases [149, 150]. Therefore, 

an octreotide challenge may have a role 

to play in determining whether or not somatostatin 

analogs would be of value in controlling 

ectopic hormone syndromes in lung 

cancer [99, 151]. 

There are now a number of case reports 

where ACTH-secreting bronchial carcinoid 

tumors have been localized leading to subsequent 

curative resection of the disease [105– 

107]. Indeed radioguided surgery employing a 

peroperative probe may facilitate complete 

tumor excision whilst, at the same time, reducing 

the extent of resection by clearly separating 

involved from uninvolved tissues 

[113]. 

Somatostatin analogs are well tolerated, 

transient diarrhea, steatorrhea, colicky abdominal 

pain and borborygmi being the most 

commonly observed problems. Other side effects 

of somatostatin analog therapy include 

pain at the injection site, glucose intolerance 

and gallstone formation. Although very rare, 

severe complications may occur including allergic 

reactions varying from skin rashes to 

anaphylaxis, acute pancreatitis and hepatitis. 

Somatostatin may also have a negative inotropic 

effect on the heart [28, 152, 153]. 

Future Directions 

Enhancing the Efficacy of Cytotoxic 

Agents 

Experimental evidence clearly demonstrates 

that somatostatin analogs may potentiate 

the cytotoxicity of a range of chemotherapeutic 

agents. Studies in vitro and in vivo in 

animal models and in patients have shown 

that somatostatin analogs may enhance the 

antitumor efficacy of 5-fluorouracil while reducing 

the incidence of known side effects 

such as neutropenia and diarrhea [154–159]. 

Using 19 F nuclear magnetic resonance spectroscopy, 

octreotide has been shown to increase 

the formation of fluorouridinephosphates 

from 5-fluorouracil in human colon 

HT-29 adenocarcinoma cells. Furthermore, 

while 5-fluorouracil arrests cells in 

the S phase, cotreatment with octreotide al- 


Steward

most eliminates the S phase cells and induces 

the appearance of DNA fragments [160]. 

Perhaps of greater interest is the finding 

that the somatostatin analog octreotide has 

been shown to synergistically enhance the antitumor 

effects of mitomycin C, doxorubicin 

and paclitaxel in AR42J pancreatic cancer 

cells in vitro suggesting that somatostatin may 

have a role to play in overcoming multidrug 

resistance. Combination therapy with doxorubicin 

and octreotide has been studied in 

vivo for time dependency and efficacy. Pretreatment 

with octreotide for 24 h prior to 

addition of doxorubicin results in additive 

antitumor activity while pretreatment with 

doxorubicin is associated with clear synergy 

[159]. With specific reference to lung cancer, 

somatuline has been shown to enhance the 

cytotoxic activity of cyclophosphamide in 

SCLC both in vitro and in vivo [161]. These 

results raise the possibility that somatostatin 

analogs may enhance the antitumor activity 

of Adriamycin, mitomycin C, cyclophosphamide 

and paclitaxel-containing regimens in 

lung cancer [3, 4]. Evidence to support this 

observation comes from a phase II study in 

prostate cancer. A number of patients initially 

treated with octreotide received chemotherapy 

at disease progression. A high response rate 

above that normally expected for cytotoxic 

chemotherapy alone was seen [143]. 

The synergy between cytotoxic agents and 

somatostatin analogs in vivo may in part be 

due to the known antiangiogenic activity of 

somatostatin analogs. This suggestion is supported 

by a number of studies where the combination 

of known antiangiogenic drugs with 

cytotoxic chemotherapeutic agents has additive 

antitumor activity in solid tumors. For 

example, the antiangiogenic agent TNP-470, 

a derivative of fumagillin, and minocycline, 

an inhibitor of collagenase IV activity, potentiate 

the cytotoxic effects of cyclophosphamide 

in the treatment of Lewis lung carci- 



noma and murine FSaIIC fibrosarcoma. The 

combination of both antiangiogenic agents 

with cyclophosphamide is additive [162]. 

As discussed earlier, tumor angiogenesis is 

an important prognostic factor in surgically 

resected, stage I and II, NSCLC [138]. Platelet-derived 

endothelial cell growth factor 

overexpression (PD-ECGF) is observed in approximately 

20% of NSCLC tumors and correlates 

with increased tumor angiogenesis. 

PD-ECGF is thymidine phosphorylase, an 

important enzyme in the pathway leading to 

the conversion of 5-fluorouracil to its active 

metabolites including 5-fluoro-2)-deoxyuridine-5)-monophosphate 

[163]. Taken together, 

the growth inhibitory effects on NSCLC 

xenografts, the antiangiogenic activity and the 

modulation of 5-fluorouracil metabolism by 

somatostatin analogs suggest a role for the 

combination of 5-fluorouracil or other fluoropyrimidine 

analogs with RC-160 in the treatment 

of NSCLC. 

Early phase II studies suggest that the combination 

of octreotide with tamoxifen may be 

effective in the treatment of patients with 

pancreatic cancer [164]. Tamoxifen has been 

shown to enhance the antitumor activity of 

cisplatin [165]. Cisplatin is the principal cytotoxic 

agent in the management of NSCLC 

[166]. These data indicate that somatostatin 

analogs, with or without tamoxifen, should be 

evaluated in combination with cytotoxic regimens 

– platinum agents, the taxanes, ifosphamide, 

mitomycin C, vinca alkaloids, and 

antimetabolites, such as the fluoropyrimidines 

and gemcitabine – in the treatment of 

NSCLC [4, 166, 167]. 

A number of cytotoxic agents have been 

coupled to somatostatin analogs with encouraging 

results both in vitro and in vivo. Methotrexate 

has been linked, through the 7-carboxyl 

group of its glutamic acid moiety, to the free 

phenylalanine amino acid of the octapeptide 

somatostatin analog, RC-121. This analog, 


termed AN-51, has antitumor activity in vivo 

against the SSTR-expressing human pancreatic 

cancer cell line Mia PaCa-2 [168]. Cytotoxic 

analogs of somatostatin-containing 

potent anthracyclines have recently been developed. 

The superactive doxorubicin derivative, 

2-pyrrolinodoxorubicin, has been linked 

to RC-121 and RC-160 yielding AN-238 and 

AN-258, respectively [169, 170]. These agents 

have shown promising antitumor activity in 

vitro and in vivo in a number of SSTR-positive 

solid tumors including breast, prostate, 

pancreatic, gastric and lung cancer. The possibility 

of specifically targeting such agents to 

SSTR-rich lung tumors in patients holds 

promise for the future. 

Adjuvant Therapy 

A recent overview meta-analysis indicates 

that adjuvant chemotherapy, established in 

the management of resected breast and 

Dukes’ C colorectal cancer, may have a role to 

play in NSCLC. Recent in vivo work indicates 

that wound healing following surgical 

wounding of normal tissues may stimulate the 

growth of malignant disease even if the primary 

has not been removed. This suggests that 

wound healing itself results in the induction 

and release of trophic factors that have systemic 

proliferative effects [171]. Application 

of a somatostatin analog to the wound within 

1 h of surgery significantly reduces the induction 

of tumor growth seen otherwise [172]. As 

such somatostatin analogs may have a role to 

play in the adjuvant treatment of surgically 

resected lung tumors in the immediate postoperative 

period. 

Chemoprevention 

As discussed earlier, IGF-1 is a potent trophic 

and survival factor and plays an important 

role in cell transformation for many normal 

epithelial cells. IGF-1 acts through the 

IGF-1R. The central role of IGF-1R in the 

transformation of many cell types is best illustrated 

by the effects of disruption of the IGF- 

1R signal transduction pathway. This reverses 

the transformed phenotype and/or inhibits tumorigenesis 

and/or induces loss of metastatic 

potential in human lung, breast, ovarian and 

melanoma tumor models amongst others 

[173]. Support for a central role for IGF-1 in 

the development of malignant disease comes 

from the observation that acromegalic patients 

are significantly more likely to develop 

malignant disease than the general population 

[174]. Furthermore, in two recently published 

prospective studies, high normal IGF-1 levels 

were associated with an increased relative risk 

for the development of prostate cancer in men 

(4.3) and breast cancer in premenopausal 

women (7.28 in premenopausal women aged 

!50 years, when adjusted for IGF-binding 

protein 3 levels) [175, 176]. 

The effects of somatostatin analogs on 

carcinogenesis have been evaluated in vivo. 

Fisher 344 female rats were initially exposed 

for 4 weeks to the initiator carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine 

in drinking 

water. They were then exposed to the promotor 

carcinogen mitomycin C intravesically 

for 12 weeks with or without concomitant 

subcutaneous somatostatin analog therapy. In 

the untreated group 34 rats developed transitional 

cell carcinoma. However, in the 20 rats 

treated with the octapeptide somatostatin 

analog RC-160 only 1 in situ carcinoma was 

observed [177]. Subsequent studies demonstrated 

that RC-160, infused at 2 Ìg/day 

for 14 days, significantly inhibited the progression 

of 0.5% 9,10-dimethyl-1,2-benzanthracene 

(DMBA)-initiated premalignant 

lesions in the buccal pouch of Syrian golden 

hamsters, as measured by Photofrin-induced 

fluorescence using in vivo photometry and 

histological evaluation of the lesions [178]. 

Groups of animals also had 0.5-cm incisions 

made in one cheek over the carcinogen-ini- 


Steward

tiated area by CO2 laser, a cancer promotor. 

The development of squamous cell carcinoma 

in these animals was likewise inhibited by 

RC-160 therapy. 

Further work analyzing kinase activity in 

DMBA-induced premalignant and malignant 

lesions demonstrated that phosphorylation 

increases continuously in a linear fashion 

from the first application of DMBA. This is 

independent of stimulation by growth factors 

such as EGF. RC-160 reduces phosphorylation 

in vitro at weeks 6–10 after DMBA application 

to the premalignant lesions and week 

12 after DMBA application to the malignant 

tissues. The results suggest that one of the 

principal pathways of the inhibitory action of 

RC-160 on carcinogenesis is through activation 

of phosphotyrosine phosphatase activity 

and that this in turn is secondary to enhanced 

kinase activity [179]. 

These findings suggest that somatostatin 

analogs through the sustained suppression of 

IGF-1 levels [28, 180, 181] and through the 

inhibition of cell signal transduction pathways 

[10–18, 19–23] may have an important 

role to play in the chemoprevention of solid 

tumors including lung cancer. 

Conclusion 

Lung cancer is a plague of the late 20th century 

and will remain one of the prinicipal 

health issues well into the next century even if 

cigarette smoking stopped tomorrow. Despite 

progress in the diagnosis and treatment of 

lung cancer, with improvements in surgical 

techniques and the development of effective 

radiotherapeutic and chemotherapeutic regimens, 

the overall prognosis is appalling and 

novel approaches to treatment are urgently 

required if a significant impact is to be made 

on overall survival. 



The precise role for somatostatin analogs 

in the evaluation and treatment of lung cancer 

remains to be defined. SSTR may be expressed 

by lung tumors, particularly SCLC 

and bronchial carcinoid disease. Scintigraphic 

imaging with [ 111 In]pentetreotide 

may play a role in the clinical evaluation of 

neoplastic lung disease both before and following 

treatment, and in detecting relapsed 

disease. 

The potential role of somatostatin analogs 

linked to radiotherapeutic isotopes in the 

management of SCLC is currently being explored. 

Cytotoxic somatostatin analogs containing 

2-pyrrolinodoxorubicin have shown 

encouraging antitumor activity in a range of 

solid tumors including breast and prostate 

cancer. These analogs, including AN-238 and 

AN-258, hold promise as future therapeutic 

agents in the treatment of lung tumors. 

Somatostatin analog therapy inhibits the 

growth of SSTR-positive and SSTR-negative 

lung tumors in vivo. Furthermore, experimental 

evidence suggests that somatostatin 

analogs may enhance the efficacy of a range of 

chemotherapeutic agents in the treatment of 

solid tumors, including cisplatin, the anthracyclines 

and the taxanes. Based on the encouraging 

preclinical data we have set up a phase 

I/II study evaluating increasing doses of octreotide 

in combination with standard chemotherapy 

in the treatment of SCLC. Similar 

studies are indicated for NSCLC. 


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Steward


Octreotide in the Management of 

Hormone-Refractory Prostate Cancer 

Iraklis G. Vainas 

Department of Endocrinological Oncology, Theagenion Cancer Center, Thessaloniki, Greece 

Key Words 

Prostate cancer, hormone-refractory W 

Octreotide W Antiandrogen blockade, 

complete W Hormonal maneuvers, alternative 

Abstract 

Patients with advanced or metastatic prostate 

cancer (PC), a partially hormone-resistant 

disease, will require some form of hormonal 

manipulations or some new therapeutic 

modalities. Octreotide, as somatostatin 

(SST) analogs, has been found to inhibit 

the growth of experimental PCs via several 

mechanisms, as indirect antihormonal and 

direct antimitogenic actions, mainly due to 

inhibition of SST receptor subtypes (SSTR-1– 

5). Sporadic clinical trials with octreotide 

(alone or with a complete antiandrogen 

blockade) treatment of patients with advanced 

stage D2 PC demonstrated promising 

results. Unfortunately, at present these clinical 

trials have some disadvantages and leave 

some uncertainty with regard to the trial design, 

the SSTR subtype determination and 

tumor localization with SSTR scintigraphy 

ABC 

Fax + 41 61 306 12 34 




0009–3157/01/0478–0109$17.50/0 



before the start of a selective SST analog, 

and finally the randomization in groups according 

to hormone resistance, dosage regimen 

and route of administration. 

Epidemiology 

Dr. Iraklis Vainas 

Theagenion Cancer Center 

2, Al. Simeonidis Street 

GR–54007 Thessaloniki (Greece) 

Tel. +30 31 82 92 12, Fax +30 31 84 55 14 


Prostate cancer (PC) is the most common 

cancer in males and is secondary in incidence 

only to breast cancer as the most common 

type of hormone-dependent neoplasm in the 

USA. In Europe it accounted for 20% of all 

newly diagnosed cancers in 1990 and for 

160,000 patients only in 1993 [1]. Furthermore, 

PC is the second most common cause 

of death due to cancer in men, with 35,000 

deaths in 1993. Thus, it had been suggested 

that PC will become the leading cause of cancer 

death in men by the year 2000 [2]. In more 

than 50% of patients the disease is only diagnosed 

at a late stage, usually in men between 

the ages of 45 and 67, when it has already 

spread to distant sites, particularly to the 

bone, and at a time when most men have their

highest level of social responsibilities [3]. 

Thus, advanced-stage PC is a significant 

health problem in the male population. 

Natural History – Clinical Course of 

the Disease 

The natural history of PC should be reflected 

by its stage, describing the burden and 

the extent of the tumor at the time of diagnosis 

[1]. All staging maneuvers (Whitemore- 

Jewett or Tumor Node Metastasis system) 

determine if the disease is widespread or confined 

to the prostate, but understaging is a 

great problem clinically. 

The natural history of stage A1 PC remains 

unclear, because 16% of the patients will progress 

3.5–8 years after the initial diagnosis, 

and 61% actually have stage A2 or diffuse disease. 

Stage A2 or B1–3 PC patients treated 

with radical prostatectomy may have an 

equivalent risk for disease spread and death 

from PC [4]. Advanced-stage disease (C, D1, 

D2) will be identified in more than 40% of 

these cases [5]. About 60% of the patients 

with untreated stage C PC will exhibit evidence 

of disease progression at 5 years, at 

rates of 10–20% annually [5–7]. 85% of the 

patients with stage D1 PC demonstrate a disease 

progression within 5 years of diagnosis 

[5, 8], although diploid tumors have a biologically 

indolent course [9]. Finally, stage D2 PC 

patients (with distant metastases) have a median 

survival of about 30 months with a 20% 

5-year survival rate. 

Endocrinological Aspects 

The role of testicular androgens in the evolution 

of PC has been recognized since 1941 

[10]. Since then surgical castration or treatment 

with estrogens has been reported to 

110 Chemotherapy 2001;47(suppl 2):109–126 Vainas 

result in subjective-objective improvement in 

60–80% of patients, due to neutralization of 

androgens, but for limited time intervals. The 

endocrine relationship between the testis, hypophysis 

and hypothalamus is shown in figure 

1. Ninety percent of the circulating androgen 

pool in the normal male is derived from 

the testes and 10% from adrenal cortex 

sources, regulated by the hypothalamus (via 

CRF) and directly by the pituitary (via 

ACTH) [11]. The prostate gland has androgen 

receptors, so the circulating testosterone (T) is 

rapidly internalized into its cytosol and its 

receptors, and converted to dehydro-T (DHT) 

by the enzyme 5-reductase. DHT is 3 times 

more potent than T, with T being 5–10 times 

more potent than adrenal androgens [12]. 

DHT, from testicular or adrenal sources, is 

the primary (growth-promoting) intracellular 

messenger in androgen-responsive target cells 

and is internalized into the nucleus, where an 

mRNA clone is transcribed, which ultimately 

effects translation of androgen-dependent 

proteins, necessary for cellular existence [12, 

13]. 

Current Therapeutic Approach in PC 

General Therapeutic Considerations 

As a general therapeutic strategy, patients 

with localized stages A and B PC will be managed 

by local external radiotherapy (ER) or 

radical prostatectomy [4]. In contrast, stage D 

(T3N0–3M0–1) disease is associated with systemic 

spread and should be treated with systemic 

cytostatic therapy. Node-positive PC 

(D1) is also associated with systemic disease, 

and therefore does not respond to ER or radical 

prostatectomy treatment, but can be controlled, 

at least for some time, with systemic 

therapy, in particularly early androgen deprivation. 

The therapeutic strategy for stage C3 

PC (large volume local disease) is similar,

Fig. 1. Endocrine relationship between hypothalamus, pituitary, testis, adrenal and prostate 

gland. Hormonal therapies in advanced PC. LHRH = Luteinizing hormone-releasing hormone; 

CRH = corticotropin-releasing hormone; LH, FSH = luteinizing and follicle-stimulating 

hormone; ¢4-dione = androstenedione; DHEA = dehydroepiandrosterone; T = testosterone; 

DHT = dihydrotestosterone; AR = androgen receptor. 

which cannot be controlled by local therapies. 

The decision for stage C1–2 (local extension) 

is more complex, combining local radiotherapy 

and androgen deprivation [11]. 

Specific Therapeutic Modalities for 

Advanced PC 

Advanced or metastatic PC is a partially 

hormone-resistant disease, which needs systemic 

therapy from the outset. Adjuvant ER is 

attempted but is associated with undesirable 

side effects (13% bowel obstruction or severe 

cystitis or urethra strictures) and the longterm 

benefit of radiotherapy has yet to be 

demonstrated. Major surgical therapies (other 

than radical prostatectomy) such as cystoprostatectomy, 

total pelvic exenteration, or 

salvage surgery do not achieve a complete 

resection of the tumor either, nor do they 

delay the progression of the cancer or prolong 

survival [14]. These procedures are also risky 

being associated with a high incidence of postoperative 

incontinence. Almost all stage C 

and D PC patients will require some form of 

hormonal manipulations, vitamin therapy, 

immune modulation, cytostatics or some new 

therapeutic modalities [11]. 

Surgical or chemical castration or estrogens 

are the first and main endocrine therapies 

for patients with advanced PC (table 1). 

These treatments have similar efficacies with 

respect to survival, relief of symptoms and the 

prevention of metastatic spread [12, 15]. 

However, androgen deprivation may result in 

Octreotide and Prostatic Carcinoma Chemotherapy 2001;47(suppl 2):109–126 111

Table 1. Conventional hormonal manipulations in 

advanced PC 

Castration 

Surgical (orchidectomy, hypophysectomy) 

Chemical (LHRH analogs, estrogens) 

Antiandrogens 

Gestagenic compounds (cyproterone acetate) 

Pure nongestagenic compounds (flutamide, 

nilutamide, Casodex) 

Progesterone compounds 

(medroxyprogesterone, megestrol) 

Adrenal corticolytic agents 

Aminoglutethimide 

Ketoconazole 

Ablative hormonal manipulations 

Hypophysectomy 

Adrenalectomy 

CAB 

Castration + antiandrogens 

Table 2. Recent hormonal therapies in advanced PC 

(under research) 

Reductase inhibitors (finasteride) 

LHRH antagonists 

Specific SST analogs with high antitumor activities 

LHRH analogs with cytotoxic radicals 

Bombesin/GRP antagonists 

CAB + chemotherapy 

CAB + suramin 

CAB + synthetic retinoids 

Chemotherapy following androgen priming 

Specific radiolabeled ( 123 I, 131 I, 111 In) SST analogs 

(with ß-emitting radiation) 

unpleasant largely minor side effects (loss of 

libido, flushes, gynecomastia, impotence), but 

some are also serious (mainly due to estrogens), 

as the 7–11% incidence of thromboembolic 

and cardiovascular complications [14]. 


Adrenal corticolytic agents (aminoglutethimide, 

ketoconazole), synthetic progesterone 

compounds (megestrol, medroxyprogesterone) 

and nonsteroidal pure antiandrogens 

(flutamide, nilutamide, Casodex) appear to be 

beneficial as palliative therapy in 20% of patients, 

but with a high percentage of side 

effects [12]. Complete androgen blockade 

(CAB) combines surgical or chemical castration 

with a pure antiandrogen, and eliminates 

both testicular and adrenal androgens in PC 

patients [11, 16]. Labrie et al. [16] found complete 

response rates of 29% at 22 months compared 

to the 5% response rate usually associated 

with monotherapies; similar results were 

reported by Navartil’s group in France with 

70% response rates following surgical and 

chemical castration at 18 months versus 45% 

with monotherapies. In a large multicenter 

trial in the USA of 603 metastatic PC patients, 

CAB showed a longer disease-free survival 

than either drug alone and had a survival 

advantage of approximately 7 months, particularly 

among the 82 patients with a good 

performance status and with minimal disease 

[17]. Thus, the CAB has some advantage, the 

side effects are no more than with each drug 

alone, but the cost of the combined treatment 

is very high. 

Other Therapeutic Modalities 

PC is a biologically heterogeneous tumor, 

with an increasing number of hormone-resistant 

cell populations at late stages [18]. Thus, 

hormone treatment alone does not appear to 

be an effective long-term (or even curative) 

therapy. Unfortunately, the efficacy of several 

alternative modes of systemic drug treatment, 

including chemotherapy alone [19] or combined 

with hormone therapy or following androgen 

priming [20], suramin [21], or natural 

synthetic retinoids [22], has yet to be determined. 

Alternative endocrine treatment (table 

2) with LHRH antagonists, bombesin an-

tagonists or LHRH analogs with cytotoxic 

radicals, or recently with somatostatin (SST) 

analogs are still at the research stage [23, 24]. 

Somatostatin and Somatostatin 

Analogs in the Treatment of 

Metastatic PC 

Introduction 

Natural or synthetic somatostatin (SST- 

14) has numerous exocrine/endocrine antisecretory 

effects on a variety of systems [25– 

27]. In addition SST-14 also acts as an endogenous 

growth inhibitor [28]. The growth 

inhibitory effects of the hormone have been 

documented in multiple experimental and 

human benign and malignant tumors [26], 

such as hypophyseal [25], endocrine pancreatic 

[29], ectopic and various solid tumors 

[30]. SST-14 has, therefore, nonselective, 

multiple actions, and a short duration 

of antisecretory or antitumor effects, because 

of its short biological half-life (1–2 min). 

Consequently SST analogs have been designed 

and synthesized, which are more resistant 

to metabolic degradation and have a 

more prolonged duration of actions [29, 30]. 

Due to substitutions and incorporation of Damino 

acids into the SST molecule, the resistance 

of SST analogs to digestion by tissue 

enzymes is increased [26, 31]. For example, 

9 of the 14 amino acids were replaced with a 

single proline residue to produce a long-acting 

analog of somatostatin [32, 33]. Veber et 

al. [33] retained the sequence 7–10 of SST- 

14 (Phe-Trp-Lys-Trp) as essential for the 

biological activity of native somatostatin, 

and incorporated the Trp residue into the D 

configuration (series of cystine-bridged SST 

analogs). Octreotide (SMS 201-995), an SST 

analog produced by Sandoz, has a longer duration 

of action (up to 113 min), is more 

potent than SST-14 (40–70 times) and is 

more selective for hGH suppression than insulin 

or glucagon [33, 34]. 

Although the greater potency of SST analogs 

is only due to resistance to degradation by 

enzymes and to their prolonged half-lives, 

there is some doubt about the selectivity of 

the analogs, unless the tissues express the 

receptor subtypes, to which they bind with 

approximately equal efficacy as the native 

hormone. The five cell surface SST receptor 

(SSTR) subtypes have been characterized 

within the past 5 years and have been termed 

SSTR-1 through SSTR-5 according to the 

chronology of their discovery. The tissue distribution 

of the SSTRmRNAs (by Northern 

blotting, RT-PCR and in situ hybridization) 

showed that SSTR-1smRNA and 

SSTR-2smRNA occur in central as well as 

peripheral tissues (stomach, jejunum, colon 

and pancreatic islets), while SSTR-3smRNA 

and SSTR-4smRNA are limited to brain and 

endocrine pancreas [35–38]. The SSTR-5smRNA 

is present in the pituitary and a variety 

of peripheral tissues including the small 

intestine [39]. SST-14 (as SST-28) binds to 

all SSTRs with affinities ranging from 0.2 to 

2.6 nM, but SST-28 shows a 10- to 20-fold 

higher affinity for SSTR-4 and SSTR-5. 

SMS 201-995 (Sandostatin) has 3- and 10fold 

higher affinities for SSTR-2 and SSTR-4, 

and a much lower affinity for the SSTR-1, 

SSTR-3 and SSTR-5 subtypes. Other SST 

analogs, such as MK-618, CGP-23996 and 

BIM-23014, bind mainly to SSTR-3, while 

CGP-23996 also binds to SSTR-5 with high 

affinity. 

These different affinities of SST-14 and 

SST-28 to the SSTR subtypes, which are consistent 

with tissue location of the SSTR subtypes 

and with their relative potency, suggest 

different functional properties for the various 

SSTRs [40]. However, the overlapping of the 

distribution of these five SSTR subtypes 

makes the ascription of a given physiological 


Table 3. Antitumor effects of modern octapeptide 

analogs in various animal or human cancers 

SCLC cell lines 

Dunning PC in rats 

Ductal pancreatic cancers in hamsters 

Human exocrine pancreas cancer 

Human PC 

Human breast cancer 

Human lung cancer 

Bladder cancer 

Carcinoma of the colon 

Primary brain tumors 

function to a specific SSTR subtype difficult. 

In this respect, the availability of long-acting 

and relatively specific SST analogs would be 

of crucial interest. In particular, the SSTR-2 

agonist octreotide and other modern SST 

analogs, besides their antisecretory effects on 

gastric, pancreatic and intestinal secretions, 

were reported (1) to inhibit in vitro and in 

vivo cultured tumor cell growth, (2) to enhance 

cell apoptosis, and (3) to activate cell 

cycle-regulated phosphatases at the cytoplasmic 

and nuclear levels [40]. Subsequently, 

Schally et al. [30] synthesized (1) nearly 300 

octapeptide analogs with disulfide linkages, 

using also a C-terminal amide, (2) slow release 

preparations for intramuscular injections 

once monthly [27], and finally (3) new, 

modern SST analogs (RC-95-1, RC-121, RC- 

160-II), by incorporation of Tyr and Val in 

position 3 and 6 (corresponding to residues 7 

and 10), with high antitumor activities [41, 

42]. The specific antitumor activities of the 

modern octapeptide analogs have been studied 

in various animal and human tumors (table 

3). SST analogs, and especially octreotide, 

are well tolerated and have a favorable riskbenefit 

ratio, even in overdosage regimens 

with 3,000 Ìg/daily [43]. The observed main 

side effects were facial flushing, headache, 


nausea, vomiting, abdominal cramps, abdominal 

bloating and/or flatulence, steatorrhea 

and cholelithiasis [31, 43]. Although side effects 

of the octreotide treatment are usually 

mild, there is also the possibility of them 

being serious, fortunately in a minority of 

patients. Thus, occasionally steatorrhea may 

be serious enough to discontinue octreotide 

treatment, despite injecting octreotide between 

meals or giving pancreatic enzymes 

during the meals [24, 31, 43]. High-dose octreotide 

treatment may reduce gut motility 

and lead to more serious abdominal side effects 

mimicking gut obstruction and ileus 

[43]. Complications of the octreotide treatment, 

such as heavily symptomatic cholecystitis 

or acute pancreatitis, have been rare, but 

we observed them in 2 patients [24], which 

has also been observed by others [44–46]. 

Actual liver cell damage, pulmonary dysfunction 

and serious anaphylactoid reactions are 

some other very rare, worrying side effects of 

octreotide treatment [43]. 

Presence of SSTR in PC Cells 

Since 1986, low- and high-affinity SST-14 

receptors have been identified and measured 

in various experimental and human tumors, 

such as brain, pituitary, endocrine gastrointestinal, 

prostate, pancreatic, colon and ovarian 

tumors, as well as in SCLC cell lines [30, 

47–51]. The first studies have clearly shown 

the distribution of SSTRs in a wide variety of 

human tumors, but these SSTRs are localized 

in selected types of such tumors; for example, 

there is a very high incidence of high-affinity 

and specific SSTRs in meningiomas, in GRFproducing 

tumors, pituitary adenomas from 

acromegalics, but only in a small percentage 

of mammary cancers [48]. Interestingly, 

SSTRs are also present, often in high density, 

in tumors (e.g. meningiomas originating from 

tissue, arachnoidal cells of the human leptomeninx), 

without an established link to an

SSTR mechanism. The same is also true for 

mammary tumors; therefore, only tumorously 

transformed cells of breast cancer bear 

SSTRs, although it has never been shown that 

SST-14 plays a functional role in normal 

mammary glands. 

Specific SST-14 receptors of low affinity 

(1.3 Nm) and very high capacity (Bmax 543 

fmol/mg) were detected on Dunning R- 

3327H rat PC cell membranes [52]. Modern 

SST analog RC-160 decreased the weight and 

volume of this prostate tumor, when given 

combined with the LHRH analog. This effect 

was due to a significant suppression of the 

SSTR capacity, as well as of the capacity and 

number of PRL receptors. In contrast, Fekete 

et al. [53] did not find a binding capacity to 

SST-14 on the Dunning rat or on normal and 

tumorous human prostate cell membranes. 

Reubi et al. [54] using 125 I-(Tyr3)-octreotide, 

with in vitro receptor autoradiography 

techniques, suggested the presence of various 

SSTR subtypes on PC cells, expressing highaffinity 

receptors for SST-14 and SST-28, but 

low affinity for octreotide. Thus, human PC 

may be a target for SST therapy. However, 

SST analogues with different selectivities, 

particularly binding affinities, for SSTR subtypes 

cloned in PC would be required to 

achieve a response [55–57]. The cloning of 5 

SSTR subtypes, using in situ hybridization, in 

a large variety of human tumors initiated a 

number of studies on SSTR subtypes in PC 

[55]. Reubi et al. [55] first detected, via in situ 

hybridization studies, that PC preferentially 

expressed the SSTR-1 subtype compared with 

the SSTR-2 or SSTR-3 subtypes. Furthermore, 

the presence of SSTR-2- or SSTR- 

3mRNAs generally correlated with the presence 

of octreotide binding sites. It was 

pointed out that octreotide, which mainly 

binds to the SSTR-2 subtype, would not be 

the ideal SST analogue in the treatment of PC. 

In other words, octreotide will have no effect 

on PC (or other tumors), which express the 

SSTR-1, SSTR-3 and SSTR-4 subtypes, because 

it has little or no binding affinities for 

these receptors. Thus, especially SSTR-2 represents 

an SSTR subtype target for the development 

of more specific SST analogues with 

higher affinities to these receptor subtypes 

[55]. In contrast, Prevost et al. [58] demonstrated 

a 57-kD SSTR-2 subtype in all prostatic 

normal and tumoral tissues; thus, the 

SSTR-2 subtype probably represents the 

SSTR subtype target for the specific SST analogs. 

Sinisi et al. [59] also demonstrated with 

the PCR technique that the SSTR-1 subtype 

was expressed only in the epithelial cells of 

PC, the SSTR-2 only in the epithelial cells of 

normal prostate, while the SSTR-3 subtype 

was undetectable in normal and tumor epithelial 

cells, but the SSTR-4 and SSTR-5 subtypes 

were expressed in the epithelial as well 

as in the stromal cells of PC. Thus, there are 

differences between normal and tumoral samples 

in the SSTR expression in the human 

prostate epithelial and stromal cells in vitro 

[57, 59]. Because some SSTR-2-selective SST 

analogs (e.g. Sandostatin) are probably ineffective 

in the treatment of PC, this observation 

would suggest that the absence of SSTR-2 

could inhibit the growth and development of 

PC by analogs with a high binding for this 

receptor subtype. The three SSTRsmRNAs 

(1, 2 and 3) are expressed simultaneously not 

only in tumoral tissue but also in the host peritumoral 

vascular system; thus, some prostate 

tumor tissues bind octreotide due to a direct 

action on tumor cell SSTRs or through action 

on peritumoral vessels (due to SSTRs or 

growth factors), by altering the hemodynamics 

of the tumoral blood circulation [55]. 

The SSTR can be generally measured [60] 

using (1) biochemical techniques, i.e. binding 

assays on tissue homogenates in vitro, 

(2) autoradiography for visualization in tissue 

sections, (3) systemic injection of a radio- 


Fig. 2. Mechanisms of antiproliferative actions of SST-14 and SST analogs in advanced PC. 

chemical-coupled SST analog into normal 

subjects, which specifically labels SST target 

tissue and localizes it by a subsequent in vitro 

autoradiography and (4) in vivo visualization 

of SST receptor-positive tumors, with the injection 

of [ 123 I or 131 I]-coupled Tyr3- or 111 In- 

[DTPA]-coupled octreotide. Radiolabeled 

with 123 I, 131 I or 111 In SST analogs are synthesized 

for localization of prostate tumor and its 

metastases containing SST receptors, using 

scanning techniques [49]. In 8 of 31 biopsied 

patients with metastatic hormone-refractory 

PC, SST receptors were expressed both in 

vitro and in vivo, and visualized with the 

octreoscan technique [56]. SST analog RC- 

160 labeled with 99m Tc was shown to have a 

400% higher 24-hour tumor uptake compared 

with 111 In-DTPA-octreotide due to specific 

tumor binding sites in nude mice bearing 

experimental human PCs [61]. In contrast, 

111 In-DTPA-D-Phe1-octreotide scintigraphy 

identified only 3 of 7 patients with hormoneresistant 

PC who had the highest tumor to 

background ratio and responded to octreotide 


therapy [62]. The specific binding of a ß-emitting 

isotope-coupled SST analog to high-affinity 

membrane SSTR subtypes offers the opportunity 

to give brachytherapy to those tumors, 

which have the specific SSTR subtypes. 

Mechanisms of Antiproliferative Actions 

of SST-14 and SST Analogs in 

Advanced PC 

Five possible main antitumor actions of 

SST-14 and SST analogs have been discussed 

(fig. 2, 3). First, they inhibit secretory and 

hormonal effects on tumor growth. Prolactin 

acts as a cofactor on the growth of PC, alone 

as well as synergistically with GH [31, 32]. 

GH is of great importance for the suppression 

of various tumors, among them PC, in 

which GFs, such as IGF-1, are involved. Due 

to local production of IGF-1, GH directly 

promotes cell differentiation as well as indirectly 

clonal expansion [31]. Second, somatostatin 

and its analogs act as antimitogens 

synergistically with endogenous GFs (IGF-1

Fig. 3. Molecular basis of the antiproliferative actions of octreotide in advanced PC. 

and IGF-2, PDGF, FGF, TGF-· and TGF-ß), 

which are involved in proliferation and phenotypic 

transformation, or (directly) inhibit 

DNA synthesis and proliferation [63, 64]. 

Third, Sandostatin and its analogs have direct 

antiproliferative actions due to inhibition of 

SSTR, reversing the stimulatory effect of EGF 

(1) on phosphorylation of the tyrosine kinase 

portion of EGF receptors (EGF-R) and of 

tyrosine acceptor proteins, and (2) on cell 

growth [28]. EGF promotes phosphorylation 

of cell membrane proteins of 170 kD (as EGF- 

R) and of 60 kD (as does LHRH-R). SST 

analogs (RC-160, RC-121) combined with 

LHRH analogs can increase the activity of 

tyrosine phosphatases, thus nullifying the 

EGF effects on the activation of dephosphorylation 

of such membrane peptides [65, 66]. 

Fourth, somatostatin and its analogs inhibit 

(fig. 3) the production of oncogene products 

or the overexpression of protooncogenes, 

which act in the tyrosine kinase stimulatory 

pathway [61]. Oncogene products are similar 

to GFs or are aberrant GF receptors, which 

promote tumor cell growth. The protooncogene 

c-sis codes for the B chain of PDGF, 

while the viral oncogene erbB produces aberrant 

EGF-R [65]. Also, the EGF-R shares 

homology with erbB and c-erbB-2/new oncogenes 

[63, 67, 68]. Fifth, finally, SST-14 and 

some of its analogs have actions via specific 

SSTR on the peritumoral vessels [69], and are 

able to inhibit (due to FGF-related molecules) 

angiogenesis. Thus, another potentially therapeutic 

effect of somatostatin, octreotide and 

other analogs in vivo may partially depend on 

its suppressive action on tumor angiogenesis 

[70]. 


In vitro and in vivo Studies of the 

Antitumor Actions of SST-14 and 

SST Analogs in PC: 

Animal and Human Models 

Dunning R-3327H rats (with androgensensitive 

PC) were treated with modern SST 

analogs (Sandostatin, RC-160, RC-121) alone 

or combined with D-Trp6-LHRH analog or 

castration [71–74]. Final tumor volume, percentage 

change from initial tumor and final 

tumor weight were decreased due to the inhibitory 

effect of LHRH analog (or castration), 

effects which were potentiated by the 

superactive SST analogs, i.e. RC-98-I, RC- 

160, RC-121 [71–73]. Schally’s group [50] 

demonstrated with the so-called superactive 

SST analogs higher and more specific binding 

to human and rat prostatic adenocarcinomas 

as well as to human ovarian and several human 

pancreatic cancers. Thus, different SST 

analogs had to be developed for diagnostic 

and clinical use other than octreotide, since 

octreotide is mainly effective in hormonehypersecreting 

endocrine tumors, or in those 

with the specific (for octreotide) SSTR-2 subtype. 

The combination of [D-Trp6]-LHRH and 

RC-160 in rats or in nude mice bearing xenografts 

of the hormone-dependent human 

prostate tumor PC-82 has shown a greater 

inhibition of tumor growth than [D-Trp6]- 

LHRH or RC-160 alone [31, 75]. Sustained 

release formulations of SST analogs, such as 

Somatulin, also inhibited tumor growth after 

castration of male Copenhagen rats bearing 

Dunning R-3327H prostate tumors, but 

not in combination with LHRH analogs 

[73]. Male nude mice with PC-82 tumors, 

treated with slow-acting [D-Trp6]-LHRH agonist 

or LHRH antagonist (SB-75) or RC- 

160, showed greater tumor inhibition after 

treatment with SB-75, than with LHRH agonist, 

but no significant inhibition with 


RC-160 [76]. Combination therapy with SB- 

75 plus RC-160 achieved the best results, 

when it was started soon after the diagnosis 

of PC [77]. A decrease of IGF-1 and GH or 

a downregulation of EGF-R by RC-160 may 

improve the hormonal treatment of PC [75]. 

Androgen-independent human PC cell line 

(PC-3, DU-45, R3327-AT-1 PC) xenografts 

in nude mice treated with RC-160 plus a 

GRP antagonist (RC-3095) showed a significant 

growth inhibition, when the therapy 

was started at an early stage of tumor development 

[78–80]. SST-14 inhibited cell proliferation 

and protein secretion of the relatively 

indolent tumor LNCaP, probably mediated 

by the activation of phosphotyrosyl 

protein phosphatases [81]. Lanreotide, a 

slow-acting SST analog, applied topically to 

the surgical site on xenografts of human 

prostate tumors (PC-3, DU-145, H-1579) in 

athymic male rats, inhibited tumor proliferation 

[82]. 

Long-term exposure of cultured tumor 

cells (e.g. transplantable rat pituitary tumor 

7315b or PRL-secreting cell line 7315c) to 

octreotide led to a loss of sensitivity with 

respect to its inhibitory effects on tumor cell 

growth, as well as to its hormone-inhibitory 

effects [60]. These desensitized tumor cells 

have lost their SST receptors, which reappeared 

after the withdrawal of octreotide. 

Thus, the gradual decrease of the growthinhibitory 

action of octreotide during the 

long-term treatment may be caused by the 

desensitization of SSTR, and is not due to 

selection of receptor-negative cell clones. 

50% of all PCs have neuroendocrine (NE) 

cell populations with the presence of neurohormonal 

peptides (NSE, chromogranin, serotonin, 

·-HCG, SST-14, calcitonin, ACTH, 

ß-endorphin, and others). The incidence of 

NE differentiation in PC cells is higher in 

fresh than in formalin-fixed biopsy specimens 

[83]. Certain NE peptides such as bombesin

and VIP can increase the invasive potential of 

PC cells and may contribute to the rapid progression 

of PCs containing NE cell populations, 

and RC-160 did not alter the invasion 

of these PC-3 cells [84]. Thus, PCs appear to 

be more complex and heterogeneous than previously 

thought, exhibiting endocrine differentiation. 

PC cases with carcinoid tumor and 

hypercalcemia due to PTHrP [85, 86] and a 

case with Cushing’s syndrome due to CRHproducing 

PC [87] showed that these unusual 

PC cases with overexpression of NE differentiation 

may have major life-threatening effects, 

which are not significantly affected by 

octreotide treatment [86]. A review of the 

world’s literature on this topic suggested that 

PC cells with NE differentiation (1) allow 

screening for PC and/or monitoring for recurrence 

of PC, (2) are resistant to hormone therapy, 

and thus (3) show poorer prognosis and 

correlate directly with the tumor grade [75]. 

NE cells have a regulatory role in PC growth, 

and are prognostically useful in prostatic 

high-grade adenocarcinoma [1, 88, 89]. Only 

a partial correlation was observed between 

NE serum markers and immunohistochemical 

findings in 22 patients with PC [90]. Only 

chromogranin A showed a correlation (but 

not SST, NSE, chromogranin B, pancreastatin), 

being a useful serum marker in predicting 

the extent of NE differentiation in prostate 

tumors [91]. 

Certain PCs, which secrete somatostatin, 

are difficult to localize with the in vivo visualization 

technique with an isotope-labeled SST 

analog, because of a competition at their 

SST receptors. Two observations might in 

part explain this competition at the receptor 

levels with locally produced somatostatin: 

(1) the in vitro detection of SSTR could be 

improved after repeated additional wash procedures 

of the tumor samples, and (2) higher 

doses of octreotide are necessary in patients 

with such SST-producing PCs (with NE dif- 

ferentiation) in order to suppress tumor 

growth [60]. 

In summary, many experimental findings 

suggest that both indirect and direct effects 

may play a role in the tumor growth-inhibitory 

action of SST analogs. In particular, the 

early tumor growth-inhibitory effects of SST 

analogs are probably due to the inhibition of 

the tumor angiogenesis. Finally, the decrease 

of the tumor growth-inhibitory action over 

time is mainly due to the desensitization and 

downregulation of the tumor SSTR. 

Clinical Trials of the Treatment of 

Advanced Hormone-Refractory PC 

Introduction 

PC is often (60–80%) locally advanced or 

metastatic at diagnosis, making surgical removal 

and radiotherapy ineffective. Metastatic 

PC responds to normal hormonal manipulations, 

but once progression occurs new 

treatment modalities are required; at that 

time, specific and systemic antitumor therapy 

is better than local treatment, as ER. Alternative 

hormonal therapy involves androgen deprivation 

with surgical or chemical castration 

estrogens, antiandrogens, inhibitors of androgen 

metabolism or adrenal suppression. Complete 

androgen blockade may be a more superior 

hormonal treatment. PCs have initially 

androgen-dependent or androgen-sensitive 

and androgen-independent cell populations. 

Thus, in the later stages of PC a significant 

amount of tumor is androgen-independent, 

and needs alternative antiproliferative treatment. 

Additionally, advanced PCs have been 

noted to represent chemotherapeutically relatively 

nonresponsive tumors, with a median 

response rate of only 8.7% among 26 new 

drug trials during 1987–1991 [92]. Therefore, 

because of cytotoxic drug resistance, there is a 

need to develop new methods to overcome 


such resistance with new classes of antimitogen 

agents. Many SST analogs have been 

found to inhibit the growth of animal and 

human PC cells. 

Controlled Clinical Trials 

Sporadic clinical studies in patients with 

stage D2 PC (relapsed during treatment with 

flutamide plus castration) treated with SST 

analogs alone or combined with bromocriptine 

showed some advantage in tumor growth 

inhibition [93, 94]. Schally et al. [95] reviewed 

the hormone treatment of advanced 

PC with agonistic and antagonistic LHRH 

analogs or LHRH analogs linked to cytotoxic 

radicals, with very active SST analogs (SB-75, 

RC-160) or with bombesin/GRP antagonists. 

Thus, they tried to delay or prevent the relapse, 

and to improve the therapy of PC. Parmar 

et al. [96] treated 16 of 25 poor-risk 

patients with hormone refractory metastatic 

PC (failing to respond to total androgen 

blockade) with an SST analog BIM-23014. 2 

of these 16 patients showed partial response 

and 3 no change of the disease, with only a 

few side effects, such as mild diarrhea and 

abdominal cramps. In contrast, Sandostatin 

treatment of 24 patients with hormone-resistant 

PC with a dose of 100 Ìg ! 3 times/day 

for 6 weeks did not give any objective evidence 

of tumor regression, but only of tumor 

progression [97]. The author concluded that 

Sandostatin eventually stimulates PC growth, 

but may have sensitized tumor cells to subsequent 

chemotherapy, because salvage chemotherapy 

resulted in an objective tumor regression 

in 5 of 6 patients treated after progression. 

In a small group of 5 PC patients relapsing 

during hormonal treatment with rapidly 

increasing PSA levels, octreotide administered 

as a subcutaneous infusion, at a dose of 

400–1,000 Ìg/day for a period of 2–6 weeks 

offered only a moderate and temporary inhibition 

of PC growth [97, 98]. The author con- 


Table 4. Percentage and quality of response in 8 

responding stage D2 PC patients after the combined 

treatment of CAB plus octreotide 

Previous 

treatment 

Total 

patients 

Number 

responding 

Quality 

of response 

No 6 3 (50) 3 (oPR + sCR) 

Yes 8 3 (37.5) 

CAB 6 1 (16.5) 1 (oNC + sPR) 

iHT 2 2 (100) 1 (oPR + sPR) 

Total 14 6 (33) 

Figures in parentheses represent percentage. iHT = 

Incomplete hormone treatment; CR = complete response; 

PR = partial response; NC = no change; o = 

objective; s = subjective. 

cluded that more specific SST analogs may 

give better results possibly in higher doses, 

alone or in combination with LHRH agonists 

or antagonists. Slow-acting SST analog (Somatulin) 

in continuous intravenous infusion 

and in a dose escalation trial, administered to 

patients with advanced metastatic hormonerefractory 

PC, was well tolerated but no clinical 

responses were noted, even with the highest 

doses of 24 mg/day [99]. Somatulin treatment 

should be evaluated in less advanced 

PCs, or in combination with other antiproliferative 

agents. 

In the Theagenion Cancer Center my collaborators 

and I evaluated (in total) 18 carefully 

selected patients with advanced stage D2 

PC and treated 14 of them with a combined 

treatment of CAB (castration or triptorelin 

plus flutamide) plus octreotide (Sandostatin), 

in doses of 0.2 mg ! 2 times/day, s.c. for at 

least 12 months [24]. 3 of 6 patients without 

previous hormone treatment (50%) showed 

the best response (objective partial plus subjective 

complete response). Among the 8 patients 

previously treated with hormone only 3

Table 5. Natural history and follow-up of all 18 stage D2 PC patients after the treatment with CAB plus octreotide 

or CAB alone 

n Age 

years 

Histology 

Diff. Inv. 

Duration 

of R 

months 

Survival, months 

DFS total 

Deaths Cause of death 

AHA HF Dis. 

CAB 

4 

R 2 79 2 (high) 012 12 18 1 – – 1 

NR 2 71 2 (low) 0– 02 2 1 1 – 

Octreotide + CAB 14 

R 6 68 5 (low) 1 17 17 18.5 5 1 – 4 

NR 8 68 8 (low) 3 – – 4.5 8 2 2 4 

R = Response; NR = no response; Diff. = differentiation; Inv. = invasive; DFS = disease-free survival; 

n = number; AHA = acute heart attack; HF = heart failure; Dis. = disease. 

(37.5%) responded poorly to this treatment 

regimen (2 with no change and 1 with a partial 

objective response plus a partial subjective 

response) (table 4). The total response rate 

was 33% with a mean disease-free survival of 

17 months compared to 12 months when 

CAB was given alone (table 5). Total mean 

survival was similar for the two therapy 

groups. IGF-1 and EGF serum levels during 

the combined treatment (with the addition of 

Sandostatin) decreased significantly in all responding 

patients, and corresponded to the 

drop in PSA levels, or eventually in prostatic 

acid phosphatase serum levels. These observations 

suggest that PSA and prostatic acid 

phosphatase levels as well as IGF-1 and EGF 

serum levels may be useful as a marker of SST 

analog therapy in advanced PC. 

Octreotide has a consistent and persistent 

suppressive effect on hormone release (for 

example in acromegaly), without the occurrence 

of therapy escapes. However, there are 

some escapes from the antineoplastic therapy 

of tumors. Thus, an escape from therapy occurs 

through the development of SSTR-negative 

tumor cell clones, or due to an early 

insensitivity of hormonal secretion, related to 

downregulation of the SST receptors on these 

tumors. This downregulation can be restored 

after interruption of octreotide treatment. Additionally, 

a continuing sensitivity of hormone 

secretion to octreotide with a simultaneously 

progressive tumor growth may need 

an increase in the dose of octreotide, particularly 

if the somatostatin scintigraphy in vivo 

is positive [60]. IGF-1 serum levels do probably 

not remain consistently lowered during 

long-term octreotide treatment of patients 

with PC, because its suppressive effect is 

mostly transient; additionally, one would take 

into consideration that IGF-1 serum levels in 

cancer patients tend to decrease during tumor 

progression. 

Criticism of the Design of Clinical Trials 

Clinical trials with SST analog treatment 

of patients with metastatic hormone-refractory 

PC are based on multiple in vivo and in 

vitro studies in animal models and in patients 

with human PC. Unfortunately, at present the 

studies have major disadvantages, such as 

inclusion of only a small number of patients, 


inadequate trial design, in particular patient 

randomization in groups according to hormone 

resistance, and finally, the use of widely 

varying dosage regimens and routes of administration. 

Additionally, none of the trials hitherto 

reported has been based on SSTR determination 

before starting the SST analog therapy. 

In our clinical study octreotide was combined 

with CAB from the start [24], while in 

most other trials only the LHRH analog was 

added. We believe such a clinical trial should 

be planned at specific medical centers with 

extensive experience in this field. 

In summary, in planning clinical trials 

with SST analogs in patients with metastatic 

or advanced PC, it has to be decided 

(1) whether SSTR (based on scintigraphic results) 

should be included, (2) whether IGF-1 

serum levels should be regularly measured 

during therapy, and (3) whether the dose of 

the SST analog used will be constant, increased, 

or even decreased according to the 

results of the in vivo scintigraphy measurements. 

Previous and recent clinical trials with 

octreotide in patients with PC leave uncertainty 

with regard to the optimal daily dose, 

the optimal route of administration, or the 

optimal duration of treatment. 

Conclusions 

Somatostatin seems to be an endogenous 

inhibitory GF in several organ systems, while 

exogenous SST analogs also have inhibitory 

effects on the growth of a variety of tumors; 

thus, one could speculate that the expression 

of SSTR on several PC cells might represent 

a general inhibitory control mechanism 

through which well-differentiated PC is inhibited 

in its growth. Thus SST analogs may 

have their place among the therapeutic 

antimitogen maneuvers in patients with metastatic 

and almost hormone-refractory PC. 


Radiolabeled SST analogs with 123 I, 131 I or 

111 In may detect the specific binding sites of 

these drugs, thus predicting their antiproliferative 

actions. PC could be partially visualized 

in vivo via an isotope-coupled SST analog 

and could be chronically treated with specific 

SST analogs according to a positive 

scan. Unfortunately, the value of the localization 

procedure with SSTR scintigraphy 

was lower in PCs than in other tumors. The 

detection of more than 2 SSTR subpopulations, 

of which 5 have been cloned, increases 

the possibility of using different SST analogs 

as selective antitumor agents for the treatment 

of disseminated hormone-resistant PC. 

Immunohistochemical NE differentiation of 

PC cells and serum NE hormonal markers 

may also predict the prognosis of such tumors 

or the usefulness of SST analog treatment 

in advanced PC. 

Projections for the Future 

Multicenter, prospective, clinical, controlled 

trials are needed with a great number 

of patients randomized according to their status: 

with or without previous incomplete hormone 

treatment or refractory to hormone. Patients 

should be randomized to: (1) CAB only, 

(2) CAB plus appropriate SST analog, (3) SST 

analog only, (4) SST analog with systemic 

cytotoxic therapy, (5) SST analog with cytotoxic 

radicals, (6) SST analog with LHRH 

agonists/antagonists and finally (7) SST analog 

with GRP/bombesin-antagonists. 

Specific antimitogen-acting SST analogs 

should be controlled on the basis of SSTR 

subtype determination, thus predicting the 

specific analogs with the highest binding capacity 

and having the best antiproliferative 

actions on hormone-resistant PCs. New specific 

radiolabeled (with 123 I, 131 I, 111 In) SST 

analogs, using scanning techniques, could

demonstrate SSTR-positive PCs. Thus, they 

might be used to monitor the efficacy of therapy, 

and with the coupling of ß-emitting radionuclide 

should make a kind of brachytherapy 

possible. The development of slow-release 

SST analog preparations (subcutaneous, intramuscular 

or intranasal) may increase patient 

compliance with this long-term antitumor 

treatment. 

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Gastrointestinal Cancer 

Refractory to Chemotherapy: 

A Role for Octreotide? 

Stefano Cascinu Vincenzo Catalano Paolo Giordani 

Anna Maria Baldelli Romina Agostinelli Giuseppina Catalano 

Section of Experimental Oncology, Division of Medical Oncology, 

Azienda Ospedaliera S. Salvatore, Pesaro, Italy 

Key Words 

Octreotide W Gastrointestinal cancers W 

Chemotherapy 

Abstract 

Although octreotide has been shown to inhibit 

the growth of gastrointestinal (GI) tumors 

in vitro and in vivo, preliminary clinical 

trials have reported disappointing results for 

this somatostatin analog in patients with GI 

cancers. The results of these trials probably 

reflect the difficulty in assessing the therapeutic 

potential of an agent such as octreotide 

in GI cancers. Thus, it is possible that 

treatment with octreotide could be useful in 

the stabilization of disease if it is associated 

with an improvement in survival. On the basis 

of these considerations five randomized 

trials were carried out to evaluate the therapeutic 

potential in patients with GI cancers. 

ABC 

Fax + 41 61 306 12 34 




0009–3157/01/0478–0127$17.50/0 



Four trials (one in patients with colorectal 

carcinoma and three in patients with carcinoma 

of the pancreas) did not show any advantage 

of octreotide in untreated patients; in 

contrast, one trial reported that octreotide 

prolonged survival in patients with GI cancers 

refractory to chemotherapy. Some clinical 

features of the latter study (treatment 

with chemotherapy, different schedules) 

may explain these conflicting results. Although 

data from randomized trials suggest 

that octreotide is not effective in untreated 

asymptomatic advanced GI cancer patients, 

further studies are warranted to assess the 

efficacy of octreotide in chemotherapy refractory 

patients in order to clarify the impact 

of octreotide in terms of not only survival but 

also on the patients’ quality of life. 

Stefano Cascinu, MD 

Division of Medical Oncology 

Maggiore University Hospital 

I–43100 Parma (Italy) 

Fax +39 521 995448 

Copyright © 2001 S. Karger AG, Basel

Gastrointestinal (GI) cancer accounts for a 

large proportion of all human tumors [1]. 

Although gastric cancer is declining in incidence, 

it remains the second most common 

malignancy in the world. Surgery is the only 

treatment which offers a chance of a complete 

cure for localized gastric cacarcinoma. However, 

at diagnosis 75% of all patients with gastric 

cancer have disseminated disease. Even 

among the subgroups of patients who undergo 

a potentially curative resection, relapse is 

common, consequently the 5-year survival 

ranges from 10 to 15% of all patients with 

newly diagnosed gastric cancer. Because of 

this poor outcome, the use of systemic treatment 

has been a subject of great interest. The 

currently available data indicate that with 

new combination cytotoxic regimens, approximately 

half of the patients with metastatized 

gastric cancer may benefit from chemotherapy 

by reduction of tumor-related symptoms 

and/or prolongation of survival [2]. 

In the western countries, colorectal carcinoma 

represents, after lung cancer, the second 

leading cause of deaths due to neoplasms. 

During the past decades, knowledge about 

this carcinoma has considerably increased, 

but in the advanced disease, little progress has 

been made in improving patient survival. In 

advanced colorectal cancer in fact (at least 

40% of patients will have metastases sometime 

during the course of their illness) a standard 

treatment has not yet been established. 

For more than 30 years, fluorouracil has been 

the drug of choice even if tumor response 

rates are not more than 10–15%, with a median 

survival of about 1 year. Further innovative 

compounds (irinotecan, oxaliplatin) are 

now being evaluated in clinical trials producing 

promising results [3]. 

Carcinoma of the pancreas is the fourth 

cause of cancer-related death in the United 

States, with approximately 28,000 deaths recorded 

in 1997. Although there are worldwide 

variations, similar figures have been reported 

in other western countries, and about 30,000 

deaths are reported in the European countries 

each year. Pancreatic cancer is an aggressive 

disease and only 5–22% of patients are eligible 

for a potentially curative resection at the 

time of diagnosis. Furthermore, the prognosis 

is unfavorable for this selected group of patients 

with only 10–30% 5-year survival rates. 

In patients with locally advanced or metastatic 

pancreatic cancer, conventional methods of 

treatment, including radiotherapy and chemotherapy, 

offer little benefit and their role in 

prolonging survival, ameliorating symptoms 

or improving quality of life still remains a 

matter of debate [4]. The outcome is even 

more dismal for patients with advanced gastrointestinal 

cancer nonresponsive to chemotherapy. 

Median survival for these patients is 

about 3–6 months, and symptoms are frequently 

difficult to control [5]. Consequently, 

there has been much interest in novel forms of 

therapy which may be more effective in patients 

with GI malignancies nonresponsive to 

chemotherapy. There is some evidence suggesting 

that GI tumors may be partly hormone-dependent 

and that hormonal manipulation 

may have a role to play in the management 

of these cancers [6]. In fact, previous 

studies have shown that the tumor growth and 

cellular proliferation are controlled by GI hormones 

and growth factors such as EGF and 

IGF-1 [7, 8]. One of the most important naturally 

occurring antiproliferative hormones is 

somatostatin. Somatostatin has been shown 

to inhibit proliferation of GI cancers both in 

vitro and in vivo [9]. However, the short halflife 

of native somatostatin (1–3 min) and 

the need for its intravenous administration 

makes long-term somatostatin therapy impractical 

[10]. Octreotide, a synthetic somatostatin 

analog, differs substantially from 

natural somatostatin in that it has a much 

longer half-life [11]. Octreotide inhibits the 

128 Chemotherapy 2001;47(suppl 2):127–133 Cascinu/Catalano/Giordani/Baldelli/ 

Agostinelli/Catalano

growth and development of tumor via one or 

more of the following mechanisms: a direct 

inhibitory effect on the tumor via specific 

somatostatin receptors, direct or indirect inhibition 

of the production of IGF-1 and/or other 

growth factors, inhibition of angiogenesis, 

reduction in tumor blood flow and stimulation 

of apoptosis. 

The possibility of a direct effect of octreotide 

on the tumor tissue implies that the 

tumor cells bear somatostatin receptors 

(SSTR). In recent years, it has been documented 

that many nonendocrine tumors bear 

somatostatin receptor subtypes. At present 5 

somatostatin receptor subtypes have been 

cloned and characterized [12]. It was found 

that the antiproliferative effects of octreotide 

in vitro are mediated via the activation of the 

SSTR-2 subtype which is functionally a phosphotyrosine 

phosphatase [13]. The loss of 

SSTR-2 gene expression may provide a 

growth advantage for tumors which do not 

express this subtype and may explain, at least 

in part, the failure of somatostatin analogs to 

inhibit the growth and development of cancers. 

Furthermore, the restoration of SSTR-2 

expression to human pancreatic cells resulted 

in a significant reduction in the growth of 

these cells [14]. Octreotide can also exert an 

antiproliferative effect by binding to SSTR-5 

receptors and stimulate apoptosis by binding 

the SSTR-3 subtype. However, octreotide has 

little or no binding affinity to the somatostatin 

receptor subtypes expressed in gastric, 

pancreatic and colorectal cancers [12]. Nevertheless, 

octreotide has been demonstrated 

to inhibit their growth and development. 

These observations would suggest that octreotide 

can indirectly inhibit the growth and 

development in these tumors. Several studies 

have shown that EGF and IGF-1 may be 

implicated in the autocrine control of the 

growth and development of gastric and colorectal 

tumors. In vitro both EGF and IGF-1 

promoted cell proliferation of gastric and 

colorectal cancer cell lines [15–17]. In addition, 

both growth factors enhanced the response 

of these cells to gastrin. Thus, the inhibition 

of the secretion of these trophic factors 

may have therapeutic potential in the management 

of GI cancers [18]. Recently, we have 

demonstrated that octreotide resulted in a significant 

decrease in serum IGF-1 levels in 

colorectal cancer patients which was associated 

with a decrease in the proliferative activity 

of the tumor cells [19]. Furthermore, we have 

demonstrated that there is no correlation between 

the dose of octreotide and the magnitude 

of serum IGF-1 levels [20]. Stewart et al. 

[21] and Iftikhar et al. [22] reported a similar 

interference in tumor cell kinetics after treatment 

with octreotide in patients with colonic 

and rectal cancer. 

According to data from Klijn et al. [23] no 

significant effects were observed in our patients 

on serum levels of HGH and EGF. 

The antiproliferative effects of octreotide 

may also be mediated by inhibition of angiogenesis. 

The inhibition of angiogenesis by octreotide 

in vivo could result indirectly from 

an inhibition of IGF-1 [24]. However, octreotide 

may also inhibit angiogenesis by suppression 

of paracrine angiogenic factors such as 

vascular endothelial growth factor. This suggestion 

is supported by the observation that 

octreotide significantly reduced serum and 

tissue vascular endothelial growth factor concentrations 

in patients with colorectal cancers 

[25]. 

Octreotide has been shown to inhibit the 

growth of GI tumors both in vitro and in 

experimental animal studies [15, 26, 27]. On 

the basis of these experimental data, pilot 

clinical trials with octreotide were carried out 

in GI tumors. In spite of the promising preclinical 

results, these initial studies in man 

were disappointing (table 1). Klijn et al. [23] 

treated 34 patients with gastric and colonic 

Octreotide in GI Cancers Chemotherapy 2001;47(suppl 2):127–133 129

Table 1. Octreotide in GI cancers: pilot clinical trials 

Authors, year Reference 

No. 

Tumor Number 

of 

patients 

Clinical response 

partial stable 

Survival 

months 

Savage et al., 1987 28 Colon 1004 n.r. 

Klijn et al., 199023 Colon 16 04 8 

Pancreas 14 03 2 

Stomach 4 01 n.r. 

Friess et al., 1993 31 Pancreas 22 03 5 

Rosenberg et al., 1995 33 Pancreas 12 03 12 

n.r. = Not reported. 

cancers with octreotide. Although octreotide 

treatment stabilized the disease in 27% of 

these patients there was no benefit in terms of 

survival. However, interestingly most patients 

expressed a subjective improvement in 

the absence of serious side effects. 

Savage et al. [28] treated 10 patients without 

finding any indication that octreotide can 

alter the rate of growth of advanced GI tumors. 

In contrast, Smith et al. [29] found a 

modest increase in survival in 12 colorectal 

cancer patients treated with octreotide but no 

objective responses were observed. Similar results 

have been reported for patients with 

pancreatic cancer treated with octreotide, observing 

no benefit [30–32]. Conversely, Rosenberg 

et al. [33] reported an improvement 

in survival with a concomitant treatment of 

octreotide and tamoxifen compared to historical 

controls (12 vs. 3 months). 

Overall, these preliminary results in patients 

are disappointing but may reflect the 

difficulty in assessing the activity of an agent 

such as octreotide considering only the objective 

responses of tumors. It is possible in fact 

that treatment with octreotide could be useful 

even obtaining only a stabilization of disease 

if this is associated with an improvement in 

survival. These considerations were used to 

justify five randomized trials in which the 

major end points were survival and time to 

progression of disease. Three studies tested 

octreotide in untreated advanced pancreatic 

cancer and one in untreated advanced colorectal 

cancer [34–37]. However, none of the 

trials showed any benefit for octreotide treatment 

in terms of disease progression and survival 

(table 2). 

In 1995, we published the results of a randomized 

trial comparing octreotide with the 

best available supportive care in patients with 

advanced GI cancers refractory to conventional 

chemotherapy [38]. The primary outcome 

measure was duration of survival. Fiftyfive 

patients (15 stomach, 16 pancreas, 24 

colorectal) received octreotide (200 Ìg 3 times 

a day for 5 days a week), while 52 (14 stomach, 

16 pancreas, 22 colorectal) received the 

best supportive care only. The survival of 

patients treated with octreotide was significantly 

longer (median 20 weeks) than the 11 

weeks of median survival observed in the control 

group (p ! 0.001) (table 3). This survival 

advantage of patients treated with octreotide 

was present in all three types of tumors. Furthermore, 

in 22 patients (40%) octreotide relieved 

pain and allowed discontinuation of 

analgesics. 



Table 2. Octreotide in GI cancers: randomized trials in untreated patients 

Authors, year Reference 

No. 

Goldberg et al., 1995 

34 Octreotide 

Placebo 

Burch et al., 1995 35 Octreotide 

Placebo 

Roy et al., 1998 36 Octreotide/5FU 

FU 

Pederzoli et al., 1998 37 Octreotide 

Placebo 

n.r. = Not reported. 

Treatment Tumor Number 

of patients 

Colon 131 

129 

Pancreas 42 

43 

Octreotide 15 24 16 15 22 16 

Placebo 14 22 16 8 12 8 

Survival 

weeks 

Octreotide in GI Cancers Chemotherapy 2001;47(suppl 2):127–133 131 

17 

16.8 

n.r. 

n.r. 

Pancreas 284 22.6 

21.6 

Pancreas 93 

92 

16 

16.9 

Table 3. Octreotide in GI cancers: a randomized trial in refractory chemotherapy patients 

Treatment Number of patients 

It is difficult to explain the disparity of our 

results and those of the other randomized 

trials. However, some clinical and methodological 

aspects could help to explain these 

different results. In our study, only patients 

with chemotherapy-refractory disease were 

entered, whereas other trials enrolled asymptomatic 

patients who had not been treated 

with chemotherapy. It is well known that chemotherapy 

can improve survival in patients 

with advanced GI cancer, so that cytotoxic 

drug administrations in some patients could 

have determined differences in survival. Unfortunately, 

in most of these trials the further 

treatments of patients failing octreotide therapy 

were not reported. Furthermore, there are 

stomach colorectal pancreas 

Survival, weeks 

stomach colorectal pancreas 

data suggesting that in the end stages of GI 

cancers, when bowel obstruction is present, 

octreotide may provide some symptomatic 

benefit, and may also be a determinant of survival 

[39]. 

Another problem arising from the studies 

cited above could be the continuous administration 

of octreotide for a prolonged period 

without interruptions. Preclinical data has 

shown that continuous administration of octreotide 

results in desensitization or tachyphylaxis 

of its inhibitory effects on somatostatin 

receptors and concomitant increase of 

plasma IGF-1 concentration within 6–10 

days following initiation of therapy. Possibly, 

desensitization may be prevented or delayed

if octreotide is administered intermittently as 

in our case [9]. Thus, although advanced GI 

cancer patients were included in these trials 

assessing the role of octreotide, there is a 

potential for the difference in activity due to 

the different subset of patients (untreated vs. 

refractory to chemotherapy, and so with 

‘more advanced disease’) and to the variations 

in dose and schedule of octreotide. 

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of untreated asymptomatic GI cancer patients. 

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H: Somatomedin analogue SMS 

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MBL, Castellani A, Graziano F, 

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and decrease of serum insulin 

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SWJ, Portengen H, Foekens JA: 

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V, Agostinelli R, Muretto P, Catalano 

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and advanced intestinal cancer: A 

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CM, Thompson JC: Effects of octreotide, 

a long-acting somatostatin 

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30Ebert M, Friess H, Beger HG, 

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Weber A, Kunz J, Fritsch K, Dennler 

HJ, Beger HG: Low-dose octreotide 

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with advanced pancreatic cancer. 

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32 Friess H, Büchler MW, Ebert M, 

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HG: Treatment of advanced pancreatic 

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MH, Pollak M: Low-dose octreotide 

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34 Goldberg RM, Moertel CG, Wieand 

HJS, Krook JE, Schutt AJ, Veeder 

MH, Maillard JA, Dalton RJ: A 

phase III evaluation of a somatostatin 

analogue (octreotide) in the treatment 

of patients with asymptomatic 

advanced colon carcinoma. Cancer 

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35 Burch PA, Block M, Wieand HS, 

Veeder MH, Michalak JC, Hatfield 

AK, Wright K: A phase III evaluation 

of octreotide versus chemotherapy 

with 5FU or 5FU/leucovorin in 

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36 Roy A, Jacobs A, Bukowsky R, Cunningham 

D, Hamm J, Schlag PM, 

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Oncol 1998;17:987. 

37 Pederzoli P, Maurer U, Vollmer K, 

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E, Di Carlo V, Stauder H, Bergan A, 

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995 LAR vs placebo in unresectable 

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38 Cascinu S, Del Ferro E, Catalano G: 

A randomized trial of octreotide vs 

best supportive care only in advanced 

gastrointestinal cancer patients 

refractory to chemotherapy. 


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Palliat Med 1993;7:295–299. 

Octreotide in GI Cancers Chemotherapy 2001;47(suppl 2):127–133 133


Pancreatic Cancer: 

Does Octreotide Offer Any Promise? 

Lawrence Rosenberg 

The Pancreatic Diseases Centre, McGill University Health Centre and Department of Surgery, 

McGill University, Montreal, Canada 

Key Words 

Pancreatic cancer W Somatostatin W 

Somatostatin receptors W Somatostatin 

analogs W Octreotide W RC-160 

Abstract 

The incidence of adenocarcinoma of the pancreas 

has risen steadily over the past 4 decades. 

Since pancreatic cancer is diagnosed 

at an advanced stage, and because of the 

lack of effective therapies the prognosis of 

such patients is extremely poor. Despite advances 

in our understanding of the molecular 

biology of pancreatic cancer, the systemic 

treatment of this disease remains unsatisfactory. 

Systemic chemotherapy and the administration 

of biologically active molecules 

such as tumor necrosis factor or interferons 

have not resulted in significant improvements 

in response rates or patient survival. 

New treatment strategies are obviously 

needed. This paper will discuss current advances 

in the use of somatostatin analogs in 

the management of pancreatic cancer. 

ABC 

Fax + 41 61 306 12 34 





0009–3157/01/0478–0134$17.50/0 



Introduction 

The incidence of adenocarcinoma of the 

pancreas has risen steadily over the past 4 

decades. It currently stands at approximately 

29,000 new cases per year in North America 

[1], making it the second most common gastrointestinal 

malignancy and the fifth leading 

cause of adult deaths from cancer [2]. The disease 

is characterized by its aggressive nature. 

The diagnosis of pancreatic cancer is usually 

established at an advanced stage, and a lack of 

effective therapies leads to an extremely poor 

prognosis. A meta-analysis of 144 reported 

series including approximately 37,000 patients 

found the median survival time to be 3 

months [3]. According to these findings, 65% 

of patients with pancreatic cancer will die 

within 6 months from the time of diagnosis, 

and about 90% within 1 year. Surgical resection, 

if performed early enough, is presently 

the only effective form of curative therapy [4]. 

However, fewer than 15% of patients with 

pancreatic cancer are potential candidates for 

a curative resection [5] due to spread of the 

cancer to adjacent tissues or beyond [6]. Only 

Dr. Lawrence Rosenberg 

Montreal General Hospital, 1650 Cedar Ave., L9-424 

Montreal, Que. H3G 1A4 (Canada) 

Tel. +1 514 937 6011, ext. 4346, Fax +1 514 934 8210 

E-Mail cxlw@musica.mcgill.ca

1–4% of patients with adenocarcinoma of the 

pancreas will survive 5 years after diagnosis 

[7, 8]. Thus, the incidence rates are virtually 

identical to mortality rates. 

Approximately half of all patients with 

pancreatic cancer have metastatic disease at 

the time of diagnosis [9, 10], while most of the 

rest have locally advanced, unresectable disease 

[11, 12]. Metastatic pancreatic cancer is 

one of the most chemotherapy-resistant tumors, 

as evidenced by the fact that pancreatic 

cancer has the lowest 5-year survival rate (3%) 

of any cancer listed in the Surveillance, Epidemiology 

and End Results (SEER) data base of 

the NCI [13]. 

Computed tomography (CT) and magnetic 

resonance imaging have made it easier to 

determine the diagnosis and to define the 

stage of the disease. CT-guided needle biopsies 

and laparoscopy have resulted in fewer 

unnecessary laparotomies, while biliary stenting 

can reduce the need for an invasive operative 

procedure in patients with advanced tumors. 

Unfortunately, these advances have not 

resulted in disease detection at an earlier stage 

[14]. 

Reports of 5-year survival among patients 

managed with nonsurgical therapies remain 

anecdotal. Thus, of 150 patients who have 

survived for more than 10 years after their 

diagnosis of pancreatic cancer, only 12 have 

been cured by nonsurgical therapies [3]. 

Clearly more effective therapies need to be 

developed. 

Epidemiology and Etiologic Factors 

A number of factors that may contribute to 

the pathogenesis of pancreatic cancer have 

recently been identified. These have been 

classified as environmental factors, pathological 

factors (e.g. chronic pancreatitis), genetic 

factors (e.g. familial pancreatic cancer), and 

occupational exposure [15, 16]. Currently, 

cigarette smoking is the most firmly established 

risk factor associated with pancreatic 

cancer. Pancreatic malignancies can be induced 

in animals through long-term administration 

of tobacco-specific N-nitrosamines or 

by parenteral administration of other N-nitroso 

compounds [17–19]. Induction of pancreatic 

cancer in these experimental models 

can be influenced by additional factors, including 

changes in bile acid composition, cholecystokinin 

levels, diet and pancreatic duct 

obstruction [20–23]. 

Clinically, numerous case-control and cohort 

studies have reported an increased risk of 

pancreatic cancer for smokers in both the 

United States and Europe, and current estimates 

suggest that approximately 30% of pancreatic 

cancer cases may be attributed to cigarette 

smoking [24, 25]. 

Pathology 

Most malignant pancreatic tumors (95%) 

are believed to arise from the exocrine portion 

of the gland and have light-microscopic features 

consistent with those of adenocarcinomas. 

Much more infrequent are tumors that 

arise from acinar cells or islet cells. Primary 

nonepithelial tumors of the pancreas (e.g. lymphomas 

or sarcomas) are exceedingly rare. 

Natural History of Pancreatic Cancer 

Adenocarcinoma of the pancreas metastasizes 

to regional lymph nodes at an early stage 

of the disease, and subclinical liver metastases 

are present in the majority of patients at the 

time of diagnosis, even though findings from 

imaging studies may be otherwise normal. Patients 

who undergo surgical resection for localized 

nonmetastatic cancer of the head of 

Pancreatic Cancer and Octreotide Chemotherapy 2001;47(suppl 2):134–149 135

the pancreas have a long-term survival rate of 

approximately 20% and a median survival of 

15–19 months. However, disease recurrence 

following a potentially curative Whipple resection 

is the norm. 

Local recurrence occurs in up to 85% of 

patients who undergo surgery alone, and local-regional 

tumor control may be improved 

by combined modality therapy involving both 

chemoradiation and surgery. Liver metastases 

then become the dominant form of tumor 

recurrence and occur in 50–70% of patients 

following potential curative combined modality 

treatment. Patients with locally advanced, 

nonmetastatic disease have a median survival 

of 6–10 months, while those with metastatic 

disease have a short survival (3–6 months), 

the length of which depends on the extent of 

disease and performance status. 

Because of the prognosis and the patterns 

of treatment failure associated with adenocarcinoma 

of the pancreas, any proposed treatment 

must not be worse than the disease. The 

low cure rate and modest median survival following 

Whipple’s resection mandate that treament-related 

morbidity be low and treatmentrelated 

death be rare. A recent report of the 

experience from Johns Hopkins [26] demonstrates 

that this can be achieved by careful 

selection of patients who undergo therapy. In 

addition, however, the development of innovative 

treatment strategies directed at the 

known sites of tumor recurrence should be 

directed towards improvements in patient 

survival and quality of life. 

A Brief History of Pancreatic Cancer 

Therapies 

Phase II Trials 

Single-agent phase II trials in patients with 

advanced pancreatic cancer reported large 

variations in response rates [27, 28]. In evalu- 

ating these studies, it is important to recognize 

that the clinical trial methodology and 

the criteria for judging objective response 

have changed over time [27]. Phase II trials in 

the 1970s frequently included patients with a 

variety of different tumors in a single trial, 

and therefore the published response rates 

were often based on a small number of patients 

with a particular cancer. As a result, 

these studies were difficult to interpret from a 

statistical point of view. 

Prior to 1985, trials relied primarily on an 

estimation of tumor size by physical examination, 

and responses were defined as shrinkage 

of a palpable abdominal mass by 50% or 

more, or a reduction in the palpable liver span 

by 30% or more [28]. The inherent inaccuracy 

of these techniques, intraobserver and interobserver 

variability, and the influence of confounding 

factors on the size of the measured 

lesions all contributed to the initial reports of 

high response rates for drugs such as 5-fluorouracil 

(5-FU), chlorambucil, and mitomycin, 

as well as the failure to confirm these 

promising response rates in subsequent trials, 

especially when CT scans were used to determine 

tumor response [27]. 

Phase III Trials 

Two kinds of comparative studies have 

been carried out in patients with advanced 

pancreatic cancer: (1) those that compared 

active treatment to best supportive care (to 

determine whether chemotherapy made any 

difference in the outcome of these patients), 

and (2) those that compared multiple agent 

regimens to single-agent chemotherapy (to determine 

whether combinations of drugs with 

distinct mechanisms of action could improve 

outcome compared to that achieved by single 

agents) [27]. Of the three trials that compared 

active treatment to best supportive care, two 

demonstrated no significant difference [29, 

30], and the third suggested a substantial sur- 

136 Chemotherapy 2001;47(suppl 2):134–149 Rosenberg

vival advantage in favor of a five-drug regimen 

[31]. However, subsequent trials of the 

regimen failed to duplicate the promising results 

of the original study [32]. 

Despite a number of potentially interesting 

preclinical findings and promising phase II 

studies, virtually no progress has been made 

in the chemotherapy for advanced pancreatic 

cancer during the past 30 years. 

Current Approach to Single-Agent 

Chemotherapy 

The thymidylate synthase inhibitor 5-FU 

remains the most extensively evaluated chemotherapeutic 

agent for pancreatic cancer 

[33–35]. Despite numerous trials, however, 

its efficacy remains questionable. Between 

1991 and 1994, 25 investigational new drugs 

were evaluated in phase II trials for the treatment 

of pancreatic cancer. The median response 

rate in these trials was 0% (range 0– 

14%) and the median survival was 3 months 

[28]. Inactive drugs that have undergone evaluation 

over the past 5 years include iproplatin 

[36], trimetrexate [37], edatrexate [38], fazarabine 

[39], diaziquone [40], mitoguazone 

[40], and amonafide [41]. One trial conducted 

during this period focused on gemcitabine 

(2),2)-difluoro-2)-deoxycytidine). 

Gemcitabine 

Gemcitabine is a deoxycytidine analog 

with structural similarities to cytarabine. As a 

prodrug, gemicitabine must be phosphorylated 

to its active metabolites – gemcitabine 

diphosphate and gemcitabine triphosphate. 

In both preclinical and clinical testing, gemcitabine 

demonstrated greater activity against 

solid tumors than did cytarabine [42]. These 

observations have been explained by the following 

properties of gemcitabine: (1) it is 3–4 

times more lipophilic than cytarabine, resulting 

in greater membrane permeability and 

cellular uptake; (2) it has higher affinity for 

deoxycytidine kinase, and (3) the intracellular 

retention of gemcitabine triphosphate, an active 

metabolite, is prolonged [43]. 

Following a phase I study [44], gemcitabine 

was evaluated in a multicenter trial of 44 

patients with advanced pancreatic cancer 

[45]. Although the objective response rate to 

this drug was only 11% and median survival 

was 5.6 months, a number of potentially important 

observations were made in this trial 

[45]. The 1-year survival rate was a remarkably 

high 23%, and the responses observed 

appeared to be somewhat prolonged, i.e. from 

4 to more than 20 months. Perhaps the most 

unexpected outcome of this study, however, 

was the impact of gemcitabine on tumorrelated 

symptoms. Of the 5 patients who had 

an objective response to gemcitabine, 4 were 

able to resume normal daily activities. Three 

of the 5 patients were also able to reduce their 

daily requirement for analgesics. An additional 

14 patients who did not meet the radiological 

criteria for an objective response experienced 

disease stabilization for 4 months or 

more, and, of these, 9 had an improvement in 

performance status. 

One hundred sixty patients with newly 

diagnosed, unresectable pancreatic cancer 

were recruited in a phase III trial [46]. A total 

of 126 patients completed a period during 

which pain was stabilized and then they were 

randomized to treatment with gemcitabine or 

5-FU. Fifteen patients (23.8%) treated with 

gemcitabine achieved a clinical beneficial response 

compared with only 3 patients (4.8%) 

treated with 5-FU (p = 0.002). The median 

duration of the clinical beneficial response for 

gemcitabine-treated patients was 18 weeks 

compared to 13 weeks for the 5-FU-treated 

patients. Gemcitabine also proved superior to 

5-FU in terms of the trial’s secondary endpoints. 

Median survival for gemcitabinetreated 

patients was 5.6 months compared to 

4.4 months for 5-FU-treated patients. In addi- 


tion, the probability of survival at 1 year was 

18% in the gemcitabine group, significantly 

greater than the 2% in the 5-FU group. Few 

objective responses, however, were observed 

in either treatment arm. 

A subsequent phase II study enrolled 63 

patients with pancreatic cancer that had progressed 

despite treatment with 5-FU [47]. To 

be eligible for the trial, patients had to have a 

significant degree of tumor-related symptoms. 

In this study, 17 patients (27%) experienced 

a clinically beneficial response to gemcitabine, 

the median duration of which was 14 

weeks. Median survival of all patients treated 

in this trial was 3.8 months. Objective responses 

were seen in 6 (10.5%) of the 57 

patients with measurable disease. 

While these results could suggest that gemcitabine 

should become the accepted firstline 

therapy for patients with advanced pancreatic 

adenocarcinoma, the median survival 

for patients with metastatic disease was still 

less than 6 months, with few patients achieving 

long-term disease stabilization. Furthermore, 

some of the effects attributed to chemotherapy 

may not be substantially different 

from what can be achieved with aggressive 

supportive care alone. In fact the use of clinical 

benefit response as a valid means to determine 

the efficacy of gemcitabine has itself 

been questioned [48]. Thus the median survival 

was less than 4 months, and 85% did not 

survive 7 months. Eight patients had extension 

to regional organs or lymph nodes without 

distant metastases. One patient survived 

4.4 years following the completion of a trial of 

5-FU and the start of gemcitabine. Thus, 

there is no evidence from this study that gemcitabine 

improved the survival of patients 

with pancreatic cancer. 

The quality of life one seeks to evaluate by 

defining net patient benefit must take into 

account the duration of remaining survival 

available to the patient. Gelber [48] has sug- 

gested that performing treatment comparisons 

based on the amount of time patients 

spend in clinical health states characterized 

by relatively good quality of life might be a 

better indicator of net patient benefit than 

defining a percentage of patients who achieve 

some criteria of response. The fact that treatments 

which produce higher response rates do 

not always yield better survival also argues 

against putting too much emphasis in estimating 

response rates as a guide to net benefit. 

Seventeen patients had a clinically beneficial 

response in the phase II study, and the 

investigators claimed that the treatment was 

generally well tolerated [47]. However, although 

the toxicities were reported as moderate, 

more patients had some noticeable adverse 

experiences than achieved a clinical 

benefit response. The evidence for substantial 

benefit for gemcitabine is not overwhelming, 

and additional studies will be required to 

more fully define its role in the treatment of 

pancreatic cancer. 

Other Approaches to Pancreatic 

Cancer 

Despite advances in our understanding of 

the molecular biology of pancreatic cancer, 

the systemic treatment of metastatic disease 

remains unsatisfactory. Systemic chemotherapy 

and the administration of biologically active 

molecules such as tumor necrosis factor 

or interferons [49, 50] have not resulted in significant 

improvements in response rates or 

patient survival. New treatment strategies are 

obviously needed. A number of more general 

areas of investigation may yield more promising 

results. One of these involves interruption 

or modulation of growth factors and signal 

transduction pathways. One example is the 

successful treatment of carcinoma of the 

breast that has been achieved by endocrine 


manipulation. The presence of estrogen receptors 

on neoplastic breast tissue is correlated 

with response to ovarian ablation and/or 

antiestrogen treatment. A similar approach to 

the treatment of pancreatic cancer seems justified 

because of the presence of estrogen 

receptors in pancreatic carcinoma [51–54] as 

well as in normal pancreatic tissue [55, 56]. In 

fact, the use of tamoxifen in 80 patients with 

ductal adenocarcinoma of pancreas has been 

reported in a case-control study to increase 

the median survival time from 3 to 7 months 

[57, 58]. However, steroid hormones may not 

be the most important regulator of pancreatic 

cell proliferation. Other potential influences 

include the growth factor IGF-1 and the 

growth inhibitor somatostatin. 

Scientific Background for the Use of 

Somatostatin-Based Therapies 

Somatostatin is a tetradecapeptide that 

elicits a variety of biological processes including 

inhibition of hormonal secretion and cell 

proliferation [59]. In some patients, analog 

therapy leads to an inhibition of tumor 

growth [60–62]. However, the use of native 

somatostatin is limited because of its very 

short plasma half-life and the need for continuous 

infusion. The recent development of 

long-acting somatostatin analogs, such as RC- 

160 and octreotide, however, has made clinical 

trials possible. 

These properties of somatostatin form the 

basis for the treatment of hormone-producing 

pituitary or gastroenteropancreatic tumors by 

long-acting analogs of the native hormone 

[60]. Thus, hormonal suppression is produced 

in patients with acromegaly or with neuroendocrine 

tumors such as insulinoma, glucagonoma, 

gastrinoma, vipoma, or carcinoid syndrome 

by somatostatin analogs resulting in 

symptomatic relief [60]. 

Somatostatin can exert an antiproliferative 

activity by either indirectly inhibiting angiogenesis 

or hormone and growth factor release, 

or by acting directly on neoplastic cells [59, 

60, 62]. For example, a number of gastrointestinal 

hormones, including gastrin and cholecystokinin, 

have trophic effects on pancreatic 

tissue [63] and can stimulate the growth of 

pancreatic tumors. Somatostatin suppresses 

the secretion and action of these peptides, and 

this may also contribute to its antiproliferative 

activity [64, 65]. In addition, somatostatin 

and its analogs may also act by reducing 

levels of growth factors such as EGF and IGF- 

1 that are thought to be important in neoplastic 

processes [66–70]. This latter possibility is 

of considerable interest because both tamoxifen 

[70] and octreotide [71] have been shown 

to lower circulating levels of IGF-1 and the 

combination has recently been reported to 

lower IGF-1 levels more substantially than 

either agent alone [72]. This observation 

raises the possibility of therapeutic synergy if 

the two agents were used together, a suggestion 

which is supported by a report that 

tamoxifen and octrotide are an effective treatment 

for human pancreatic cancers growing 

in nude mice [73]. However, as appealing as 

this suggestion is, Klijn et al. [74] measured 

insulin, IGF-1, and EGF levels in a clinical 

study of the use of octreotide for pancreatic 

cancer. Chronic treatment with a octroetide 

had no effect on EGF levels. However, these 

investigators observed early significant decreases 

in insulin and IGF-1; the levels of both 

growth factors had returned to pretreatment 

values by 5 days and 4 weeks, respectively. 

This may have been due to the downregulation 

of the receptors responsible for inhibiting 

the release of these trophic factors. This is a 

well-recognized effect of even short-term 

treatment with octroetide, e.g. loss of initial 

potent inhibitory effects, which may be manifested 

clinically as tachyphylaxis. This study 


does not support suppression of trophic peptides 

as an important mechanism by which 

somatostatin inhibits pancreatic cancer, but it 

does not eliminate the possibility that these 

hormones may influence pancreatic tumor 

growth. 

The direct actions of somatostatin are mediated 

by specific receptors that have been 

detected using binding assay or autoradiography 

in various human normal and tumor tissues 

[59, 60]. Recently, five somatostatin receptor 

subtypes (SSTR-1–5) and one splice 

variant have been cloned from humans, mice 

and rats [75–80]. 

Buscail et al. [81, 82] have demonstrated a 

distinct profile for binding of clinically used 

somatostatin analogs, SMS 201-995 (octreotide), 

BIM 23014 (lanreotide), and RC-160 

(vapreotide). These analogs bind with high 

affinity to SSTR-2, SSTR-3, and SSTR-5 and 

with low affinity to SSTR-1 and SSTR-4 [75– 

85]. The biological functions mediated by the 

five SSTR(s) have not yet been completely 

established. Recently, after stable expression 

of SSTR(s), it was demonstrated that only 

SSTR-2 and SSTR-5 mediated the antiproliferative 

effect of the somatostatin analogs octreotide 

and vapreotide [82, 83]. The inhibition 

of tumor growth by somatostatin and its 

analogs is rather more complex than these 

studies would imply, and many gaps remain 

in our knowledge. For instance, it is difficult 

to measure the binding affinities of the somatostatin 

analogs and their selectivity, since 

most competitive studies use different SSTR 

receptor clones from different species expressed 

in different cell lines and tested with 

different radioligands [86–88]. 

The antiproliferative action of somatostatin 

and its analogs on pancreatic cancer has 

been demonstrated in vitro and in vivo. 

Schally [62] reported that the somatostatin 

analog RC-160 reduced the weight and volume 

of the tumor and prolonged host survival 

in nitrosoamine-induced pancreatic carcinoma 

in Syrian golden hamsters. Upp et al. [89] 

demonstrated that octreotide inhibited the 

growth and development of two human pancreatic 

cancers, SKI and CAV, in nude mouse 

xenografts. 

In keeping with these findings, recent experimental 

evidence has indicated that somatostatin 

analogs may act directly on neoplastic 

cells by upregulating activity of phosphotyrosine 

phosphatases [81, 90], an activity 

which would be expected to reduce proliferation 

stimulated by growth factors that act via 

tyrosine kinase signal transduction pathways. 

In fact, Fisher et al. [91, 92] have reported 

that when somatostatin receptors were 

present on pancreatic tumor cell lines, somatostatin 

analogs inhibited their proliferation 

both in vivo and in vitro. Eleven specimens 

of pancreatic adenocarcinoma tissue were 

harvested from patients undergoing surgery 

and nine human pancreatic carcinoma cell 

lines were maintained in vitro. All tumors 

were assayed for expression of mRNA of all 

five somatostatin receptors using RT-PCR. 

Their findings with the MIA PaCa-2 cell line 

are consistent with the results of previous 

studies [73, 90, 93–95] and support the hypothesis 

that high numbers of high affinity 

somatostatin receptors on the surface of pancreatic 

tumors render the tumor susceptible 

to inhibition by somatostatin. Their study 

indicated that seven of nine pancreatic cell 

lines showed expression of at least one subtype 

of somatostatin receptor mRNA, but 

only one cell line showed functional somatostatin 

receptors on the surface. In this regard, 

these findings are consistent with previous 

studies showing that somatostatin receptors 

are rarely detected on the surface of pancreatic 

adenocarcinomas [96]. Data also suggests 

that the presence of mRNA for the somatostatin 

receptor in the clinically acquired specimens 

cannot be taken as evidence of the pres- 


ence of cell surface somatostatin receptors in 

those tumors. 

Among the recently cloned somatostatin 

receptor subtypes, SSTR-2 displays the highest 

affinity for the somatostatin analogs [75, 

79–83, 85]. It has been demonstrated that this 

subtype mediates the antiproliferative effect 

of the stable analogs octreotide and vapreotide 

through the stimulation of a tyrosine 

phosphatase activity, both in rat pancreatic 

cells that endogenously expressed SSTR-2 

and in cells transfected with SSTR-2 cDNA 

[81, 82, 97, 98]. In contrast to that observed in 

normal tissue or benign lesions, there is a loss 

of gene expression of SSTR-2 in pancreatic 

adenocarcinoma, and metastases derived 

from these primaries. 

In addition, SSTR-2 was not expressed in 

the pancreatic cancer cell lines, except in the 

MIA PaCa-2 cells. Interestingly, RC-l60 inhibited 

growth of this latter cell line both in 

vitro and in vivo through binding of highaffinity 

sites and stimulation of a tyrosine 

phosphatase activity [90]. The molecular 

mechanism responsible for downregulation of 

SSR2 gene expression could occur at the transcriptional 

or translational level. Because expression 

of the SSR2 gene appears to predict 

the response of pancreatic cancer to octreotide, 

strategies to increase SSR2 gene expression 

in tumors lacking such receptors may 

prove beneficial. 

All of these observations argue in favor of 

the role of SSTR-2 in the negative regulation 

of pancreatic cell growth. The loss of expression 

of SSTR-2 in neoplastic pancreatic cells 

may provide a growth advantage for tumors 

and their metastases. Moreover, a direct antiproliferative 

effect of somatostatin and its 

analogs may thus be excluded in the absence 

of SSTR-2 receptors. 

The mRNAs of SSTR-1, SSTR-4 and 

SSTR-5 subtypes are present both in normal 

and cancerous tissues from exocrine pancreas. 

We found previously that among these three 

subtypes, SSTR-5 also mediated the antiproliferative 

effect of somatostatin analogs [82]. 

However, the mechanism implicated in the 

mediation of cell growth inhibition does not 

involve activation of tyrosine phosphatase activity 

[82]. In these conditions, and contrary 

to SSTR-2, activation of SSTR-5 cannot 

counteract the effect of growth factors acting 

via tyrosine kinase-dependent receptors [82] 

such as epidermal growth factor, insulin-like 

growth factor, and insulin that are implicated 

in the growth of pancreatic and colon cancers 

[60, 90, 98, 99]. 

Only a few studies have so far addressed 

the potential benefit of combined treatment 

with octreotide and various chemotherapeutic 

agents. Lamberts et al. [100] combined 

octreotide with vincristine, methotrexate, 5- 

FU or suramin and found an additive interaction. 

More recently, Weckbecker et al. [101] 

demonstrated the inhibitory effect of octreotide 

in combination with the chemotherapeutic 

agents Taxol, 5-FU, doxorubicin and 

mitomycin C on the growth of AR42J pancreatic 

cancer cells in vitro. The dose-dependent 

antiproliferative effects of mitomycin C, 

doxorubicin and Taxol were synergistically 

enhanced by octreotide. Combinations of octreotide 

and 5-FU resulted either in additive 

or, at high concentrations of the chemotherapeutic 

agent, in synergistic interactions. These 

experiments suggest a modulatory role for octreotide 

in combination with widely used anticancer 

drugs. The additive to synergistic interaction 

of octreotide with these chemotherapeutic 

agents in in vitro and in vivo models 

warrants clinical studies to explore the potential 

of such combinations in the treatment of 

pancreatic cancer. 


Clinical Studies: 


Preliminary results of somatostatin analog 

therapy in patients with tumors other than 

pancreatic have been encouraging [102–106]. 

The rationale for the use of somatostatin and 

its analogs can be briefly summarized as follows. 

Somatostatin decreases growth of the 

normal pancreas [107], and at least one somatostatin 

analog, SMS 201-995, inhibits the 

growth of human pancreatic adenocarcinoma 

in nude mice [89]. The demonstration of somatostatin 

receptors in exocrine pancreatic 

adenocarcinomas [107] and the large body of 

evidence [73, 108–114] demonstrating antiproliferative 

activity of somatostatin and somatostatin 

analogs on experimental pancreatic 

neoplasms in vitro and in vivo justify clinical 

studies on the potential therapeutic role of 

these drugs in pancreatic cancer. 

The first clinical study on somatostatin 

analog treatment was published by Klijn et al. 

[115]. This group [74] went on to treat 14 

patients who had metastatic pancreatic cancer 

with three daily subcutaneous injections 

of octreotide (100–200 pg/injection) for an 

average of 7 weeks and observed no antitumor 

effect. 

Friess et al. [116, 117] and Ebert et al. 

[118], using octreotide at a low dose level 

[3 ! 100–200 Ìg/day) and a high dose level 

(3 ! 2000 Ìg/day), suggested that the effects 

of this somatostatin analog were dose-dependent. 

These observations are in accord with 

the dependent relationship of somatostatin 

analogs on the proliferation in breast cancer 

cell lines [119]. In the high-dose study of 

Friess et al. [117], the median survival increased 

from 4 to 6 months with symptomatic 

and clinical improvement. A positive impact 

on the course of disease was confirmed by a 

randomized trial of octreotide versus best 

supportive care [120] based on a low-dose 

therapy given 5 days/week. In this trial a significant 

advantage in duration of survival and 

in percentage of stable disease was observed 

for the octreotide-treated patients although no 

objective response was reached. 

The only objective response reported for 

somatostatin analogs in pancreatic cancer was 

observed by Canobbio et al. [121], who administered 

BIM 23014 in dosages between 

250 and 1,000 Ìg/day to 18 evaluable patients. 

However, only one partial response 

was observed at the highest dose level. Huguier 

et al. [122] in a randomized prospective 

study of 86 patients who were given a similar 

treatment regimen demonstrated no significant 

increase in median survival rates using 

life table analysis. 

Weckbecker et al. [123] have demonstrated 

potentiation of the anticancer effect of 

tamoxifen by concomitant infusion of highdose 

octreotide in the rat DMBA mammary 

cancer model. In order to further define a possible 

beneficial role for combination hormonal 

therapy with octreotide and tamoxifen, Rosenberg 

et al. [124] studied the effect of 

chronic administration of these two inhibitory 

agents on survival of a prospective series of 

12 consecutive patients with biopsy-proven 

ductal adenocarcinoma of the pancreas followed 

up from 1990 to 1993. Five of these 

patients had resectable disease and the remaining 

7 were deemed unresectable. Treatment 

consisted of 100 Ìg of octreotide subcutaneously 

3 times daily and 10 mg of tamoxifen 

orally twice daily. Patients had regular follow-up 

examinations at 4- to 6-week intervals 

until the time of death. The major outcome 

was the median duration of patient survival in 

months from the time of diagnosis. The outcome 

of this group of patients was compared 

to a cohort of 68 patients with a biopsy-documented 

diagnosis of ductal adenocarcinoma 

of the pancreas treated between 1985 and 

1990. Data was collected on age, gender, stage 


at diagnosis (based on the TNM classification 

of the International Union against Cancer), 

type of treatment and duration of survival 

from the time of diagnosis. 

The median survival times of the octreotide/tamoxifen-treated 

group and the historical 

cohort were 12 and 3 months, respectively, 

and the 1-year actuarial survival was 59 and 

16%, respectively. 

The median survival times of the resected 

(n = 5) and the unresected patients (n = 7) 

were 20 and 12 months, respectively, and the 

1-year actuarial survival was 80 and 31%, 

respectively. The median survival times of the 

resected octreotide/tamoxifen-treated group 

and the resected historical cohort were 20 and 

12 months, respectively, and the 1-year actuarial 

survival was 80 and 44%, respectively. 

The median survival times of the 7 unresected 

octreotide/tamoxifen-treated patients and the 

59 unresected historical patients were 12 and 

2.5 months, respectively, and the 1-year actuarial 

survival was 31 and 11%, respectively. 

Cox’s proportional hazard analysis confirmed 

that treatment and resection both independently 

predicted a longer survival (p ! 0.01). 

The significance of a possible interaction between 

both treatment and resection could not 

be fully determined due to the small sample 

size. 

Although an assessment of quality of life 

and pain control was not prospectively assessed 

in this study, a post hoc analysis demonstrated 

that morphine sulfate was not required 

until the final 4–6 weeks of illness in 9 

of 12 patients that had already succumbed to 

their disease. 

CT scanning examinations of the twelve 

cases were performed at intervals of 6–8 

weeks. No objective responses were seen in 

terms of tumor regression; rather the data was 

more consistent with a slowing of tumor progression. 

The 3 patients surviving at the time 

of publication had stable disease. 

Possible explanations for the apparent 

benefit of octreotide/tamoxifen therapy in 

this study include (1) diagnosis of the historical 

cohort later in the course of the disease, 

(2) diagnosis of the cases earlier in the course 

of the disease, or (3) a change in the biological 

aggressiveness of the disease as a consequence 

of treatment. The first two explanations are 

unlikely as the data indicated that the stage at 

which the disease was diagnosed in cases and 

the cohort was similar. While it might appear 

that more patients in the octreotide/tamoxifen-treated 

group underwent resection, and 

were therefore ‘more curable’, the TNM stage 

at the time of diagnosis was similar in both 

groups. 

The most recent report is the phase II study 

by Fazeny et al. [125], which was designed to 

investigate the efficacy and toxicity of octreotide 

combined with goserelin in patients with 

advanced pancreatic cancer. Octreotide was 

injected subcutaneously in dosages increasing 

weekly, starting with 50 Ìg twice daily, until 

the level of maintenance therapy of 500 Ìg 

3 times a day was reached. In addition, 3.8 mg 

goserelin acetate was administered subcutaneously 

at monthly intervals. A median of 7 

cycles (range 1–27 cycles) was applied. In 

comparison to the 40% of patients who had 

no change in their disease while on high-dose 

octreotide [117], Fazeny et al. [125] demonstrated 

that 500 Ìg octreotide 3 times per day 

in combination with goserelin resulted in one 

partial response and no disease progression in 

70% of participants. The observations suggest 

that combining octreotide with an LHRH 

analog might be of therapeutic benefit in patients 

with pancreatic cancer and could compensate 

for the potential advantage of a higher 

dose of octreotide. Overall, however, the regimen 

under investigation did not meet the criteria 

for sufficient antitumor effectiveness. 

Nevertheless, this study reinforces the concept 

that pancreatic cancer is principally re- 


sponsive to endocrine therapy and therefore 

the further investigation of hormonal manipulation 

seems worth while in the future. 

Conclusions 

In summary, while it is clear from the 

numerous studies conducted on experimental 

neoplasms in vitro and in vivo that somatostatin 

analogs inhibit growth of exocrine pancreatic 

cancers, clinical studies have demonstrated 

that somatostatin analog therapy 

probably does not produce an adequate clinical 

response in patients with advanced pancreatic 

cancer. 

An explanation for the discrepancy between 

the animal and human trials has not 

been elucidated. It is possible that a higher 

dose of somatostatin and its analogs should 

have been used in the human trials. Many of 

the animal studies used doses at least an order 

of magnitude greater than those used in the 

clinical trials. However, it is possible that the 

main reason for the failure of adjuvant treatment 

with somatostatin analogs is that most 

human pancreatic cancers lack receptors for 

somatostatin. Somatostatin binding sites were 

poorly expressed or not detected in many 

tumors from nonresponsive patients [60, 108, 

126], and this could be one of the explanations 

for a lack of direct antiproliferative 

effect of analog therapy. Moreover, considering 

the differences in the pharmacological 

profile and the biological function mediated 

by somatostatin receptor subtypes, the therapeutic 

response may depend on the subtype 

expression for a given tumor. In contrast to 

that observed in normal tissue or benign lesions, 

there is a loss of gene expression of 

SSTR-2 in pancreatic adenocarcinomas, and 

metastases derived from these primaries 

[127]. The loss of expression of SSTR-2 in 

neoplastic pancreatic cells may provide a 

growth advantage for tumors and their metastases. 

Therefore, a direct antiproliferative effect 

of somatostatin and its analogs may thus 

partly be excluded in the absence of SSTR-2. 

Alternatively, the different results of animal 

and human studies with different analogs of 

somatostatin may reside in the fact that there 

are different binding affinities of the various 

somatostatin analogs to somatostatin receptors 

[107, 126, 128]. 

Future Directions 

The management of pancreatic cancer has 

improved relatively little in the past few decades; 

the major advances have been better 

preoperative staging and a decrease in surgical 

morbidity and mortality. New cytotoxic 

drugs, novel biological agents or biological 

response modifiers, new surgical and radiotherapeutic 

techniques, or a combination of 

these modalities have all failed to have any 

appreciable impact on the final outcome of 

this disease. As local-regional treatment becomes 

more effective, the dominant site of 

failure has shifted to hepatic metastases. 

Therefore, future improvements in survival 

duration will result either from effective systemic 

or regional therapy directed at subclinical 

liver metastases or from strategies for 

screening and early diagnosis directed at increasing 

the number of patients eligible for 

potentially curative surgery. Further improvements 

in the quality of patient survival will 

result from the application of innovative multimodality 

therapy to carefully selected patients 

and the avoidance of unnecessary patient 

morbidity due to the inappropriate use 

of surgery, radiation, and/or chemotherapy in 

poorly selected patients with advanced disease. 

Although the indication for the use of somatostatin 

analogs in the treatment of pan- 


creatic cancer has yet to be decisively established, 

data from numerous in vitro and animal 

studies, as well as the results of several 

clinical trials reinforce the concept that pancreatic 

cancer is principally responsive to endocrine 

therapy. 

It has been suggested that improved methodology 

to assess the interaction of somatostatin 

(and its analogs) with its target at a cellular 

level may allow further development of this 

agent. A novel variation of this approach used 

an octapeptide analog of somatostatin that 

contained methotrexate attached to the ·amino 

group of D-phenylalanine in position 

1. Subsequent experiments with the MIA 

PaCa-2 human pancreatic cell lines in nude 

mice demonstrated significant inhibition of 

tumor growth [102]. 

In addition, the attractive features of this 

therapeutic concept are the absence of severe 

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Octreotide for Cancer of the Liver and 

Biliary Tree 

Elias A. Kouroumalis 

Department of Gastroenterology, University Hospital, Heraklion, Greece 

Key Words 

Octreotide W Hepatocellular carcinoma W 

Somatostatin receptors W Liver tumors 

Abstract 

Inoperable liver tumors have an unfavorable 

natural course despite various therapeutic 

modalities. Octreotide, a somatostatin 

analog, has shown considerable antitumor 

activity on animal models of various hepatic 

tumors and on isolated cell culture lines. In 

this paper, a review of the experimental evidence 

is presented. Moreover clinical papers 

of case reports of uncontrolled studies of 

patients are also reviewed. The majority of 

clinical studies provide evidence of a clinical 

and biochemical response of liver endocrine 

tumors while regression of tumor size is a 

rare event. A randomized controlled trial of 

octreotide in the treatment of advanced hepatocellular 

carcinoma has shown a significant 

survival benefit in the treated patients. 

Literature reports indicate a stimulatory ef- 

ABC 

Fax + 41 61 306 12 34 




0009–3157/01/0478–0150$17.50/0 



fect of octreotide on Kupffer cells as a possible 

antitumor mechanism, but other antiproliferative 

actions of octreotide have been suggested 

but not proved. Finally the question of 

the presence and affinity of somatostatin receptors 

on liver tumor tissue is discussed. In 

conclusion, according to our experience, octreotide 

administration is the best available 

treatment for advanced inoperable hepatocellular 

carcinoma and future better patient 

selection, based on receptor subtypes, might 

further improve the results. 

Introduction 


Although octreotide appears to have considerable 

antimitotic activity in various nonendocrine 

tumors, its use in treating liver cancers 

is mostly limited to endocrine metastatic 

or primary liver neoplasms, with only limited 

experience in other hepatic primaries. 

E.A. Kouroumalis, MD, PhD 

Associate Professor of Gastroenterology 

Head, Department of Gastroenterology 

University Hospital, PO Box 1352, Heraklion Crete (Greece) 

Fax +30 81 542085, E-Mail Kouroum@danae.med.uoc.gr

Epidemiology 

Liver neoplasms are among the most common 

tumors in many parts of the world. Hepatocellular 

carcinomas and cholangiocarcinomas 

comprise most of the liver tumors, 

while endocrine tumors, hepatoblastomas, 

bile duct cystadenocarcinomas, angiosarcomas, 

malignant hemangioendotheliomas, 

rhabdomyosarcomas and primary lymphomas 

are much rarer and have been reported 

mostly as case reports. An extensive review 

of liver tumors has recently been published 

[1]. 

Hepatocellular carcinomas have an annual 

occurrence of at least 1,000,000 new cases [2]. 

The geographical distribution is highly uneven 

with three main groups of countries being 

identified in terms of incidence rates. The 

highest rates are found in southeast Asia and 

tropical Africa with an incidence of as high as 

150,000 cases/year. The lower rates are found 

in the western countries, South America and 

India, while Japan, Middle East and the Mediterranean 

countries belong to the intermediate 

group [3, 4]. Overall hepatocellular carcinoma 

is estimated to be the seventh most 

common cancer in men and the ninth in 

women [5]. However, in Japan hepatocellular 

carcinoma is the third most frequent cause of 

male cancer deaths [6]. Furthermore, in Japan 

the number of deaths due to hepatocellular 

carcinoma is increasing constantly [7]. 

The reported increase in the hepatocellular 

carcinoma incidence in western countries is 

probably due to better diagnostic modalities 

and detection programs in patients with cirrhosis 

[8]. 

It seems that there is no racial predisposition 

to liver cancer. Differences among races 

can be explained on the basis of differences in 

exposure to well-established risk factors, like 

HBV and HCV infection and aflatoxins or 

other chemicals [3]. A similar explanation can 

be given for the observed differences among 


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immigrants when compared to the population 

in their native country. It has been established 

that the incidence of hepatocellular carcinoma 

in immigrants from countries where the 

prevalence of the disease is high falls to that of 

their country of adoption. The mean age of 

patients is lower in high incidence areas, and 

Africans seem to develop the tumor earlier in 

life than Asians. 

The incidence rates for cholangiocarcinoma 

are highest in southeast Asia, particularly 

Hong Kong and Thailand [9,10]. In these 

areas the high incidence of the disease is 

linked to infestations with liver flukes, like 

Clonorchis sinensis and Opisthorchis viverrini. 

In western countries, cholangiocarcinomas 

are much less common, but a significant incidence 

occurs in patients with inflammatory 

bowel disease and primary sclerosing cholangitis 

[11, 12]. 

Among the rarer tumors of the liver, epidemiological 

data exists for hepatoblastomas. 

The majority of hepatoblastomas (90%) occur 

under 5 years of age and account for almost 

40% of all liver tumors in childhood but are 

responsible for only 0.2–5.8% of all infant 

malignancies [13, 14]. 

Epidemiology of liver endocrine tumors 

has not been well established. 

Natural History 

Little is known about the natural history of 

untreated primary liver tumors, since some 

form of treatment is usually attempted. Survival 

in cases of hepatocellular carcinoma is 

strongly related to the Okuda classification 

[15]. In a recent study in Crete, a median survival 

of 16, 7 and 2 months for Okuda stage I, 

II and III liver tumors, respectively, was observed 

for patients who did not receive any 

therapy [16]. These findings are in agreement 

with earlier studies [17, 18]. Interestingly in 

this study, HCV positivity was not a risk factor 

for decreased survival, while HBeAg or 


anti-c positivity carried a high relative risk of 

3.8 and 3.4, respectively. This observation is 

in accord with the Japanese experience where 

HBV-related cancer has a reduced 3-year survival 

rate compared to HCV-related disease 

[19]. In our study albumin concentration was 

inversely related to mortality with an 11% 

decrease in the hazard rate for each unit 

increase of this protein [16]. The natural history 

of liver metastatic endocrine tumors is 

less well known. In a recent study of patients 

with histologically confirmed liver metastases 

of endocrine tumors (gastrinomas, carcinoids, 

nonfunctioning pancreatic tumors and calcitonin-secreting 

tumors), a 90% progression 

was observed within a mean of 11.5 months 

[20]. The natural history of cholangiocarcinomas 

is dismal. Most patients deteriorate 

steadily and die within a few months after 

diagnosis [21]. 

Current Therapeutic Approach 

Undoubtedly, the best available treatment 

for all liver tumors is complete surgical resection. 

In a recent report, 532 cirrhotics 

with hepatocellular carcinoma were evaluated. 

Some form of liver resection was feasible 

in 44.7% of them (238 patients). Hospital 

mortality was 4.6% and 5-year actuarial survival 

rate was 41.3% [22]. Forty-one patients 

in this series were transplanted with a 5-year 

actuarial survival rate of 58.1%. Moreover, in 

most countries a differential diagnosis of hepatocellular 

carcinoma is made when the tumor 

is already inoperable. 

Other therapeutic modalities for liver tumors 

include selective arterial embolization 

with either iodine-131 Lipiodol or Lipiodolepirubicin 

[23]. In a recent report [24], the 

median survival rates at 6 and 12 months following 

Lipiodol-epirubicin were less than 65 

and 50%, respectively. Only when embolization 

is performed in stage I Okuda patients, 

the 12-month survival rates are greater than 

50% [25]. Moreover, following several embolizations, 

arterial obstruction may give rise to 

the development of small collateral arteries 

that make repeated attempts to embolize the 

tumor difficult. Development of these collaterals 

may render the tumors resistant to emboli 

and their growth continues despite repeated 

treatments [26]. Arterial chemoembolization 

has been used in the treatment of metastatic 

endocrine liver tumors as well as primary 

hepatocellular carcinoma [20]. In a large 

series of carcinoid tumors, 40 patients with 

bipolar hepatic disease underwent embolization 

as primary treatment, followed by octreotide 

administration [27]. The 5-year survival 

rate was 56% and was accompanied by markedly 

decreased 5-hydroxyindole-acetic acid 

(5-HIAA) levels. 

Percutaneous ethanol injection has also 

been used extensively to treat hepatocellular 

carcinomas, especially tumors not exceeding 

2–3 cm in diameter [28]. Histopathologic examination 

after therapy revealed that in many 

cases ethanol injection can completely destroy 

the tumor [29, 30]. In addition ethanol injection 

has achieved considerably high long-term 

survival rates. In a study of 162 hepatocellular 

carcinoma patients with a single nodule the 

1-, 2- and 3-year survival rates were 90, 80 

and 63%, respectively [30]. In another Italian 

study of ethanol injection of small tumors, 

survival rates were clearly associated with the 

Child-Pugh classification. Five-year survival 

rates of 47, 29 and 0% were reported for Child 

A, B and C, respectively [31]. Similar findings 

were found in 105 western patients with hepatocellular 

carcinoma smaller than 5 cm in 

diameter where the 5-year overall survival 

rate was 32% on Child A and B patients [32]. 

However, local recurrences are frequent, particularly 

when the tumor size exceeds 3 cm in 

diameter [33]. Moreover, in our experience, 

ethanol injection of larger tumors is of limited 

value, mainly because the alcohol diffuses 

152 Chemotherapy 2001;47(suppl 2):150–161 Kouroumalis

apidly into the surrounding liver parenchyma, 

because these large liver cancers are well 

vascularized (unpubl. observations). Fewer reports 

exist on the use of ethanol injection in 

metastatic liver tumors [34, 35] and cholangiocarcinomas 

[36]. Long-term survivals have not 

been reported so far for these tumors, but surgical 

excision of some tumors after ethanol 

injection showed an extensive necrosis ranging 

from 50 to 90% of the tumor. 

Hepatocellular carcinomas are assumed to 

be radioresistant. However radiation therapy 

has been recently reported in 22 patients with 

hepatocellular cancer receiving a total dose of 

58–68 Gy [37]. In these patients the tumor 

size never exceeded that prior to radiotherapy 

except in 1 patient. The 1-year survival rate 

was 68%, but definitive conclusions on this 

form of treatment cannot be reached, without 

further studies since the treated tumors in this 

group were very heterogeneous and additional 

modalities were also used. Three of the patients 

had multiple ethanol injections and 17 

others had undergone transarterial embolization 

before the radiation therapy. Only 2 patients 

had radiation as the only therapeutic 

modality. 

Hormonal manipulations have been used 

for the treatment of hepatocellular carcinomas. 

In a recent randomized controlled study, 

80 patients with Okuda II and Okuda III 

hepatocellular carcinoma were randomized to 

either tamoxifen treatment or no treatment. 

Tamoxifen-treated patients were reported to 

have a 22% 1-year survival compared to almost 

10% of the nontreated patients. Only 

minor side effects were attributable to tamoxifen 

[38]. 

The antiandrogen flutamide has been 

shown to have no therapeutic benefit in advanced 

hepatocellular carcinoma. The median 

survival time of patients treated with the 

drug was 2–5 months [39]. In a large antiandrogen 

trial of 244 patients with hepatocel- 


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lular carcinoma there was no survival advantage 

and indeed survival rates seemed even 

better for the placebo group [40]. In cholangiocarcinomas 

no effective drug treatment 

has been reported. 

Chemotherapy has been unsuccessful in 

the treatment of hepatocellular carcinoma as 

emphasized by two recent reports using combination 

chemotherapy. In a pilot study, intrahepatic 

arterial chemotherapy with methotrexate, 

5-fluorouracil, cisplatin and subcutaneous 

interferon-·2b were used in 16 patients 

with advanced hepatocellular carcinoma with 

portal thrombosis [41]. Median survival was 7 

months only. In another phase II Italian multicenter 

study, 5-fluorouracil plus high-dose 

levofolinic acid and hydroxyurea were used in 

50 patients with hepatocellular carcinoma. 

Median survival was again a disappointing 

5.8 months and many patients developed 

mild leukopenia and thrombocytopenia [42]. 

Scientific Background 

Presence of Somatostatin Receptors in 

Neoplastic Tissue 

The diverse biological effects of somatostatin 

are mediated through somatostatin receptors 

that are coupled to a variety of signal 

transduction pathways. These include adenylate 

cyclase, ionic conductance channels and 

protein phosphatase [43]. Recently, five such 

receptors have been cloned. They belong to 

the family of G-protein-coupled receptors [44, 

45]. The SSTR-2 receptor has so far been best 

characterized, and its negative effect on cell 

growth has been established [45]. According 

to these recent findings, the tyrosine phosphatase 

SHP1 is an essential component of 

the inhibitory growth signalling mediated 

through this receptor [46]. In vitro studies 

have shown that octreotide demonstrates 

high affinity binding properties to SSTR-2, 


SSTR-3 and SSTR-5 receptors, while no binding 

affinity is found towards receptors 

SSTR-1 and SSTR-4 [47–49]. Therefore when 

octreotide receptor studies are performed using 

labelled octreotide only three out of the 

five known receptors are identified. 

The presence of somatostatin receptors has 

been verified in many endocrine tumors by 

autoradiographic techniques. Moreover, the 

presence of somatostatin receptors has been 

extensively investigated in vivo by using 

111 In-labelled octreotide scintigraphy [50, 51]. 

In a recent study of metastatic liver colorectal 

carcinomas, somatostatin receptors were 

identified in only 1 out of 10 patients included 

in that study. This study would suggest 

that either octreotide scintigraphy is not a sensitive 

method for detection of somatostatin 

receptors in these patients or that the tumors 

do not express such receptors [52]. 

Interestingly, in a small series, octreotide 

scintigraphy revealed SSTR receptors in 57% 

of patients with metastatic liver neuroblastomas, 

and patients with receptors had a better 

outcome than those who were negative [53]. 

Similar findings were found in a single case of 

neuroblastoma [54]. 

In a large series of patients with the Zollinger-Ellison 

syndrome, octreotide scintigraphy 

proved to be very accurate in detecting extrahepatic 

disease but the specificity of liver hot 

spots was only 60% [55]. Similar findings 

were reported for carcinoid tumor, where extrahepatic 

abdominal metastases were easily 

detected by scintigraphy but the detection of 

liver tumors was not superior to CT or ultrasonography 

[56–58]. 

In another study of 18 patients with hepatic 

neuroendocrine tumors, octreotide scintigraphy 

showed a sensitivity of 94%, indicating 

that at least in these tumors, there is a 

large number of receptors easily detected by 

111 In-octreotide [59]. In contrast, it seems that 

medullary thyroid carcinomas contain very 

few somatostatin receptors as identified by 

scintigraphy [60]. Since octreotide mostly 

binds to SSTR-2 receptors and to a lesser 

extent to SSTR-3 and SSTR-5 receptors, octreotide 

scintigraphy will demonstrate only 

the presence of these subtypes. Receptors in 

hepatocellular carcinomas were detected by a 

radioligand method in our own study, but 

identification of the receptor subtypes was not 

done [61]. 

Inhibition of Tumor Growth: 

In vitro Studies 

There are very few data from in vitro studies. 

In pancreatic tumor cells, somatostatin 

and analogs antagonize the mitogenic effect of 

growth factors, acting on tyrosine kinase receptors 

such as epidermal growth factor [62]. 

In human hepatocellular cell cultures, a 4-fold 

increase in the expression of IGF-1 binding 

protein has been reported after incubating the 

cells with octreotide [63]. Since IGF-1 is considered 

to be a trophic factor in hepatocellular 

carcinomas, this upregulation suggests that 

any antimitotic effect of octreotide on hepatocarcinomas 

is not likely to be mediated via 

inhibition of trophic hormones. However, 

further studies need to be done. 


Octreotide: Animal Models 

Octreotide has been found effective in inhibiting 

tumor growth in a variety of experimental 

models. Early studies demonstrated 

that experimentally derived (fibrosarcoma 

and adenocarcinoma) liver metastases are inhibited 

by octreotide [64, 65]. In an interesting 

study, nude mice were xenografted with a 

neuroendocrine cell line and received treatment 

with either high-dose octreotide or interferon-· 

or a combination of both. A 3-fold 

increase of apoptotic cells was observed in the 

octreotide group while the interferon-· group 

showed no evidence of increased apoptosis. 


However, tumor growth inhibition was more 

pronounced in the combination group [66]. 

Hepatocarcinogenesis induced by nitrosomorpholine 

in rats was significantly less in animals 

treated with somatostatin [67]. Morris hepatoma 

3924A cells were implanted in the liver and 

subcutaneous tissues of rats which were partially 

hepatectomized and treated with either 

octreotide or placebo. Partial hepatectomy significantly 

increased tumor growth but treatment 

with octreotide resulted in a 10-fold 

decrease in liver tumor growth and a 3-fold 

reduction in subcutaneous tumor growth compared 

to controls [68]. 

Inhibition of liver regeneration after partial 

hepatectomy by octreotide has been reported 

in another study. Octreotide did not 

influence hepatic or portal blood flow. However, 

octreotide significantly increased reticuloendothelial 

system activity [69]. In the same 

study the growth of adenocarcinoma and fibrosarcoma 

cells implanted into the partially 

hepatoctomized rat livers was significantly 

decreased by octreotide. These results confirm 

earlier observations by the same group 

who demonstrated that blockade of the reticuloendothelial 

system resulted in an increased 

tumor growth while octreotide increased the 

activity of the reticuloendothelial system [70, 

71]. However, octreotide only partially reversed 

the inhibition of growth and development 

of hepatic metastases in rats with gadolinium 

chloride-induced blockade of the 

Kupffer cells. This observation suggests that 

apart from stimulation of reticuloendothelial 

system, octreotide might have other mechanisms 

of action in inhibiting the growth 

of hepatic tumors. Two other mechanisms 

might be implicated. First, a direct antiproliferative 

effect through receptor-mediated 

growth inhibition has been postulated but 

never proved. Second, a reduction in tumor 

blood flow is a further possibility whereby 

octreotide may inhibit the growth of hepatic 


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metastases. Interestingly, the results from the 

above mentioned group do not confirm earlier 

studies in experimental hepatic metastases 

attributing the arrest of tumor growth to 

a reduction of hepatic arterial flow [72]. It 

should be noted, however, that reduction of 

tumor blood flow by octreotide may be dependent 

on the vascularity of the tumor. Fibrosarcomas 

are well vascularized while adenocarcinomas 

are relatively avascular and this difference 

might account for the divergent results 

reported in these two studies. Moreover, since 

tumor blood vessels lack receptors for vasoactive 

substances, any change of blood flow 

could be indirect through an effect on blood 

flow of the normal liver vessels. The distribution 

of octreotide receptors in normal liver 

blood vessels has not been studied. Finally, 

another possibility for the antitumor effect of 

octreotide could be an indirect action through 

inhibition of hormonal trophic factors. Although 

this possibility has not been adequately 

explored, there is evidence that this might 

not be an important factor, as previously 

mentioned. 

Rats were subcutaneously inoculated with 

mammary adenocarcinoma cells. A combination 

treatment with somatostatin plus insulin, 

which greatly increased the insulin/glucagon 

ratio, resulted in a reversed cachexia of the 

host, an effect not found with somatostatin 

alone. No appreciable effect on tumor growth 

was reported [73]. 

Clinical Studies 

Results from Case Reports 

Most, if not all case reports refer to metastatic 

liver disease either from primary endocrine 

malignancies or from adenocarcinoma 

of the large bowel. An extremely rare case of a 

28-year-old woman with a metastatic ACTHsecreting 

pituitary carcinoma has been re- 


ported. Liver metastases from this ACTHsecreting 

pituitary carcinoma have been 

treated with octreotide for almost 2 years. 

Paradoxically ACTH production was stimulated 

by octreotide treatment [74]. 

Despite this unexplained secretion of 

ACTH, the development of the disease was 

very slow. Unfortuantely, the influence of octreotide 

cannot be fully assessed since the 

patient had a complementary hepatic chemoembolization 

treatment. 

Most case reports deal with either metastatic 

or the rare primary liver carcinoids. 

Only 18 cases of primary liver carcinoids have 

been reported so far. One such case of a 

patient with a malignant carcinoid of the liver 

with 18 years of follow-up has recently been 

reported [75]. Artery chemoembolization, hepatic 

lobectomy and octreotide treatment 

have all been used for the treatment of carcinoid 

in this patient who continues to be 

asymptomatic at the time of publication. A 

5-year survival has also been reported in a 

patient with the carcinoid syndrome after octreotide 

administration [76]. Two cases of primary 

liver VIPomas treated with octreotide 

and followed by liver surgery also resulted 

in amelioration of symptoms. One of the 

patients experienced diarrhea, hypokalemia 

and hypercalcemia. All these manifestations 

were reversible after treatment. Again arterial 

liver embolization was also used limiting the 

assessment of octreotide benefit [77]. This 

study confirms earlier case reports of longterm 

successful treatment of hepatic VIPomas 

with octreotide [78–80]. Patients with metastatic 

medullary thyroid carcinomas in the 

liver treated with octreotide have been reported 

to have a good symptomatic and biochemical 

response [81] despite the fact that 

results from octreotide scintigraphy indicated 

a relative lack of receptors in this type of 

tumor [60]. However, caution should be exercised 

in interpreting this finding. As men- 

tioned before scintigraphy will only detect 

SSTR-2, SSTR-3 and SSTR-5 receptors to 

which octreotide mostly binds. Moreover, 

since this is not a sensitive method, relatively 

large doses of octreotide might act on low 

receptor levels, not detected by scintigraphy. 

From case reports the only conclusion that 

can be drawn is that octreotide provides an 

effective symptomatic control. There is only 

one case report of a 68-year-old male with 

advanced hepatocellular carcinoma, who was 

successfully treated with the long-acting somatostatin 

analog lanreotide [82]. No case 

reports of hepatocellular carcinoma treated 

with octreotide have been published. 

Clinical Trials 

Clinical trials of octreotide in liver tumors 

are limited and mostly uncontrolled. In an 

early study of octreotide effectiveness on liver 

metastases derived from endocrine tumors, 

a significant reduction in tumor blood 

flow was caused by octreotide in 8 patients 

[83]. This finding was associated with a slight 

temporary reduction of the size of the tumors. 

Octreotide has been used as a palliative 

treatment of metastatic carcinoids of the liver. 

In an uncontrolled trial, 40 patients with 

bipolar liver disease were treated this way. 

Urinary 5-HIAA levels were still reduced by 

55% after 71 B 11 months of follow-up. The 

5-year survival was 56%. Symptomatic relief 

was found in 85% of patients. Most deaths 

were related to cardiovascular incidents. For 

comparison, 14 patients were treated by surgical 

resection alone, which achieved anatomical 

and biochemical cure. 5-HIAA levels were 

normal after 69 B 6.2 months of follow-up 

and these patients were asymptomatic. Two 

out of 14 patiens died of causes unrelated to 

the tumor. Despite the fact that there was no 

control group for the octreotide group, it is 

concluded that administration of octreotide 


offers a symptomatic and survival benefit 

[84]. This report confirms earlier trials. In the 

largest report from the Mayo Clinic, 66 patients 

with metastic carcinoid of the liver were 

treated with octreotide. Complete or nearcomplete 

control of symptoms of diarrhea 

was obtained in 77%, of flushing in 87% and a 

50% reduction of urinary 5-HIAA was obtained 

in 70% of patients. The mean survival 

was more than 3 years, which is longer than in 

previous reports with combination chemotherapy 

[85]. 

In another smaller uncontrolled clinical 

trial, 10 patients with metastatic liver carcinoids 

were treated with artery embolization, 

intra-arterial 5-fluorouracil and octreotide. In 

60% of the patients the tumor size was reduced 

by 50%, while the mean survival was 

58 months [86]. 

In a phase II clinical trial, patients with 

metastatic carcinoid liver tumors were treated 

with either 500 or 1,000 Ìg t.i.d. of octreotide. 

Some patients with metastatic medullary thyroid 

carcinoma, pancreatic islet cell tumors 

and Merkel cell carcinomas were also included. 

The carcinoid syndrome was documented 

in 16 patients and abnormal urinary 

5-HIAA excretion in 15. Median treatment 

duration was 5 months. Tumor regression, 

symptom response and biochemical response 

were evaluated. Symptomatic and biochemical 

responses were reported as satisfactory 

with an overall response of 73 and 77%, 

respectively. However, tumor regression was 

reported in only 3% of patients [87]. In 27 

patients, the disease was stabilized for at least 

6 months (range 6–32 months). The median 

survival for all patients was 22 months (range 

1–32 months). 

In the prospective German octreotide multicenter 

phase II trial, 200 Ìg octreotide t.i.d. 

were given daily for 1 year to 103 patients 

with advanced nonoperable endocrine tumors. 

Sixty-four patients had a functional 


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tumor. Most of the patients had either carcinoids 

or islet cell tumors. Fifty-two patients 

had a CT-confirmed tumor progression before 

treatment. Thirty-seven percent of patients 

from this group experienced stabilization 

of tumor growth for at least 3 months. 

Median duration of stable disease was 18 

months. Tumor regression has not been seen 

in any patient [88]. Different results have 

been reported in an uncontrolled trial of somatostatin 

in liver metastatic endocrine tumors, 

where no objective response was found 

[20]. In conclusion, octreotide seems to have a 

beneficial effect on symptomatology and biochemical 

response of endocrine tumors. It 

also seems to stabilize the tumor growth in 

some patients while tumor regression is not 

observed. 

There is only one randomized controlled 

trial of octreotide in the management of hepatocellular 

carcinoma [61]. Somatostatin receptors 

were identified in liver biopsy tissue 

from various diseases, including hepatocellular 

carcinomas, using a radioligand method. 

Fifty-eight patients, the majority of whom 

had Okuda stage II and III tumors, were randomized 

to receive either no treatment or 

subcutaneous octreotide 250 Ìg twice daily. 

Treated patients had a significantly increased 

median survival (13 months) compared to 

controls (4 months) and a significantly increased 

cumulative survival rate at 6 and 12 

months (75 vs. 37% and 56 vs. 13%, respectively). 

Furthermore, the quality of life was 

improved in the treatment group. In 5 patients, 

small satellite tumors, below 3 cm in 

diameter, disappeared after 6–12 months of 

treatment. In 4 additional patients, the size of 

the tumor remained unchanged. In view of 

the results from this trial carried out in our 

unit [61], we currently believe that octreotide 

is the treatment of choice for inoperable hepatocellular 

carcinoma. Hitherto no trial has 

been done on cholangiocarcinomas. 


Conclusions 

There is substantial evidence from experimental 

studies and from a controlled clinical 

trial in man that octreotide is a useful drug for 

the treatment of not only metastatic liver 

endocrine tumors, but also of primary hepatocellular 

carcinoma, either as an adjuvant therapy 

after surgical resection, or a sole treatment. 

The relative lack of side effects of 

octreotide is particularly promising in this 

respect. Caution should be excercised in patients 

with diabetes since hyperglycemia can 

be a problem. 

Treatment of hepatic metastases derived 

from colon carcinoma also seems to be another 

area in which octreotide treatment is justified, 

although controlled trials in patients are 

necessary to assess the efficacy of this somatostatin 

analog in this indication. 

Evidence that the antiproliferative effect of 

octreotide on hepatic tumors is immune-mediated 

via the stimulation of the reticuloendothelial 

system of the liver has been carefully 

documented [70, 71]. However, other modes 

of action of octreotide on hepatic tumors 

require further investigation. 

Projections for the Future 

In a recent study, gallbladder visualization 

was obtained with octreotide scintigraphy, indicating 

that somatostatin receptors are also 

found in the gallbladder mucosa [89]. If this 

finding can be verified by more specific studies, 

octreotide may prove to be useful for the 

treatment of cholangiocarcinomas. 

Careful examination of the receptor subtypes 

in liver and bile duct tissue in health and 

disease using more sophisticated techniques 

than octreotide scintigraphy is urgently required. 

Moreover, the mode of antiproliferative 

action of octreotide should be delineated. 

Besides the possible immune modulation 

through stimulatory effects on Kupffer cells, 

there are certain other possibilities that have 

not been adequately explored. There is also 

evidence for a possible effect of octreotide 

on hepatic tumor angiogenesis, but further 

studies are required. Similarly a direct antiproliferative 

effect through somatostatin receptors, 

or through inhibition of tumor trophic 

hormones should be examined. Moreover, 

a recent report indicates that a somatostatin 

analog activates hepatoma cell apoptosis 

in vitro in both drug-sensitive and drugresistant 

cell lines [90]. This is a possible 

mechanism of octreotide antitumor activity 

that should be further explored. Another area 

for future research is the development of longacting 

octreotide or somatostatin analogs, 

making protracted treatment with octreotide 

more acceptable to patients. In this respect 

Sandostatin-LAR and lanreotide development 

might prove of particular significance. 

Note added in proof 

Recent studies [91, 92] have explored the clinical 

potential of lanreotide (30 mg i.m. every 14 days) in 

the treatment of advanced hepatocellular carcinoma. 

Besides a successful case report [91], 38% of patients 

had stable disease while the remaining ones progressed 

during treatment. Since in vitro studies [92] clearly 

demonstrated the ability of lanreotide to decrease the 

S phase fraction along with induction of apoptosis in 

Hep G2 cells in a dose-dependent fashion, the disappointing 

clinical results could be ascribed to the use of 

suboptimal doses of the peptide. 


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Somatostatin Analogs in Oncology: 

A Look to the Future 

Spencer A. Jenkins a Howard G. Kynaston b Nick Davies c 

John N. Baxter a David M. Nott d 

a Academic Department of Surgery, Postgraduate Medical School, Morriston Hospital, 

Swansea, b Department of Urology, University Hospital of Wales, Cardiff, c Departments of 

Surgery, Royal Bournemouth Hospital, and d Chelsea and Westminster Hospital, London, UK 

Key Words 

Somatostatin analogs W Neoplasms W 

Therapy W Review 

Abstract 

In the past 15 years considerable advances 

have been made in our understanding of the 

molecular pharmacology of the mechanisms 

whereby somatostatin and its analogs mediate 

their direct and indirect antineoplastic 

effects. However, some important issues remain 

to be resolved, in particular the functional 

roles of the individual somatostatin 

receptors (SSTR-1–5) in tumor tissue and 

up- or downregulation of the hSSTRs with 

prolonged administration of somatostatin 

analogs. Answers to these questions are essential 

before we can maximize the therapeutic 

efficacy of somatostatin analogs in 

cancer. For example, is continuous administration 

more or less effective than intermittent 

therapy? The role of somatostatin 

analogs in the management of acromegaly 

ABC 

Fax + 41 61 306 12 34 




0009–3157/01/0478–0162$17.50/0 



and to a lesser extent neuroendocrine tumors 

is firmly established. The development 

of depot preparations of all 3 somatostatin 

analogs currently available for clinical use 

will undoubtedly improve both patient compliance 

and quality of life in patients with 

these conditions. There are only likely to be 

minor differences in the therapeutic efficacy 

of octreotide, lanreotide and vapreotide 

since all three analogs exert the majority of 

their antineoplastic effects via hSSTR-2 and 

hSSTR-5 and at the end of the day, price 

may well dictate which of these drugs oncologists 

use to provide symptomatic palliation 

of acromegaly and neuroendocrine tumors. 

Apart from some notable exceptions, 

somatostatin analog therapy has proven to 

be very disappointing in the management of 

advanced malignancy. Improvements in the 

management of solid tumors are likely to 

come only from combination therapy of somatostatin 

analogs with cytotoxic agents or 

other hormones in both advanced malignancy 

and in the adjuvant setting. Clinical 

S.A. Jenkins, MD 

Departments of General Surgery & Urology 

Ward 5-A, University Hospital of Wales 

Health Park, Cardiff CF 14 4XW (UK) 

Tel. +44 2920 744971, Fax +44 2920 744179

trials with clear-cut objective outcome measures 

and health-related quality of life assessment 

are needed to evaluate the therapeutic 

efficacy of combination treatment in 

advanced malignancy and as an adjuvant to 

surgery. Particular attention needs to be paid 

to possible adverse effects of somatostatin 

analog therapy on the immune response to 

cancer. Further studies are required to establish 

whether the adverse effects of somatostatin 

analog therapy alone or in combination 

with cytotoxics or other hormones can be 

reversed with appropriate immunomodulatory 

treatment. Targeted somatostatin analog 

radiotherapy and chemotherapy are currently 

being investigated and the results of 

these studies are awaited with interest. Novel 

approaches using combinations of somatostatin 

analogs with antiangiogenic drugs 

or gene therapy are of particular interest and 

may provide important advances in the management 

of cancer in the not too distant 

future. 

Introduction 


Hypothalamic factors which regulate the 

secretion of growth hormone were first identified 

in 1968 by Krulich et al. [1]. Subsequently, 

in 1973, Brazeau et al. [2] identified a 14amino 

acid peptide inhibitor of growth hormone 

release-inhibiting factor (SRIF), the 

name subsequently being changed to somatostatin. 

Following production of a synthetic 

replicate of the native hormone [3] it soon 

became apparent that somatostatin had a 

wide variety of effects on the endocrine, gastrointestinal, 

immune, circulatory and central 

nervous systems. 

Although somatostatin is widely distributed 

throughout the body, immunochemical 

studies indicated that the peptide is confined 

to three cell types. Somatostatin is found in 

classic ‘open type’ endocrine cells from which 

it is directly excreted into the blood [4], paracrine 

cells with long cytoplasmic extensions 

which terminate on putative effector cells [5] 

and in neurones where it may function as a 

neurotransmitter [6–8] or is released from the 

nerve endings into the blood [4]. Thus, depending 

on its site of elaboration, somatostatin 

may function as a hormone, a neurohormone, 

a neurotransmitter or a parahormone. 

Consequently, the sites of elaboration 

and release of somatostatin in the body, together 

with a short half-life of approximately 

2 min [9], make it the almost ideal regulatory 

peptide. 

The plethora of effects mediated by somatostatin 

led to the suggestion that the hormone 

could have a therapeutically beneficial 

effect in a wide variety of indications. However, 

the short half-life of somatostatin restricts 

its application as a drug since it has to 

be administered by a continuous infusion 

to maintain a sustained biological effect and 

hence a therapeutic response. Although intravenous 

administration of somatostatin does 

not present a problem in the management of 

patients hospitalized for acute indications 

such as variceal and nonvariceal upper gastrointestinal 

bleeding or acute pancreatitis, its 

short plasma half-life is a serious disadvantage 

to the exploitation of its full therapeutic 

potential in those conditions requiring longterm 

treatment. Not surprisingly therefore, 

following determination of the structure of 

somatostatin, peptide chemists began to try 

and synthesize more stable agonists with a 

longer duration of action. Furthermore, since 

somatostatin inhibits the release of such a vast 

array of hormones, the other and perhaps the 

most formidable challenge for the peptide 

chemists was to design analogs which were 

not only stable, but more selective in their 

mode of action. 

Somatostatin Analogs in Oncology Chemotherapy 2001;47(suppl 2):162–196 163

Mechanism of Action of 


In the past 15 years substantial advances 

have been made in elucidating the mechanisms 

whereby somatostatin and its analogs 

exert their antineoplastic effects [for comprehensive 

reviews see 10–15]. In brief, somatostatin 

and its analogs elicit direct antineoplastic 

effects via a complex variety of intracellular 

transduction pathways leading to inhibition 

of cell proliferation or by stimulation of 

apoptosis. Clearly, the direct antineoplastic 

effects of somatostatin and its analogs are 

confined to cells expressing hSSTRs. However, 

somatostatin and its analogs can exert 

antineoplastic effects via a number of indirect 

mechanisms including inhibition of the release 

and end-organ effects of trophic growth 

factors and hormones, angiogenesis and a reduction 

in tumor blood flow. Stimulation of 

the reticuloendothelial system (RES) appears 

to be a very important mechanism whereby 

somatostatin and its analogs inhibit the 

growth and development of liver tumors [11]. 

The indirect antineoplastic effects of somatostatin 

and its analogs are independent of the 

presence of hSSTRs on the tumor cells. Therefore, 

a possible beneficial effect of somatostatin 

analog therapy is not restricted to tumors 

expressing hSSTRs. 

Future Prospects 

Before discussing how it may be possible to 

improve somatostatin analog therapy of neoplasia 

it is important at the outset to emphasize 

the limitations of such treatment. Thus, 

apart from the stimulation of apoptosis by 

somatostatin and its analogs which could be 

considered cytotoxic, the remainder of their 

antineoplastic effects are cytotoxic. Therefore, 

somatostatin analog therapy of neoplasia 

in symptomatic patients cannot be expected 

to be curative but only to provide remission 

and palliation of unpleasant and sometimes 

life-threatening side effects, thereby increasing 

survival and improving the quality of life. 

This is well illustrated by the experience of 

octreotide in the management of hypersecretory 

GEP tumors. Control of hormone hypersecretion 

by octreotide is observed in approximately 

55% of patients with vasoactive intestinal 

polypeptide (VIP)-omas and a reduction 

in the size of liver metastases has been reported 

in approximately 10%. Control of tumor 

growth occurs in approximately 50% of 

VIP-oma patients treated with octreotide. 

However, the reduction in the size of liver 

metastases secondary to VIP-omas is temporary 

and transient and control of tumor 

growth in response to octreotide therapy is 

lost after 8–16 months of treatment. Eventually, 

all the patients escape from the inhibitory 

effects of octreotide therapy on tumor progression 

and hormonal hypersecretion and become 

symptomatic. The major challenge for 

somatostatin analog therapy in oncological indications 

is, therefore, to determine how we 

can take full advantage of their antineoplastic 

effects which, of course, will vary with the 

type of cancer being treated. For most solid 

tumors, surgery offers the only chance of cure 

and should be offered to all patients who are 

fit enough to undergo surgical intervention. 

However, for the majority of patients, a truly 

curative resection of their tumor(s) may not be 

feasible. In such patients debulking or neoadjuvant 

therapy to reduce the tumor burden 

may improve the response to adjuvant therapies 

and, in some cancers, increase the resectability 

rate. Finally, in patients with advanced 

metastatic malignancy, surgery may be contraindicated 

and in this situation effective palliation 

to maintain quality of life for as long 

as possible is the primary challenge for the 

oncologist. It seems likely, therefore, that the 

164 Chemotherapy 2001;47(suppl 2):162–196 Jenkins/Kynaston/Davies/Baxter/Nott

major role of somatostatin analog therapy is an 

adjuvant to surgery and in providing effective 

palliation for patients with advanced malignancies 

for most of the major cancers. There 

are, however, some exceptions to this rule. For 

example, elderly acromegalics with small tumors 

are particularly sensitive to the antineoplastic 

effects of octreotide. Furthermore, no 

escape from the inhibitory effects of octreotide 

on the hypersecretion of hormones by pituitary 

tumors occurs in the vast majority of acromegalics 

even after 10 years of therapy. Therefore, 

in elderly acromegalics, somatostatin analog 

therapy is the treatment of choice since the 

life expectancy of such patients is unlikely to be 

influenced by their pituitary tumor. 

In order to maximize the therapeutic potential 

of somatostatin analog therapy in neoplasia 

there are a number of areas which 

require further investigation, in particular, 

the significance of heterogeneous expression 

of individual hSSTRs within and between different 

tumors, and their functional role and 

their desensitization and downregulation. 

Expression and Functional Role of 

Somatostatin Receptors in Human 

Tumors 

Early competitive binding assays using radiolabelled 

somatostatin and its analogs and 

autoradiography indicated that somatostatin 

receptors were expressed in a wide variety of 

normal tissue and tumors such as those of the 

nervous system, pituitary, gastrointestinal 

tract, pancreas, endocrine glands and lymphoid 

tissue [15–17]. The early binding studies 

indicated that the majority of human tumors 

expressed somatostatin receptors with 

a high binding affinity for somatostatin-14, 

somatostatin-28 and octreotide. However, a 

number of tumors appeared to express somatostatin 

receptors with a high binding affinity 

for somatostatin but a low binding affinity for 

octreotide, e.g. pituitary adenomas, glial tumors, 

meningiomas, some GEP tumors, medullary 

thyroid carcinomas, ovarian cancers 

and breast tumors. Furthermore, normal and 

cancerous gastric and colonic tissue were 

demonstrated to express somatostatin receptors 

with a high binding affinity for the native 

hormone, low binding affinities for lanreotide 

and somatuline but with little or no binding 

affinity for octreotide [18]. Interestingly, 

these early binding receptor studies suggested 

that somatostatin receptors were preferentially 

expressed in well-differentiated compared 

to less differentiated tumors [19, 20]. 

These observations suggest somatostatin receptors 

may represent markers of differentiation 

in some cancers and that loss of functional 

hSSTRs may be of clinical importance in 

the progression of neoplasia. Thus, since somatostatin 

receptors play an important role in 

the physiological control of cell proliferation, 

loss of hSSTR expression in neoplastic cells 

would confer a proliferative advantage to 

those cells and their progeny. The net result 

would be the emergence of a dominant rapidly 

proliferating clone of hSSTR-negative cells 

and the progression of the neoplasm to a more 

aggressive, less differentiated tumor. Although 

it has not yet been established which 

of the 5 hSSTR are responsible for the progression 

of a tumor to a less differentiated 

more aggressive phenotype, the genes which 

encode for these receptors and their proteins 

which mediate their intracellular transduction 

pathways should be regarded as tumor 

suppressor genes. This suggestion is supported 

by the observation that a point mutation in 

the gene encoding for hSSTR-2 results in a 

proliferative advantage in small cell lung cancer 

cells in vitro [21]. These observations have 

two important clinical correlates. Firstly, it 

is well established that long-term somatostatin 

analog therapy results in downregula- 


tion of hSSTRs. Clearly, it will be important 

to establish whether or not long-term therapy 

with somatostatin analogs results in well-differentiated 

tumors becoming phenotypically 

more aggressive, thereby adversely affecting 

survival. Secondly, restoration or modulation 

of hSSTR expression in anaplastic tumors by 

gene transfer may revolutionize somatostatin 

analog therapy of neoplasia. 

More recently, cloning of 5 hSSTR has 

enabled the expression of individual somatostatin 

receptor expressions to be determined 

using techniques such as in situ hybridization, 

RNA-ase protection and reverse transcriptase 

polymerase chain reactions (RT-PCR) [22– 

37]. Studies using these techniques indicate 

that there is considerable heterogeneity between 

and within individual tumors with respect 

to the density of the individual hSSTRs 

expressed. Thus, in most tumors, hSSTR-2 

which is thought to be the receptor whereby 

somatostatin analogs exert the majority of 

their antiproliferative effects was expressed in 

the highest density. The other hSSTRs were 

also expressed in tumors expressing hSSTR-2, 

but in lower densities and in differing patterns 

in individual neoplasms. Perhaps more importantly 

with respect to the present generation 

of somatostatin analogs available for clinical 

use, some of the most common malignancies 

such as cancers of the pancreas, stomach 

and prostate do not express hSSTR-2 [18, 34]. 

In addition there is some controversy on 

whether or not colorectal adenocarcinomas 

express hSSTR-2. In an early report using 

competitive binding assays, primary cultures 

of both normal and cancerous colonic tissue 

were reported not to bind to octreotide suggesting 

that these cells do not express hSSTR- 

2 [18]. However, in a subsequent study using 

RT-PCR the same group reported that the 

mucosa of colonic cancer and adjacent normal 

tissue expressed all 5 hSSTRs [37]. One 

possible explanation for these divergent re- 

sults is that high affinity somatostatin receptors 

have been reported on vascular and stromal 

cells [34, 38, 39]. Thus, in the second 

study by the Southampton group [37], the 

highly sensitive PT-PCR technique used to 

determine the hSSTR expression in colonic 

biopsies may have detected hSSTR-2 in contaminating 

peritumoral blood vessels and stroma 

rather than on the tumor cells per se. Finally, 

a proportion of tumors which normally 

express a high density of hSSTR-2 do not 

express this subtype [15, 16]. The variable 

expression of the hSSTRs between various 

tumors emphasizes the need to define the precise 

characteristics of the receptor subtypes in 

tumor tissue prior to somatostatin analog therapy 

if the direct antineoplastic effects of these 

drugs are to be maximized. Clearly such studies 

should be carried out on tumor cells per se 

and not on whole tissue homogenates, because 

of possible confounding contamination with 

peritumoral blood vessels and/or stroma. In 

addition, there is a need to define the proportion 

of binding attributable to each of the 

hSSTRs on the neoplastic cell to further optimize 

somatostatin analoge therapy and maximize 

the direct antineoplastic effects of these 

drugs. However, determination of hSSTR expression 

may not in itself be sufficient to fully 

exploit the direct antineoplastic effects of somatostatin 

analog therapy since it has yet to be 

determined whether or not detection of 

hSSTR mRNA implies the presence of functional 

proteins on the cell surface and intact 

intracellular pathways. Clearly, the relationship 

between hSSTR expression and functional 

receptor-proteins requires the development 

of specific antibodies to the latter. Not surprisingly 

therefore, the biological roles of each of 

the hSSTRs remains to be elucidated and defining 

the functional role of each of the subtypes 

requires the development of specific 

analogs, antagonists and antibodies. The complexity 

of the problems provides a major chal- 


lenge to peptide chemists and molecular biologists 

but such studies are essential to fully 

exploit the therapeutic potential of somatostatin 

analog therapy in neoplasia. 

Desensitization and Downregulation 

Cells can regulate their sensitivity to ligands 

such as drugs or hormones by modifying 

their response (desensitization) or altering 

receptor density (downregulation or 

upregulation). Desensitization or tachyphylaxis 

may be achieved rapidly through functional 

uncoupling of the receptor proteins on 

the cell membrane that activate intracellular 

transduction pathways and is thought to be 

the initial response whereby cells regulate 

their response to continuous application of 

agonists. Cells can also modulate their response 

to continuous exposure of an agonist 

via a decrease in receptor density achieved by 

internalization of receptors (downregulation). 

In the case of persistent presence of an agonist, 

the agonist-receptor complex is internalized 

the structurally intact receptors stored 

within the cell and at this stage could be recycled 

if the stimulus was withdrawn. If stimulation 

persists the receptors are eventually broken 

down but can be resynthesized when the 

stimulus is eventually removed. Through the 

uncoupling and downregulation of receptors, 

cells are capable of decreasing the magnitude 

of their response to a constant level of agonist 

stimulation. This phenomenon is well illustrated 

by the effects of somatostatin on the 

modulation of potassium channels in neocortical 

cells [40]. Thus, some cells rapidly desensitize 

to continuous somatostatin application 

(less than 30 s) whereas other neurones are 

only partially desensitized or are refractory 

to more prolonged exposure of the hormone 

(5 min). However, with prolonged exposure 

(30 min) to somatostatin all neocortical cells 

are completely desensitized [40]. It seems 

likely that rapid desensitization of some neocortical 

cells following that exposure to somatostatin 

(less than 30 s) results from uncoupling 

of the G proteins from the somatostatin 

receptors whereas desensitization of neurones 

initially refractory to continuous exposure of 

hormone may require downregulation of the 

receptor. 

Desensitization and downregulation have 

important consequences for the clinical use of 

somatostatin analogs. As long ago as 1989 

Londong et al. [41] demonstrated that the initial 

potent inhibition of gastric secretion by 

relatively low doses of subcutaneous administration 

of octreotide was lost after 7 days of 

continuous administration. Subsequently, the 

initial potent inhibitory effects of octreotide 

on pancreatic enzyme excretion were also 

demonstrated to be lost after 7 days’ continuous 

subcutaneous administration [42]. The 

important question with respect to oncology 

is whether or not long-term somatostatin analog 

therapy results in downregulation of the 

receptors responsible for mediating their antineoplastic 

effects and which of the hSSTR are 

affected. There is good evidence that somatostatin 

and its analogs can upregulate or downregulate 

SSTR expression in a variety of cell 

lines and in tumor-bearing experimental animals 

[43–52]. It is now clear that regulation of 

individual SSTR expression by somatostatin 

and its analogs is cell subtype- and agonistspecific 

[43–52]. Furthermore, there is considerable 

evidence to suggest that SSTR expression 

is sensitive to the regulatory effects 

of glucocorticoids, thyroid hormones, estrogens, 

insulin and growth factors [53–57], 

which, at least in part, may explain why somatostatin 

analogs exhibit both a proliferative 

and antiproliferative effect on the same 

cell line depending on the culture conditions 

[58–62]. Although much progress has been 

made in our understanding of SSTR expres- 


sion at the cellular level the molecular events 

responsible for these effects are poorly under 

stood. In addition, the functional significance 

of either upregulation or downregulation of 

the individual SSTRs has yet to be elucidated, 

and in particular, with respect to the therapeutic 

and diagnostic use of somatostatin analogues, 

whether or not the expression of 

mRNAs for the individual hSSTRs by neoplastic 

cells implies a functional receptor protein 

and intact signal transduction mechanism(s). 

It is also important to distinguish 

between internalization and downregulation. 

Thus, internalization of the hSSTRs after 

brief exposure to somatostatin or its analogs is 

cell-, agonist- and receptor-specific [43–52] 

and involves endocytosis of the receptorligand 

complex which may be accompanied 

by recruitment of cellular SSTRs to the cell 

membrane [46] and may represent an important 

upregulatory mechanism whereby cells 

can rapidly modulate their response to agonist 

stimulation. Upregulation, whereby neoplastic 

cells increase the density of cell membrane 

SSTRs, has obvious implications in both the 

visualization (somatostatin scintigraphy) and 

therapy (targeted chemotherapy or radiotherapy) 

of tumors using somatostatin analogs. 

However, as described earlier in this section, 

internalization is also the first step involved 

in downregulation in response to a persistent 

stimulus. It should be possible to distinguish 

between internalization resulting in upregulation 

from internalization heralding the onset 

of downregulation by repeat somatostatin receptor 

scintigraphy, if these were the only 

mechanisms involved in determining the response 

to escape from the antineoplastic effects 

of somatostatin analog therapy. Moreover, 

clinically, the situation is more complex 

since there are other mechanisms which may 

be responsible for escape from the inhibitory 

effects of somatostatin analog therapy on 

tumor growth and hypersecretory states. 

For example, the antineoplastic effects of 

somatostatin analogs on tumor growth would 

be limited to those cells bearing hSSTRs or 

whose growth is inhibited by their indirect 

antiproliferative effects. Thus, a proportion of 

cells in each tumor will not respond to either 

the direct or indirect antineoplastic effects of 

somatostatin analog therapy, the net result 

being the growth and development of clones 

of differentiated cells refractory to analog 

treatment. It seems likely that escape is a combination 

of these phenomena since in a small 

proportion of VIP-oma patients the initial 

inhibitory effects octreotide on hormone hypersecretion 

is lost after as little as 4 days’ 

therapy [63]. Downregulation or desensitization 

of hSSTRs responsible for the inhibitory 

effects of octreotide would appear to be the 

only plausible explanation for escape in 

these patients. However, for the majority 

of VIP-oma patients escape appears after a 

much longer period of octreotide therapy (6– 

16 months) suggesting that downregulation 

and possibly the growth of rapidly proliferating 

clones of cells may both be responsible for 

loss of efficacy of analog therapy. Possibly, 

somatostatin scintigraphy before and after somatostatin 

analog therapy may, at least in 

part, be able to differentiate between the relative 

roles of downregulation and the growth of 

hSSTR-negative clones in the phenomenon of 

escape, but is unlikely to provide a definitive 

answer to this problem. Irrespective of the 

mechanisms responsible for escape from somatostatin 

analog therapy, this phenomenon 

represents a considerable problem to the longterm 

use of these drugs in oncology. However, 

the problem of developing resistance to drug 

therapy is not new and applies to a wide variety 

of therapeutic agents. For example, it is 

well established that chronic antibiotic therapy 

is the best way to induce antibiotic resistance. 

Similarly with respect to oncology, it 

has long been recognized that prolonged che- 


motherapy leads to the development of cytotoxic 

resistant clones of tumor cells. More 

recently, it has been generally accepted that 

androgen blockade with luteinizing hormonereleasing 

hormone (LHRH) or antiandrogens 

needed to be permanent to normalize surrogate 

end points such as prostatic-specific antigen 

(PSA) and improve survival in patients 

with prostatic cancer. This hypothesis was 

based on the assumption that total androgen 

deprivation resulted in a rapid sustained response 

which outweighed the development of 

hormone resistance. More recently, intermittent 

androgen blockade in a relatively small 

number of patients was demonstrated to be 

without risk and to significantly improve 

quality of life after initial normalization of 

PSA in patients with prostate cancer [64, 65]. 

It remains to be established in randomized 

controlled trials whether intermittent androgen 

blockade, by delaying development of 

hormone resistance, improves survival compared 

to continuous therapy in patients with 

carcinoma of the prostate. However, there are 

no good data on whether or not intermittent 

somatostatin analog therapy prevents or reduces 

the rate of downregulation or the development 

of hormone resistant clones of differentiated 

cells. Unfortunately, the three analogs 

currently available for clinical use, octreotide, 

vapreotide and lanreotide, have very 

similar antineoplastic effects, the majority of 

which are mediated predominantly via the 

same hSSTR. Therefore, a treatment option 

alternating octreotide, vapreotide and lanreotide 

is unlikely to delay escape. A more realistic 

approach may be intermittent administration 

of long-acting depot preparations of octreotide, 

lanreotide and vapreotide, but such 

clinical studies will require careful monitoring 

until the reliability and safety of such an 

approach can be justified. 

Future Clinical Studies 

In the past 15 years by far and away the 

most successful use of octreotide has been in 

the treatment of acromegaly. As discussed 

earlier, although octreotide and other somatostatin 

analogs effectively control hypersecretion 

of growth hormone or insulin-like growth 

factor-1 (IGF-1) in acromegalics, these drugs 

are cytotaxic and not cytotoxic. Consequently, 

in younger patients surgery is the treatment 

of choice since it offers the change of a 

complete cure. If surgery is not curative, radiotherapy 

is a second option but normalization 

of growth hormone and IGF-1 can take 

up to 2 years following such treatment. Octreotide 

is very effective in providing good 

long-term (112 years) control of hormone hypersecretion 

in acromegalics who fail surgery 

and/or radiotherapy. Since no escape occurs 

from octreotide inhibition of hypersecretion 

even during very prolonged periods of treatment 

in acromegalics, somatostatin analog 

therapy is the treatment of choice in elderly 

patients with this pituitary tumor. A number 

of reports suggest that lanreotide and vapreotide 

are as effective as octreotide in the management 

of acromegaly, but since these analogs 

have only fairly recently become available 

for clinical use, there is obviously no 

information on very long-term therapy in 

acromegalics. An important advance in the 

management of acromegaly with somatostatin 

analog therapy has been the development 

of long-acting depot preparations of octreotide, 

lanteotide and vapreotide which will 

improve patient compliance and more importantly 

quality of life. 

The role of somatostatin analog therapy in 

GEP tumors is limited because relapse occurs 

in all patients usually within 2 years following 

commencement of treatment. Consequently, 

somatostatin analog therapy is now 

considered to be palliative and should be 


eserved for when other treatment options 

have failed. Surgery is the only treatment 

which offers the chance of a complete cure in 

patients with GEP tumors even when liver 

metastases are present. There is little doubt 

that surgery for GEP tumors has been greatly 

enhanced by somatostatin scintigraphy [66] 

or positron emission tomography for in vivo 

studies of 5-hydroxytryptophan metabolism 

[67]. Both techniques are superior to conventional 

radiological techniques in localizing 

small lesions preoperatively and enable the 

surgeon to increase the chance of achieving a 

curative resection. There is some evidence 

that surgery can alter the natural history of 

gastrinomas [68] but there is an urgent need 

for good randomized controlled trials to establish 

the benefits of radical surgical intervention 

in patients with GEP tumors. Furthermore, 

even if radical curative surgery 

cannot be performed, debulking procedures 

should be considered to reduce the tumor load 

which may enhance the efficacy of medical 

treatments such as chemotherapy with or 

without liver embolization, tumor-targeted 

radiotherapy, immunotherapy and somatostatin 

analog treatment. The precise role and 

timing of the adjuvant therapies has yet to be 

fully determined and a multimodality approach, 

using different therapies synchronously 

or metachronously, is required to maximize 

the benefits of medical treatment of 

GEP tumors which are not resectable. Such 

studies should take the form of controlled 

trials, survival and quality of life being the 

primary outcome measures. Interestingly, 

neuroendocrine tumors of the gastrointestinal 

tract and pancreas are the only cancers where 

hepatic metastases are not a contraindication 

to liver transplantation. However, extrahepatic 

disease is a contraindication to liver transplantation. 

Thus, several reports indicate that 

liver transplantation provides good symptomatic 

relief and is occasionally curative in 

patients with neuroendocrine tumors in 

whom resection is not feasible [69–72]. Disease 

recurrence is common but good palliation 

can be achieved with medical therapy 

and survival is longer in patients with carcinoid 

tumors than other neuroendocrine tumors 

following liver transplantation [72]. 

However, the indications and timing of transplantation 

still needs to be evaluated for 

neuroendocrine tumors. Furthermore, liver 

transplantation is not a realistic treatment option 

for the majority of patients with metastatic 

GEP tumors because of the shortage of 

donor livers. 

With respect to somatostatin analog therapy 

of GEP tumors, it is generally accepted 

that it should be reserved for patients in 

whom all treatment options have failed. However, 

somatostatin analog therapy can potentiate 

cytotoxic therapy in vitro and in experimental 

animals [73–75]. Furthermore, there 

is compelling experimental evidence that octreotide 

is a very potent inhibitor of the 

growth and development of hepatic metastases 

in experimental animals [11]. Consequently, 

it is feasible that short-term somatostatin 

analog therapy of GEP tumors in combination 

with cytotoxic therapy, liver embolization 

and hepatic resection may potentiate 

the palliative effects of these treatment modalities. 

Such an approach may prolong the 

time during which these adjuvant therapies 

provide symptomatic control without precluding 

the use of somatostatin analogs as a 

palliative therapy when all other treatment 

options have been exhausted. However, further 

controlled trials are required to substantiate 

this hypothesis. 

Clinical experience with somatostatin analogs 

over the past 15 years has clearly demonstrated 

that these compounds are very successful 

in the management of acromegaly and 

are a valuable palliative therapy for neuroendocrine 

tumors. In contrast, although there 


is considerable evidence that somatostatin 

analogs have a potent antineoplastic effect 

on neoplasms of the breast, colon, pancreas, 

prostate, lung and other common malignancies 

in experimental animals and in vitro, the 

results of clinical trials of these drugs have 

been very disappointing (see other papers in 

this volume for detailed reviews on the results 

of somatostatin analog therapies in individual 

malignancies). However, the vast majority of 

early clinical trials were uncontrolled and carried 

out in patients with advanced metastatic 

disease and the methodology used to assess 

health-related quality of life (HRQL) inadequate. 

It is important to recognize that we 

should not be deterred by the lack of a therapeutic 

benefit of somatostatin analogs in advanced 

malignancy since the majority of antineoplastic 

treatments are also ineffective in 

this clinical setting but are substantially more 

effective in patients with a relatively low tumor 

burden. There is no reason to suspect that 

somatostatin analog therapy will not be more 

effective in patients with a low tumor burden 

compared to those with advanced disease 

and, indeed, there is a wealth of preclinical 

evidence to suggest that this is the case. However, 

there is a paucity of good studies in 

man to support this hypothesis, and as yet, we 

must accept that the clinical efficacy of somatostatin 

analog therapy in patients with a 

low tumor burden is unproven. This immediately 

raises ethical problems of conducting 

controlled trials of somatostatin analog therapy 

in patients with a relatively low tumor burden 

if other treatments have been previously 

demonstrated to exert a clinically beneficial 

effect. This problem can be overcome by 

carrying out randomized controlled trials 

comparing a therapy with established clinical 

efficacy alone or combined with somatostatin 

analogs. Such an approach has an advantage 

in patient recruitment since more will be 

amenable to participate in a trial in which 

they are randomized to receive a treatment 

with an established therapeutic benefit alone 

or in combination with a novel drug with as 

yet unproven clinical efficacy. On the other 

hand, such an approach requires very large 

numbers of patients to be recruited into the 

trial to identify significant differences in outcome 

attributable to somatostatin analog 

therapy over and above that observed with 

the established therapy with adequate power. 

There can be little argument that future 

trials of somatostatin analog therapy of neoplasia 

should be randomized controlled studies 

wherever possible. In general, the methodology 

for the design of clinical trials is well 

documented and investigators should take 

care to include all the data required by medical 

journals for the reporting and publication 

of such studies in preparing the protocol [76]. 

With respect to somatostatin analog therapy 

of neoplasia, additional problems need to be 

addressed, in particular HRQL and dosing 

regimes. HRQL includes both specific and 

generic instruments and care must be taken in 

analyzing the data since there are methodological 

difficulties which have not been completely 

resolved for randomized controlled 

trials. Thus, generic and specific questionnaires 

used to assess the HRQL have multiple 

questions covering several domains which 

give rise to analytical problems. Analysis of 

individual questions or subscales would increase 

the likelihood of obtaining a considerable 

number of significant difference by 

chance whereas combining a large number of 

question into a single HRQL index may not 

be advisable as information may be lost. A 

reasonable compromise is to limit the number 

of individual questions analyzed to those relevant 

to the disease and expected treatment 

effects and to combine only those that are 

related. However, advice should be sought 

from an expert in statistics and health services 

research, particularly experienced with 


HRQL, prior to commencing any study, not 

only to select the best generic and specific 

instruments and how to analyze the data, but 

also to check that the study has sufficient power 

to detect important changes in HRQL where 

they exist with 95% confidence intervals. 

The dosing regime for somatostatin analog 

therapy in controlled studies of their efficacy 

in solid tumors is difficult to define. It may 

well be that higher doses of somatostatin analog 

are required to control tumor growth than 

to control hormone hypersecretion characteristic 

of acromegaly and neuroendocrine tumors, 

indications in which the greater part of 

the evidence of clinical efficacy of these drugs 

in neoplasia has been accumulated. Unlike 

chemotherapy, somatostatin analogs are well 

tolerated even at very high doses and hence 

the dosage cannot be based on maximal tolerable 

side effects. It is tempting to select a highdose 

regime for somatostatin analog therapy 

but this may not be advisable since as will be 

discussed in a subsequent section, these drugs 

may have adverse effects on the immune system. 

Therefore, care must be taken to ensure 

that any increased antineoplastic effects of 

high-dose somatostatin analog therapy are 

not negated by increasing suppression of the 

immune system, the body’s major defense 

against neoplasia. In addition, high-dose somatostatin 

analog therapy may result in more 

rapid downregulation of the hSSTRs responsible 

for mediating the antineoplastic effects 

of somatostatin analogs and/or the development 

of somatostatin-resistant clones of tumor 

cells. At present, therefore, the dosing 

regime for somatostatin analog therapy of solid 

tumors has to be somewhat empirical and 

based on information from the few studies 

which have demonstrated a clinical benefit in 

patients with advanced malignancy or extrapolation 

of doses that result in plasma levels 

of these drugs in experimental animals in 

which antineoplastic effects have been ob- 

served. The latter approach is fraught with 

difficulties, however, since extrapolation of 

results obtained in experimental animals can 

be very misleading when applied to man. At 

present, there is perhaps arguably, only one 

really well-designed prospective randomized 

control of somatostatin analog therapy in advanced 

malignancy which has clearly demonstrated 

the therapeutic potential of these 

drugs as antineoplastic agents [77]. In this 

study, patients with advanced inoperable somatostatin 

receptor-positive hepatocellular 

carcinoma were randomized to 500 Ìg octreotide 

s.c. b.d. or no treatment. The results of 

this study clearly indicated that the survival 

of octreotide treated patients was significantly 

better than that of controls. Multivariate analysis 

confirmed that octreotide was a major 

factor influencing survival. Tumor size was 

also investigated at regular intervals in both 

groups of patients. In patients randomized to 

receive no treatment all tumors continued to 

grow until the death of the patient. Similarly 

in the octreotide-treated patients, all large tumors 

continued to grow. However, small satellite 

tumors (!3 cm in diameter) either disappeared 

or remained the same size after prolonged 

octreotide therapy [77]. Therefore, for 

the present, it would be reasonable to use a 

dose of 500 Ìg somatostatin analog twice a 

day in initial formal clinical trials to evaluate 

the therapeutic potential of these drugs in 

patients with advanced malignancy and possibly 

a reduced dose in patients with a relatively 

low tumor load. The response to somatostatin 

analog therapy may vary with both the hSSTR 

expression of individual tumors and any therapy 

used in combination with these drugs. 

There is no information available on how 

these confounding factors may influence the 

response to somatostatin analog therapy, and 

until such data becomes available, it would be 

unwise to speculate on varying dosing regimes. 


With respect to clinical trial methodology 

of the efficacy of somatostatin analog therapy 

it is important to specify in the eligibility criteria 

that only patients with somatostatin receptor-positive 

tumors are included. Fortunately, 

most human solid tumors express 

hSSTR-2 and hSSTR-5 and can be detected 

by somatostatin scintigraphy using stable radioisotopes 

of octreotide and vapreotide or by 

positron emission tomography (PET). However, 

there are exceptions such as cancer of 

the prostate which do not express hSSTR-2 or 

hSSTR-5 and in these tumors the presence of 

somatostatin receptors needs to be based on 

tissue obtained by biopsy or at operation. 

Indeed, ideally tissue should be obtained from 

all tumors prior to therapy with somatostatin 

analog therapy to establish the hSSTR profile 

in order to determine whether or not this may 

influence the response to therapy with these 

drugs. 

Combination Therapy 

Chemotherapy 

In many ways, the role of cytotoxic therapy 

in malignancy resembles that of somatostatin 

analogs. Thus, early dramatic responses 

achieved by chemotherapy in fairly uncommon 

malignancies such as Hodgkin’s disease, 

histiocytic lymphoma, germ cell tumors, choriocarcinoma 

and various solid tumors of 

childhood led to a bewildering number of 

clinical studies of cytotoxic therapy in all cancers. 

However, it is now greatly accepted that 

chemotherapy alone is rarely curative and in 

the majority of patients is used to provide palliation. 

In this situation, a decision to use 

cytotoxic drugs inevitably entails balancing 

the potential benefits against the toxic side 

effects of chemotherapy. Consequently, the 

use of toxic and hence potentially fatal cytotoxics 

should be questioned unless they are 

likely to lead to a high incidence of durable 

complete remissions with the occasional cure 

or regression of the tumor to such an extent 

that symptomatic relief offers a prolonged improvement 

in HRQL. However, for most advanced 

metastatic cancers the effects of chemotherapy 

have been largely disappointing, 

cytotoxics providing only modest improvements 

in response rates and survival. A good 

example is provided by a critical meta-analysis 

of the large number of randomized controlled 

trials comparing single agent versus 

polychemotherapy in the management of recurrent 

early breast cancer [78]. In general, 

this meta-analysis indicated that polychemotherapy 

resulted in a modest increase in response 

and survival compared to single agent 

chemotherapy but at the expense of increased 

toxicity. However, the clinical relevance of 

this large meta-analysis of chemotherapy of 

early breast cancer recurrence is limited because 

of the paucity of data on HRQL [78]. 

Fortunately, in the case of breast cancer, these 

tumors respond to less toxic hormonal treatment. 

Thus, in recurrent early breast cancer, 

hormonal treatment, single agent or combination 

of tamoxifen, megestrol and aromatase 

inhibitors compared favorably in terms of 

response rate and survival with the majority 

of chemotherapeutic regimes [78]. However, 

there was no improvement in response rates 

or survival in trials comparing chemotherapy 

alone or combined with hormone treatment 

[79]. For the medical oncologist, the results of 

these randomized controlled trials of chemotherapy 

and hormonal treatment allow for 

some limited clinical decision making in the 

management of advanced metastatic breast 

cancer. Hence, most oncologists would prefer 

single agent or combination hormonal therapy 

to chemotherapy because of the relatively 

reduced toxicity. For many solid tumors, 

however, cytotoxic therapy may be the only 

therapeutic modality available for the man- 


agement of advanced metastatic malignancy. 

In these situations it is much more difficult to 

decide whether or not cytotoxic therapy has 

any overall beneficial effects particularly because 

of the lack of good HRQL data. 

Somatostatin analogs potentiate the cytotoxic 

effects and decrease the toxicity of cytotoxic 

agents [73–75], suggesting they may improve 

the response rate, survival and HRQL 

of chemotherapy of advanced metastatic disease. 

This hypothesis merits further investigation 

in the form of large randomized controlled 

trials and particular emphasis should 

be placed on the HRQL component of the 

studies which hitherto has largely been neglected. 

Targeted Chemotherapy 

An interesting and challenging concept is 

the targeting of chemotherapy to somatostatin 

receptor-positive tumors by synthesizing 

conjugates of somatostatin analogs and cytotoxics 

[79, 80]. These preliminary studies indicated 

that the antineoplastic effects of the 

cytotoxic radicals in these conjugates on 

growth of a variety of human cancer effects 

was preserved in vitro. Although conjugation 

of the cytotoxic somatostatin analogs reduced 

their binding affinities to somatostatin receptors, 

the conjugates were still capable of inhibiting 

the release of growth hormone in the 

nanomolar range. Finally, conjugates of somatostatin 

analogs and cytotoxics were less 

toxic and more potent in inhibiting the 

growth of breast and pancreatic tumors in 

experimental animals than the cytotoxic 

agents alone following intravenous administration 

[79, 80]. Although these preliminary 

results are a potentially exciting development 

in the use of somatostatin analogs in oncology 

there are a number of problems which require 

further evaluation. Firstly, somatostatin statin 

receptor-positive cells are widely distributed 

throughout the body and hSSTR-2 is 

the most commonly expressed subtype in 

both normal and neoplastic tissue. Unfortunately, 

the present generation of somatostatin 

analogs all bind to hSSTR-2 with high affinity. 

Therefore, synthesis of conjugates of octreotide, 

lanreotide and vapreotide cytotoxics 

would not really target chemotherapy to neoplastic 

tissue per se, but to all cells expressing 

hSSTR-2 or hSSTR-5. In the preliminary 

studies of conjugates or somatostatin analogs 

and cytotoxics tissues distribution was not 

determined and toxicity was defined only in 

terms of death during a very short treatment 

period [79, 80]. Clearly much work is required 

to address these issues to establish the relative 

toxicities of the conjugates of cytotoxics and 

somatostatin analogs compared to the chemotherapeutic 

agent alone. In addition, targeting 

of chemotherapy to tumors after systemic administration 

of somatostatin analog and cytotoxics 

will require the development of newer 

hSSTR-selective analogs to tumors not expressing 

hSSTRs to which octreotide, lanreotide 

and vapreotide do not bind. If, however, 

these problems can be resolved somatostatin 

analog targeting of cytotoxics to neoplastic 

cells may prove to be a valuable treatment 

option for advanced metastatic cancer. 

Hepatic Metastases Derived from 

Colorectal Primaries 

At present, the most promising role of chemotherapy 

in cancer is as an adjuvant to surgery 

and/or radiotherapy. Of particularly interest 

with respect to somatostatin analog 

therapy is their potential benefit when used in 

combination with cytotoxics as an adjuvant to 

surgery in common abdominal malignancies. 

Space does not allow for a comprehensive discussion 

of the natural history of all types of 

gastrointestinal malignancies and the rationale 

for adjuvant cytotoxic therapy in these 


Table 1. Colorectal cancer stage, 

definitions, frequency at diagnosis 

and survival 

Dukes 

stage 

indications following surgery, but perhaps is 

best illustrated by colorectal cancer. The prognosis 

for patients with colorectal cancer is 

summarized in table 1 and is associated with 

the staging of the disease, which in turn, is 

predominantly influenced by the development 

of liver metastases which have traditionally 

been equated with the imminent 

demise of the patient. For patients who undergo 

a theoretically curative resection of 

their colorectal primary and in whom no 

overt hepatic metastases are present at the 

time of operation, only 35–40% will be truly 

cured. A small proportion (12–15%) will develop 

extrahepatic hepatic disease (including 

local recurrence) and the remainder will develop 

liver metastases within 2–5 years of 

their theoretically curative resection. These 

observations would suggest that in those patients 

who develop hepatic metastases, occult 

micrometastases are present in the liver at the 

time of their theoretically curative resection 

of their colorectal primary or that tumorigenic 

cells are shed into the portal circulation during 

surgery and seed in the hepatic parenchyma. 

Not surprisingly, therefore, there has 

been considerable interest in the use of adjuvant 

chemotherapy, systemic or regional, to 

prevent or delay the development of hepatic 

Definition Approximate 

frequency 

at diagnosis 

% 

5-year 

survival 

A Cancer confined to bowel wall 10 80–85 

B1 Cancer which penetrates the bowel 

wall without spread through serosa 10–15 70–75 

B2 Cancer which penetrates wall of 

bowel beyond serosa 20–30 60–70 

C Lymph node involvement 25 35–40 

D Liver metastases 30 3–6 

metastases and hence improve survival after a 

theoretically curative resection of a colorectal 

primary. In brief, as long ago as 1988 a metaanalysis 

of randomized adjuvant trials of 5fluorouracil 

(5-FU) for up to 1 year demonstrated 

a marginal overall reduction in the relative 

risk of death by approximately 17% and 

an absolute 5-year survival benefit of 3–4% 

[81, 82]. More recently, however, much more 

impressive results have been reported using 

6–12 months’ adjuvant combination therapy 

with 5-FU and the immunomodulatory drug 

levamisole or by biomodulating 5-FU with 

leucovorin [81]. However, the statistical significant 

improvement in survival of these systemic 

therapies was confined to patients with 

Dukes C tumors and correlated with a similar 

reduction in the incidence of hepatic metastases 

[81]. Similar improvements in survival 

and the incidence of liver metastases is associated 

with a 7-day perioperative portal vein 

infusion of 5-FU following resection of a colorectal 

primary [81]. As would be expected, the 

toxicity of 7 days of 5-FU was markedly less 

than 6–12 months’ treatment with this cytotoxic. 

The major risk reduction of developing 

overt hepatic metastases and overall survival 

improvement, with portal vein infusion of 5- 

FU, was confined to patients with Dukes C 

Somatostatin Analogs in Oncology Chemotherapy 2001;47(suppl 2):162–196 175 

%

Fig. 1. Percentage of hepatic replacement 

by K12Tr tumor in octreotide-treated 

rats with or without 

blockade of RES with gadolinium 

chloride (GAD). Octreotide 

almost completely inhibited the 

growth of hepatic tumor in rats 

with a functional hepatic RES. 

Blockade of the hepatic RES with 

GAD significantly increased tumor 

growth compared to controls. Octreotide 

inhibited tumor growth in 

rats with hepatic RES blockade but 

not to the same extent as it did in 

animals with a functional hepatic 

RES [after 90]. 

disease [81]. Furthermore, the benefits of 6– 

12 months of treatment with 5-FU and levamisole 

or folinic acid are equivalent to 

those of 7 days’ perioperative portal vein with 

5-FU, although the combination of the two 

could be additive. Consequently, there is now 

a substantial body of evidence to suggest that 

all patients with Dukes C colorectal primaries 

should be treated with adjuvant systemic cytotoxic 

therapy using 5-FU combined with 

levamisole or folinic acid or a perioperative 

intraportal infusion of 5-FU. The situation in 

patients with Dukes B lesions is less certain 

since they are less likely to develop hepatic 

metastases than those with Dukes C disease, 

and hence, could be entered into a trial comparing 

surgery alone or combined with cytotoxic 

therapy. We have clearly demonstrated 

that octreotide inhibits the growth and development 

of hepatic tumors derived by intraportal 

injection of a variety of tumorigenic 

cells [11]. The mechanisms whereby octreotide 

inhibits the growth and development of 

hepatic tumors is mediated primarily via 

stimulation of the hepatic RES system (fig. 1) 

although direct and indirect antiproliferative 

effects of the somatostatin analogs are also 

contributory [11]. Levamisole stimulates hepatic 

RES activity, and this may partly explain 

its beneficial effect when used with 5- 

FU as an adjuvant to surgical resection of 

colorectal tumors [81]. However, octreotide 

is significantly more potent than levamisole 

in stimulating hepatic RES activity [11]. 

Furthermore, since octreotide has additional 

direct and indirect antineoplastic effects 

apart from stimulation of hepatic RES activity, 

it may be superior to levamisole when 

combined with 5-FU in inhibiting the development 

of liver metastases after surgical resection 

of a primary colorectal tumor. Finally, 

since somatostatin and its analogs are cytoprotective 

with respect to the liver [11], 

concomitant administration of cytotoxics 

with somatostatin analogs may improve the 

response rates [73–75] and at the same time, 

protect the liver from hepatotoxic effects of 

the chemotherapeutic agents. We believe 

that the available evidence, although experimental, 

suggests that somatostatin analogs 

may have a beneficial effect on the development 

of liver metastases when used as an 


adjuvant to surgery in colorectal cancer and 

that this area warrants urgent clinical investigation. 

Pancreatic Cancer 

The possible therapeutic potential of somatostatin 

analogs as an adjuvant to surgery 

is not confined to the development of hepatic 

metastases derived from colorectal primaries. 

Thus, other gastrointestinal malignancies 

such as those of the stomach, pancreas, small 

intestine, gallbladder and extrahepatic bile 

ducts frequently metastasize to the liver. 

Some of these cancers such as pancreatic adenocarcinoma 

have low resectability rates and 

curative surgery is only possible in 6–8% of 

patients [see 82]. Furthermore, even following 

a theoretically extensive resection of adenocarcinoma 

of the pancreas the 5-year survival 

is only approximately 25%. Following surgical 

resection for adenocarcinoma of the pancreas 

there are three major patterns of recurrence 

which occur with approximately equal 

frequency, namely local recurrence, hepatic 

metastases undetected at the time of operation 

and local recurrence with metastatic disease. 

There is now compelling evidence that 

the best means of preventing local recurrence 

after resection for pancreatic adenocarcinoma 

is radiotherapy whereas for metastatic spread 

chemotherapy is the treatment of choice. 

However, since the pattern of recurrence after 

pancreatic resection is both local and systemic, 

an improvement in survival is only 

likely to be observed with combinations of 

radiotherapy and chemotherapy. In view of 

the poor prognosis, even after a theoretically 

curative resection and because there is some 

limited evidence from phase 2 trials that adjuvant 

chemotherapy and radiotherapy may 

improve survival of patients with pancreatic 

adenocarcinoma, it is both surprising and dis- 

appointing that there are a paucity of randomized 

controlled trials to evaluate the efficacy 

of adjuvant therapies in this indication. 

Clearly, there is an urgent need for confirmation 

of these putative benefits of adjuvant 

radiotherapy and chemotherapy in patients 

with resectable pancreatic tumors in the form 

of large controlled randomized trials. Somatostatin 

analog therapy could be a valuable 

option for such phase III studies since there is 

good evidence that these compounds potentiate 

the cytotoxic effects and reduce the side 

effects of chemotherapy [73–75]. In addition, 

as discussed above, stimulation of hepatic 

RES activity by somatostatin analogs may 

be particularly important in inhibiting the 

growth and development of liver metastases 

[11]. All patients with pancreatic cancer in 

which surgery is possible should be entered 

into such randomized controlled trials irrespective 

of the size of the tumor and such 

studies should be sufficiently large to detect 

differences between the therapies under investigation 

and between predefined subgroups 

with sufficient power. 

Gastric Cancer 

Like pancreatic adenocarcinoma, gastric 

cancer has a very dismal prognosis and a high 

proportion of patients develop liver metastases. 

As discussed by Cascinu et al. [83] in 

another paper in this volume, there is an 

urgent need for large controlled trials to evaluate 

the efficacy of adjuvant therapies after 

surgery. Somatostatin analog therapy may, as 

discussed earlier for colorectal and pancreatic 

cancer, be a valuable treatment for gastric 

cancer to potentiate the effects of chemotherapy 

and via their stimulatory effect on hepatic 

RES activity inhibit the growth and development 

of liver metastases. Since colorectal, 

pancreatic and gastric cancers do not express 


hSSTR-2, the receptor subtype whereby octreotide, 

vapreotide and lanreotide exert their 

direct and antineoplastic effects, the development 

of specific analogs with high binding 

affinities for individual hSSTRs would be required 

to maximize somatostatin analog therapy 

of any of these tumor cells remaining after 

resection. It is unlikely, however, that such 

analogs will be available for clinical use in the 

near future. An alternative strategy could be 

to use native somatostatin rather than one 

of its analogs perioperatively in conjunction 

with intraportal 5-FU in those cancers which 

do not express hSSTR-2 to maximize the potential 

antineoplastic effects of the hormone. 

Subsequently, 6–12 months of systemically 

administered 5-FU which may provide additional 

benefits to 7 days of intraportal administration 

of this cytotoxic [81] could be again 

given concomitantly with somatostatin analogs. 

Such an approach would, however, be 

very expensive and the therapeutic advantage 

of such therapy would have to be demonstrated 

to be very beneficial to justify the 

costs. Furthermore, in order to demonstrate a 

marked therapeutic advantage of somatostatin 

and its analogs currently available for clinical 

use, over and above adjuvant cytotoxic 

and radiotherapy in patients with gastric, 

pancreatic and colorectal cancer would require 

very large randomized controlled trials 

which would be both difficult to organize and 

fund. 

Liver Tumors 

The presence of overt liver metastases is 

not uncommon in gastrointestinal malignancies 

and is associated with a very poor prognosis. 

Colonic cancer is unique among solid 

tumors in that surgical resection of hepatic 

and pulmonary metastases can prolong longterm 

survival and offers the only real possibil- 

ity of cure [84–86]. Nevertheless, even after a 

technically curative resection of colorectal hepatic 

metastases, recurrence occurs in approximately 

60% of patients [86] suggesting 

that there is an urgent need for postoperative 

adjuvant therapy. The role of chemotherapy, 

immunotherapy, hepatic artery or portal vein 

embolization, brachytherapy, cryotherapy, interstitial 

laser hypothermia and alcohol injection 

as adjuvant and neoadjuvant therapies in 

the management of colorectal hepatic metastases 

has been critically examined in a recent 

review [87]. A strong case can be made for a 

multimodality approach using combinations 

of techniques to optimize the management of 

colonic liver metastases and hence prolong 

survival and increase the chance of cure. 

However, the efficacy of new adjuvant and 

neoadjuvant therapies have yet to be rigorously 

evaluated in randomized controlled trials 

before they are incorporated into formal 

structured management strategies for the 

management of colonic metastases. Theoretically, 

somatostatin analog therapy may have a 

potentially beneficial effect when used in conjunction 

with these adjuvant or neoadjuvant 

treatment modalities for the management of 

colonic hepatic metastases. Thus, somatostatin 

analogs may potentiate the effects of adjuvant 

or neoadjuvant chemotherapy and reduce 

the hepatoxicity of cytotoxic agents [11, 

73–75]. Perhaps more importantly, however, 

the growth and development of hepatic tumors 

is significantly increased following partial 

hepatectomy [88, 89]. Octreotide inhibits 

the growth of hepatic tumors after partial 

hepatectomy, possibly via stimulation of hepatic 

(RES) activity which is significantly reduced 

after liver resection [89]. However, the 

direct and indirect antineoplastic effects of 

octreotide may also be contributory to the 

inhibition of tumor growth by this somatostatin 

analog after partial hepatectomy [11]. On 

the negative side, in addition to inhibiting the 


growth of hepatic tumors, octreotide also suppresses 

liver regeneration following partial hepatectomy. 

The potential for inhibition of 

regeneration in the human liver by somatostatin 

analogs may cause some concern. However, 

anecdotal evidence suggests that octreotide 

has no clinically detectable effect on liver 

regeneration in patients undergoing hepatic 

resection [Wu, pers. commun.]. Nevertheless, 

the potential detrimental effect of octreotide 

on liver resection after partial hepatectomy 

needs to be addressed more formally prior to 

advocating the use of somatostatin analogs as 

an adjuvant to surgery in patients with liver 

metastases. There is an urgent need for further 

investigation of the effects of somatostatin 

analogs in this area since the benefits of 

such treatment combined with other adjuvant 

and neoadjuvant therapies to surgery could be 

considerable in the management of hepatic 

metastases. 

Hormonal Therapy 

There is compelling experimental evidence 

to suggest that somatostatin analog therapy 

may be of value when used in combination 

with other hormonal treatments in the management 

of estrogen-positive breast cancer 

and prostate cancer which is discussed in 

detail in another paper in this volume [90– 

92]. However, the results of clinical studies of 

somatostatin analogs in combination with 

other hormonal therapies in the management 

of breast and prostate cancer have been very 

disappointing [91]. It is generally accepted 

that tamoxifen is the hormonal treatment of 

choice for estrogen-positive metastatic breast 

cancer. In spite of compelling evidence that 

octreotide in combination with tamoxifen 

may be more effective than tamoxifen alone 

in the management of metastatic breast cancer 

there is now good evidence from two ran- 

domized controlled trials that this is not the 

case [92, 93]. Thus, in both trials the time to 

disease progression, objective response rates 

and survival were not significantly different 

between patients treated with tamoxifen 

alone or combined with octreotide [92–94]. 

Moreover, in both trials the incidence of side 

effects was higher in patients treated with 

combination therapy than with tamoxifen 

alone [92, 93]. One of these studies initially 

randomized patients to tamoxifen or octreotide 

alone or combination therapy [92]. The 

octreotide only arm of the trial was dropped 

when the somatostatin analog was found to be 

associated with a rapid time to disease progression 

and to produce no objective response 

[92]. Finally, in one of these trials, combined 

tamoxifen and octreotide treatment resulted 

in a significantly greater reduction in serum 

IGF-1 than tamoxifen alone in a limited cohort 

of patients [92]. Both these clinical trials 

can be criticized on the grounds that they 

were underpowered, particularly since multiple 

outcome measures were assessed, to completely 

evaluate any possible benefit of octreotide 

in the management of metastatic breast 

cancer. However, both studies are strongly 

suggestive that combined tamoxifen and octreotide 

therapy is unlikely to confer any 

worthwhile clinical benefit over tamoxifen 

alone, particularly since combination therapy 

was associated with an increased number of 

side effects which could adversely affect 

HRQL. It is unlikely that vapreotide or lanreotide 

are more effective than octreotide 

when used in combination with tamoxifen in 

the management of metastatic breast cancer 

since all three analogs exhibit similar biological 

effects. Therefore, any benefit of these two 

newer analogs over octreotide is likely to be 

only marginal. 

The mechanisms whereby octreotide and 

tamoxifen in combination do not confer any 

therapeutic benefit over and above that of 


antiestrogen therapy alone is not clear. In the 

trial carried out by Ingle et al. [92], combined 

octreotide and tamoxifen therapy resulted in 

significantly greater reductions in serum IGF- 

1 than tamoxifen alone in patients with metastatic 

breast cancer without conferring any 

clinical benefits over and above that obtained 

with antiestrogen alone. However, in this 

study, serum IGF-1 levels were only measured 

in a cohort of patients before and 6 weeks after 

commencing combined tamoxifen and octreotide 

therapy or tamoxifen alone [92]. It has 

previously been reported that the initial suppression 

of serum IGF-1 levels by octreotide 

in patients with breast cancer is gradually lost 

approximately 8–14 weeks after commencing 

therapy [95]. Possibly, therefore, the failure of 

combined octreotide and tamoxifen to confer 

any additional clinical benefits compared to 

antiestrogen alone in patients with breast cancer 

may be due, at least in part, to the gradual 

loss of efficacy in the control of IGF-1 and possibly 

other mitogenic factors, with prolonged 

administration of the somatostatin analog. 

This hypothesis requires further investigation 

in patients with breast cancer since it could 

suggest alternative dosing regimes which may 

provide improvements in clinical outcome. 

For example, withdrawal of octreotide therapy 

as soon as IGF-1 levels begin to increase and 

recommencement when the serum levels of 

this mitogen are within the range of those 

observed in patients with breast carcinoma 

treated with tamoxifen alone may prolong the 

period whereby combination therapy potentiates 

suppression of this growth factor. Intermittent 

octreotide administration combined 

with continuous tamoxifen therapy may delay 

complete loss of efficacy of the somatostatin 

analog in the control of IGF-1 secretions thereby 

possibly conferring a clinical benefit in 

patients with breast cancer. 

The molecular pharmacology of the relationship 

between the effects of estrogen, an- 

tiestrogens and somatostatin analogs on the 

expression of hSSTRs is complex and not fully 

understood. Firstly, estrogen has been reported 

to upregulate hSSTR-2 and hSSTR-3 

expression in prolactin-secreting rat pituitary 

tumor 7315b cells both in vivo and in vitro 

[56]. Secondly, tamoxifen either decreases 

or increases estrogen-induced expression of 

hSSTRs in different human breast cancer cell 

lines in vitro [96]. Thirdly, in vitro studies 

have demonstrated that the antineoplastic effects 

of somatostatin on MCF-7 estrogenreceptor-positive 

human breast cancer cells 

are attenuated by estradiol [97]. Fourthly, tamoxifen 

potentiates the suppression of both 

IGF-1 expression and serum levels of IGF-1 

[98, 99]. Finally, octreotide potentiates the 

antineoplastic effects of tamoxifen in oophorectomized 

rats with 7,12-dimethylbenz(a)anthracene-induced 

mammary tumors [100]. 

The above observations clearly indicate that 

the relationships between somatostatin analogs, 

estrogens and antiestrogens are complex 

and require further investigation. Of particular 

importance is the as yet unknown effects of 

tamoxifen on individual hSSTR expression in 

patients with breast cancer. Studies in vitro 

indicate that this antiestrogen can upregulate 

or downregulate somatostatin receptor expression 

in different human breast cancer cell 

lines [96]. Clearly, depending on its overall 

effect on in vivo hSSTR expression in patients 

with breast cancer, tamoxifen could potentiate 

or attenuate the direct antineoplastic 

effects of somatostatin analog therapy. However, 

it should be pointed out that we do not 

as yet know the functional roles of hSSTRs in 

breast cancer and, hence, the possible therapeutic 

benefits of somatostatin analogs in 

terms of their direct antineoplastic effects. 

There is some preliminary evidence to suggest 

that hSSTR expression may play a functional 

role in the growth and development of breast 

cancer in man. Thus, preliminary observa- 


tions indicate that the presence of hSSTRs in 

the tumor of patients with breast cancer increases 

the probability of a longer disease-free 

survival compared to those in whom the tumors 

are hSSTR-negative [20]. It should be 

borne in mind, however, that hSSTRs are not 

homogeneously distributed in breast cancer 

[101]. Furthermore, the expression of individual 

hSSTRs in human breast cancer is variable 

[27]. The majority of human breast cancers 

do express hSSTR-2, the subtype whereby 

the current generation of somatostatin analogs 

mediate most of their antineoplastic effects. 

Some breast tumors do not, however, 

express hSSTR-2 [27]. These observations 

suggest that hSSTR-positive areas of the tumor 

may respond to the direct antineoplastic 

effects of somatostatin analog therapy thereby 

conferring a growth advantage compared to 

those neoplastic cells which do not express 

somatostatin receptors. However, any beneficial 

effects that somatostatin analog therapy 

may have in terms of their direct antineoplastic 

cells may be lost during long-term administration 

due to the development of somatostatin-resistant 

clones of breast tumor cells. At 

present, there is no clear indication of the 

temporal relationships between the commencement 

of somatostatin analog therapy 

and downregulation of the hSSTRs which mediate 

their direct antiproliferative effect in 

breast cancer. Furthermore, it is unknown 

whether tamoxifen, by upregulating hSSTR 

expression, potentiates the direct antineoplastic 

effects of somatostatin analogs. Alternatively, 

if tamoxifen downregulates hSSTR expression 

in breast cancer it could attenuate 

the direct antineoplastic effects of somatostatin 

analog therapy. Finally, tamoxifen may 

not have any effect on hSSTR expression in 

patients with breast cancer. Clearly, the issues 

discussed above are complex and will not be 

easy to resolve in patients with breast cancer. 

Nevertheless, there is an urgent need to an- 

swer at least some of these questions in order 

to fully rationalize the therapeutic potential 

of combination tamoxifen and somatostatin 

analog therapy in breast cancer. For example, 

intermittent somatostatin analog administration 

may be more beneficial than continuous 

treatment to delay the downregulation of 

hSSTR expression and the loss of efficacy in 

suppressing IGF-1 secretion during combination 

therapy with tamoxifen in breast cancer. 

There are a considerable number of permutations 

of how to maximize somatostatin analog 

therapy for breast carcinoma in combination 

with tamoxifen alone, as an adjuvant to chemotherapy 

prior to commencing tamoxifen 

treatment or intermittent administration, and 

all eventualities need to be explored in good 

phase 2 trials before proceeding to phase 3 

randomized controlled trials. All we can conclude 

at present is that somatostatin analogs 

in combination with tamoxifen confer no advantage 

over antiestrogen treatment alone in 

the management of metastatic breast cancer. 

Indeed in both randomized controlled trials 

the complication rate was higher with combination 

therapy than with tamoxifen alone 

which may adversely affect the HRQL [91, 

92]. 

In a third very small randomized controlled 

trial tamoxifen was compared with triple 

therapy comprising the antiestrogen in 

combination with octreotide and a prolactin 

inhibitor in patients with breast cancer [102]. 

Interestingly, unlike previous controlled trials 

[91, 92], serum IGF-1 levels were not significantly 

different between the two groups of 

patients [102]. The objective response rates 

were better in patients receiving triple therapy 

compared to tamoxifen alone but survival 

was not improved [102]. However, it is very 

difficult to make any definitive conclusions 

on the efficacy of triple therapy compared 

with tamoxifen alone since the study was considerably 

underpowered. Furthermore, in our 


opinion it would be unwise to proceed to controlled 

trials comparing tamoxifen with polyhormonal 

therapies until the issues relating to 

combining the antiestrogen with somatostatin 

analogs have been fully resolved. 

It has been suggested that tamoxifen plus 

somatostatin analog therapy may be more 

effective than tamoxifen alone in the adjuvant 

setting than in metastatic breast cancer. This 

hypothesis is based on phase 2 studies suggesting 

that somatostatin analogs potentiate the 

effects of tamoxifen in suppressing serum 

IGF-1 levels [99] and from experimental studies 

which indicate that combination therapy 

is more effective than monotherapy in rats 

with a low tumor burden from those with 

more advanced neoplasia [100]. Indeed, clinical 

trials are currently in progress to examine 

this hypothesis. However, in view of the very 

disappointing results obtained with combined 

tamoxifen and somatostatin analog therapy in 

patients with metastatic breast disease [91, 

92] adjuvant trials of such combination therapy 

should be monitored carefully by independent 

Safety Monitoring and Advisory Committees 

(SMAC). Furthermore, adjuvant tamoxifen 

therapy for patients with early breast 

cancer is established as being both safe and 

effective [103]. The only controversy over 

tamoxifen as an adjuvant therapy for early 

breast cancer is for how long treatment should 

be continued after surgery for early breast 

cancer, i.e. 1, 2 or 5 years [103]. Given that we 

know that prolonged somatostatin analog 

therapy can lead to downregulation of hSSTR 

expression and loss of efficacy in controlling 

IGF-1 secretion, it is very difficult to see a role 

for these drugs in very long-term adjuvant 

management programs for preventing recurrent 

early breast cancer. Furthermore, in view 

of the increased risk of side effects of combined 

tamoxifen and somatostatin analog 

therapy compared with tamoxifen alone in 

patients with metastatic breast cancer [91, 

92], particularly attention should be paid to 

HRQL by SMAC’s monitoring adjuvant trials 

of this combination therapy. When assessing 

HRQL account must also be taken of the pattern 

of the method of delivery of the somatostatin 

analogs, since although facilitated by the 

availability of long-acting depot preparations 

of octreotide, vapreotide and lanreotide, this 

still involves injections. Finally, although not 

always the ideal setting for carrying out complex 

economic analyses, this does need to be 

taken into account when considering prolonged 

expensive adjuvant therapies. Perhaps 

somatostatin analog therapy in combination 

with tamoxifen may prove to be superior to 

antiestrogen alone in the prevention of recurrent 

early breast cancer but we will not be able 

to answer this until the results of such trials 

become available. 

The rationale for the use of somatostatin 

analogs in the management of advanced prostatic 

cancer and the results of preliminary 

phase 1 and phase 2 clinical trials are discussed 

in detail by Vainas [91] in a separate 

paper in this volume. In brief, hSSTR expression 

is different in normal and neoplastic cells 

and between stromal and epithelial cells [34]. 

Of particular importance is that apart from 

hSSTR-5, the other hSSTRs expressed in primary 

cultures of epithelial and stromal cells 

(table 2) do not bind with high affinity to the 

somatostatin analogs currently available for 

clinical use [34]. These observations would 

suggest that any beneficial effects of octreotide, 

vapreotide or lanreotide in advanced 

prostatic cancer are likely to be mediated by 

their indirect rather than direct antineoplastic 

mechanisms of action. Exploitation of the full 

direct antineoplastic effects of somatostatin 

analog therapy in prostate cancer patients 

awaits (1) the development of novel analogs 

specific for hSSTR-1 or hSSTR-5 subtypes 

or (2) effective methods of delivering the 

hSSTR-2 gene to neoplastic cells. Thus, at 


Table 2. Expression of somatostatin 

receptor subtypes (hSSTR) in 

primary cultures of epithelial 

and stromal cells on normal human 

prostates and prostate 

cancers [after 34] 

present, any benefit of somatostatin analog 

therapy in prostatic cancer is likely to be 

mediated largely by their indirect antineoplastic 

effects. 

With respect to the clinical trials of somatostatin 

analog therapy in advanced prostate 

cancer it is difficult to make any conclusions 

on their therapeutic efficacy [91] since such 

studies in general included (1) patients with 

hormone-refractory or non-hormone-refractory 

disease, (2) relatively small numbers of 

patients, (3) used somatostatin analog therapy 

alone or combined with bromocriptine or 

complete androgen blockade, (4) used wide 

variations in the dosing regimes and 

(5) lacked objective outcome measures including 

HRQL. Consequently, at present it 

would be unwise to embark on large randomized 

controlled trials of somatostatin analog 

therapy in cancer of the prostate but rather to 

carry out good quality phase 2 trials to determine 

the therapeutic efficacy and tolerability 

of octreotide, lanreotide and vapreotide in 

this indication. 

An obvious clinical setting to initially examine 

the therapeutic efficacy and tolerability 

of somatostatin analogs is in patients with 

hormone-refractory prostate cancer since at 

present there are no clear-cut treatment algorithms 

for second-line management. Hormone-refractory 

prostate cancer usually manifests 

itself after complete androgen blockade 

and is thought to be the result of selection 

hSSTR-1 hSSTR-2 hSSTR-3 hSSTR-4 hSSTR-5 

Normal epithelial cells – + – + + 

Normal stromal cells – – – – – 

Neoplastic epithelial cells + – – + + 

Neoplastic stromal cells – – – – – 

– = Not detectable; + = detectable. 

and/or cloning of preexisting or de novo hormone-independent 

cell lines. Hormonal escape 

of prostate cancer cells during complete 

androgen blockade is a gradual event and 

monitoring of PSA has become accepted as 

the diagnostic test of choice to measure the 

progression of disease. Early diagnosis of hormonal 

escape based on a rise in PSA levels in 

patients with advanced prostate cancer who 

are still asymptomatic provides an opportunity 

for early institution of adjuvant therapies, 

and hence gives a reasonable chance for investigating 

both the efficacy and tolerability of 

the additional treatment being investigated. 

The principal outcome measure should be 

survival and the main secondary end point 

HRQL, the latter being assessed by both specific 

and generic instruments. With respect to 

somatostatin analog therapy as adjuvant to 

complete androgen blockade some consideration 

should be given to whether treatment 

should be intermittent or continuous. It has 

been demonstrated that octreotide in combination 

with complete androgen blockade in 

patients with advanced prostate cancer resulted 

in significant reductions in the serum 

levels of IGF-1 and epidermal growth factor 

(EGF) which paralleled the reduction in PSA 

[104]. Possibly therefore, serum IGF-1 and 

EGF levels could be used as serum markers of 

early escape from somatostatin analog therapy. 

Somatostatin analog therapy could then 

be stopped and re-instituted when the serum 


levels of IGF-1 and EGF return to those 

observed prior to commencing treatment. A 

reduction of serum IGF-1 and EGF levels 

after recommencing somatostatin analog therapy 

to those observed when these drugs were 

initially administered would be strongly suggestive 

that intermittent treatment dosing regimes 

may be preferable to continuous administration. 

This hypothesis clearly needs to 

be initially substantiated in phase 2 trials. It is 

mandatory that serum PSA levels are monitored 

at regular intervals in patients with advanced 

prostate cancer being treated with a 

somatostatin analog as an adjuvant in the 

event that combination therapy results in rapid 

progression of disease. 

In patients with advanced prostate cancer 

in whom the disease is completely refractory 

to complete androgen blockade, somatostatin 

analog therapy appears to be of very limited 

value [91]. Only in this setting should 

phase 2 trials of somatostatin analog therapy 

combined with other treatment modalities 

such as bombesin antagonists, LHRH antagonists 

or chemotherapy be considered. The 

principal primary and secondary outcome 

measures should again be survival and 

HRQL. As discussed above, consideration 

should be given as to whether somatostatin 

analog therapy should be intermittent or 

continuous. 

In recent years, there has been increasing 

interest on whether or not intermittent complete 

androgen blockade may delay the onset 

of hormone-refractory prostate cancer compared 

to continuous treatment and hence improve 

survival and increase the tolerability of 

chemical castration [64, 65]. Although the 

results of preliminary trials suggest that intermittent 

complete androgen blockade may be 

superior to continuous treatment [64, 65], a 

comparison of these two forms of treatment 

urgently requires confirmation in a randomized 

controlled trial. It is tempting to specu- 

late that somatostatin analog therapy may 

confer an additional benefit, if used for limited 

periods between cycles of androgen suppression 

in patients with advanced prostate 

cancer. Increases in the serum levels of IGF-1 

or EGF could be used as indicators of escape 

from hormone suppression by the somatostatin 

analogs and to discontinue treatment. 

Serum PSA could be used to both detect any 

deleterious effect of somatostatin analog therapy 

on tumor progression and for recommencing 

androgen suppression. Intermittent 

androgen suppression and somatostatin analog 

therapy may be a tempting therapeutic 

modality for the management of advanced 

prostate cancer, particularly in the younger 

male but it has to be borne in mind that intermittent 

androgen blockade has yet to be demonstrated 

to be superior to continuous therapy 

in prolonging survival. Furthermore, the 

potential for harm exists for both intermittent 

androgen suppression and for somatostatin 

analog therapy. Any trials evaluating alternating 

androgen suppression with somatostatin 

analog therapy should be very carefully monitored. 

Pancreatic cancer is associated with an extremely 

poor prognosis even following a theoretically 

curative resection. The etiology, 

prognosis and therapeutic modalities for adenocarcinoma 

of the pancreas are discussed in 

detail by Rosenberg [82] in another paper in 

this volume. In brief, pancreatic adenocarcinoma 

cells express receptors for estrogens, 

progesterone and androgens suggesting that 

this neoplasm may be responsive to hormonal 

treatment. Indeed, there is some evidence to 

suggest that somatostatin analog therapy combined 

with either tamoxifen [105] or LHRH 

analogs [106] may have some clinically beneficial 

effects in adenocarcinoma of the pancreas 

and the results of these studies are discussed 

in detail by Rosenberg [82]. Suffice it 

to say that both studies suggest that pancreatic 


cancer may be responsive to hormonal manipulation 

with somatostatin analog therapy 

combined with either tamoxifen [105] or 

LHRH analogs [106] and warrants further 

investigation particularly in patients with 

small tumors who undergo a theoretically curative 

resection. 

Immunotherapy 

Cancer cells expressing tumor-specific antigens 

initiate a complex immune response 

involving a complex cascade of cellular and 

molecular interactions to destroy the tumor 

cell [107]. There is accumulating evidence to 

suggest that the failure of the immune system 

to eliminate a tumor results from the ability of 

tumor antigens to stimulate an effective immune 

response [107]. Possibilities for such 

failure include loss of major histocompatibility 

class 1 or its costimulator B7 expression, 

aberrant antigen presentation and the inhibition 

of the cellular and molecular components 

of the immune system by factors secreted 

from or expressed on tumor cells [107]. Further, 

surgical or anesthetic trauma compromise 

immune function [108–114] and can 

stimulate the release of growth factors [115]. 

Thus, in the immediate postoperative period 

in the cancer patient, these changes in immune 

function may accelerate the growth of 

microscopic local tumor cells and distant micrometastatic 

deposits and increase the risk of 

tumor cells that shed into the circulation during 

resection of the primary cancer establishing 

themselves as distant micrometastases. 

Not surprisingly, in the past 20 years 

there has been increasing interest in developing 

therapies to stimulate the immune response 

against tumors in patients with advanced 

metastatic disease to stabilize disease 

progression and as an adjuvant to surgery to 

increase the chances of achieving a curative 

resection. A variety of immunotherapies have 

been suggested to stimulate the immune system 

in cancer patients including (1) intralesional 

administration of nonspecific immunostimulants 

such as BCG or Cryptosporidium 

parvum, (2) administration of cytokines, 

(3) adoptive immunotherapy with lymphokine-activated 

killer cells administered 

either systematically or regionally, alone or in 

combination with cytokines or chemotherapy 

and (4) combination therapy with cytokines 

and immunomodulating hormones [116– 

120]. It is beyond the scope of this paper to 

discuss the clinical efficacy of all these therapeutic 

modalities except to state that none of 

these immunotherapies for neoplasia have 

fulfilled their potential and that future strategies 

are likely to focus on genetic immunotherapy. 

Of particular relevance to this paper 

are the consequences of somatostatin analog 

therapy on the immune response to cancer 

and whether or not the clinical efficacy of 

these drugs could be improved by concomitant 

immunotherapy. 

Initial interest in the use of combination 

somatostatin analog and immunotherapy focused 

on the possible synergistic effects of 

octreotide and interferon-· in inhibiting the 

proliferation of endocrine tumor cells [120]. 

This approach appeared to be justified by early 

anecdotal reports suggesting that octreotide 

and interferon-· in combination appeared to 

be a valuable immunoendocrine therapy for 

metastatic carcinoid tumors [121, 122]. However, 

interferon-· elicits a number of other 

immune responses apart from its antiproliferative 

effect on endocrine cells including stimulation 

of natural killer cell activity [118] suggesting 

that it may be a valuable adjuvant to 

somatostatin analog treatment of nonendocrine 

tumors. Unfortunately, the therapeutic 

potential of somatostatin analog therapy combined 

with immunotherapies has been relatively 

ignored as an option for the manage- 


ment of cancer. This may represent a considerable 

oversight since hSSTRs are expressed 

on a variety of normal and neoplastic lymphoid 

cells [38]. Furthermore, somatostatin 

analogs inhibit the proliferation of a variety of 

lymphoid cells, immunoglobulin production 

and natural killer cell activity [38, 123–126]. 

These inhibitory effects of somatostatin analog 

therapy on the immune system may have 

profound implications on their therapeutic efficacy 

in neoplasia. Apart from suggesting 

that somatostatin analog therapy may play a 

role in the management of lymphomas, these 

drugs may attenuate or completely negate any 

potential therapeutic benefit in terms of the 

direct and indirect antineoplastic effects on 

tumor growth. It is even possible that the 

immunosuppressive effects of somatostatin 

analogs outweigh their therapeutic beneficial 

effects resulting in a more rapid tumor progression. 

Although purely speculative at 

present the immunosuppressant effects of somatostatin 

analog may account, at least in 

part, for the very disappointing results of 

these drugs in advanced malignancy. Furthermore, 

careful consideration should be given 

to the use of adjuvant somatostatin analog 

therapy as an adjuvant to surgery in the immediate 

postoperative period. As discussed 

above, surgery and anesthesia compromise 

the immune system [108–114] and administration 

of somatostatin analogs intra- or postoperatively 

may, by further immunocompromising 

the patient, accelerate the growth 

of tumor deposits remaining after radical resection. 

There is an abundance of evidence to 

indicate that somatostatin analog therapy 

used as and adjuvant to surgery may prevent 

the growth and development of hepatic metastases 

via stimulation of hepatic RES activity 

[11] but this may be at the expense of early 

local recurrence. Similarly, somatostatin analogs, 

because of their inhibitory effects on other 

functions of the immune system, may ac- 

celerate the growth of established micrometastases 

in locations other than the liver. 

Again these hypotheses require further investigation. 

Finally, and perhaps more importantly, 

investigations are required to determine 

whether or not it is possible to potentiate 

the individual benefits of somatostatin 

analog and concomitant therapies such as the 

administration of cytotoxics, by stimulating 

immune function by adoptive immunotherapy 

or genetic immunotherapy by combination 

treatments. Resolving all the problems discussed 

above represent a considerable challenge 

to oncologists and immunologists and 

require carefully designed studies in experimental 

animals and in man. Nevertheless, 

such studies are required to substantiate the 

above hypotheses since they are critical to 

optimizing somatostatin analog therapy of 

neoplasia. 

Novel Therapeutic Approaches to the 

Management of Neoplasia 

Targeted Radiotherapy 

Somatostatin scintigraphy using stable radiolabelled 

compounds of octreotide and 

more recently vapreotide is a well-established 

technique for the localization of primary and 

metastatic tumors expressing hSSTR-2 and 

hSSTR-5. Somatostatin receptor scintigraphy 

can, and indeed should, be used for the selection 

of patients with neuroendocrine and other 

solid tumors who are likely to benefit from 

somatostatin therapy and for monitoring 

treatment. The major limitation of somatostatin 

receptor scintigraphy using radiolabelled 

ligands of octreotide is that the technique 

will only allow detection of those tumors 

expressing hSSTR-2 and hSSTR-5 and 

possibly those neoplasms expressing hSSTR-3 

in sufficient density to allow visualization. 

Radioligands of vapreotide may be more use- 


ful than radiolabelled ligands of octreotide in 

visualizing those tumors that express hSSTR- 

4 in a sufficient density, but not hSSTR-2 and 

hSSTR-5. Visualization of tumors by vapreotide 

scintigraphy but not by octreotide scintigraphy 

may provide a rationale for the selection 

of patients that are likely to benefit from 

therapy with vapreotide or lanreotide rather 

than octreotide, but this hypothesis requires 

confirmation in prospective controlled trials. 

Targeted radiotherapy based on the binding 

of somatostatin analog radioligands to tumors 

expressing hSSTRs is an obvious extension 

of somatostatin scintigraphy. This is not 

a new concept and as long ago as 1995 Wiseman 

and Kvols [127] reviewed the results 

of targeted radiotherapy using 131 I-metaiodobenzylguanidine 

( 131 I-MIBG) and 111 In- 

DTPA-D-Phe1octreotide ( 111 In-pentetreotide) 

in patients with pheochromocytoma, 

neuroblastoma, carcinoid tumors, medullary 

thyroid carcinoma and paragangliomas. Targeted 

radiotherapy with 131 I-MIBG resulted 

in variable tumor responses with the most 

encouraging results being observed in patients 

with pheochromocytomas [127]. 111 In-pentetreotide 

has also been used for targeting radiotherapy 

in a very small number of patients 

with neuroendocrine tumors and resulted in 

objective tumor responses [127]. These authors 

concluded that targeted radiotherapy 

with somatostatin analogs coupled to ß- or ·emitting 

radioisotopes would be necessary to 

obtain a significant and desirable tumor response 

[127]. This point has been emphasized 

repeatedly by medical oncologists and indeed 

there are a number of experimental studies 

evaluating ß- or ·-emitting somatostatin radioligands. 

For example, rhenium-188 (t 1 /2 

16.9 h; beta-max 2.5 units) coupled to vapreotide 

administered intralesionally (prostate) or 

intracavitarily (mammary and small cell lung 

cancer) significantly reduced or eliminated 

the tumor burden in nude mice [128]. Local 

or regional administration of radiolabelled 

high energy ß- or Á-radioligands of somatostatin 

analogs may have some advantages over 

intravenous administration. Firstly, local or 

regional administration of such radioligands 

may reduce systemic toxicity. Secondly, somatostatin 

receptors are widely distributed in 

normal tissues throughout the body and intravenous 

administration of high energy ß- or Áradioligands 

of somatostatin analogs may produce 

side effects over and above those observed 

with regional conventional or somatostatin 

analog-targeted radiotherapy. Finally, 

recent studies have suggested that there may 

be a blood-tumor barrier, thereby possibly 

preventing diffusion of radiolabelled somatostatin 

analogs from the capillary tumor to 

neoplastic cells [129]. 

The concept of targeted radiotherapy of 

tumors using radioligands of somatostatin 

analogs remains a very attractive approach 

for the treatment of neoplasia. The fact that it 

is over 12 years since the concept of octreotide-targeted 

radiotherapy of neoplasia was 

first proposed and we are still awaiting any 

good phase 2 clinical trials of the efficacy and 

tolerability of this technique highlights the 

practical difficulties involved in developing 

this therapy. Nevertheless, a number of 

groups are actively investigating targeted radiotherapy 

of tumors using high energy ß- and 

Á-emitters of somatostatin analog radioligands 

and the results of early studies in patients 

are awaited with interest. 

Angiogenesis 

Angiogenesis is defined as the development 

of de novo capillaries from preexisting 

blood vessels and is an important process in 

the growth of solid cancers. The pathophysiology 

of angiogenesis in solid tumors and the 

potential role of somatostatin analogs as antiangiogenic 

drugs in neoplasia has been comprehensively 

reviewed by Danesi and Del 


Tacca [130] and Woltering et al. [131]. In 

brief, using in vitro models of angiogenesis, 

octreotide inhibits the development but not 

the growth of new capillaries [130, 131]. Furthermore, 

octreotide has been demonstrated 

to inhibit angiogenesis after chemical-induced 

corneal injury in rats and possibly in 

patients with diabetic retinopathy [130]. Although 

it is almost impossible to quantify the 

antiangiogenic effects of somatostatin analog 

therapy on tumor progression directly, inhibition 

of angiogenesis is theoretically an important 

mechanism whereby these drugs exert 

their antineoplastic effects. Thus, tumor cells 

are genetically diverse and unstable and hence 

the direct and indirect antineoplastic effects 

of somatostatin analog therapy may not result 

in complete elimination of all cancer cells. In 

contrast, endothelial cells in tumor vessels are 

genetically more stable and less likely to develop 

resistance to therapeutic procedures. 

For example, endogenous antagonists to angiogenesis 

such as angiostatin and endostatin 

which selectively inhibit endothelial cells to 

respond to antigenic signals elicit marked regression 

of tumors in experimental animals 

[132, 133]. Furthermore, gene transfer of angiostatin 

significantly inhibits tumor growth 

in experimental animals [134]. Alternatively, 

although a large number of angiogenic factors 

are implicated in tumor vascularization, strategies 

targeted at blocking these factors can 

reduce tumor growth [131]. A promising approach 

to inhibition of tumor growth by inhibiting 

angiogenesis is the development of 

gene therapies. For example, transfection of 

tumor cells with antisense oligonucleotides 

against vascular endothelial growth factor 

mRNA has been reported to reduce the 

growth rate of gliomas [135]. Similarly, genetic 

transfer of a soluble Tie 2 receptor (endothelium-specific 

receptor tyrosine kinase) 

blocks activation of Tie 2 receptors on tumor 

cells [135]. Furthermore, these investigators 

demonstrated that treatment of tumor-bearing 

animals with the soluble Tie 2 receptor 

using recombinant adenovirus as a vector almost 

completely inhibited angiogenesis but 

significantly inhibited the growth of both the 

primary tumor and metastases [135]. Although 

the efficacy and tolerability of the specific 

antagonists and genetic therapy of angiogenesis 

has not yet been reported in man, clinical 

studies are ongoing. It appeared logical to 

us that the direct and indirect antineoplastic 

effects of somatostatin analog therapy combined 

with its antigenic action could potentiate 

the effects of specific antagonists and 

gene therapy of angiogenesis. We are currently 

evaluating this hypothesis intensively and if 

the results of our studies suggest that somatostatin 

analogs potentiate that of specific antiangiogenic 

therapies, this may prove to be a 

very valuable approach to the management of 

neoplasia. 

Gene Therapy 

Gene therapy has immense potential for 

the treatment of many forms of diseases including 

cancer [136]. Although there are a 

number of problems which remain to be resolved 

before gene therapy can be routinely 

applied to patients with malignancy, initial 

studies in man are very promising [136]. With 

respect to somatostatin analog therapy there 

are a number of areas in which effective gene 

therapy may be used to potentiate the antineoplastic 

effects of these drugs. Perhaps the 

most obvious application of gene therapy to 

somatostatin analog treatment of neoplasia is 

the delivery of hSSTR-2 and hSSTR-5 genes 

together with the genes that encode their 

membrane proteins to cancers such as pancreatic, 

gastric and colorectal cancers that do 

not express these receptor subtypes. The somatostatin 

analogs currently available for 

clinical uses, octreotide, vapreotide and lanreotide, 

exert the majority of their antineo- 


plastic effects via hSSTR-2 and hSSTR-5 and 

it follows therefore that effective transfer of 

genes encoding for hSSTR-2 and hSSTR-5 as 

well as their membrane proteins to cancers 

which do not express these receptors subtypes 

may render them responsive to the direct antineoplastic 

effects of the current generation of 

somatostatin analogs. In some tumors such as 

breast cancer, hSSTRs are not uniformly distributed 

throughout the neoplastic tissue 

[100]. Using genetic transfer of genes encoding 

for hSSTR-2 and hSSTR-5 and their 

membrane proteins, it may be possible to 

increase the number of cells expressing 

hSSTRs, thereby enhancing the efficacy of 

somatostatin analog therapy. Tissue targeting 

is crucial to effective gene therapy and this 

problem has still to be overcome before such 

treatment can become part of routine clinical 

practice for common malignancies. The use of 

retroviral vectors which preferentially target 

cancer cells by their specific integration into 

proliferating cells may be one option. However, 

perhaps a more practical approach to 

ensure tumor-restricted expression of the 

transgenes is the use of tumor-specific promoters 

or high affinity monoclonal antibodies. 

Currently, there is an explosion of 

activity in researching effective, specific and 

less toxic delivery of genes to target tissue and 

it is not overoptimistic to speculate that in the 

not too distant future, genetic transfer of 

hSSTRs and their membrane proteins will potentiate 

the direct antineoplastic effects of 

somatostatin analogs in tumors which do not 

express hSSTR-2 or hSSTR-5. It is also not 

inconceivable that genetic transfer of hSSTRs 

to hormone-resistant tumor cells in tumors 

resulting from prolonged somatostatin analog 

administration may prevent or delay escape 

from the antineoplastic effects of these drugs. 

Somatostatin analog therapy of cancer 

may also be enhanced by genetic therapy of 

oncogenes and replacement of tumor suppres- 

sor genes. For example, antisense inhibition 

of IGF-1 has been demonstrated to induce 

apoptosis in rat hepatocellular carcinoma 

cells [137]. A number of tumors express IGF- 

1 receptors and suppression of IGF-1 levels by 

somatostatin analogs, as discussed previously, 

provides a rationale for the indirect antineoplastic 

effects of these drugs in a variety of 

human neoplasms. A combination of somatostatin 

analog therapy alone or combined 

with other hormonal treatments or chemotherapy 

on tumor cells transfected with antisense 

inhibitors of IGF-1 may well result in 

increased tumor responses. 

A high proportion of human cancers contain 

mutations of the p53 suppressor gene 

[138]. There is considerable evidence to suggest 

that p53-dependent apoptosis plays an 

important role in enhancing the therapeutic 

efficacy of chemotherapy and radiotherapy. 

Conversely, tumors that contain p53 mutations 

generally, but not always, are more resistant 

to chemotherapy and radiotherapy. Not 

surprisingly, therefore, there has been considerable 

interest in restoration or modulation of 

p53 function by gene therapy to increase 

apoptosis and enhance tumor sensitivity to 

chemotherapy and radiotherapy. Studies on 

human cancer cell lines and experimental animals 

suggest that restoration of p53 function 

using retroviral or adenoviral vectors inhibits 

cell proliferation in vitro, the growth of tumors 

in vivo and sensitizes tumor cells to chemotherapy 

[139–141]. Further, as long ago as 

1996, Roth et al. [139] reported that retroviral 

wild-type p53 gene transfer in 9 patients with 

non-small-cell lung cancer, in whom conventional 

therapy had failed, resulted in increased 

apoptosis and tumor regression in 3 

patients. These data suggest that gene replacement 

with p53 is a promising therapeutic 

approach to the management of malignancy. 

However, it should be pointed out that as yet, 

available gene vectors for p53 are not highly 


efficient but work is ongoing to increase p53 

transduction efficiency. Furthermore, malfunctions 

of other components of the p53 

pathway may be important in the development 

of malignancy. For example, overexpression 

of the mdm-2 oncogene (which encodes 

for a phosphoprotein which blocks the 

activity of p53) in human sarcomas may be 

responsible for the development towards malignancy 

although p53 per se is normal [142]. 

Since mdm-2 interacts with p53 via a small 

molecular interface to inhibit its function, it is 

possible that a small molecule could be designed 

to disrupt this interaction. Nevertheless, 

in spite of the complexity of p53 function 

in carcinogenesis, the observation that p53 

can be restored by gene therapy in some 

tumors raises the possibility of combining 

such treatment with somatostatin analog administration. 

This suggestion is based on observations 

which suggest somatostatin analogs 

upregulate p53 function and hence apoptosis 

by activation of hSSTR-3 [143]. Possibly, 

therefore, the beneficial effects of genetic 

transfer of p53 to tumors that contain mutations 

of this suppressed gene may be enhanced 

by combination therapy with somatostatin 

analogs. Upregulation of p53 function 

by combination with somatostatin analogs 

may also increase the sensitivity of the tumors 

to chemotherapy and radiation therapy. 

Clearly, further studies are required to substantiate 

these hypotheses. 

The examples of a possibility of potentiating 

gene therapy by concomitant somatostatin 

analog administration discussed above and in 

the sections on Angiogenesis and Immunotherapy 

only represent a small number of the 

large number of possibilities for maximizing 

the therapeutic efficacy of these drugs by taking 

advantage of the impact that the ‘genetic 

revolution’ is likely to make on the management 

of neoplasia in the not too distant future. 

Summary and Conclusion 

The role of somatostatin therapy in the 

management of acromegaly is well established. 

Similarly, somatostatin analog therapy 

of neuroendocrine tumors is accepted as a 

valuable treatment option for providing excellent 

palliation when all else fails, although 

there may be room for improvement. In contrast 

the therapeutic efficacy of somatostatin 

analog monotherapy in the management of 

nonendocrine solid tumors has proven to be 

largely very disappointing. Combination therapy 

of somatostatin analogs with cytotoxics 

or other hormonal treatments targeted somatostatin 

analog chemotherapy or radiotherapy 

in both advanced malignancy and in 

the adjuvant setting may prove to be very 

much more effective than somatostatin analog 

monotherapy. Carefully controlled clinical 

studies with objective outcome measures and 

HRQL assessments are required to evaluate 

combination therapies. Particular attention 

should be given to the possible adverse effects 

of somatostatin analog therapy on the immune 

response to neoplasia and consideration 

given to the possibility of concomitant 

immunostimulatory therapy. The question of 

whether or not intermittent somatostatin 

analog therapy is preferable to continuous 

treatment needs to be addressed formally. 

This is now possible with slow-release preparations 

of octreotide, vapreotide and lanreotide. 

Other possible novel therapeutic approaches 

such as combination treatment with 

antiangiogenic drugs require investigation. Of 

particular importance in the future is the need 

to exploit the major advances in gene therapy 

to optimize the full potential of somatostatin 

analogs in the management of neoplasia. Although 

somatostatin analogs have not turned 

out to be the ‘magic bullet’ for the management 

of cancer as many oncologists thought 

they would when octreotide was first intro- 


duced into clinical medicine all is not doom 

and gloom. Indeed, if we heed the lessons 

learned from previous experience with somatostatin 

analog therapy in the management of 

neoplasia and logically and formally explore 

possible combinational treatments to maximize 

the therapeutic potential of these drugs in 

cancer the rewards could be significant. To 

quote Winston Churchill at the end of the 

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ABC 

Fax + 41 61 306 12 34 






Author Index Vol. 47, Suppl. 2, 2001 

Agostinelli, R. 127 

Amoroso, D. 62 

Baldelli, A.M. 127 

Baxter, J.N. 162 

Boccardo, F. 62 

Bousquet, C. 30 

Buscail, L. 30 

Carney, D.N. 78 

Cascinu, S. 127 

Catalano, G. 127 

Catalano, V. 127 

Davies, N. 162 

Dean, A. 54 

Giordani, P. 127 

Jenkins, S.A. 162 

Kouroumalis, E.A. 150 

Kynaston, H.G. 162 

Nott, D.M. 162 

Öberg, K. 40 

O’Byrne, K.J. 78 

Pelosini, I. 1 

Puente, E. 30 

Rosenberg, L. 134 

Scarpignato, C. 1 

Schally, A.V. 78 

Steward, W.P. 78 

Susini, C. 30 

Thomas, A. 78 

Vainas, I.G. 109 

Vaysse, N. 30 

197

ABC 

Fax + 41 61 306 12 34 






Subject Index Vol. 47, Suppl. 2, 2001 

Antiandrogen blockade, complete 

109 

Breast cancer 62 

Cancer treatment 1 

Chemotherapy 78, 127 

Gastrointestinal cancers 127 

[ 111 In]pentetreotide 78 

Hepatocellular carcinoma 150 

Hormonal maneuvers, alternative 

109 

Lanreotide 1, 40 

Liver tumors 150 

Lung cancer 78 

Neoplasms 162 

Neuroendocrine tumors 40 

Octastatin 40 

Octreoscan 40 

Octreotide 1, 40, 109, 127, 134, 

150 

Opioids 54 

Palliative care 54 

Pancreatic cancer 134 

Proliferation 30 

Prostate cancer, hormonerefractory 

109 

RC-160 134 

Receptor 78 

– signaling 30 

Review 162 

Somatostatin 1, 54, 62, 78, 134 

– analogs 62, 134, 162 

– receptors 30, 134, 150 

– – scintigraphy 1 

– receptor-targeted radiotherapy 

1 

Therapy 162 

Vapreotide 1

Somatostatin Analogs for Cancer Treatment and Diagnosis

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