Efficacy and safety of viscum fraxini-2 in advanced hepatocellular

10330
Chinese-German Journal of Clinical Oncology Volume 9 • Number 8 • August 2010 pp 435–496
ISSN 1610-1979 (Paper)
1613-9089 (Online)
CN 42-1654/R
Volume 9 • Number 8 • August 2010
Chinese-German
Journal of
Clinical Oncology
Wirksamkeit und Sicherheit von
Viscum Fraxini-2 bei fortgeschrittenem
hepatozellulärem Karzinom:
Eine Phase II Studie
Efficacy and safety of viscum fraxini-2
in advanced hepatocellular carcinoma:
a phase II study
Mohamed A. Ebrahim, Hend A. El-Hadaad, Omyma A. Alemam,
Salah A Keshta

Reprint from:
Chinese-German Journal of Clinical Oncology
Vol. 9, No. 8/2010
pp 452 – 458
© Huazhong University of Science and Technology and
Springer-Verlag Berlin Heidelberg 2010 ABNOBA 2010/2011

Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8
Wirksamkeit und Sicherheit von Viscum Fraxini-2* bei
fortgeschrittenem hepatozellulärem Karzinom:
cotoxins cause membranolysis. Polysaccharides activate
natural killer cells. Vesicles enhance T-cell proliferation
especially helper cells [11, 12] .
In a systematic review on controlled clinical trials, 23
studies were identified: 16 randomized, 2 quasi-randomized
and 5 non-randomized. Cancer sites included breast,
lung, stomach, colon, rectum, head and neck, kidney,
bladder, melanoma, and genital. Among these studies,
statistically significant positive outcomes were reported
for survival (n = 8), tumor remission (n = 1), overall quality
of life (n = 3), and quality of life in relation to side
effects during cytoreductive therapy (n = 3) [10] . A more
recent review evaluated the therapeutic effectiveness of
viscum album extract on gynecological and breast cancer.
The review included 19 randomized, 16 non-randomized
controlled studies, and 11 single-arm cohort studies. Nine
randomized controlled trials and 13 non-randomized
controlled studies assessed survival; 12 reported a statistically
significant benefit, the others either a trend or no
difference. Single-arm cohort studies investigated tumor
behavior, and safety. Tumor remission was observed after
high dosage and local application. The treatment was well
tolerated [13] Eine Phase II Studie
Ziel
Um die Prognose von Patienten mit hepatozellulärem
Karzinom im fortgeschrittenen Stadium zu verbessern,
werden neue systemische Therapien benötigt. Diese Studie
wurde durchgeführt, um die Wirksamkeit und Sicherheit
von Viscum Fraxini-2 (abnobaVISCUM Fraxini
20 mg*) bei fortgeschrittenem hepatozellulärem Karzinom
(HCC) zu ermitteln.
Methoden
Es handelt sich um eine Phase II Studie mit einem
2-Phasen-Design, . These in positive welche results 120 Chemo-naive and the need Patienten for effec-
mit tive fortgeschrittenem safe systemic agents HCC for patients eingeschlossen with advanced wurden. HCC Das
in prompted der Studie this verwendete phase II study Mistelpräparat to determine ist eine the response wässrige
Injektionslösung, rate to viscum fraxini-2 welche in ein advanced Milliliter HCC. abnobaVISCUM
The second-
Fraxini ary objectives 20 mg were enthält. to evaluate Es wurden the zwei safety Ampullen of the drug, einmal the
wöchentlich predictive factors subkutan of tumor verabreicht. response, and to estimate the
progression free and overall survival in studies patients.
Patients Ergebnisseand
methods
Die chronische Infektion mit dem Hepatitis-C Virus
war This der überwiegende was a prospective Grund uncontrolled (60 %) der Lebererkrankun-
phase II trial in
patients gen in der with Patientenpopulation. advanced HCC. The Gemessen protocol an was den approved Respon-
by se-Kriterien the institutional für solide review Tumoren board. erreichten Informed 24 consent Patien was ten
(20 obtained %) eine from „Objective each patient. Response“ (davon 2 mit „Complete
Response“) und 40 Patienten (33,3 %) erreichten „Stable
Disease“. Patient characteristics
Das mediane progressionsfreie Überleben aller
Patienten The study betrug population 4 Monate consisted (1–28 Monate; of patients 95 % with Konfiaddenz-Intervall:vanced-stage HCC. 3,3–4,7 The diagnosis Monate). of Das HCC mediane was confirmed Gesamtüberleben
by pathological für alle analysis Patienten or α-fetoprotein betrug 8 Monate > 400 (1–28 ng/mL Monate;
with a 95 hepatic % Konfidenz-Intervall: tumor highly suggestive 6,3–9,7 of HCC Mo nate). by imag- Für
Patienten, ing studies. welche Patients eine were „Stable classified Disease“ as having oder ein advanced Tumoransprechen
disease if they erreichten, were not betrug eligible die for mediane surgical Überlebens- or locorezeitgional
16 therapies. Monate. Patients were required to have at least
one Die target Nebenwirkungen, lesion that could hauptsächlich be measured in one Form dimen- einer
sion. Lokalreaktion (an der Injektionsstelle)* und Fieber, waren
im Exclusion Allgemeinen Criteria schwach included: und die (1) Eastern Verträglichkeit Cooperative war
Oncology gut. Es gab Group keinen (ECOG) arzneimittelbedingten performance status Studienabbruch > 2; (2) Advanced
und keine hepatic Nebenwirkungen decompensation mit (Child-Pugh tödlichem Ausgang. class C); (3)
Advanced medical co-morbidity; (4) Previous systemic
therapy; (5) Other malignancy or concomitant anti-tumor
therapy including tamoxifen and interferon.
4533
Treatment schedule and toxicity assessment
The mistletoe preparation for the study is an aqueous
injectable solution. It contains one milliliter of viscum
fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe
herb from ash tree, diluted in di-natrium-monohydrogen
phosphate, ascorbic acid and water) which
is equivalent to 10 000 ng/mL injection ampoules. Two
ampoules of viscum fraxini-2 were administered subcutaneously
once weekly. The treatment was administered
till unacceptable toxicity or documented progression or
if the patient chose to discontinue treatment. Toxicity
was evaluated according to the National Cancer Institute
Common Toxicity Criteria, version 3.0.
Pretreatment, follow-up, and
response evaluation
Prior to treatment all patients provided a complete
history and underwent thorough physical examination.
Laboratory studies included a complete blood count,
biochemical liver function tests, serum creatinine, electrolyes
and AFP. Radiological evaluation included chest
X-ray, ultrasonography (US) and triphasic computerized
scan (CT) of the abdomen, and a nuclear bone scan when
needed.
Patients were seen on a weekly basis during treatment
for history taking and physical examination. A complete
blood count serum creatinine and liver functions were
performed every 4 weeks. The tumor was assessed by CT
scan of the abdomen every 8 weeks. Responses were evaluated
by independent staff radiologists and confirmed by
CT after 4 weeks. Tumor response was classified on the
basis of the response evaluation criteria in solid tumors
guidelines (RECIST) [14] Zusammenfassung
Die Therapie mit abnobaVISCUM Fraxini 20 mg stellt
eine wirksame und sichere Behandlung für Patienten mit
fortgeschrittenem HCC dar. Es wird empfohlen, weitere
randomisierte und kontrollierte Studien durchzuführen.
*) Die mit „*” gekennzeichneten Ergänzungen
dienen dem besseren Verständnis. Das hier mit
„Viscum Fraxini-2” bezeichnete Arzneimittel entspricht
abnobaVISCUM Fraxini 20 mg und wird in
Ägypten unter der o. g. Bezeichnung vertrieben.
.
Statistical analysis
A phase II study designed with a 90% power to exclude
a true response rate of < 10% and detect a true response
rate of ≥ 20%. The study progressed using the Simon’s
two-stage design [15] , recruiting a total of 42 patients in
the first stage; the trial will be terminated if 4 or fewer
patients respond. If the trial goes on to the second stage,
a total of 120 patients will be studied. If the total number
responding is less than or equal to 17, the drug is rejected.
The first interim analysis suggested potential activity (10
patients responded); therefore, patient enrollment was
permitted to continue.
Data were analyzed on a personal computer running
SPSS © for windows (Statistical Package for Social Scientists)
Release 15. All tests are considered significant if (P <
0.05). For descriptive statistics of qualitative variables the
Frequency distribution procedure was run with calculation
of the number of cases and percentages. For descriptive
statistics of quantitative variables the Mean, Range
and Standard Deviation were used to describe central

Chinese-German Journal of Clinical Oncology August 2010, Vol. 9, No. 8, P452–P458
DOI 10.1007/s10330-010-0629-y
Efficacy and safety of viscum fraxini-2 in advanced
hepatocellular carcinoma: a phase II study
Mohamed A. Ebrahim 1 , Hend A. El-Hadaad 2 , Omyma A. Alemam 1 , Salah A Keshta 3
1 Lecturer of Medical Oncology, Oncology Center-Mansoura University, Mansoura, Egypt
2 Lecturer of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Consultant Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt
Received: 27 May 2010 / Revised: 19 June 2010 / Accepted: 5 July 2010
© Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2010
Abstract Objective: New systemic therapies are needed to improve the prognosis of patients with advanced-stage hepatocellular
carcinoma. The study was conducted to determine the efficacy and safety of viscum fraxini-2 in advanced Hepatocellular
carcinoma. Methods: A phase II study with a two-stage design that enrolled a total of 120 patients with chemotherapy
naïve advanced hepatocellular carcinoma. The mistletoe preparation for the study is an aqueous injectable solution that
contains one milliliter of viscum fraxini. Two ampoules of viscum fraxini were administered subcutaneously once weekly. Results:
Chronic hepatitis C virus infection was the predominant cause of liver disease (60%) in studied cases. According to the
response evaluation criteria in solid tumors 24 patients (20%) achieved objective response (including 2 complete responses)
and 40 patients (33.3%) achieved stable disease. The median progression free survival for all patients was 4 months (range
1–28 months; 95% CI 3.3:4.7 months). The median overall survival for all patients was 8 months (range 1–28 months; 95%
CI 6.3:9.7 months). The median survival for patients who achieved responsive or stable disease was 16 months. The toxicity
was generally mild and well tolerated, mainly in the form of local reaction and fever. There were no drug related discontinuation
or toxic deaths. Conclusion: Viscum fraxini-2 is an effective, safe treatment for patients with advanced hepatocellular
carcinoma. Further randomized controlled trials are recommended.
Key words viscum; fraxini-2; HCC; phase II
Hepatocellular carcinoma (HCC) is a major health
problem with a rising incidence all over the world [1] . It
is the fifth most common neoplasm in the world, and the
third most common cause of cancer-related mortality [2] .
Several treatment modalities are available for patients
with HCC, including resection, liver transplantation,
local ablation, transarterial therapy, systemic chemotherapy,
hormonal therapy, immunotherapy and radiation
therapy. Surgical resection, local ablation and liver
transplantation are the mainstay of treatment of localized
HCC. Unfortunately, only 25% of patients will present
with localized disease and can receive such a potentially
curative therapy [3] . So the majority of patients with HCC
present at an intermediate or advanced stage where, effective
systemic chemotherapy agents are needed [4] .
Large numbers of controlled and uncontrolled clinical
studies have been performed with most of the major
classes of cancer chemotherapy, given intravenously as
Correspondence to: Mohamed A. Ebrahim.
Email: drmohamedawad@gmail.com
single agent or in combination. The consensus was that no
single agent or combination of agents given systemically
reproducibly leads to more than 25% response rates or has
any effect on survival. No combination of these drugs had
been associated with survival beyond that of untreated
controls [4–7] . Recently a large randomized phase III study,
the SHARP trial [8] , was conducted and in this study, 602
patients with biopsy-proven advanced HCC were randomized
to receive either sorafenib (400 mg twice daily,
n = 299) or a placebo (n = 303). This trial represents the
first randomized systemic therapy trial that demonstrates
the overall survival benefit of systemic treatment in patients
with advanced HCC, and proofs that development
of novel agents will improve the management of HCC.
Viscum album L. is a semi parasitic plant growing on
different host trees [9] . The extracted mistletoe preparations
are among the most widely used unconventional
cancer therapies in Central Europe. Viscum Fraxini is an
aqueous extract of mistletoe [10] . It has many biologically
active substances, the best investigated include: Lectins
inhibit tumor growth and metastasis by increasing apoptosis,
direct cytotoxicity and inhibiting angiogenesis. Vis-

6454 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8
www. springerlink. com/content/1613-9089 453
cotoxins Table 1 Patient cause characteristics membranolysis. Polysaccharides activate
natural killer cells. Vesicles enhance T-cell proliferation
n %
especially helper cells
Sex
Male 83 69.2
Female 37 30.8
Performance Status (ECOG)
0 3 2.5
1 59 49.2
2 58 48.3
Ascites
Absent 56 46.7
Present 64 53.3
Hepatitis
HCV (+) 72 60.0
HbsAg (+) 26 21.7
Both (+) 10 8.3
Virology (–) 12 10.0
Child-pugh class
A 37 30.8
B 83 69.2
Number of lesions
Single 48 40.0
Multifocal 72 60.0
Okuda stage
I 30 25.0
II 90 75.0
Metastasis/macro-vascular invasion
Absent 53 44.2
Present 67 55.8
Age
Mean (SD) 56.0 (9.0)
Range 38.0–81.0
Bilirubin (mg/dL)
Mean (SD) 2.4 (2.1)
Range 0.3–12.0
Albumin (gm/dL)
Mean (SD) 3.2 (0.5)
Range 2.2–4.7
INR
Mean (SD) 1.5 (0.3)
Range 1.0–2.3
AFP (ng/mL)
Mean (SD) 1508 (3329)
Range 4–22040
tendency and dispersion. Association between categorical
variables was tested by the Chi Square Test. Survival
and time to progression analyses were calculated by the
Kaplan-Meier Product-Limit Estimator. Progression free
survival was calculated from the date of entry to the date
of objective disease progression or death. Overall survival
was measured from the date of entry to the date of last
follow up or death. The study outcomes were assessed according
to the intention-to-treat principle. All statistical
tests were two-sided.
[11, 12] .
In a systematic review on controlled clinical trials, 23
studies were identified: 16 randomized, 2 quasi-randomized
and 5 non-randomized. Cancer sites included breast,
lung, stomach, colon, rectum, head and neck, kidney,
bladder, melanoma, and genital. Among these studies,
statistically significant positive outcomes were reported
for survival (n = 8), tumor remission (n = 1), overall quality
of life (n = 3), and quality of life in relation to side
effects during cytoreductive therapy (n = 3) [10] . A more
recent review evaluated the therapeutic effectiveness of
viscum album extract on gynecological and breast cancer.
The review included 19 randomized, 16 non-randomized
controlled studies, and 11 single-arm cohort studies. Nine
randomized controlled trials and 13 non-randomized
controlled studies assessed survival; 12 reported a statistically
significant benefit, the others either a trend or no
difference. Single-arm cohort studies investigated tumor
behavior, and safety. Tumor remission was observed after
high dosage and local application. The treatment was well
tolerated [13] . These positive results and the need for effective
safe systemic agents for patients with advanced HCC
prompted this phase II study to determine the response
rate to viscum fraxini-2 in advanced HCC. The secondary
objectives were to evaluate the safety of the drug, the
predictive factors of tumor response, and to estimate the
progression free and overall survival in studies patients.
Patients and methods
This was a prospective uncontrolled phase II trial in
patients with advanced HCC. The protocol was approved
by the institutional review board. Informed consent was
obtained from each patient.
Patient characteristics
The study population consisted of patients with advanced-stage
HCC. The diagnosis of HCC was confirmed
by pathological analysis or α-fetoprotein > 400 ng/mL
with a hepatic tumor highly suggestive of HCC by imaging
studies. Patients were classified as having advanced
disease if they were not eligible for surgical or locoregional
therapies. Patients were required to have at least
one target lesion that could be measured in one dimension.
Exclusion Criteria included: (1) Eastern Cooperative
Oncology Group (ECOG) performance status > 2; (2) Advanced
hepatic decompensation (Child-Pugh class C); (3)
Advanced medical co-morbidity; (4) Previous systemic
therapy; (5) Other malignancy or concomitant anti-tumor
therapy including tamoxifen and interferon.
Treatment Table 2 Tumor schedule response* and toxicity assessment
The mistletoe preparation for the study is 95% an CI aqueous
n %
injectable solution. It contains one milliliter Lower of viscum Upper
fraxini Complete in response dilution stage-2 2 (15 mg 1.7 extract 0.0 of 20 mg 4.2 mistletoe
Partial response herb from ash tree, 22 diluted 18.3 in di-natrium-mono-
11.7 25.0
hydrogen Stable diseasephosphate, 40 ascorbic 33.3 acid and 25.0 water) 42.5 which
is Progressive equivalent disease to 10 000 50ng/mL 41.7 injection 32.5 ampoules. 50.8 Two
ampoules Not Assessedof viscum fraxini-2 6 were 5.0 administered 1.7 subcu- 9.2
taneously • Intention-to-treat once analysis weekly. The treatment was administered
till unacceptable toxicity or documented progression or
if Results the patient chose to discontinue treatment. Toxicity
was evaluated according to the National Cancer Institute
Common
Patient characteristics
Toxicity Criteria, version 3.0.
A total of 120 patients were enrolled between June
Pretreatment,
2007 and January 2009.
follow-up,
Baseline
and
characteristics are shown
response
in (Table 1);
evaluation
the mean age of studied cases was 56 years
with
Prior
a male
to treatment
to female ratio
all patients
of 2.2/1.
provided
Chronic
a
hepatitis
complete
C
history
virus infection
and underwent
was the
thorough
predominant
physical
cause
examination.
of liver dis-
Laboratory
ease (60%), followed
studies included
by hepatitis
a complete
B (22%). The
blood
diagnosis
count,
biochemical
of HCC was based
liver function
on fine needle
tests, serum
cytology
creatinine,
in 55 patients
electrolyes
(46%). The
and
remaining
AFP. Radiological
65 patients
evaluation
(54%) were
included
diagnosed
chest
X-ray,
by marked
ultrasonography
elevation of
(US)
α-fetoprotein
and triphasic
level
computerized
and imaging
scan
studies
(CT)
indicating
of the abdomen,
HCC. Distant
and a nuclear
metastasis
bone
were
scan
present
when
needed.
in 37 cases (31%), 18 cases (15%) lymph node metastasis,
11
Patients
cases (9%)
were
bone
seen
metastasis,
on a weekly
and
basis
8 cases
during
(7%)
treatment
lung me-
for
tastasis.
history
Thrombosis
taking and
of
physical
the main
examination.
portal vein or
A
one
complete
of its
blood
two major
count
branches
serum creatinine
was present
and
in 51
liver
cases
functions
(43%).
were
performed
All patients
every
were
4 weeks.
chemotherapy
The tumor
naive.
was assessed
The median
by CT
scan
duration
of the
of
abdomen
treatment
every
on
8
viscum
weeks.
fraxini-2
Responses
is
were
17 weeks
evaluated
(range
by
2–121
independent
weeks).
staff radiologists and confirmed by
CT after 4 weeks. Tumor response was classified on the
basis
Response
of the response evaluation criteria in solid tumors
guidelines
According
(RECIST)
to the RECIST 24 patients (20%) achieved
objective response, 2 patients (1.7%) achieved complete
response and 22 patients (18.3%) achieved partial response.
Forty patients (33.3%) achieved stable disease.
Progressive disease has been shown in 50 patients (41%).
6 patients (5%) did not have evaluation of response due to
early death (Table 2).
The overall objective response rate was significantly
higher in cases with: good PS (32% in patients with PS
0–1 vs. only 7% in patients with PS 2), well compensated
cirrhosis (32% in Child-Pugh class A vs. 15% in Child-
Pugh class B), and earlier tumor stage (47% in Okuda
Stage I vs. 11% in Okuda stage II) (Table 3). On multivariate
regression analysis only PS 0-1 and Okuda Stage I was
associated with better response to treatment (Table 4).
Survival
By the end of follow up 20 patients (20%) remained
progression free, the median progression free survival for
all patients was 4 months (range 1–28 months; 95% CI
3.3:4.7 months) (Fig. 1). The median overall survival for
all patients was 8 months (range 1–28 months; 95% CI
[14] .
Statistical analysis
A phase II study designed with a 90% power to exclude
a true response rate of < 10% and detect a true response
rate of ≥ 20%. The study progressed using the Simon’s
two-stage design [15] , recruiting a total of 42 patients in
the first stage; the trial will be terminated if 4 or fewer
patients respond. If the trial goes on to the second stage,
a total of 120 patients will be studied. If the total number
responding is less than or equal to 17, the drug is rejected.
The first interim analysis suggested potential activity (10
patients responded); therefore, patient enrollment was
permitted to continue.
Data were analyzed on a personal computer running
SPSS © for windows (Statistical Package for Social Scientists)
Release 15. All tests are considered significant if (P <
0.05). For descriptive statistics of qualitative variables the
Frequency distribution procedure was run with calculation
of the number of cases and percentages. For descriptive
statistics of quantitative variables the Mean, Range
and Standard Deviation were used to describe central

454 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8
www. springerlink. com/content/1613-9089 4537
cotoxins cause membranolysis. Polysaccharides activate
natural killer cells. Vesicles enhance T-cell proliferation
especially helper cells [11, 12] .
In a systematic review on controlled clinical trials, 23
studies were identified: 16 randomized, 2 quasi-randomized
and 5 non-randomized. Cancer sites included breast,
lung, stomach, colon, rectum, head and neck, kidney,
bladder, melanoma, and genital. Among these studies,
statistically significant positive outcomes were reported
for survival (n = 8), tumor remission (n = 1), overall quality
of life (n = 3), and quality of life in relation to side
effects during cytoreductive therapy (n = 3) [10] . A more
recent review evaluated the therapeutic effectiveness of
viscum album extract on gynecological and breast cancer.
The review included 19 randomized, 16 non-randomized
controlled studies, and 11 single-arm cohort studies. Nine
randomized controlled trials and 13 non-randomized
controlled studies assessed survival; 12 reported a statistically
significant benefit, the others either a trend or no
difference. Single-arm cohort studies investigated tumor
behavior, and safety. Tumor remission was observed after
high dosage and local application. The treatment was well
tolerated [13] Table 1 Patient characteristics
n %
Sex
Male 83 69.2
Female 37 30.8
Performance Status (ECOG)
0 3 2.5
1 59 49.2
2 58 48.3
Ascites
Absent 56 46.7
Present 64 53.3
Hepatitis
HCV (+) 72 60.0
HbsAg (+) 26 21.7
Both (+) 10 8.3
Virology (–) 12 10.0
Child-pugh class
A 37 30.8
B 83 69.2
Number of lesions
Single 48 40.0
Multifocal 72 60.0
. These positive results and the need for effec-
Okuda stage
tive safe systemic agents for patients with advanced HCC
I 30 25.0
prompted this phase II study to determine the response
II 90 75.0
rate
Metastasis/macro-vascular
to viscum fraxini-2
invasion
in advanced HCC. The secondary
Absent objectives were to evaluate the safety 53 of the drug, 44.2 the
predictive Present factors of tumor response, and 67 to estimate 55.8 the
progression Age free and overall survival in studies patients.
Mean (SD) 56.0 (9.0)
Patients Range and methods 38.0–81.0
Bilirubin (mg/dL)
Mean This (SD) was a prospective uncontrolled phase 2.4 (2.1) II trial in
patients Range with advanced HCC. The protocol 0.3–12.0 was approved
by
Albumin
the
(gm/dL)
institutional review board. Informed consent was
Mean (SD) 3.2 (0.5)
obtained from each patient.
Range 2.2–4.7
INR
Patient characteristics
Mean (SD) 1.5 (0.3)
Range
The study population consisted of patients
1.0–2.3
with advanced-stage
AFP (ng/mL) HCC. The diagnosis of HCC was confirmed
by Mean pathological (SD) analysis or α-fetoprotein 1508 > (3329) 400 ng/mL
with Range a hepatic tumor highly suggestive of 4–22040 HCC by imaging
studies. Patients were classified as having advanced
disease if they were not eligible for surgical or locoregional
tendency
therapies.
and dispersion.
Patients
Association
were required
between
to have
categori-
at least
one
cal variables
target lesion
was tested
that could
by the
be
Chi
measured
Square
in
Test.
one
Survival
dimension.
and time to progression analyses were calculated by the
Kaplan-Meier
Exclusion Criteria
Product-Limit
included:
Estimator.
(1) Eastern
Progression
Cooperative
free
Oncology
survival was
Group
calculated
(ECOG)
from
performance
the date of
status
entry
>
to
2;
the
(2)
date
Advanced
of objective
hepatic
disease
decompensation
progression or
(Child-Pugh
death. Overall
class
survival
C); (3)
Advanced
was measured
medical
from
co-morbidity;
the date of entry
(4) Previous
to the date
systemic
of last
therapy;
follow up
(5)
or death.
Other
The
malignancy
study outcomes
or concomitant
were assessed
anti-tuacmorcording
therapy
to the
including
intention-to-treat
tamoxifen
principle.
and interferon.
All statistical
tests were two-sided.
Treatment schedule and toxicity assessment
The mistletoe preparation for the study is an aqueous
injectable solution. It contains one milliliter of viscum
fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe
herb from ash tree, diluted in di-natrium-monohydrogen
phosphate, ascorbic acid and water) which
is equivalent to 10 000 ng/mL injection ampoules. Two
ampoules of viscum fraxini-2 were administered subcutaneously
once weekly. The treatment was administered
till unacceptable toxicity or documented progression or
if the patient chose to discontinue treatment. Toxicity
was evaluated according to the National Cancer Institute
Common Toxicity Criteria, version 3.0.
Pretreatment, follow-up, and
response evaluation
Prior to treatment all patients provided a complete
history and underwent thorough physical examination.
Laboratory studies included a complete blood count,
biochemical liver function tests, serum creatinine, electrolyes
and AFP. Radiological evaluation included chest
X-ray, ultrasonography (US) and triphasic computerized
scan (CT) of the abdomen, and a nuclear bone scan when
needed.
Patients were seen on a weekly basis during treatment
for history taking and physical examination. A complete
blood count serum creatinine and liver functions were
performed every 4 weeks. The tumor was assessed by CT
scan of the abdomen every 8 weeks. Responses were evaluated
by independent staff radiologists and confirmed by
CT after 4 weeks. Tumor response was classified on the
basis of the response evaluation criteria in solid tumors
guidelines (RECIST) [14] .
Statistical analysis
A phase II study designed with a 90% power to exclude
a true response rate of < 10% and detect a true response
rate of ≥ 20%. The study progressed using the Simon’s
two-stage design [15] , recruiting a total of 42 patients in
the first stage; the trial will be terminated if 4 or fewer
patients respond. If the trial goes on to the second stage,
a total of 120 patients will be studied. If the total number
responding is less than or equal to 17, the drug is rejected.
The first interim analysis suggested potential activity (10
patients responded); therefore, patient enrollment was
permitted to continue.
Data were analyzed on a personal computer running
SPSS © Table 2 Tumor response*
95% CI
n %
Lower Upper
Complete response 2 1.7 0.0 4.2
Partial response 22 18.3 11.7 25.0
Stable disease 40 33.3 25.0 42.5
Progressive disease 50 41.7 32.5 50.8
Not Assessed 6 5.0 1.7 9.2
• Intention-to-treat analysis
Results
Patient characteristics
A total of 120 patients were enrolled between June
2007 and January 2009. Baseline characteristics are shown
in (Table 1); the mean age of studied cases was 56 years
with a male to female ratio of 2.2/1. Chronic hepatitis C
virus infection was the predominant cause of liver disease
(60%), followed by hepatitis B (22%). The diagnosis
of HCC was based on fine needle cytology in 55 patients
(46%). The remaining 65 patients (54%) were diagnosed
by marked elevation of α-fetoprotein level and imaging
studies indicating HCC. Distant metastasis were present
in 37 cases (31%), 18 cases (15%) lymph node metastasis,
11 cases (9%) bone metastasis, and 8 cases (7%) lung metastasis.
Thrombosis of the main portal vein or one of its
two major branches was present in 51 cases (43%).
All patients were chemotherapy naive. The median
duration of treatment on viscum fraxini-2 is 17 weeks
(range 2–121 weeks).
Response
According to the RECIST 24 patients (20%) achieved
objective response, 2 patients (1.7%) achieved complete
response and 22 patients (18.3%) achieved partial response.
Forty patients (33.3%) achieved stable disease.
Progressive disease has been shown in 50 patients (41%).
6 patients (5%) did not have evaluation of response due to
early death (Table 2).
The overall objective response rate was significantly
higher in cases with: good PS (32% in patients with PS
0–1 vs. only 7% in patients with PS 2), well compensated
cirrhosis (32% in Child-Pugh class A vs. 15% in Child-
Pugh class B), and earlier tumor stage (47% in Okuda
Stage I vs. 11% in Okuda stage II) (Table 3). On multivariate
regression analysis only PS 0-1 and Okuda Stage I was
associated with better response to treatment (Table 4).
for windows (Statistical Package for Social Scientists)
Survival
Release 15. All tests are considered significant if (P <
0.05).
By
For
the
descriptive
end of follow
statistics
up 20
of
patients
qualitative
(20%)
variables
remained
the
Frequency
progression
distribution
free, the median
procedure
progression
was run
free
with
survival
calcula-
for
tion
all patients
of the number
was 4 months
of cases
(range
and percentages.
1–28 months;
For descrip-
95% CI
tive
3.3:4.7
statistics
months)
of
(Fig.
quantitative
1). The median
variables
overall
the Mean,
survival
Range
for
and
all patients
Standard
was
Deviation
8 months
were
(range
used
1–28
to
months;
describe
95%
central
CI

8454 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8
www. springerlink. com/content/1613-9089 455
Table 1 Patient characteristics
Table 2 Tumor response*
Sex
Male
Female
Performance Status (ECOG)
0
1
2
Ascites
Absent
Present
Hepatitis
HCV (+)
HbsAg (+)
Both (+)
Virology (–)
Child-pugh class
A
B
Number of lesions
Single
Multifocal
Okuda stage
I
II
Metastasis/macro-vascular invasion
Absent
Present
Age
Mean (SD)
Range
n
83
37
3
59
58
56
64
72
26
10
12
37
83
48
72
30
90
53
67
%
69.2
30.8
2.5
49.2
48.3
46.7
53.3
60.0
21.7
8.3
10.0
30.8
69.2
40.0
60.0
25.0
75.0
44.2
55.8
56.0 (9.0)
38.0–81.0
95% CI
n %
Lower Upper
Complete response 2 1.7 0.0 4.2
Partial response 22 18.3 11.7 25.0
Stable disease 40 33.3 25.0 42.5
Progressive disease 50 41.7 32.5 50.8
Not Assessed 6 5.0 1.7 9.2
• Intention-to-treat analysis
Results
Patient characteristics
A total of 120 patients were enrolled between June
2007 and January 2009. Baseline characteristics are shown
in (Table 1); the mean age of studied cases was 56 years
with a male to female ratio of 2.2/1. Chronic hepatitis C
virus infection was the predominant cause of liver disease
(60%), followed by hepatitis B (22%). The diagnosis
of HCC was based on fine needle cytology in 55 patients
(46%). The remaining 65 patients (54%) were diagnosed
by marked elevation of α-fetoprotein level and imaging
studies indicating HCC. Distant metastasis were present
in 37 cases (31%), 18 cases (15%) lymph node metastasis,
11 cases (9%) bone metastasis, and 8 cases (7%) lung metastasis.
Thrombosis of the main portal vein or one of its
two major branches was present in 51 cases (43%).
All patients were chemotherapy naive. The median
duration of treatment on viscum fraxini-2 is 17 weeks
(range 2–121 weeks).
Bilirubin (mg/dL)
Mean (SD) 2.4 (2.1)
Range 0.3–12.0
Albumin (gm/dL)
Mean (SD) 3.2 (0.5)
Range 2.2–4.7
INR
Mean (SD) 1.5 (0.3)
Range 1.0–2.3
AFP (ng/mL)
6.3:9.7 Mean (SD) months) (Fig. 2). The median survival 1508 (3329) for patients
who Range achieved disease control (responsive + 4–22040 stable disease)
was 16 months (95%CI 8–24 months), while the median
survival for cases who suffered progressive disease was 4
tendency months (95% and CI dispersion. 3–5 months), Association the difference between was categoristatisticalcally variables significant was (Log-Rank tested by the 70, Chi P < 0.001) Square (Fig. Test. 3). Survival
and time to progression analyses were calculated by the
Toxicity Kaplan-Meier Product-Limit Estimator. Progression free
survival No hematologic was calculated toxicity from has the date been of encountered; entry to the date the
spectrum of objective of disease non-hematologic progression toxicity or death. was Overall generally survival mild
and was well measured tolerated. from Pain the and date erythema of entry at to the the injection date of site last
developed follow up or in death. 94 patients The study (78.3%). outcomes Analgesics were and assessed anti-inacflammatorycording to the drugs intention-to-treat were used in 10 principle. patients (8.3%) All statistical to alleviate
tests were severe two-sided. pain and erythema. The treatment was post-
Response
poned
According
for 1–2
to
weeks
the RECIST
till resolution
24 patients
of the
(20%)
local
achieved
reaction
and
objective
the dose
response,
had to
2
be
patients
reduced
(1.7%)
to one
achieved
ampoule
complete
in subsequent
response
courses
and 22
in
patients
3 patients
(18.3%)
(2.5%).
achieved
The local
partial
reactions
re-
gradually
sponse. Forty
abate
patients
with subsequent
(33.3%) achieved
injections
stable
to be
disease.
nearly
painless
Progressive
after
disease
a median
has been
of 5
shown
injections.
in 50
Drug
patients
related
(41%).
fever
6 patients
developed
(5%)
in
did
39
not
patients
have evaluation
(32.5%). It
of
fever
response
was
due
grade
to
1
early
in most
death
patients,
(Table 2).
only two patients suffered grade 2 fever
The
that
overall
was alleviated
objective
by
response
administration
rate was
of paracetamol.
significantly
Drug
higher
related
in cases
fever
with:
gradually
good PS
abate
(32%
with
in
subsequent
patients with
injec-
PS
tion.
0–1 vs.
There
only
were
7% in
no
patients
drug related
with PS
discontinuation
2), well compensated
or toxic
deaths.
cirrhosis (32% in Child-Pugh class A vs. 15% in Child-
Pugh class B), and earlier tumor stage (47% in Okuda
Stage Discussion I vs. 11% in Okuda stage II) (Table 3). On multivariate
regression analysis only PS 0-1 and Okuda Stage I was
associated HCC is with a major, better and response often therapeutically to treatment (Table frustrating 4).
oncologic problem with a rising incidence of all over the
world Survival
By the end of follow up 20 patients (20%) remained
progression free, the median progression free survival for
all patients was 4 months (range 1–28 months; 95% CI
3.3:4.7 months) (Fig. 1). The median overall survival for
all patients was 8 months (range 1–28 months; 95% CI
[1] . Studies carried out on HCC in Egypt presumed
an increasing trend [16, 17] Table 3 Univariate analysis of factors that could predict response to treatment with viscum
RR
χ
. HCC is a relatively chemo-resistant
tumor and is highly refractory to cytotoxic chemotherapy.
This resistance is partly related to its tumor
biology, pharmacokinetic properties, and both intrinsic
and acquired drug resistance. In addition to intrinsic re-
2 Sex
Male
Female
Performance status
0–1
2
Ascites
Absent
Present
Underlying Liver Disease*
Viral
Other
Child-Pugh Class
A
B
Number of lesions
Single
Multifocal
Metastasis/Macro-vascular Invasion
Absent
Present
AFP (at the median cut-off)
< 300
> 300
Okuda stage
I
II
* Fisher’s exact test
n
19
5
20
4
12
12
22
2
12
12
12
12
13
11
16
8
14
10
Response
%
22.9
13.5
32.3
6.9
21.4
18.8
20.4
16.7
32.4
14.5
25.0
16.7
24.5
16.4
26.7
13.3
46.7
11.1
No Response
P
n %
64 77.1
1.4 0.24
32 86.5
42 67.7
12.0 0.001
54 93.1
44 78.6
0.1 0.71
52 81.3
86 79.6
* 0.76
10 83.3
25 67.6
5.2 0.023
71 85.5
36 75.0
1.3 0.26
60 83.3
40 75.5
1.2 0.27
56 83.6
44 73.3
3.3 0.68
52 86.7
16 53.3
80 88.9
17.8 < 0.001
Table 4 Multivariate analysis of variables with significant relation to
the response to viscum
95% CI
Odds ratio
P
Lower Upper
PS 0.25 0.066 0.95 0.041
Child 5.54 0.630 48.66 0.123
Okuda 0.07 0.008 0.62 0.017

456 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8
www. springerlink. com/content/1613-9089 4539
cotoxins cause membranolysis. Polysaccharides activate
natural killer cells. Vesicles enhance T-cell proliferation
especially helper cells [11, 12] .
In a systematic review on controlled clinical trials, 23
studies were identified: 16 randomized, 2 quasi-randomized
and 5 non-randomized. Cancer sites included breast,
lung, stomach, colon, rectum, head and neck, kidney,
bladder, melanoma, and genital. Among these studies,
statistically significant positive outcomes were reported
for survival (n = 8), tumor remission (n = 1), overall quality
of life (n = 3), and quality of life in relation to side
effects during cytoreductive therapy (n = 3) [10] . A more
recent review evaluated the therapeutic effectiveness of
viscum Fig. 1 Progression album extract free survival on gynecological in studied casesand
breast cancer.
The review included 19 randomized, 16 non-randomized
controlled studies, and 11 single-arm cohort studies. Nine
randomized controlled trials and 13 non-randomized
controlled studies assessed survival; 12 reported a statistically
significant benefit, the others either a trend or no
difference. Single-arm cohort studies investigated tumor
behavior, and safety. Tumor remission was observed after
high dosage and local application. The treatment was well
tolerated [13] . These positive results and the need for effective
safe systemic agents for patients with advanced HCC
prompted this phase II study to determine the response
rate to viscum fraxini-2 in advanced HCC. The secondary
objectives were to evaluate the safety of the drug, the
predictive factors of tumor response, and to estimate the
progression free and overall survival in studies patients.
Fig. 2 Overall survival in studied cases
Patients and methods
This was a prospective uncontrolled phase II trial in
patients with advanced HCC. The protocol was approved
by the institutional review board. Informed consent was
obtained from each patient.
Patient characteristics
The study population consisted of patients with advanced-stage
HCC. The diagnosis of HCC was confirmed
by pathological analysis or α-fetoprotein > 400 ng/mL
with a hepatic tumor highly suggestive of HCC by imaging
studies. Patients were classified as having advanced
disease if they were not eligible for surgical or locoregional
therapies. Patients were required to have at least
one target lesion that could be measured in one dimension.
sistance, Exclusion underlying Criteria liver included: cirrhosis (1) most Eastern often Cooperative precludes
Oncology the use of several Group (ECOG) cytotoxic performance agents status > 2; (2) Advanced
hepatic decompensation (Child-Pugh class C); (3)
Advanced medical co-morbidity; (4) Previous systemic
therapy; (5) Other malignancy or concomitant anti-tumor
therapy including tamoxifen and interferon.
[4] Fig. 3 Overall survival in cases with controlled disease (responsive or
stationary) vs. progressive disease
.
Extracts from European mistletoe or Viscum album L
have been reported to exert direct cytotoxic and immunomodulatory
effects in vitro and in vivo. The mechanism
of its anti-tumoral activity is largely related to immunostimulatory
effects, increasing apoptosis, direct cytotoxic-
Treatment schedule and toxicity assessment
The mistletoe preparation for the study is an aqueous
injectable solution. It contains one milliliter of viscum
fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe
herb from ash tree, diluted in di-natrium-monohydrogen
phosphate, ascorbic acid and water) which
is equivalent to 10 000 ng/mL injection ampoules. Two
ampoules of viscum fraxini-2 were administered subcutaneously
once weekly. The treatment was administered
till unacceptable toxicity or documented progression or
if the patient chose to discontinue treatment. Toxicity
was evaluated according to the National Cancer Institute
Common Toxicity Criteria, version 3.0.
Pretreatment, follow-up, and
response evaluation
Prior to treatment all patients provided a complete
history and underwent thorough physical examination.
Laboratory studies included a complete blood count,
biochemical liver function tests, serum creatinine, electrolyes
and AFP. Radiological evaluation included chest
X-ray, ultrasonography (US) and triphasic computerized
scan (CT) of the abdomen, and a nuclear bone scan when
needed.
Patients were seen on a weekly basis during treatment
for history taking and physical examination. A complete
blood count serum creatinine and liver functions were
performed every 4 weeks. The tumor was assessed by CT
scan of the abdomen every 8 weeks. Responses were evaluated
by independent staff radiologists and confirmed by
CT after 4 weeks. Tumor response was classified on the
basis of the response evaluation criteria in solid tumors
guidelines (RECIST) [14] .
Statistical analysis
A phase II study designed with a 90% power to exclude
a true response rate of < 10% and detect a true response
rate of ≥ 20%. The study progressed using the Simon’s
two-stage design [15] , recruiting a total of 42 patients in
the first stage; the trial will be terminated if 4 or fewer
patients respond. If the trial goes on to the second stage,
a total of 120 patients will be studied. If the total number
responding is less than or equal to 17, the drug is rejected.
The first interim analysis suggested potential activity (10
patients responded); therefore, patient enrollment was
permitted to continue.
Data were analyzed on a personal computer running
SPSS © ity and inhibition of angiogenesis
for windows (Statistical Package for Social Scientists)
Release 15. All tests are considered significant if (P <
0.05). For descriptive statistics of qualitative variables the
Frequency distribution procedure was run with calculation
of the number of cases and percentages. For descriptive
statistics of quantitative variables the Mean, Range
and Standard Deviation were used to describe central
[18–23] .
Several reviews are available on controlled and uncontrolled
trials aiming to determine the effectiveness,
tolerability and safety of mistletoe extracts given either
as monotherapy or as an adjunct to conventional cancer
treatments. The most recent and authoritative systematic
review was conducted by Horneber et al [24] . Outcome
measures considered included survival times, tumor response,
quality of life, adverse effects of cancer therapies
and safety of mistletoe extracts. Twenty one randomized
clinical trials met all the inclusion criteria, 13 provided
data on survival, 7 on tumor response, 16 on measures of
quality of life or reduction of adverse effects of chemotherapy,
12 on side effects of mistletoe treatment; overall
comprising 3484 randomized cancer patients. Of the 13
trials investigating survival, 6 showed some evidence of
a benefit, but none of them was of high methodological
quality. Of the 16 trials investigating the efficacy of mistletoe
extracts for either improving quality of life, or the
reduction of adverse effects of chemotherapy, 14 showed
some evidence of a benefit, but only 2 of them were of
higher methodological quality. Data on side effects indicated
that mistletoe extracts were usually well tolerated
and had few side effects.
With a disease control rate of 53%, an overall response
rate of 20%, a median progression free survival of
4 months, our result compares favorably with other systemic
therapies for HCC. One of the most frequently used
single agents, doxorubicin, has a response rate of less than
20%. Single agents such as 5- fluorouracil, cisplatin, paclitaxel,
raltitrexed, irinotecan, and nolatrexed have been
[5, 6,
evaluated but all have shown disappointing results
25–27] . Combination chemotherapy regimens such as PIAF
(cisplatin, interferon, doxorubicin, and 5-fluorouracil)
achieved an overall response of 21% however, have not
shown to improve survival when compared to singleagent
doxorubicin in a randomized phase III study [28] .
These positive effects on tumor response confirm the
results of a previous phase II study on the efficacy and
safety of mistletoe in advanced HCC. The study included
23 patients with chemotherapy-naive, advanced HCC.
The drug was administered by subcutaneous injection
once weekly. Three patients (13.1%) achieved CR, and
two patients (8.1%) achieved a PR. The median survival
was 5 months [29] .
The recent introduction of single agent sorafenib, in
the treatment of advanced HCC patients, indeed represents
an important advance in this challenging disease [8] .
However, one has to be reminded that this study included
patients with mostly pristine liver function (95% or more
with Child-Pugh A score in both groups) and excellent
performance status (mainly ECOG 0–1). Added to this,
the low response rate reported for this novel agent (only
2%) prompted a modified response criteria for HCC tak-

10 454 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8
www. springerlink. com/content/1613-9089 457
ing Table into 1 Patient account characteristics the viability of hepatic tumors rather
than tumor shrinkage. The subsets of patients in the cur-
n %
rent study presenting with similar criteria (early stage of
the Sex disease with minimal or no symptoms) gained the best
Male 83 69.2
benefit from palliative treatment with viscum fraxini-2.
Female 37 30.8
The overall objective response rate was significantly bet-
Performance Status (ECOG)
ter in cases with: good PS (32% in patients with PS 0–1),
0 3 2.5
and earlier tumor stage (47% in Okuda Stage I).
1 59 49.2
2The treatment in the current study 58 was well tolerated; 48.3
the Ascites most common drug-related adverse events were pain
and Absent erythema at the injection site and 56 drug related 46.7 fever.
The Present adverse events were generally mild, 64 manageable 53.3 and
gradually Hepatitis abate with subsequent injections. There were
no HCV drug (+) related discontinuation or toxic 72 deaths. 60.0
HbsAg The median (+) overall survival was 8 months; 26 this 21.7 cannot
be Both compared (+) to other studies due to differences 10 in 8.3 study
design, Virology selection (–) criteria and etiology 12 of cirrhosis. 10.0 However
Child-pugh in our classstudy
a remarkable median overall survival
of A16 months was recorded in patients 37 who achieved 30.8 a
disease B control on treatment. 83 69.2
Number On the of lesions basis of the study results, it can be concluded
Single 48 40.0
that, Viscum Fraxini-2 is an effective treatment for pa-
Multifocal 72 60.0
tients with advanced HCC. It can achieve a disease control
Okuda stage
rate of 53% including a 20% overall response, with some
I 30 25.0
occasional complete responses. The response is higher in
II 90 75.0
patients
Metastasis/macro-vascular
with good performance
invasion
status and earlier stage of
the Absent disease (Okuda Stage I). Cases who 53achieve a 44.2 disease
control Presentare expected to obtain a significantly 67 higher 55.8 overall
Agesurvival.
Given the high safety of viscum fraxini-2 and
the Mean previous (SD) reports on its ability to reduce 56.0 (9.0) the side effects
Range of chemotherapy, further phase II trials 38.0–81.0 in combination
Bilirubin with (mg/dL) other active agents in HCC are highly indicated.
Analysis Mean (SD) with a larger number of patients 2.4 in (2.1) a controlled
phase Range III clinical trial is clearly warranted. 0.3–12.0
Albumin (gm/dL)
Mean (SD) 3.2 (0.5)
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B, et
evaluation
al. Critical role
of response
of reactive
due
oxygen
to
early species death and (Table mitochondrial 2). membrane potential in Korean mistletoe
The lectin-induced overall apoptosis objective in human response hepatocarcinoma rate was significantly
cells. Mol Phar-
higher macol, in 2004, cases 66: with: 1383–1396. good PS (32% in patients with PS
0–1 23. Harmsma vs. only M, 7% Ummelen in patients M, Dignef with W, PS et 2), al. well Ramaekers, compensated Effects of
cirrhosis mistletoe (32% (Viscum in album Child-Pugh L.) extracts class Iscador A vs. on cell 15% cycle in and Child- sur-
Pugh vival class of tumor B), cells. and Arzneimittelforschung, earlier tumor stage 2006, (47% 56: 474–482. in Okuda
Stage
24. Horneber
I vs. 11%
MA, Bueschel
in Okuda
G, Huber
stage
R,
II)
et
(Table
al. Mistletoe
3). On
therapy
multivari-
in oncology.
Cochrane Database Syst Rev, 2008, 2: CD003297.
ate regression analysis only PS 0-1 and Okuda Stage I was
25. Chao Y, Chan WK, Birkhofer MJ, et al. Phase II and pharmacokinetic
associated
study of paclitaxel
with better
therapy
response
for unresectable
to treatment
hepatocellular
(Table
carcinoma
4).
patients. Br J Cancer, 1998, 78: 34–39.
Survival 26. Rougier P, Ducreux M, Kerr D, et al. A phase II study of raltitrexed
By ('Tomudex') the end in of patients follow with up hepatocellular 20 patients carcinoma. (20%) remained Ann Oncol,
progression 1997, 8: 500–502. free, the median progression free survival for
all 27.
patients Stuart K, Tessitore was 4 J, months Rudy J, (range et al. A Phase 1–28 II months; trial of nolatrexed 95% CI di-
3.3:4.7 hydrochloride months) in (Fig. patients 1). with The advanced median hepatocellular overall survival carcinoma. for
all patients
Cancer, 1999,
was
86:
8
410–414.
months (range 1–28 months; 95% CI

458 Chinese-German J Clin Oncol, August 2010, Vol. 9, No. 8
www. springerlink. com/content/1613-9089 453 11
cotoxins cause membranolysis. Polysaccharides activate
natural killer cells. Vesicles enhance T-cell proliferation
especially helper cells [11, 12] .
In a systematic review on controlled clinical trials, 23
studies were identified: 16 randomized, 2 quasi-randomized
and 5 non-randomized. Cancer sites included breast,
lung, stomach, colon, rectum, head and neck, kidney,
bladder, melanoma, and genital. Among these studies,
statistically significant positive outcomes were reported
for survival (n = 8), tumor remission (n = 1), overall quality
of life (n = 3), and quality of life in relation to side
effects during cytoreductive therapy (n = 3) [10] . A more
recent review evaluated the therapeutic effectiveness of
viscum album extract on gynecological and breast cancer.
The review included 19 randomized, 16 non-randomized
controlled studies, and 11 single-arm cohort studies. Nine
randomized controlled trials and 13 non-randomized
controlled studies assessed survival; 12 reported a statistically
significant benefit, the others either a trend or no
difference. Single-arm cohort studies investigated tumor
behavior, and safety. Tumor remission was observed after
high dosage and local application. The treatment was well
tolerated [13] Treatment schedule and toxicity assessment
The mistletoe preparation for the study is an aqueous
injectable solution. It contains one milliliter of viscum
fraxini in dilution stage-2 (15 mg extract of 20 mg mistletoe
herb from ash tree, diluted in di-natrium-monohydrogen
phosphate, ascorbic acid and water) which
is equivalent to 10 000 ng/mL injection ampoules. Two
ampoules of viscum fraxini-2 were administered subcutaneously
once weekly. The treatment was administered
till unacceptable toxicity or documented progression or
if the patient chose to discontinue treatment. Toxicity
was evaluated according to the National Cancer Institute
Common Toxicity Criteria, version 3.0.
Pretreatment, follow-up, and
response evaluation
Prior to treatment all patients provided a complete
history and underwent thorough physical examination.
Laboratory studies included a complete blood count,
biochemical liver function tests, serum creatinine, electrolyes
and AFP. Radiological evaluation included chest
X-ray, ultrasonography (US) and triphasic computerized
. These positive results and the need for effec- scan (CT) of the abdomen, and a nuclear bone scan when
tive safe systemic agents for patients with advanced HCC needed.
prompted this phase II study to determine the response Patients were seen on a weekly basis during treatment
rate to viscum fraxini-2 in advanced HCC. The second- for history taking and physical examination. A complete
ary objectives were to evaluate the safety of the drug, the blood count serum creatinine and liver functions were
predictive factors of tumor response, and to estimate the performed every 4 weeks. The tumor was assessed by CT
progression free and overall survival in studies patients. scan of the abdomen every 8 weeks. Responses were evaluated
by independent staff radiologists and confirmed by
Patients and methods
CT after 4 weeks. Tumor response was classified on the
basis of the response evaluation criteria in solid tumors
This was a prospective uncontrolled phase II trial in guidelines (RECIST)
patients with advanced HCC. The protocol was approved
by the institutional review board. Informed consent was
obtained from each patient.
Patient characteristics
The study population consisted of patients with advanced-stage
HCC. The diagnosis of HCC was confirmed
by pathological analysis or α-fetoprotein > 400 ng/mL
with a hepatic tumor highly suggestive of HCC by imaging
studies. Patients were classified as having advanced
disease if they were not eligible for surgical or locoregional
therapies. Patients were required to have at least
one target lesion that could be measured in one dimension.
Exclusion Criteria included: (1) Eastern Cooperative
Oncology Group (ECOG) performance status > 2; (2) Advanced
hepatic decompensation (Child-Pugh class C); (3)
Advanced medical co-morbidity; (4) Previous systemic
therapy; (5) Other malignancy or concomitant anti-tumor
therapy including tamoxifen and interferon.
[14] .
Statistical analysis
A phase II study designed with a 90% power to exclude
a true response rate of < 10% and detect a true response
rate of ≥ 20%. The study progressed using the Simon’s
two-stage design [15] , recruiting a total of 42 patients in
the first stage; the trial will be terminated if 4 or fewer
patients respond. If the trial goes on to the second stage,
a total of 120 patients will be studied. If the total number
responding is less than or equal to 17, the drug is rejected.
The first interim analysis suggested potential activity (10
patients responded); therefore, patient enrollment was
permitted to continue.
Data were analyzed on a personal computer running
SPSS © 28. Yeo W, Mok TS, Zee B, et al. A randomized phase III study of 29. Mabed M, El-Helw L, Shamaa S. Phase II study of viscum fraxini-2 in
doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil
(PIAF) combination chemotherapy for unresectable hepatocellular
carcinoma. J Natl Cancer Inst, 2005, 97: 1532–1538.
patients with advanced hepatocellular carcinoma. Br J Cancer, 2004,
90: 65–69.
《中德临床肿瘤学杂志》2011年征稿启事
《中德临床肿瘤学杂志》是由中华人民共和国教育部主管,华中科技大学主办的医学肿瘤学学术期刊(全英文
月刊),是中国科技论文统计源期刊、中国科技核心期刊,被德国SpringerLink、中国知网、万方数据等国内外多
家数据库收录。国际、国内刊号为:ISSN 1610-1979 (纸版),1613-9089 (网络版);CN 42-1654/R,邮政代号:
38-121。
本刊主要刊登世界各国作者,特别是中国作者在肿瘤学领域的优秀科研成果和临床诊疗经验,包括与临床肿
瘤学密切相关的基础理论研究等成果,并全文以英语发表,在国内外公开发行。辟有述评、专家笔谈、论著、临
床研究、实验研究、综述、病例报道、人物专栏等栏目。
本刊具有编审效率高、出版周期短、学术价值高、临床实用性强、印刷精美等特点。承诺将一如既往地以广
大作者为依托,积极为作者和读者服务,严格做到对所有来稿处理及时、审稿认真、退修详细、发稿迅速。对具
有国际领先水平的创新科研成果及国家重点项目开辟“绿色通道”,审稿迅速,刊登及时。
欢迎全国各级肿瘤学医务工作者踊跃投稿、组稿!
《中德临床肿瘤学杂志》2011年重点专栏报道计划如下:
1,肺癌;2,肝癌;3,胰腺肿瘤;4,胃肠肿瘤;5,乳腺肿瘤;6,甲状腺癌;7,骨肿瘤;8,泌尿生殖系
肿瘤;9,脑肿瘤;10,血液系统疾病;11,妇科肿瘤;12,耳鼻喉科肿瘤;13,皮肤肿瘤;14,肿瘤诊断学(特
别是肿瘤影像诊断学);15,肿瘤化疗;16,肿瘤放疗;17,肿瘤心理学;18,其他。
敬请您关注,欢迎您踊跃投稿、组稿!具体投稿和联系方式请参见杂志版权页。
for windows (Statistical Package for Social Scientists)
Release 15. All tests ——中德临床肿瘤学杂志编辑部
are considered significant if (P <
0.05). For descriptive statistics of qualitative variables the
Frequency distribution procedure was run with calculation
of the number of cases and percentages. For descriptive
statistics of quantitative variables the Mean, Range
and Standard Deviation were used to describe central