(PRRT) of Gastro-Entero-Pancreatic NeuroEndocrine Tumors

Molecular Medicine
Same Molecule/Target Agent
Imaging
Radiotherapy
Individual Approach
EP Krenning, MD, PhD, FRCP
ROTTERDAM , NL

Targeted Radionuclide Therapy with 131 I
First radiotherapy with 131 I in 1941
67 years of experience with targeted
radionuclide therapy

Targeted Radionuclide Therapy with 131
Thyroid Cancer
131 I
Papillary thyroid carcinoma:
Long-term development of recurrent disease (left panel) or death (right panel) from
thyroid cancer patients without distant metastases at presentation, who received
either The 131-I principle ablation (red of dashed targeted lines) or radionuclide no ablation (blue solid therapy lines). works!
Data from Mazzaferri, EL, Jhiang, SM, Am J Med 1994; 97:418.

Molecular Medicine
in Patients with Inoperable
Gastro-Entero-Pancreatic NeuroEndocrine
Tumors (GEPNET)
with Somatostatin Receptor
as Target

Molecular Medicine of GEPNET
Introduction about GEPNET
Targeting of the somatostatin receptor
Examples of antitumor effects of LuTate
QoL, Survival
Case presentation and conclusion
Plenary session : Future
Based on “Proof of Principle” with GEPNET
Extension to other tumors
e.g. Breast and Prostate cancer

Incidence of GEPNET
country incidence [ / 100 000]
UK/Scottland 0,87 0,71 1979-1989
Denmark 1,1 1978-1981
Italy (Tuscany) 0,65 1985-1991
Schwitzerland (Vaud) 2,65 2,24 1974-1991
Netherlands 1,9 1,8 1989-1996
Sweden 2,4 2,0 1983-1998
USA (SEER) 3,98 2,47 (caucasians) 1973-1994
2,58 4,18 (african americans)
Newton et al BJC 1994
Westergaard et al Cancer 1995
Crocetti et al Eur J Epidemiol 1997
Levi et al BJC 2000
Quaedvlieg et al Ann Oncol 2001
Hemminki & Li Cancer 2001
Modlin et al Cancer 2003
Taal & Visser Neuroendocrinol 2004
Prevalence: + 1.6 / 10.000

Cytoreductive therapies for inoperable
neuroendocrine tumors
• Somatostatin analogues, interferon-alpha
• RFA or (Chemo-)Embolization
• Chemotherapy
• VEGF pathway interaction/Pipeline products
Disappointing antitumor effects, short lasting,
serious side effects and complications
Standard Care is: chemotherapy for Islet cell
tumors, supportive only by octreotide
• Peptide Receptor Radionuclide Therapy (PRRT)
GEPNET express somatostatin receptors
Radio-resistant solid tumor !

Somatostatin Somatostatin Analogues Analogues
octreotide
[Tyr 3 ]octreotide
[Tyr 3 ]octreotate
D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr (ol) (ol)
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr (ol)
D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr
additional negative charge
DTPA
HOOC-CH 2
H 2 C-COOH
N-(CH 2 ) 2 -N-(CH 2 ) 2 -N
HOOC-CH 2
CH 2 -COOH
CH 2 -COOH
DOTA
HOOC
NN
NN
NN
NN
COOH
stable radiolabeling
with 111 In, 67 Ga, 90 Y, 177 Lu
HOOC
COOH

Structure of a
Radiopeptide
Receptor
on Cell-Surface
radionuclide
linker
peptide
target
“key”
“lock”
“ 177 Lu” “OctreoTate”
“Receptor”
“LuTate”

Principle of in vivo peptide receptor targeting of cancer
J.C.Reubi
Peptide Receptors as Molecular Targets for Cancer Diagnosis and Therapy
Endocrine Reviews 2003; 24 (4): 389-427

Molecular Imaging at ErasmusMC

CD-Nummer
68 Ga-DOTA
DOTA-TOC, TOC, a magic bullet
Predictive imaging
PET
PET / CT
!
Hofmann M, Knapp W,
MH Hannover
Bockisch A, Essen
CT
PET
+
CT

Molecular Medicine at ErasmusMC

[ 177 Lu-DOTA,Tyr 3 ]octreotate scan

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy
in practice
•IV Aminoacids 4 h
•IV Granisetron 3mg
•IV 177 Lu-Octreotate 30 min
•Hospitalization 1 night

PRRT with radiolabelled somatostatin analogues
Subacute and Longterm (< 6.5 yrs) Side effects
• Temporary hairloss, no baldness (grd I)
• No effect on pituitary function
• No important effect on thyroid function
• Common: mild bone marrow suppression
• Common: Lymphocytopenia
• Rare: MDS, Leukemia (< 800 mCi) (3*)
• No Kidney failure with AA protection
• Rare: Liver toxicity (2*)
• Temporary impaired spermatogenesis
• Hormonal crises, need for special care 1 %

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy:
A Patient with a Pancreatic NE Tumor
OctreoScan
Pre Therapy
May 2001
Lu-octreotate
Therapy 1
Oct 2001
Lu-octreotate
Therapy 2
Dec 2001
Lu-octreotate
Therapy 3
Feb 2002
OctreoScan
Post Therapy
Aug 2002
• The patient had PR (small lesions on CT and SPECT Octreoscan) and
was progression free until July 2003 (2 yr)
• Note the higher tumor uptake on the first octreotate scan compared to
the OctreoScan
• Note the decrease in tumor uptake after each treatment cycle

1st cycle
2nd cycle
3rd cycle
4th cycle
> 48
CT-scan pretherapy
CT-scan 6 weeks after 4th cycle
CT-scan 3 months after 4th cycle

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy:
Nonfunctioning Tumor of the Pancreas
• CT before and 6 weeks after the last treatment. PR; decrease in liver size.
• Octreoscan before and 1 year after therapy. Normalization.

ectal neuroendocrine tumour, hepatic metastases

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy
Patient H
A
B
5.00
10000
Gastrin (ng/L)
0.50
0.10
0.05
1000
100
10
0 200 400 600 800 3 mo
Cumulative Dose (mCi)/ Follow-up time
CGA (ng/L)

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy:
Nonfunctioning Tumor of the Pancreatic Tail
• CT before and 6 weeks after the last treatment. Identical scaling.
• The patient had lost > 15 kg bodyweight before the treatment, and
regained 14 kg in the interval (8 months).
• Note the decrease in tumor size and increase in body circumference.

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy:
Inoperable Tumor of the Head of the Pancreas
• Initially inoperable tumor. CT before (May 2004) and 3 months after the
last treatment (March 2005). Identical scaling. PR.
• Increase in bodyweight: 14 kg.
• CT at 6 months identical. Successful Whipple procedure plus
reconstruction portal vein July 2005. Resection edges and lymphnodes
free of tumor. Discharge August 2005.

PRRT with LuTate in GEPNET shows
anti-tumor effects not shown before
QoL
Survival

[177Lu-DOTA0,Tyr3]Octreotate Therapy
N = 50 GEP-NET
EORTC-QLQ-C30 Questionnaire
Percentage of Patients with Improvement
100
90
80
70
60
50
40
30
20
10
0
9/12
30/43
29/43
21/29
15/25
16/22
9/25
Global QoL Fatigue Nausea Pain Dyspnea Insomnia Diarrhea
Symptom Scales
Overall improvement in 70 % of patients, excl for dyspnea
50 % of patients were already on SS analogs !!

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy:
Comparison of survival data
Overall Survival (months)
150
100
50
0
72
1.WDEC
128
92
2.Carcinoid
155
115
3.Carcinoid
155
43
5.Carcinoid liver mets
4.Dutch carcinoid liver mets at Dx
97
82
154
54
5.PNET liver mets
94
137 310 256188 304 188 58 100 35 172 18 76
Reference study
177 Lu-octreotate
Kwekkeboom D. et al, J Clin Oncol, 2008,
Reference Studies:
1. Clancy et al.; Dig Dis Sci 2006
2. Janson et al. ; Ann Oncol 1997
3. Update 2.Oberg ; personal comm 2007
4. Quaedvlieg et al. ; Ann Oncol 2001
5. Mazzaglia et al. ; Surgery 2007
• Survival benefit: 40-72 months
from day of initial diagnosis

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy
GEP NET
Conclusions
• PRRT is a fascinating new tool, at least for patients with
inoperable disease
• High tumor response rate
• Limited side-effects (only 1 % SAE)
• Improvement in quality of life
• Long progression free period
• Compared to historical controls: survival benefit 3.5-6 yrs
• New strategies are underway Cure

Future Developments for PRRT
in GEPNET
“towards CURE”
• Treatment in earlier stage !
• Higher cumulative dose (> 800 mCi)
• PRRT in combination with Chemosensitization; angiogenesis
inhibitors; etc
• Combination of radionuclides
• Increasing the receptor density in tumors (e.g. epigenetic
modulation) and/or
• Decreasing the radiation effects on normal tissues: enlarging
the therapeutic window
• Better somatostatin analogs , antagonists

December 2006
• Carcinoid with liver metastases. Severe diarrhoea in 2001
• Good clinical and radiological response after 4 cycles LuTate PRRT in 2001/2
• Dec 2006: Clear progression, start additional LuTate cycles
• Good response, still in remission 21 mo after additional therapy

Radiolabelled [DOTA 0 ,Tyr 3 ]Octreotate Therapy:
Randomized Trial; Phase I started June 2006
Randomization
177
Lu-Octreotate 4*200 mCi
177
Lu-Octreotate 4*200 mCi
+ Capecitabine (Xeloda)
Phase I data: van Essen M et al, EJNM 2008
1650 mg/m 2 per day/2 weeks
Phase II started 2007 in Rotterdam

Targeted Drugs
Imaging, therapy, new target finding
Systematic search
Target finding
Mol. Imaging
Radionuclide Therapy
Genetic profiling
“Fishing”
Diagnosis
Localization
Therapy selection
Evaluation/Monitoring

Proof of Concept in Prostate Cancer
Bombesin
[ 111
In-DTPA] DTPA]-ProPro 1 ,Tyr 4 -BN SPECT scan 24 h p.i.
111 In
A
2
SPECT
bone scan
1
3
B
2
SPECT
[ 111
In-DTPA] DTPA]-ProPro 1 ,Tyr 4 -BN
111 In
1
3

[ 177 Lu-DOTA 0 ,Tyr 3 ]Octreotate Therapy for GEP-NET:
PRRT at Erasmus MC, Rotterdam, NL
WWW . PRRT . NL