Overview and evidence based management of Neuroendocrine Tumors (NET)

1. ROLE OF TARGETED THERAPY
IN NEUROENDOCRINE TUMORS
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Kasr Al-Aini School of Medicine
Cairo University
Target Therapy: Future Directions
Helnan Palestine Hotel
Thursday, 30/04/2015

2. Origin:
Neuroendocrine
Cells
Neuropeptides
Catecholamines
Hormonal
Syndromes
Lawrence B, Gustafsson BI, Chan A, et al. The epidemiology of gastroenteropancreatic neuroendocrine
tumors. Endocrinol Metab Clin North Am 2011; 40:1.

3. descendin
g colon
(<1%)
sigmoid
colon (-
12%)
Primary Tumor Localizations
est. % of all NEN
thymus
bronchus
esophagus
stomach
duodenum
pancreas
jejunum/ileum
cecum
appendix
colon
rectum
<1
15
<1
15
4
15
15
2
15
1
10
thymus (1%)
bronchus (-15%)
esophagus (<1%)
pancreas (-15%)
duodenum (-4%)
ascending
colon (-
1%)
jejunum (-5%)
ileum (-10%)
cecum (-2%)
appendix (-15%)
rectum (-10%)
stomach (-15%)
Pape UF, et al. Gastroenterol up2date. 2011;7:313-
339.

4. 2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
1980
1979
1978
1977
1976
1975
1974
1973
0.00
1.00
2.00
3.00
4.00
5.00
6.00
0
100
200
300
400
500
600
Incidenceper100,000-NETs
Incidenceper100,000–Allmalignantneoplasms
All malignant neoplasm
Neuroendocrine tumors
Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
Increasing Incidence
Plateau
1.09
5.25

5. Incidence of NETs Is Increasing*
5 5
SEER = Surveillance, Epidemiology, and End Results (for malignant NETs)
*Approximate 5-fold increase between 1975 and 2004
Approximate 7-fold increase also evident in Norwegian registry
IncidencePer100,000
1.40
Year
NET Site
1.20
1.00
0.80
0.60
0.40
0.20
0
Lung
Colon
Small intestine
Rectum
Pancreas
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.

6. Colon Neuroendocrine Stomach
29-year limited duration prevalence analyses based on SEER
Pancreas Esophagus Hepatobiliary
0
100
1,100
NET Prevalence in the US, 2004
1,200
Median survival (1988 –
2004)103,312
cases
(35/100,000)
No.ofcases
(thousands)
Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
NETs Are the 2nd-Most Prevalent
Gastrointestinal Tumor:
• Localized
• Regional
• Distant
203 months
114 months
39 months

7. NET: Demographics:
Lepage C, et al. Gut. 2004;53(4):549-553.

8. Niederle MD, et al. Endocr Relat Cancer. 2010;17(4):909-918.
Biologicalbehavior
Malignant
Uncertain
Benign
NET: Not all the same:

9. [TITLE]
Presented By Pamela L. Kunz, MD at 2012Annual Meeting

10. Key Issues in The Management:
1. How do we define the disease?
Nomenclature, Classification & Pathology.
2. Who needs treatment and when?
Patient Selection.
3. Which treatment and in what sequence?
Treatments.
4. What is the role of combined biologics,
somatostatin analogues, cytotoxics and
biomarkers?
Unanswered Questions.

11. 1.How do we define the disease?
Nomenclature, Classification and
Pathology

12. Evolution of Terminology & Classification:
Historic Evolution:
1907 1963 1970 1980 1995
Carcinoid
Williams &
Sandler
Soga &
Tazawa
Histologic
WHO
Granular
Stain
Techniques
Capella
Size &
Invasion
• Benign.
• Benign or Low
Grade Malignant.
• Low Grade
Malignant.
• High Grade
Malignant.
No Prognostic or Predictive
Validation

13. Evolution of Terminology & Classification:
Histopathologic Differentiation:
Well
Differentiated
Poorly
Differentiated

14. Evolution of Terminology & Classification:
AJCC Criteria of Grading:
Grade Mitotic
Count (per
10 HPF)
Ki 67
Index (%)
G1 < 2 < 2
G2 2 – 20 3 – 20
G3 > 20 > 20
AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.

15. Evolution of Terminology & Classification:
Correlation of Tumor Grade With Survival:
1. Rindi G, Klöppel G, Alhman H, et al. Virchows Arch. 2006;449:395-401. 2. Rindi G, Klöppel G, Couvelard A, et al.
Virchows Arch. 2007;451:757-762. 3. Pape UF, Jann H, Müller-Nordhorn J, et al. Cancer. 2008;113:256-265.
0 50 100 150 200 250
Survival Time (mo)
0.0
0.2
0.4
0.6
0.8
1.0
CumulativeSurvival
G1
G2
G3
G1 vs G2
G1 vs G3
G2 vs G3
P=0.040
P<0.001
P<0.001
N=193

16. Scarpa A, et al. Mod Pathol. 2010;23(6):824-
833.
Prognostic Influence of Ki67-
Labelling
< 2% 15% 75%
Pape UF, et al. Endocr Relat
Cancer. 2008;15(4):1083-1097.
Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798-
7803. Vilar E, et al. Endocr Relat Cancer. 2007;14(2):221-
232.

17. Evolution of Terminology & Classification:
Correlation of TNM Staging With Survival:
17 17
La Rosa S, Klersy C, Uccella S, et al. Hum Pathol.
2009;40:30-40.
Patients With Well-Differentiated Pancreatic NET
Stage I
P<0.001
ProportionAlive
Stage II
Stage III
Stage IV
I (n = 44)
II (n = 44)
III (n = 34)
IV (n = 33)
Time (mo)
0.00
0.25
0.50
0.75
1.00
0 48 96 144 192 240

18. Evolution of Terminology & Classification:
Metastatic Disease Is Common at Presentation:
Localized Metastatic
50%
27%
23%
Distant metastases
Regional spread
Data from an analysis of 28,515 cases of NET identified in the SEER registries
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.
*These data are of the cases in which stage was reported.
20% of cases did not provide disease stage information

19. Evolution of Terminology & Classification:
NETs Are Often Diagnosed Late:
Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889.
1 2 3 4 5 6 7 8 9
Time (yr)
Primary tumour growth
Metastases
Flushing
Diarrhea
Death
Vague abdominal symptoms
Estimated time to diagnosis: 5 to 7 yr
*
*
*Symptoms of carcinoid syndrome

20. 2. Role of Biomarkers & Imaging:

21. Pan-neuroendocrine markers
Cytosolic NSE, PGP 9.5
Related to secretory
granules
Chromogranin
Related to synaptic vesicles Synaptophysin, VMAT
Intermediate filaments NF, CK HMW
Adhesion molecules N-CAM
Immunohistochemical NE markers:

22.  Chromogranin A*
(in 70%-90% increased in metast. NET)
 Pancreatic Polypeptide, PP
(in 40%-55 % elevated);
 a-HCG, β-HCG
(in ~ 30% elevated)
 Neuron specific enolase (NSE)
(in ~33% elevated)
*The height of Chromogranin A level correlates with tumor load,
an increase over time indicates tumor progression
Circulating Tumor Markers:

23. CgA correlates with hepatic tumor load
Heigher CgA levels indicate lower survival
Arnold R, et al. Clin Gastroenterol Hepatol. 2008;6(7):820-827
Prognostic Value of CgA:

24. HR = 0.25
95% CI: 0.13-0.51
P = .00004
Median PFS
Early response = 13.3 mos.
No early response = 7.5 mos.
0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24
HR = 0.25
95% CI: 0.10-0.58
P = .00062
CgA NSE Median PFS
Early response = 8.6 mos.
No early response = 2.9 mos.
PFS(%)
0
20
40
60
80
100
0
20
40
60
80
100
Time Since Study Start, months Time Since Study Start, months
Pts at Risk Pts at Risk
Resp. 33 29 26 19 12 5 3 2 0 Resp. 28 23 16 9 6 3 1 0 0
Nonresp 38 26 12 5 1 1 0 0 0 Nonresp. 11 5 2 0 0 0 0 0 0
Yao JC, et al. J Clin Oncol. 2010;28(1):69-76.
RADIANT-1 (Stratum I)
Predictive Value of Biomarkers:
PFS by Early CgA and NSE Responses:

25. Modlin IM, et al. Ann Surg Oncol. 2010;17(9):2427-2443.
PPI
Chronic Atrophic
Gastritis
PPI
H2RAs
Small cell lung cancer
Prostate cancer
Breast cancer
Ovary Cancer
Chronic atrophic gastritis
Pancreatitis
Inflammatory bowel disease
Irritable bowel syndrome
Liver cirrhosis
Chronic hepatitis
Colon cancer
HCC
Pancreatic adenocarcinoma
Pheochromocytoma
Hyperparathyroidism
Pituituary tumors
Medullary thyroid carcinoma
Hyperthyroidism
CgA
ENDOCRINE
DISEASE
GASTRO-
INTESTINAL
DISORDERS
NON-GI
CANCER
Arterial hypertension
Cardiac insufficiency
Acute coronary syndrome
Giant cell arteritis
CARDIOVASCULAR
DISEASE
Systemic rheumatoid arthritis
Systemic inflammatory response syndrome
Chronic bronchitis
Airway obstruction in smokers
INFLAMMATORY
DISEASES
Renal Insufficiency
RENAL DISORDERS
DRUGS
Causes of Chromogranin A Elevation:

26. Diagnosis: Imaging Primary Tumor/Tumor
Spread:
 Whole body Screening
& Staging
 Endocrine Pancreatic tumor
< 1cm
 Routine imaging
 Primary tumour Screening
& Staging (optional)
 Octreoscan (111Indium-DTPA-
Octreotide)/ SPECT: 1. choice
 Endoscopic ultrasonography
 ultrasonography of the liver
 CT (+ angiography), MRI
 Positron emission tomography (PET)
with 11C-5 HTP,11C-L-dopa or 18F-FDG
 SMS-R-PET: 68Gallium-DOTATOC-
PET
 PET/CT
ENETS-Guidelines 2011

27. 3. Therapy for Advanced Disease

28. Therapy of NETs
Three principles
• Control of hormonal
symptoms
• Control of tumor
growth
• Improvement of
survival?
Symptomatic
therapy
Surgical
therapy
Antiproliferative
therapy
• Cure
• Debulking
• Treatment /
Prevention of
complications

29. Somatostatin Receptors (SSTR) Are
Expressed by the Majority of NETs
• SSTR2 is most prevalent in GEP-NETs and induces
inhibitory effects on hormone secretion and proliferation
in NETs
• Somatostatin is effective in controlling NET-related
hormonal symptoms
• Clinical use of somatostatin is limited by its short half life
Basu B, et al. Endocr Relat Cancer. 2010;17(1):R75-R90. Modlin IM, et al. Aliment Pharmacol Ther.
2010;31(2):169-188. Hofland LJ. J Endocrinol Invest. 2003;26(8 Suppl):8-13. Ferrante E, et al. Endocr Relat
Cancer. 2006;13(3):955-962.
Prevalence on NET type: SSTR1 SSTR2 SSTR3 SSTR4 SSTR5
Pancreas 68% 95% 46% 93% 57%
Midgut 80% 86% 65% 35% 75%
Inhibitory effect:
Hormone secretion + + +
Proliferation + + + +
Induction of apoptosis + +

30. • Octreotide and lanreotide show high affinity for the
SSTR2 and are approved for antisecretory treatment in
NETs
LAR, long lasting release
Susini C, et al. Ann Oncol. 2006;17(12):1733-
1742.
Octreotide LAR
(10-30 mg / 28 days im)
Lanreotide
(60-120 mg / 28 days sc)
Octreotide
(2-3 x 50-500 ug sc / d)
Biotherapy of Functional Active NETs
With Somatostatin Analogs (SSA)
S
S
a
l
a
g
l
y
ly asn
s
cys p
h
e
p
h
e
p
h
e tr
p
l
y
s
t
h
r
p
h
e
t
h
r
s
e
r
cys
D-phe c
y
s
phe
l
y
s
c th
y r
s
Octreotide
acetate
D-trp
Thr
-
ol
D-phe c
l
y
s
v
al
c
y
y
s
S
ty
r
s
Lanreotid
e
D-trp
Thr
-
NH2
S
Somatostatin
S
S

31. Phase III Study of Octreotide LAR:
Patients:
• Well-differentiated
midgut NET
• Treatment-naïve
• Locally inoperable
or metastasized
N = 85
Octreotide LAR
30 mg im/28 days
Placebo
im/28 days
Primary endpoint:
• Median time to tumour progression
Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
1:1
R
A
N
D
O
M
I
Z
E
Secondary endpoints:
•Objective tumour response rate
• Symptom control
• Overall survival
Treatment
until CT/MRI
documented
tumour
progression
or death
Randomized, Double-blind, Placebo-controlled Study

32. Octreotide LAR 30 mg
Significantly Prolongs TTP:
HR = hazard ratio. PROMID = Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients
with metastatic neuroendocrine MIDgut tumours; TTP = time to progression
Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
Octreotide LAR vs placebo
HR=0.34 P=0.000072
[95% CI: 0.20–0.59]
Based on conservative ITT analysis
ProportionWithout
Progression
1.0
.75
.50
.25
0
0 6 12 18 24 30 36 42
Time (mo)
48 54 60 66 72 78
Octreotide LAR (n = 42)
Median 14.3 mo
Placebo (n = 43)
Median 6.0 mo

33. Octreotide LAR 30 mg Extends TTP in Patients With
Functioning and Nonfunctioning Tumours:
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Based on the per-protocol analysis
P=0.0008; HR=0.25 (95% CI: 0.10–0.59)
ProportionWithoutProgression
P=0.0007; HR=0.23 (95% CI: 0.09–0.57)
ProportionWithoutProgression
Patients with nonfunctioning tumours Patients with functioning tumours
Time (mo)Time (mo)
Octreotide LAR 30 mg: 17 pts/11 events
Median TTP 14.26 mo
Placebo: 16 pts/14 events
Median TTP 5.45 mo
Octreotide LAR 30 mg: 25 pts/9 events
Median TTP 28.8 mo
Placebo: 27 pts/24 events
Median TTP 5.91 mo
1. Arnold R, Müller H, Schade-Brittinger C, et al. J Clin Oncol. 2009;27(suppl):15s. Abstr 4508.
2. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.

34. Octreotide LAR: Symptomatic Relief:
J Clin Oncol. 2009, 27:4656-4663.

35. Lanreotide Acetate in NET:
• Patient Characteristics: Clarinet Trial:
• Well to Moderately differentiated.
• Ki 67 < 10%
• Pancreas, mid-gut, hind-gut, or Unknown origin.
N Engl J Med 2014;371:224-33.

36. The SYM-NET StudyDESIGNASSESSMENTS
A non-interventional cross sectional study to assess SYMptom
control in neuroendocrine tumors (NET)
Non-interventional, cross-sectional study
273 patients suffering from NET, already treated with lanreotide for at least 3
months and with history of diarrhea due to carcinoid syndrome were
enrolled
Subject questionnaires
Investigator review
of medical record
Likert scales
• Patient satisfaction
• Symptom severity
• Perception change
diarrhea
• Feelings about conse-
quences on daily life
QoL
• EORTC C30
• EORTC GI-
NET21
Demography
Medical
history
Treatment with
lanreotide
Diarrhea
Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract 411ˆ
characteristics
• At Tt initiation
• Day of visit
Other clinical
data
• At Tt initiation
• Day of visit
Qol = quality of life

37. SYM-NET Study – Results and Conclusion
Ruszniewski PB, et al. J Clin Oncol. 2014.32(5s): Abstract
411ˆ
• An improvement was observed for the majority
of patients in all symptoms
– 76 % patient satisfaction with diarrhea control (primary
objective)
– 73 % patient satisfaction with flushing control
– QoL questionnaires showed a high level of activity
capacity and low symptoms score
• Patient-reported "subjective" information was
consistent with investigator’s observation
• Confirms in real life setting the satisfactory effect
of lanreotide on symptoms of hormonal excess in
GEP- NETs

38. Chemotherapy for Well-Differentiated
NETs of the Pancreas and
Duodenum:
Author
Turner NC, et al. Br J Cancer. 2010;102(7) 1106-1112.
Chemotherapy
Pt
(n)
RR mOS
(%) (months)
Cheng (1999)1 & Mc Collum (2003)2 STZ + DOX 16 & 16 8 -----
Eriksson (1990)3
Dealunoit (2004)4
Rivera et al. (1998)5
Kouvaraki et al. (2004)6
Turner et al. (2010)7
STZ + DOX
STZ + DOX
STZ + 5-FU + DOX
STZ + 5-FU + DOX
STZ + 5-FU + cispl.
84
45
12
84
47
36 ------
36 24
55 21
39 37
38§ 31.5
1. Cheng PN, et al. Cancer. 1999;86(6):944-948. 2. McCollum AD, et al. Am J Clin Oncol. 2004;27(5):485-488.
3. Eriksson B, et al. J Intern Med. 1990;228(2):103-113. 4. Delaunoit T, et al. Eur J Cancer. 2004;40(4):515-
520. 5. Rivera E, et al. Am J Clin Oncol. 1998;21(1):36-38. 6. Kouvaraki MA, et al. J Clin Oncol.
2004;22(23):4762-4771. 7.

39. Chemotherapy for G3 NET: NORDIC Trial:
Annals of Oncology 24: 152–160, 2013

40. Temozolomide in Pancreatic
Neuroendocrine Carcinoma
Strosberg JR, et al. Cancer 2011;117(2):268-275
Capecitabine
Temozolomide
every 28 days
750 mg/m2 x 2 x tgl. (days 1–
14)
200 mg/m2 x 1 (days 10–14);
n = 30: 22 NF; 2 gastrinoma; 2 insulinoma; 2 VIPoma; 1
glucagonoma;
1 gastrinoma/glucagonoma
70% PR
(RECIST
)
Median
PFS: 18
months
Retrospective analysis
G3–4 adverse events (12%): anemia, thrombocytopenia, elevation of liver
enzymes
100
80
60
40
20
0
–20
–40
–60
–80
–100
Progressive
Disease
Partial Response

41. Molecular Events & Therapeutic Implications:
1. Angiogenesis:
vHL Gene OxygenationHypoxia
+++ VEGFAngiogenesis
PFS 96% 68%
Bevacizumab
+ Octreotid LAR
INF
+ Octreotid LAR

42. Neuroendocrinal Tumors:
Molecular Events & Therapeutic Implications:
2. mTOR Inhibitor:
Mammalian Target of Rapamycin
Cellular
Growth
Protein
Synthesis
Autophagy
Resistance to
Apoptosis
++
Proliferation
Altered
Metabolism

43. RADIANT-3
PFS by Investigator Review:
• P value obtained from stratified 1-sided log-rank test
• Hazard ratio is obtained from stratified unadjusted Cox model
%Event-free
0 2 4 6 8 10
No. of patients still at risk
Kaplan-Meier median PFS
Everolimus:
Placebo:
11.0 mo
4.6 mo
Hazard ratio = 0.35; 95% CI 0.27–0.45
P value: <.0001
PFS rate (18 mos.)
Everolimus 34.2%
Placebo 8.9%
Yao JC, et al. N Engl J Med. 2011;364(6):514-
12 14 16 18
Time (mo)
100
80
Censoring times Everolimus
(n/N = 109/207) Placebo
(n/N = 165/203)
60
40
20
0
20 22 24 26 28 30

44. RADIANT-3: Treatment-Related G3/4
AE:
Yao JC, et al. N Engl J Med. 2011;364(6):514-
523.
*Related toxicities grouped for
calculation
Occurring in >10%
Everolimus n = 204
All Grades (%) Grade 3/4 (%)
Placebo n = 203
All Grades (%) Grade 3/4 (%)
Stomatitis* 64 7 17 0
Rash 49 <1 10 0
Diarrhea 34 3 10 0
Fatigue 31 2 14 <1
Nausea 20 2 18 0
Infections* 23 3 6 1
Peripheral edema 20 <1 3 0
Decreased appetite 20 0 7 1

45. RADIANT-2 Study Design:
Everolimus 10 mg/day +
Octreotide LAR 30 mg/28 days
n = 216
Placebo +
Octreotide LAR 30 mg/28 days
n = 213
Treatment
until disease
progression
R
A
N
D
O
M
I
Z
E
1:1
Multiphasic CT or MRI performed every 12 wk
Crossover
Primary endpoint:
• PFS (RECIST)
Secondary endpoints:
• Tumour response, OS, biomarkers, safety, PK
Enrollment January 2007–May 2008
Phase III, Double-blind, Placebo-controlled Trial
Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.
Patients with advanced NET
(N=429)
• Advanced low- or intermediate-
grade NET
• Radiologic progression <12
months
• History of secretory symptoms
(flushing, diarrhea)
• Prior antitumour therapy allowed
• WHO PS ≤2

46. PFS by Central Review:*
Time (mo)
No. of patients still at risk
E + O
P + O
216
213
202
202
167
155
129
117
120
106
102
84
81
72
69
65
63
57
56
50
50
42
42
35
33
24
22
18
17
11
11
9
4
3
1
1
1
0
0
0
* Independent adjudicated central review committee
• P-value is obtained from 1-sided log-rank test
• HR is obtained from unadjusted Cox model
E + O = everolimus + octreotide LAR
P + O = placebo + octreotide LAR
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
PercentageEvent-free
Kaplan-Meier median PFS
Everolimus + octreotide LAR: 16.4 mo
Placebo + octreotide LAR: 11.3 mo
HR = 0.77; 95% CI (0.59–1.00)
P=0.026
Total events = 223
Censoring times
E + O (n/N = 103/216)
P + O (n/N = 120/213)
Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.

47. Subgroup PFS Analysis:
*Independent adjudicated central review
HR = everolimus + octreotide/placebo + octreotide
Unstratified Cox model was used to obtain HR
E + O = everolimus + octreotide LAR
P + O = placebo + octreotide LAR
Subgroups (N)
Central review *(429)
Local investigator review (429)
Age group
<65 yr (286)
≥65 yr (143)
Gender
Male (221)
Female (208)
WHO Performance Status
WHO = 0 (251)
WHO > 0 (176)
Tumour histology grade
Well-diff. (341)
Moderately diff. (68)
Primary tumour site
Small intestine (224)
Lung (44)
Colon (28)
Other (132)
Prior long-acting SSA
Yes (339)
No (90)
Prior chemotherapy
Yes (130)
No (299)
HR
Median PFS
(mo)
E + O P + O
0.77 16.4 11.3
0.78 12.0 8.6
0.78 19.2 13.0
0.75 13.9 11.0
0.85 13.7 13.0
0.73 17.1 11.1
0.67 21.8 13.9
0.81 13.6 8.3
0.74 18.3 13.0
0.82 13.7 7.5
0.77 18.6 14.0
0.72 13.6 5.6
0.39 29.9 13.0
0.77 14.2 11.0
0.81 14.3 11.1
0.63 25.2 13.6
0.70 13.9 8.7
0.78 19.2 12.0
Hazard Ratio
Favors E + O Favors P + O
0 10.4 0.8 1.4
Pavel M, Hainsworth J, Baudin E, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan, Italy. Abstr LBA8.

48. 5050
Sunitinib vs Placebo in Advanced pNET:
• Phase III randomized, placebo-controlled, double-blind trial
• Trial stopped after early unplanned analysis showed efficacy and safety
benefit
Primary Endpoint: PFS
Secondary Endpoints: OS, ORR, TTR, duration of response, safety, and patient-reported
outcomes
Patients with
advanced pNET,
N = 171/340
patients enrolled
Sunitinib 37.5 mg/day orally
Continuous daily dosing*
n = 86
Placebo*
n = 85
*With best supportive care
Somatostatin analogues were permitted
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
1:1
R
A
N
D
O
M
I
Z
E

49. 51 51
0.8
0.6
0.4
0.2
0
1.0
ProportionofPatients
5 10 15 20 250
Sunitinib
39 19 4 0 086Sunitinib
28 7 2 1 085Placebo
Number at risk
Time (mo)
Placebo
Kaplan-Meier median PFS
Sunitinib: 11.4 mo
Placebo: 5.5 mo
HR = 0.42 (95% CI, 0.26–0.66)
P<0.001
Progression-free Survival:*
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
* Local review

50. 1.0
PRRT
Objective
response: Stable
disease: Median
survival:
34%
5%
94.6
months
Open phase II study, 1,109 patients
with progressive NET (within 12
months), 2,472 cycles 90Y-DOTA-
TOC-therapy, median follow up 23
months
• Objective response rates 30% - 40%
• Survival benefit in responders likely
• Limitations: safety concerns (renal, bone marrow
toxicity), limited availability, lacking randomized studies
0 2 4 6 8 10
12
Time Since Start of Treatment,
years
14
0.2
0.4
0.6
0.8
OverallSurvival,probability
Imhof A, et al. J Clin Oncol. 2011;29(17):2416-
1423.
No. of
patient
s
No. of
deaths
Median
survival
Hazard
ratio
P
Disease
control
671 280 3.8 years 0.41 vs
progress
<.001
Progress 438 211 1.4 years

53. Final Take Home Message:
• NET not rare.
• Surgery is the Cornerstone in Curative
Management.
• Serum Biomarkers Are Still There to Share.
• Tissue Markers Should be more Highlighted.
• Molecular Targeted Therapies are The Hope for
Tomorrow.