Dr Chandan K DasDepartment of Medical OncologyInstitute Rotary Cancer Hospital

All India Institute of Medical Science

Management of Neuroendocrine Tumor

Neuroendocrine System

Neuroendocrine System

20042003200220012000199919981997199619951994199319921991199019891988198719861985198419831982198119801979197819771976197519741973

0.00

1.00

2.00

3.00

4.00

5.00

6.00

0

100

200

300

400

500

600

Inci

denc

e pe

r 100

,000

- NE

Ts

Inci

denc

e pe

r 100

,000

– A

ll m

alig

nant

neo

plas

ms

All malignant neoplasm

Neuroendocrine tumors

Adapted from: Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

Incidence

Plateau

1.09

5.25

Colon NeuroendocrineStomach

29-year limited duration prevalence analyses based on SEER

Pancreas Esophagus Hepatobiliary0

100

1,100

NET Prevalence in the US, 20041,200

Median survival (1988 – 2004)103,312

cases (35/100,000)

No.

of c

ases

(th

ousa

nds)

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 months114 months39 months

NET: Demographics:

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

Sites (SEER data)• Common sites of origin are:

• GI tract• Lungs• Pancreas

7

Primary Location of NET Asia Pacific Region

Stomach 6%Liver 4%

Bile duct and gallbladder 3%Omentum/abdominal lining 1%Rectum 1%Ovary 1%Lung 1%

Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.

IRCH AnalysisPatient Characteristics N=55Median Age years (Range)

50 years (14-74)

Male: Female 1.2:1Presenting Symptoms  

 Abdominal Pain(81.8%)Diarrhoea(23.6%)Flushing(5.4%)Weight Loss(38.18%)Anorexia (25.45%)

ECOG PS  Ps<2 45.45%Primary Site 

 Pancreas(34.54%)>unknown18%>SI 17%>colon 11%>Stomach 11%

Metastatic 87.27%Metastatic Sites  Liver 85.41%>LN37%>bone 6%

Mallick et al, 2015 Unpublished

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 biologics, somatostatin analogues, cytotoxics

and biomarkers?Unanswered Questions.

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

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

Oberndorfer

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.

Evolution of Terminology & Classification:AJCC Criteria of Grading:

AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.

Grade Gastroenteropancreatic (GEP) NETs Differentiation

Low Grade (G1) <2 mitoses/10 HPF AND/OR <3% Ki-67 index

Well-differentiated NET

Intermediate Grade (G2)

2–20 mitoses/10 HPF AND/OR 3–20% Ki-67 index

Well-differentiated NET

High Grade (G3) >20 mitoses/10 HPF AND/OR >20% Ki-67 index

Poorly differentiated neuroendocrine carcinoma

G1 G3G2

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

Cum

ulat

ive

Surv

ival

G1

G2

G3

G1 vs G2G1 vs G3G2 vs G3

P=0.040P<0.001P<0.001

N=193

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 9Time (yr)

Primary tumour growth

Metastases

Flushing

Diarrhea

Death

Vague abdominal symptoms

Estimated time to diagnosis: 5 to 7 yr

*

*

*Symptoms of carcinoid syndrome

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.

2. Diagnostic Evaluation:

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:

Solcia E, Kloppel G, Sobin LH. Histological Typing of Endocrine Tumours, 2nd ed, 2000.

Histology

CgA

synapto

SSTR

HE

Ki67

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:

Modlin IM, et al. Ann Surg Oncol. 2010;17(9):2427-2443.

PPI

Chronic AtrophicGastritis

PPI H2RAs

Small cell lung cancer Prostate cancer Breast cancer Ovary Cancer

Chronic atrophic gastritis PancreatitisInflammatory bowel disease Irritable bowel syndrome Liver cirrhosisChronic hepatitis Colon cancer HCCPancreatic 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 arthritisSystemic inflammatory response syndrome Chronic bronchitisAirway obstruction in smokers

INFLAMMATORYDISEASES

Renal Insufficiency

RENAL DISORDERS

DRUGS

Causes of Chromogranin A Elevation:

Diagnostic Imaging:

Whole body Screening& Staging

Endocrine Pancreatic tumor< 1cm

Routine imaging

Primary tumour Screening& Staging

Octreoscan (111Indium-DTPA- Octreotide)/ SPECT:

Endoscopic ultrasonography

ultrasonography of the liver CT (+ angiography), MRI

Positron emission tomography (PET)with 11C-5 HTP,11C-L-dopa or 18F-FDG

68Gallium-DOTANOC-PET

ENETS-Guidelines 2011/NCCN NET Guideline 2015

3. Therapy for Advanced/Metastatic Disease

Therapy of NETsThree principles

• Control of hormonal symptoms

• Control of tumor growth

• Improvement of survival?

Symptomatictherapy

Surgicaltherapy

Antiproliferativetherapy

• Cure• Debulking• Treatment /

Prevention of complications

Surgery of primary NET

GI NET• < 1cm – excision or

endoscopic removal• 1 to 2cm – conservative

surgery if superficial, exophytic• > 2cm - radical surgery• Upper abdominal exenteration –

in selected individuals

pNET• Enucleation, distal

pancreatectomy,pancreaticoduodenectomy

Encasement of coeliac axis / SMA / SMPV confluence is considered UNRESECTABLE

Surgery of metastatic NETDebulking/ palliative surgery –

1)Resectable primary tumor and non-operable liver metastases

2)Small bowel primary :might cause intestinal obstruction

“ Debulking surgery can be attempted when 90% of tumor is removable”

Liver transplantation

• Investigational• Age < 50 yrs• Primary tumor in lung or bowel• Pretransplantation somatostatin therapy• Median time to recurrence is 1.9 yrs

• Significantly better survival for functional as opposed to non-functional tumours (69% at 5 years vs. 8% at 4 years)

• Overall 5 yr survival is 36% - 90% and disease free survival is 12% - 77%

Roseanu et al Transplantation 2002; 73:386–394.

J Hepatol 2007;47:460–466.

Liver directed therapy

• Hepatic artery embolization: lipiodal, small plastic particles, gelatin foam particles (response rate - 25 to 35%)

• Hepatic artery chemoembolization: streptozocin >doxorubicin response rate – 50%

• Radiofrequency ablation- for tumors <3cm .• Median survival of 3.9 yrs. • Symptomatic relief in 76%.

“Post embolization syndrome”- abdominal pain,nausea, fever , fatigue, elevated liver enzymes. Crises related to massive release of hormones

Susini et al ,Annal of Oncology 2006, 17(12)

Prevalence on NET type: SSTR1 SSTR2 SSTR3 SSTR4 SSTR5Pancreas 68% 95% 46% 93% 57%Midgut 80% 86% 65% 35% 75%Inhibitory effect:Hormone secretion + + +Proliferation + + + +Induction of apoptosis + +

Somatostatin Receptors (SSTR)

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)

Pasireotide LAR40-60 mg IM q28 Days

Octreotide(2-3 x 50-500 ug sc / d)

Somatostatin Analogs Therapy

S

S

al a

g ly

lyasns

cys ph e

ph e

ph e tr

p lyst

h r

ph e

t h r

s e r

cys

D-phe cy s

phe

ly sc

thyrs

Octreotide acetate

D-trp

Thr- ol

D-phe c

ly sv

alc y

y sS

tyr

s

Lanreotide

D-trp

Thr

- NH2

S

SomatostatinS

S

Phase III Study of Octreotide LAR: PROMID

Patients:• Well-differentiated

midgut NET• Treatment-naïve • Locally inoperable or

metastasized N = 85

Octreotide LAR 30 mg im/28 days

Placeboim/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

RANDOMI

ZE

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

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 placeboHR=0.34 P=0.000072[95% CI: 0.20–0.59]

Based on conservative ITT analysis

Prop

ortio

n W

ithou

t Pr

ogre

ssio

n

1.0

.75

.50

.25

00 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

Lanreotide Acetate in NET: CLARINET Trial

Caplin et al,N Engl J Med 2014;371:224-33.

Octreotride LAR PROMID Rinke et al

Lanotride CLARINETCaplin et al

Pasireotide

Wolin et al

SSTR SSTR2 SSTR2 SSTR1-5

N 85 204 110

BASELINE DISEASE 40 CS70%Liver rescected

96%SD NA

Functional status both Non functional only Both

Ki 67 <2% <10% NA

Resected primary 70% 40% na

Response 66%ORR 60% RR

PFS 14.3 vs 6 m 11.8 vs 6.8 m

SSTR Analogues

Chemotherapy for NET

ESMO clinical practice guideline on NET 2015

Capecitabine-Temozolomide in NET

Strosberg JR, et al. Cancer 2011;117(2):268-275

Capecitabine Temozolomide every 28 days

750 mg/m2 . (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

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

70% ORR18m PFS

Gem-Ox in NET

• Metastatic NETs n=144 (37 pancreatic NETs, 33 gastrointestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin)

• GEMOX: median 6#• ORR: 23%• PFS: 7.8m and OS 31.6 months

Dussol as et alCancer. 2015 Oct 1;121(19):3428-34. doi: 10.1002/cncr.29517. Epub 2015 Jun 8.

Neuroendocrinal Tumors:Molecular Events & Therapeutic Implications:2. mTOR Inhibitor:

Mammalian Target of Rapamycin

Cellular Growth

ProteinSynthesis AutophagyResistance to

Apoptosis++

ProliferationAltered

Metabolism

Everolimus in NET : RADIANT-2

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

RANDOMIZE

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

PFS by Central Review:*

Time (mo)No. of patients still at riskE + OP + O

216213

202202

167155

129117

120106

102 84

8172

6965

6357

5650

5042

4235

3324

2218

1711

11 9

43

11

10

00

* 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 LARP + 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

Perc

enta

ge E

vent

-free

Kaplan-Meier median PFSEverolimus + octreotide LAR: 16.4 moPlacebo + octreotide LAR: 11.3 mo

HR = 0.77; 95% CI (0.59–1.00) P=0.026

Total events = 223Censoring timesE + 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.

4242

Sunitinib in Advanced pNET:

• Phase III randomized, placebo-controlled, double-blind trial• Trial stopped after early unplanned analysis showed efficacy and safety benefit

Primary Endpoint: PFSSecondary 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 orallyContinuous daily dosing*

n = 86

Placebo*n = 85

*With best supportive careSomatostatin analogues were permitted

Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.

1:1

RANDOMIZE

Progression-free Survival:*

4343

0.8

0.6

0.4

0.2

0

1.0

Prop

ortio

n of

Pat

ient

s

5 10 15 20 250

Sunitinib

39 19 4 0 086Sunitinib28 7 2 1 085Placebo

Number at riskTime (mo)

Placebo

Kaplan-Meier median PFSSunitinib: 11.4 moPlacebo: 5.5 moHR = 0.42 (95% CI, 0.26–0.66) P<0.001

Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.

PFS at 6 months was 71.3% vs 43.2%

Peptide Receptor Radionuclide Therapy (PRRT) 177Lu-DOTA,Tyr3]octreotate

Higher affinity for somatostatin receptorsGamma emission allow post-therapeutic biodistribution studiesPR, MR and SD responses are reported in the majority of patientsTumor regression was correlate with a high uptake on Octreoscan imaging

Lu 177Linker(DOTA)

Vector(NOC)

STR2

Concept & design by M Schultz

Modified Somatostatin

Lu 177Linker(DOTA)

Vector(NOC)

β

PRRT Evidence till nowSTUDY N O.S in

YrRESPONSE ORR HEMATOLOGIC

TOXICITY(GRADE 3 OR 4)

RENAL TOXICITY

Imhof et al(1-10cycles)

1109 (NETs)

3.8 CR O.6%PR 34%SD 5.2%

30% 12.8% transient

grade 3 or 4

9.2%permanent

grade 4

Cwikla et al(2-3cycles)

60(GEP-NETs)

2.2 23% PR50% SD

72% 5%persistent

grade 3 or 4

10% grade 2 or

3

Kwekkeboom et al

(4 cycles)

504(NETs)

3 2% CR28% PR16% MR35% SD

(GEP NETs)

9.5%transient

grade 3 or 4

Few and mild

(NETs)

Kwekkeboom et al, JNM, Vol. 26 Nr13 May 1 2008/Cwikla et al, Annals of Oncology 21: 787–794, 2010/Imhof et al Journal of Clinical Oncology 2011, Jun 10;29(17):2416-23

Take Home Message:

• NET not rare.

• Surgery is the cornerstone in curative management.

• Serum Biomarkers Are helpful for monitoring and prognostication

• Molecular targeted therapies/PRRT are the hope for tomorrow.

Remembering Steve Jobs