Milano 25.05.2007

Milano 25.05.2007

Salvatore ArtaleOncologia Medica FalckOspedale NIguarda Ca’ Granda Milano

L’evoluzione della terapia medica: dagli analoghi della somatostatina alle terapie a

bersaglio molecolare

WHO ClassificationWHO Classification 20002000

Well differentiated endocrine tumorsWell differentiated endocrine tumors (benign or low grade malignancy) (benign or low grade malignancy)

Well differentiated endocrine carcinomasWell differentiated endocrine carcinomas

Poorly differentiated endocrine carcinomasPoorly differentiated endocrine carcinomas (small cell carcinomas)(small cell carcinomas)

Mixed exocrine and endocrine carcinomas Mixed exocrine and endocrine carcinomas

Tumor-like lesionsTumor-like lesions


THE DIFFERENTIATION IS BASED ON : HISTOMORPHOLOGY PRESENCE/ABSENCE OF LOC.INVASION/METASTASIS

PROLIFERATION INDEX (Ki67): < 2% Well Diff.Tumors > 2% / <15% Well.Diff.Carcinomas > 15 % Poorly Diff.Carcinomas

Neuroendocrine tumorsNeuroendocrine tumorsFrequencyFrequency

Incidence: 1-2/ 100.000

Autopsy series 8/100.000

Carcinoid tumors are the most frequent type (40% of all NETs)

5-year survival rate:70%








Well differentiated endocrine Well differentiated endocrine carcinomascarcinomas

Which is the best treatment ?

Medical Medical treatmenttreatment

Biotherapy ?Biotherapy ?

Chemotherapy ?Chemotherapy ?


Biotherapy Biotherapy

Somatostatin analogs

Interferon-

Targeted therapy

Objectives of Medical Objectives of Medical TreatmentTreatment

EfficacyEfficacy

– Symptom controlSymptom control– Biochemical controlBiochemical control– Control of tumor burdenControl of tumor burden

Criteria for evaluating the tumor responseAccording to ITMO Group. Bajetta et al Q J Nucl Med 2000

Clinical Clinical Presentation:Presentation: non functioning non functioning tumourstumours

– Symptoms related to the mass effect:Symptoms related to the mass effect:

– Bowel obstructionBowel obstruction– GI bleeding (rare)GI bleeding (rare)

Clinical Clinical Presentation:Presentation: functioning functioning tumourstumours

– Carcinoid syndrome < 20%:Carcinoid syndrome < 20%:

– Cutaneous flushing: upper part of the Cutaneous flushing: upper part of the body (80%)body (80%) Watery diarrhea and abdominal cramp Watery diarrhea and abdominal cramp

(80%)(80%) BronchospasmBronchospasm Endocardial fibrosis( 30-40 %): Endocardial fibrosis( 30-40 %):

arrhythmia. Right heart insufficiency. arrhythmia. Right heart insufficiency.

Well Differentiated carcinomaWell Differentiated carcinomaand biotherapyand biotherapy

Rationales: Rationales:

NETs carry receptor(s) for growth factor responsable in NETs carry receptor(s) for growth factor responsable in cellular proliferation, angiogenesis,hormone secretion cellular proliferation, angiogenesis,hormone secretion and clinical symptoms:and clinical symptoms:

– Insulin like growth factor-1Insulin like growth factor-1– PDGF-alphaPDGF-alpha– TGF-alphaTGF-alpha– TGF-betaTGF-beta– VEGF expression

80-90% of NETs show high-affinity somatostatin receptors

OctreotideOctreotide Octreotide LAROctreotide LAR Pasireotide SOM 230Pasireotide SOM 230 LanreotideLanreotide Lanreotide autogel (Lan ATG)Lanreotide autogel (Lan ATG)

Somatostatin Analogues

Well differentiated neuroendocrine carcinomas:Well differentiated neuroendocrine carcinomas:Results of studies of somatostatin analogsResults of studies of somatostatin analogs

Non randomized studiesNon randomized studies

Kvols et al 1986Kvols et al 1986 Octreotide 450 Octreotide 450 µg/dayµg/day

Souquet et al 1987Souquet et al 1987 Octreotide 300 Octreotide 300 µg/dayµg/day

Janson and Oberg 1993Janson and Oberg 1993 Octreotide,variableOctreotide,variable

Di Bartolomeo et al 1996Di Bartolomeo et al 1996 Octreotide 1500-3000 Octreotide 1500-3000 µg/dayµg/day

Arnold et al 1996Arnold et al 1996 Octreotide 600-1500 Octreotide 600-1500 µg/dayµg/day

Scherubl et al 1994Scherubl et al 1994 Lanreotide 30 mg /14 daysLanreotide 30 mg /14 days

Ruszniewski et al 1996Ruszniewski et al 1996 Lanreotide 30 mg /14 daysLanreotide 30 mg /14 days

Wymenga et al 1999Wymenga et al 1999 Lanreotide 30 mg /14 daysLanreotide 30 mg /14 days

Well differentiated neuroendocrine carcinomas:Well differentiated neuroendocrine carcinomas:Results of studies of somatostatin analogsResults of studies of somatostatin analogs

Non randomized studiesNon randomized studies

Ricci et al 2000Ricci et al 2000 Lanreotide 30 mg /14 daysLanreotide 30 mg /14 days

Tomassetti et al 2000Tomassetti et al 2000 Octreotide LAR 20 mg /28 Octreotide LAR 20 mg /28 daysdays

Welin et al 2004Welin et al 2004 Octreotide pamoate 160 Octreotide pamoate 160 mg /14 daysmg /14 days

Ruszniewski et al 2004Ruszniewski et al 2004 Lanreotide autogel 60-120 Lanreotide autogel 60-120 mg/28 daysmg/28 days

Somatostatin analogsSomatostatin analogs

OR: 5%

SD: 35-50%

Med Dur SD: 18 months

SR: 30-75%

BR: 30-60%Standard dose

Somatostatin analogsSomatostatin analogs

OR: 13%

SR: 42%

BR: 75%

High dose

Carcinoid Syndrome and Carcinoid Syndrome and somatostatin somatostatin analogsanalogs

Randomized trials: 5

Efficacy Studies

Randomized trials

Carcinoid Syndrome and Carcinoid Syndrome and somatostatin somatostatin analogsanalogs

Oberg et al. 1989Oberg et al. 1989 Octreotide sc vs Octreotide sc vs placeboplacebo

Jacobsen and Jacobsen and Hanssen 1995Hanssen 1995

Octreotide sc vs Octreotide sc vs placeboplacebo

Saslow et al.1997Saslow et al.1997 Octreotide sc vsOctreotide sc vs

PlaceboPlacebo

Rubin et al.1999 Rubin et al.1999 Octreotide LAR vs Octreotide LAR vs Octreotide scOctreotide sc

O’Toole et al.2000O’Toole et al.2000 Octr. sc Lanreot Octr. sc Lanreot imim

Lanreotide ATG 120 mg every 6 weeks = Lanreotide 60 mg

every 3 weeks in well differentiated neuroendocrine

tumors

Bajetta et al .Cancer 2006

SOM 230 is effective in metastatic Carcinoid tumors

refractory or resistant to octreotide LAR

Kvols et al. ASCO 2006

What about interferon ?

Interferon-α

Subjective 40–70%

Biochemical 40–50%

Tumor 10–15%

Response.

Regular dose 3–9 MU 3–7 times a week

Interferon-α/somatostatin analoguesin combination: randomized trials

AuthorsAuthors N°PtsN°Pts ArmsArms SymptSympt BiochBioch RadRad 5-y Surv 5-y Surv %%

KolbyKolby

200320036868 IFNIFN

OCT+IFNaOCT+IFNaNRNR NRNR NRNR 3636

5858

FaissFaiss

200320038080 IFNIFN

LANLAN

IFN+LANIFN+LAN

BetterBetter

P=0.0037P=0.0037No DiffNo Diff PR4/SD8PR4/SD8

PR4/PR4/SD26SD26

PR7/PR7/SD18SD18

NONO

DIFFDIFF

1-y 1-y

PFSPFS

P=0.132P=0.132

ArnoldArnold

20052005109109 OCTOCT

OCT+IFNaOCT+IFNaNRNR NRNR 3535

5151

Med sur Med sur (months)(months)

P=0.55P=0.55

Fazio et al. Annals of Oncol 2006 ( review)

Responses

Pts treated with IFN had reduced risk ofTumour progression P= 0.008

Interferon-α/somatostatin analoguesin combination: Non randomized trialsAuthor N.

ptsSubjective response n. pts (%)

Biochemical response n. pts (%)

Radiological response n. pts

Janson et al. (1992)

2424 NRNR 17/22 (77)17/22 (77) 1515

Frank et al. (1999)

2121 NRNR 9/13 (69)9/13 (69) 1414

Fjällskog et al (2002)

1616 NRNR 10/16 (63)10/16 (63) 11SD 11SD

3 PR3 PR

Artale et alArtale et al

(2005)(2005)1111 3/4(75)3/4(75) 6/9 (66%)6/9 (66%) 7 SD7 SD

4PR4PR

Pavel et al Pavel et al

(2006)(2006)1717 NRNR 6/15 (40%)6/15 (40%) 11 SD11 SD

2 PR2 PR

Fazio et al Ann of Oncol 2006








Poorly differentiated endocrine Poorly differentiated endocrine carcinomascarcinomas

Which is the best treatment ?


Chemotherapy Chemotherapy

Cytotoxic therapy for carcinoid Cytotoxic therapy for carcinoid tumorstumors

Oberg. K. Annals of Oncol 2004

DrugDrug N° PtsN° Pts Overall Overall

Response %Response %MedianMedian

DurationDuration

(months)(months)

DoxorubicinDoxorubicin 8181 2121 66

FluorouracilFluorouracil 3030 17-2617-26 33

StreptozotociStreptozotocinn

1414 0-170-17 22

DacarbazinDacarbazin 1515 1313 4.54.5

CisplatinCisplatin 1616 66 4.54.5

SINGLE

AGENTS

Cytotoxic therapy for carcinoid Cytotoxic therapy for carcinoid tumorstumors


DrugDrug N° PtsN° Pts Overall Overall

Response %Response %MedianMedian

DurationDuration

(months)(months)

Strepto+FluoStrepto+Fluorr

175175 7-337-33 3-73-7

Strepto+DoxStrepto+Doxoo

1010 4040 55

Strepto+CiclStrepto+Cicloo

2424 3939 66

Fu+Det+EpiFu+Det+Epi 7070 2626 1010

POLICHEMOTHERAPY

Chemotherapy of endocrine Chemotherapy of endocrine pancreatic tumorspancreatic tumors


DrugDrug N° PtsN° Pts Objective Objective

Response %Response %DurationDuration

(months)(months)

Strepto+FluoStrepto+Fluorr

170170 45-6345-63 18-3618-36

Strepto+DoxStrepto+Doxoo

5050 40-6940-69 12-2412-24

Cispl+EtopCispl+Etop 1414 5050 99

DacarbazineDacarbazine 1111 99 66

PaclitaxelPaclitaxel 1515 77 55

Strepto-DoxoToxicity:

Chronic renal insufficiencyCardiotoxicity

Vomiting

Failure to Confirm Major Objective Antitumor Activity for Streptozotocin And Doxorubicin in the treatment of Patients with Advanced Islet Cell Carcinoma

Cheng et al Cancer 1999

MSKCC. 2/92-2/98

16 patients with ICC treated with STZ + Doxo

Results:1/16 ( 6%) with imaging PR9/16 (56%) with stable disease 6/16 (38%) progressed during treament

Lack of Efficacy of Streptozocin and Doxorubicin in Patients

With Advanced Pancreatic Endocrine Tumors.

McCollum, A David MD *; Kulke, Matthew H. MD +; Ryan, David P. MD [S]; Clark, Jeffrey W. MD [S]; Shulman, Lawrence N. MD +; Mayer, Robert J. MD +; Bartel, Sylvia RPH ++; Fuchs, Charles S. MD, MPH +

Methods: We retrospectively reviewed the records of 16 consecutive patients who received streptozocin and doxorubicin for advanced PETs at Dana Farber/Partners Cancer Care institutions. Baseline patient characteristics, radiographic response to therapy, treatment-related toxicity, progression-free and overall survival were analyzed.

Results: One patient demonstrated an objective partial response to therapy (objective response rate [ORR], 6%; 95% confidence interval [CI], 0-18%). Six patients achieved stable disease (38%; 95% CI, 14-62%) and 9 patients demonstrated disease progression on initial restaging (56%; 95% CI, 33-77%). The median progression-free survival and overall survival were 3.9 months (95% CI, 2.8-8.8) and 20.2 months (95% CI, 9.7-37.4), respectively.

American Journal of Clinical Oncol 2004

Conclusions: In this retrospective cohort, the combination of treptozocin and doxorubicin failed

to demonstrate substantial antitumor activityin patients with advanced PET. Our findings underscore the need for

therapeutic options in this patient population.

Cisplatin Based Cisplatin Based TherapyTherapy

Well differentiatedWell differentiated Poorly differentiatedPoorly differentiated

Patient no.Patient no. 44 1111

Overall responseOverall response % 45% 45 % 67% 67

BiochemicalBiochemical % 45% 45 % 0% 0

RadiologicalRadiological % 27% 27 % 50% 50

StableStable % 36% 36 % 25% 25

ProgressiveProgressive % 18% 18 % 0% 0

RESPONSE TO CISPLATIN AND ETOPOSIDE COMBINATION ACCORDING TO CELLULAR DIFFERENTION

Fjallskog Cancer 2001

Well diff Poorly diff

ANT ICANCER

RESEARCH

2005

36%

37%

ANT ICANCER

RESEARCH

2005

Artale et al. Anticancer Research 2005

0%

67%66%

88%

Targeted Targeted TherapyTherapy

Monoclonal antibody anti-VEGF:Monoclonal antibody anti-VEGF: Bevacizumab:Bevacizumab: suppression of tumor blood flow suppression of tumor blood flow and prolungation of PFS. and prolungation of PFS. Yao et al ASCO 2005Yao et al ASCO 2005

Small multi-TK inhibitorsSmall multi-TK inhibitors:: SunitinibSunitinib:RR 15% islet cell, 2% carcinoid, SD :RR 15% islet cell, 2% carcinoid, SD JCO 2006 JCO 2006

SorafenibSorafenib, Vatalanib : Phase II ongoing, Vatalanib : Phase II ongoing

Imatinib (Gleevec):Imatinib (Gleevec): no activity no activity Gross et al .Endocrine related Cancer 2006Gross et al .Endocrine related Cancer 2006

Endostatin:Endostatin: only SD. only SD. Kulke et al JCO 2006Kulke et al JCO 2006

EGFR inhibitors:EGFR inhibitors: GefitinibGefitinib: no Object.resp. : no Object.resp. ASCO 2005ASCO 2005

Mammallian target of rapamycin inhibitors

TEMSIROLIMUS ( CCI-779)

EVEROLIMUS (RAD 001)

Role of angiogenesis in Role of angiogenesis in NETNET

Angiogenic growth factors contribute to tumor growthAngiogenic growth factors contribute to tumor growth

– VEGF is found in 84% of carcinoid and 59% of islet cell VEGF is found in 84% of carcinoid and 59% of islet cell tumorstumors

– VEGFR is found in 71% of carcinoid and 67% of islet cell VEGFR is found in 71% of carcinoid and 67% of islet cell tumorstumors

– Suggests Suggests autocrineautocrine stimulation in carcinoid and islet cell stimulation in carcinoid and islet cell tumorstumors

The mTOR pathway regulates production The mTOR pathway regulates production of angiogenic growth factors and the of angiogenic growth factors and the proliferation of vascular endothelial cellsproliferation of vascular endothelial cells

Hobday et al. Proc ASCO. 2003;22:269. Abstract 1078. Hobday et al. Proc ASCO. 2003;22:269. Abstract 1078.

IGFR/VEGFR

mTOR TSC1

PI3K

PKDI

AKT

TSC2

PTEN

p53

Nutrient

Rapamycin analogue

RAD001, CCI-779

AutophagyType 2 program cell death

Translationp70S6K

IGF

VEGFSomatostatin analogue

mTOR in neuroendocrine mTOR in neuroendocrine tumorstumors

Tuberous sclerosis is associated with islet cell carcinoma

mTOR and angiogenesismTOR and angiogenesis

Tumor cell

Protein production

Angiogenic

growth factors

Growth factors

mTOR

PTEN

PI3-K

Akt

TSC1/TSC2

Endothelial cell

HIF-1VHL

mTOR

PI3-K

Akt

mTOR

PI3-K

Akt

Cell growth and proliferation

Angiogenesis

Smooth muscle cell (pericyte)

mTOR regulates HIF-1mTOR regulates HIF-1αα and HIF-2and HIF-2αα expression expression

HIF-1 and HIF-2 are HIF-1 and HIF-2 are transcription factors for transcription factors for hypoxic stress-related hypoxic stress-related genesgenes

HIF-1α/2HIF-1α/2αα are normally are normally degraded by VHL proteindegraded by VHL protein

HIF-1 and HIF-2 condition HIF-1 and HIF-2 condition the tumor to adapt to the tumor to adapt to growth under hypoxic growth under hypoxic conditions and promote conditions and promote angiogenesis and angiogenesis and metastasismetastasis

In pancreatic NET, HIFs In pancreatic NET, HIFs may contribute to tumor may contribute to tumor growth through growth through mechanisms unrelated tomechanisms unrelated to VEGFVEGFHIF = hypoxia-inducible factor; VHL = von Hippel-Lindau

protein.

mTOR inhibitionmTOR inhibitionAnti-NET activity via HIF-1Anti-NET activity via HIF-1 suppressionsuppression

Preliminary Results of a Phase 2 study Preliminary Results of a Phase 2 study with RAD001 and Octreotide LAR in with RAD001 and Octreotide LAR in patients with advanced NET patients with advanced NET (SMSUS52)(SMSUS52)

Octreotide LAR 30 mg IM q 28 d

RAD001 5 mg PO daily

CT / MRI

0 4 8 12Week

Single-arm phase 2Single-arm phase 2 Metastatic or unresectable well-differentiated NETMetastatic or unresectable well-differentiated NET No prior chemotherapy No prior chemotherapy 5 mg: safe and active dose for phase 2 studies5 mg: safe and active dose for phase 2 studies

Objectives

• Response (RECIST) and PFS every 12 weeks• Safety

*Yao et al. ASCO 2006. Abstract 4042.

Inhibiting NET growth pathways Inhibiting NET growth pathways with combination therapy*with combination therapy*

Ras/Raf

Abl

ER

Ras/Raf pathway kinases

Protein Production

Akt/PKB

4E-BP1

PI3-K

PTEN

S6

S6K1

elF-4E

Growth FactorsIGF-1, EGF, TGFα, VEGF,

etc

Cell Growthand Proliferation

Angiogenesis

mTOR

Oxygen, energy, and nutrients

TSC2 TSC1

RAD001

PP

PP

P

P

PP

*Yao et al. ASCO. Abstract 4042.†Cascinu et al. Cancer Invest. 2001;19:8-12.

‡Pollak et al. Anticancer Res. 1989;9:889-891.

Octreotide LAR• Inhibits IGF and VEGF

production†‡

• Blocks signaling downstreamof IGF-1, VEGF, and TSC

Efficacy (RECIST): Efficacy (RECIST): Phase 2 study in advanced NET Phase 2 study in advanced NET (SMSUS52)(SMSUS52)

OveralOveral

ll

n = 30n = 30

CarcinoCarcino

id id

n = 17n = 17

Islet Islet

CellCell

n = 13n = 13

Partial responses Partial responses (PR)(PR)

4 (13)4 (13) 2 (12)2 (12) 2 (15)2 (15)

Stable disease Stable disease (SD)(SD)

22 22 (73)(73)

14 (82)14 (82) 8 (62)8 (62)

Progressive Progressive disease (PD)disease (PD)

4 (13)4 (13) 1 (6)1 (6) 3 (23)3 (23)

PFS (24 wk)PFS (24 wk) 64%64% *Yao et al. ASCO 2006. Abstract 4042.

No. of Patients (%)

-100

-80

-60

-40

-20

0

20

40

60

80

100

1 5 9 13 17 21 25 29 33

Patient Number

Max

imu

m %

Red

uct

ion

in T

um

or

Mea

sure

men

tRAD001 in advanced RAD001 in advanced NET: Waterfall plotNET: Waterfall plot

Maximum percent tumor reductionpreliminary data as of ASCO 06

69.7% of patients

RAD001 Safety:RAD001 Safety:Phase 2 study in advanced NET Phase 2 study in advanced NET (SMSUS52 (SMSUS52))

34 patients evaluable for toxicity (CTC v3.0)34 patients evaluable for toxicity (CTC v3.0)– Most frequent AE: mild aphthous ulcerationMost frequent AE: mild aphthous ulceration– Grade 3/4Grade 3/4

Fatigue (n = 3)Fatigue (n = 3) Aphthous ulcers, diarrhea, rash (each n = 2)Aphthous ulcers, diarrhea, rash (each n = 2) Anemia, thrombocytopenia, neutropenia, Anemia, thrombocytopenia, neutropenia,

leukocytosis, hyperglycemia, hypoglycemia, leukocytosis, hyperglycemia, hypoglycemia, hypokalemia, hypophosphatemia, nausea, hypokalemia, hypophosphatemia, nausea, pruritus (each n = 1)pruritus (each n = 1)

Yao et al. ASCO 2006. Abstract 4042.

ConclusionsConclusions ((I)I) Management with either biotherapy and chemotherapy Management with either biotherapy and chemotherapy

can be guided by WHO classification in patients with can be guided by WHO classification in patients with malignant carcinoid. malignant carcinoid.

Ki-67 proliferation index might be considered as an Ki-67 proliferation index might be considered as an additional parameter for choosing between additional parameter for choosing between chemotherapy or biotherapy chemotherapy or biotherapy

Combination chemotherapy with Cisplatin, lederfolin, Combination chemotherapy with Cisplatin, lederfolin, fluororuracil represents a valid therapeutic option in fluororuracil represents a valid therapeutic option in malignant carcinoid, having a good therapeutic index malignant carcinoid, having a good therapeutic index and favourable toxicity profile and favourable toxicity profile

Conclusions (II)Conclusions (II)

Among targeted therapies, RAD001 may arrest Among targeted therapies, RAD001 may arrest NET growth by blocking downstream signaling NET growth by blocking downstream signaling through IGF-1R, TSC1/2, and mTOR and, in through IGF-1R, TSC1/2, and mTOR and, in combination with Octreotide LAR, may act combination with Octreotide LAR, may act synergistically to arrest NET growth and alleviate synergistically to arrest NET growth and alleviate symptomssymptoms

Open QuestionsOpen Questions

A standard chemotherapy is still not in existence A standard chemotherapy is still not in existence because a small number of patient cases and because a small number of patient cases and consequently a small number of randomized trials consequently a small number of randomized trials

What is the best treatment for Endocrine What is the best treatment for Endocrine Pancreatic Tumors?Pancreatic Tumors?

How can we select the best method of treatment How can we select the best method of treatment for patients in the grey area (Ki-67 2-15%) ? for patients in the grey area (Ki-67 2-15%) ?

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Milano 25.05.2007