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Milano 25.05.2007

L’evoluzione della terapia medica: dagli analoghi della somatostatina alle terapie a bersaglio molecolare. Salvatore Artale Oncologia Medica Falck Ospedale NIguarda Ca’ Granda Milano. Milano 25.05.2007. WHO Classification 2000.

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Milano 25.05.2007

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  1. L’evoluzione della terapia medica: dagli analoghi della somatostatina alle terapie a bersaglio molecolare Salvatore Artale Oncologia Medica Falck Ospedale NIguarda Ca’ Granda Milano Milano 25.05.2007

  2. WHO Classification 2000 • Well differentiated endocrine tumors (benign or low grade malignancy) • Well differentiated endocrine carcinomas • Poorly differentiated endocrine carcinomas (small cell carcinomas) • Mixed exocrine and endocrine carcinomas • Tumor-like lesions

  3. WHO Classification 2000 • 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

  4. Neuroendocrine tumorsFrequency • Incidence: 1-2/ 100.000 • Autopsy series 8/100.000 • Carcinoid tumors are the most frequent type • (40% of all NETs)

  5. 5-year survival rate: 70%

  6. WHO Classification 2000 • Well differentiated endocrine tumors (benign or low grade malignancy) • Well differentiated endocrine carcinomas • Poorly differentiated endocrine carcinomas (small cell carcinomas) • Mixed exocrine and endocrine carcinomas • Tumor-like lesions

  7. WHO Classification 2000 • Well differentiated endocrine carcinomas Which is the best treatment ?

  8. Medical treatment • Biotherapy ? • Chemotherapy ?

  9. Medical treatment • Biotherapy Somatostatin analogs Interferon-a Targeted therapy

  10. Objectives of Medical Treatment • Efficacy • Symptom control • Biochemical control • Control of tumor burden Criteria for evaluating the tumor response According to ITMO Group. Bajetta et al Q J Nucl Med 2000

  11. Clinical Presentation: non functioning tumours • Symptoms related to the mass effect: • Bowel obstruction • GI bleeding (rare)

  12. Clinical Presentation: functioning tumours • Carcinoid syndrome < 20%: • Cutaneous flushing: upper part of the body (80%) • Watery diarrhea and abdominal cramp (80%) • Bronchospasm • Endocardial fibrosis( 30-40 %): arrhythmia. Right heart insufficiency.

  13. Well Differentiated carcinomaand biotherapy • Rationales: NETs carry receptor(s) for growth factor responsable in cellular proliferation, angiogenesis,hormone secretion and clinical symptoms: • Insulin like growth factor-1 • PDGF-alpha • TGF-alpha • TGF-beta • VEGF expression 80-90% of NETs show high-affinity somatostatin receptors

  14. Somatostatin Analogues • Octreotide • Octreotide LAR • Pasireotide SOM 230 • Lanreotide • Lanreotide autogel (Lan ATG)

  15. Well differentiated neuroendocrine carcinomas:Results of studies of somatostatin analogs Non randomized studies

  16. Well differentiated neuroendocrine carcinomas:Results of studies of somatostatin analogs Non randomized studies

  17. Somatostatin analogs SR: 30-75% OR: 5% BR: 30-60% Standard dose SD: 35-50% Med Dur SD: 18 months

  18. Somatostatin analogs OR: 13% High dose SR: 42% BR: 75%

  19. Carcinoid Syndrome and somatostatin analogs Efficacy Studies Randomized trials: 5

  20. Carcinoid Syndrome and somatostatin analogs Randomized trials 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

  21. What about interferon ?

  22. Interferon-α Regular dose 3–9 MU 3–7 times a week Response.

  23. Interferon-α/somatostatin analoguesin combination: randomized trials Responses Pts treated with IFN had reduced risk of Tumour progression P= 0.008 Fazio et al. Annals of Oncol 2006 ( review)

  24. Interferon-α/somatostatin analoguesin combination: Non randomized trials Fazio et al Ann of Oncol 2006

  25. WHO Classification 2000 • Well differentiated endocrine tumors (benign or low grade malignancy) • Well differentiated endocrine carcinomas • Poorly differentiated endocrine carcinomas (small cell carcinomas) • Mixed exocrine and endocrine carcinomas • Tumor-like lesions

  26. WHO Classification 2000 • Poorly differentiated endocrine carcinomas Which is the best treatment ?

  27. Medical treatment • Chemotherapy

  28. Cytotoxic therapy for carcinoid tumors S I N G L E A G E N T S Oberg. K. Annals of Oncol 2004

  29. Cytotoxic therapy for carcinoid tumors P O L I C H E M O T H E R AP Y Oberg. K. Annals of Oncol 2004

  30. Chemotherapy of endocrine pancreatic tumors Strepto-Doxo Toxicity: Chronic renal insufficiency Cardiotoxicity Vomiting Oberg. K. Annals of Oncol 2004

  31. Failure to Confirm Major Objective Antitumor Activity for Streptozotocin And Doxorubicin in the treatment of Patients with Advanced Islet Cell Carcinoma MSKCC. 2/92-2/98 16 patients with ICC treated with STZ + Doxo Results: 1/16 ( 6%) with imaging PR 9/16 (56%) with stable disease 6/16 (38%) progressed during treament Cheng et al Cancer 1999

  32. 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. 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. American Journal of Clinical Oncol 2004

  33. Cisplatin Based Therapy

  34. RESPONSE TO CISPLATIN AND ETOPOSIDE COMBINATION ACCORDING TO CELLULAR DIFFERENTION Fjallskog Cancer 2001

  35. Well diff Poorly diff

  36. A N T I C A N C E R R E S E A R C H 2005 36% 37%

  37. A N T I C A N C E R R E S E A R C H 2005

  38. 88% 67% 66% 0% Artale et al. Anticancer Research 2005

  39. Targeted Therapy • Monoclonal antibody anti-VEGF: Bevacizumab: suppression of tumor blood flow and prolungation of PFS. Yao et al ASCO 2005 • Small multi-TK inhibitors: Sunitinib:RR 15% islet cell, 2% carcinoid, SD JCO 2006 Sorafenib, Vatalanib : Phase II ongoing Imatinib (Gleevec): no activity Gross et al .Endocrine related Cancer 2006 Endostatin: only SD. Kulke et al JCO 2006 • EGFR inhibitors: Gefitinib: no Object.resp. ASCO 2005

  40. Mammallian target of rapamycin inhibitors EVEROLIMUS (RAD 001) TEMSIROLIMUS ( CCI-779)

  41. Role of angiogenesis in NET • Angiogenic growth factors contribute to tumor growth • VEGF is found in 84% of carcinoid and 59% of islet cell tumors • VEGFR is found in 71% of carcinoid and 67% of islet cell tumors • Suggests autocrine stimulation in carcinoid and islet cell tumors • The mTOR pathway regulates production of angiogenic growth factors and the proliferation of vascular endothelial cells Hobday et al. Proc ASCO. 2003;22:269. Abstract 1078.

  42. mTOR in neuroendocrine tumors IGF VEGF IGFR/VEGFR Somatostatin analogue PI3K Nutrient PKDI PTEN Autophagy Type 2 program cell death AKT p53 Rapamycin analogue RAD001, CCI-779 mTOR TSC2 TSC1 Tuberous sclerosis is associated with islet cell carcinoma Translation p70S6K

  43. PI3-K PI3-K PI3-K mTOR and angiogenesis Endothelial cell Growth factors Smooth muscle cell (pericyte) Tumor cell PTEN Akt Akt Akt TSC1/TSC2 mTOR mTOR mTOR • Protein production HIF-1a VHL Angiogenicgrowth factors Cell growth and proliferation Angiogenesis

  44. mTOR inhibitionAnti-NET activity via HIF-1 suppression • mTOR regulates HIF-1α and HIF-2α expression • HIF-1 and HIF-2 are transcription factors for hypoxic stress-related genes • HIF-1α/2α are normally degraded by VHL protein • HIF-1 and HIF-2 condition the tumor to adapt to growth under hypoxic conditions and promote angiogenesis and metastasis • In pancreatic NET, HIFs may contribute to tumor growth through mechanisms unrelated toVEGF HIF = hypoxia-inducible factor; VHL = von Hippel-Lindau protein.

  45. Preliminary Results of a Phase 2 study with RAD001 and Octreotide LAR in patients with advanced NET (SMSUS52) • Single-arm phase 2 • Metastatic or unresectable well-differentiated NET • No prior chemotherapy • 5 mg: safe and active dose for phase 2 studies RAD001 5 mg PO daily 4 8 12 0 Week Octreotide LAR 30 mg IM q 28 d • Objectives • Response (RECIST) and PFS every 12 weeks • Safety CT / MRI *Yao et al. ASCO 2006. Abstract 4042.

  46. P P P P P P P P PI3-K TSC2 TSC1 Akt/PKB S6K1 Inhibiting NET growth pathways with combination therapy* Growth Factors IGF-1, EGF, TGFα, VEGF, etc Octreotide LAR • Inhibits IGF and VEGFproduction†‡ PTEN Oxygen, energy, and nutrients Ras/Raf Abl ER RAD001 Ras/Raf pathway kinases mTOR • Blocks signaling downstreamof IGF-1, VEGF, and TSC 4E-BP1 elF-4E S6 Protein Production *Yao et al. ASCO. Abstract 4042.†Cascinu et al. Cancer Invest. 2001;19:8-12. ‡Pollak et al. Anticancer Res. 1989;9:889-891. Angiogenesis Cell Growth and Proliferation

  47. Efficacy (RECIST): Phase 2 study in advanced NET (SMSUS52) No. of Patients (%) *Yao et al.ASCO 2006. Abstract 4042.

  48. RAD001 in advanced NET: Waterfall plot Maximum percent tumor reduction preliminary data as of ASCO 06 69.7% of patients

  49. RAD001 Safety:Phase 2 study in advanced NET (SMSUS52) • 34 patients evaluable for toxicity (CTC v3.0) • Most frequent AE: mild aphthous ulceration • Grade 3/4 • Fatigue (n = 3) • Aphthous ulcers, diarrhea, rash (each n = 2) • Anemia, thrombocytopenia, neutropenia, leukocytosis, hyperglycemia, hypoglycemia, hypokalemia, hypophosphatemia, nausea, pruritus (each n = 1) Yao et al. ASCO 2006. Abstract 4042.

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