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Pancreatic Endocrine Tumors

Pancreatic Endocrine Tumors. Lawrence S. Blaszkowsky MD. Pancreatic Endocrine Tumors. Account for 3-5% of all pancreatic neoplasms Most are sporadic Familial Syndromes MEN-1 Tuberous sclerosis Neurofibromatosis (ampulla of Vater) Von Hippel-Lindau

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Pancreatic Endocrine Tumors

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  1. Pancreatic Endocrine Tumors Lawrence S. Blaszkowsky MD

  2. Pancreatic Endocrine Tumors • Account for 3-5% of all pancreatic neoplasms • Most are sporadic • Familial Syndromes • MEN-1 • Tuberous sclerosis • Neurofibromatosis (ampulla of Vater) • Von Hippel-Lindau • Hormonal secretion: insulin, gastrin, glucagon, VIP, serotonin, ACTH

  3. Incidence of Neuroendocrine Tumors Yao, JC, et al. J Clin Oncol 2008;26:3063-3072.

  4. Pancreatic Endocrine Tumors-Survival by SEER 2005 Yao, JC, et al., Annals of Surg Oncol 2007;14:3492-3500.

  5. Management of Unresectable/Metastatic Disease • Systemic therapy • Somatostatin analogues • Chemotherapy • “Targeted” Agents • Peptide receptor therapy • Regional Therapies • Hepatic arterial embolization (± chemotherapy) or radioembolization • Ablative therapy (RFA, cryo, microwave) • Radiation • Surgical Intervention • Resection • Hepatic arterial ligation • Liver Transplant

  6. Dphe ala gly cys lys asn phe cys thr ol cys ser thr phe cys Amino acids essential for receptor binding Somatostatin and Octreotide:Molecular Characteristics Octreotide Human somatostatin phe phe Dtrp trp lys lys thr thr Harris AG. Drug Invest. 1992;4(suppl 3):1-54.

  7. Octreotide • Somatostatin analog • High affinity for sst2 and sst5 • Moderate affinity for sst3 • Symptoms of flushing and diarrhea relieved in 75-80% • 50% become refractory • Stabilize disease in 50% • Tumor regression in 4% • Arnold R et al. Digestion. 1993;54(suppl 1):72-75.

  8. Pasireotide (SOM230) • Multi-ligandsomatostatin analog • 30x greater affinity for sst1 • 5x greater affinity for sst 3 • 40x greater affinity for sst5 • Inhibits GH and IGF-1 • 45 patients who had progressive symptoms on long-acting octreotide • Symptomatic RR 27% • Kvols, L, et al. ProcASCO 2006, abst 4082.

  9. Interferon • Interferon alpha • Biochemical response in 40% • Stabilizes tumor in 15-40% • Tumor regression in 12% • Toxicity: • Fatigue • Myelosuppression • Fever • Flu-like illness • Depression • Öberg K. Ann Oncol. 2001;12(suppl 2):S111-S114. • Shnirer, II, et al. ActaOncol 2003;42:672-692.

  10. Chemotherapy • Generally ineffective • Low mitotic rate • High bcl-2 expression • MDR gene expression • Agents • Streptozocin • Doxorubicin • Fluoropyrimidines • DTIC/temozolamide

  11. Streptozocin-Based Combination Chemotherapy Survival Study N Regimen RR Moertel, CG, et al. Cancer Clin Trials 1979;2:327. Engstrom, PF, et al. J Clin Oncol 1984;2:1255. Bukowski, RM, et al. Cancer 1987;60:2891.

  12. Chemotherapy Drug N RR TTP Survival Bukowski, RM, et al. Cancer 1994;73:1505. Ansell, SM, et al. Am J Clin Oncol 2004;27:232-5. Sun, W, et al. J Clin Oncol 2005;23:4897. Ansell, SM, et al. , Cancer 2001;91:1543-48. Kulke, MH, et al. Cancer 2004;101:934. Kulke, MH, et al. Cancer Investigation 2004;22:353-9.

  13. Temozolamide • 36 patients received temozolamide 200 mg/m2 for 5 days every 4 weeks • RR 14% (4 of 5 responses had low MGMT expression) • PET 8% • Bronchial carcinoids 31% • SD 53% • TTP 7 months Ekeblad, S, et al. Clin Cancer Res 2007;13:2986.

  14. Temozolamide and MGMT Expression • MGMT is an enzyme responsible for DNA repair induced by alkylating agents • 76 patients with well-differentiated NET received TEM-based regimen • 0 of 16 with MGMT expression responded (all carcinoid) • PFS 9.3 months • 4 of 5 without MGMT expression responded (all PNET) • PFS 19.2 months Kulke, MH, et al. Clin CancerRes 2009;15:338.

  15. Temozolamide + Thalidomide • 29 patients with neuroendocrine carcinomas received temozolamide 150 mg/M2 x 7 days q 14 days + thalidomide 50-40 mg QD Kulke, MH, et al. J ClinOncol 2006;24:401-406.

  16. Temozolamide + Capecitabine • 17 (30) previously untreated patients received capecitabine 750 mg/M2 on days 1-14 and temozolamide 200 mg/M2/d on days 10-14 q 28 days • PR 71% • SD 5% Strosberg, JR, et al. ProcASCO 2008, abstract 4612.

  17. Targeted Agents • VEGF • Bevacizumab • Sunitinib • Sorafenib • Pazopanib • mTOR • Everolimus • IGF-1 • AMG-479

  18. Temozolamide + Bevacizumab • 34 patients with neuroendocrine carcinomas received temozolamide 150 mg/M2 BID x 7d q 14 days + bevacizumab 5 mg/kg IV q 14 days Kulke, MH, et al. ProcASCO 2006, abstract 4044.

  19. Temozolamide + Bevacizumab 2/06 7/06 1/07 6/10

  20. FOLFOX + Bevacizumab • 13 patients with progressive NET received mFOLFOX6 + bevacizumab 5 mg/kg q 14d *1 unconfirmed Bergsland, EK, et al. ASCO GI Cancer Symposium 2010, abstract 216.

  21. XELOX + Bevacizumab • 40 patients with NETs received capecitabine 850 mg/M2 BID x 14d, oxaliplatin 130 mg/M2 + bevacizumab 7.5 mg/kg q 21d Kuntz, PL, et al. ProcASCO 2010, abstract 4104.

  22. Sunitinib Phase III Trial-PET • 171 patients randomized to sunitinib 37.5 mg or placebo • Crossover allowed • Study closed early due to benefit of treatment Niccoli, P, et al. Proc ASCO 2010, abstract 4000.

  23. Progression-Free Survival Median PFS Sunitinib 11.4 months (95% CI 7.4, 19.8) Placebo 5.5 months (95% CI 3.6, 7.4) 1.0 0.8 0.6 0.4 0.2 0 HR=0.418 (95% CI 0.263, 0.662) P=0.0001 Proportion of patients 0 5 10 15 20 25 Time (months) Number at risk Sunitinib Placebo 86 39 19 4 0 0 85 28 7 2 1 0

  24. Overall Survival 1.0 0.8 0.6 0.4 0.2 0 Proportion of patients HR=0.409 (95% CI 0.187, 0.894) P=0.0204 Sunitinib Placebo 0 5 10 15 20 25 Time (months) Number at risk Sunitinib Placebo 86 60 38 16 3 0 85 61 33 12 3 0

  25. Sorafenib • 93 patients received sorafenib 400 mg BID • Ki-67 correlates with response (<2% RR 0, >2% RR 22%) • 2/3 of patients discontinued for reasons other than progression (toxicity) Hobday, TJ, et al. ProcASCO 2007, abstract 4504.

  26. Pazopanib + Sandostatin LAR • Pazopanib 800 mg orally QD + octreotide LAR • Carcinoid enrollment stopped early Phan, AT. ProcASCO 2010, abstract 4001.

  27. RADIANT-1:Everolimus in PET • PET patients who progressed on or after chemotherapy, stratified by prior octreotide Yao, JC, et al. J Clin Oncol 2010;28:69-76.

  28. RADIANT-3 • 410 patients with advanced PET randomized to everolimus 10 mg + BSC or BSC • Crossover at progression • ESMO October 2010

  29. Temozolamide + Everolimus • Phase I/II trial of TMZ 150 mg/M2 x 7d q 2 weeks + everolimus 5mg or 10 mg QD • RR 35% • SD 53% • PD 12% • CgA 45% Kulke, MH, et al. ASCO GI Symposium 2010, abstract 223.

  30. Temozolamide + Everolimus 10/08 6/09 3/10

  31. Everolimus Pulmonary Toxicity

  32. Bevacizumab + Everolimus • 39 patients with low or intermediate grade NET • PR/PR confirmed 26%/21% • SD 69% • PD 3% • PFS 14.6 months • 6/12 month 92%/74% • OS NR • 1y/2y 92%/80% Yao, JC, et al. ProcASCO 2010, abstract 4002.

  33. Cisplatin + VP-16 • 45 patients with neuroendocrine tumors received VP-16 130 mg/M2 d1-3 + CDDP 45 mg/M2 days 2, 3. • Well-differentiated tumors • 7% • Anaplastic tumors • RR 67% • DOR 8 months • MS 19 months Moertel, C, et al Cancer 1991-have

  34. CDDP + VP-16 • 36 patients with poorly differentiated histology or rapidly progressive course • RR 36% • MS 19 months Fjallskog, ML, et al. Cancer 2001;92:1101.

  35. Conclusions • PET may be sensitive to cytotoxic chemotherapy • Small studies • VEGF inhibitors have some activity • Suntinib positive phase III trial • mTOR inhibitors have some activity • RADIANT-1 and RADIANT-3 • Combinations of targeted therapy with chemotherapy or other targeted agents

  36. Gastrointestinal Stromal Tumors (GIST)

  37. GIST • 4000-6000 cases annually in US (estimated) • 11-14.5 per million yearly • 80% of GI sarcomas • Highest incidence in 40-60 year old range • Previously misclassified as leiomyosarcomas and other spindle cell neoplasms • Most commonly in stomach and proximal small bowel, but also in omentum, mesentery and peritoneum Nilsson, B, et al. Cancer 2005;103:821-9. Tryggvason, G, et al. Int J Cancer 2005;117:289-3.

  38. Staging: AJCC 7ed T1 Tumor ≤ 2 cm T2 Tumor 2.1-5 cm T3 Tumor 5.1-10 cm T4 Tumor > 10 cm G1 Low grade; mitotic rate ≤ 5/50 HPF G2 High grade; mitotic rate > 5/50 HPF AJCC Cancer Staging Handbook, 7 ed. 2010.

  39. Recurrence-Free Survival-Size and Mitotic Rate DeMatteo, RP, et al. Cancer 2008;112:608-615.

  40. Recurrence-Free Survival-LocationMSKCC 1983-2002 DeMatteo, RP, et al. Cancer 2008;112:608-615.

  41. KIT and PDGFRA Mutations in GIST (<1%) (10%) (1%) (67%) (<1%) (1%) (5%) (<1%) Rubin, BP, et al. Lancet 2007;369:1731-1741.

  42. Recurrence-Free Survival-Mutation DeMatteo, RP, et al. Cancer 2008;112:608-615.

  43. Normal KIT Signaling Rubin, BP, et al. Lancet 2007;369:1731-1741.

  44. Imatinib Inhibition Rubin, BP, et al. Lancet 2007;369:1731-1741.

  45. NEJM-First Report of Imatinib Before 4 weeks Before 4 weeks 8 weeks Joensuu, H et al. N Engl J Med. 2001;344:1052.

  46. Imatinib: Pivotal Phase II Trial Imatinib mesylate (400 mg/d) Continue as long as benefits Metastatic or unresectable GIST (N=147) PD Imatinib mesylate (600 mg/d) Functional imaging was performed with CT scan or MRI.PET scan imaging was performed at the discretion of the investigator. Demetri et al. N Engl J Med. 2002;347:472.

  47. Imatinib:Evolution of Tumor Responses Over Time Confirmed Objective Responses 400 mg/d (n=73) 67 65 66 600 mg/d (n=74) 70 62 58 60 49 43 50 33 40 % of patients 30 20 10 0 7(Imatinib mesylate PI) 9 (Demetri et al) 15 (von Mehren et al) 34 (Blanke et al) Median follow-up (mo) Gleevec® (imatinib mesylate) PI. Demetri et al. N Engl J Med. 2002;347:472.von Mehren et al. Proc Am Soc Clin Oncol. 2002;21:403a. Abstract 1608. Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.

  48. GIST: KIT Mutation Location Predicts Imatinib Responsiveness 100 PD/NE 80 SD 60 PR % of total 40 20 0 KIT Exon 11(n=85) KIT Exon 9(n=23) No mutation(n=9) • KIT mutations are predictive of response to imatinib mesylate • Exon 11 mutants respond best Blanke et al. ASCO 2004 Gastrointestinal Cancers Symposium. Abstract 2.

  49. Imatinib Phase II-Survival by “Best Response” Blanke, CD, et al. J Clin Oncol 2008;26:620.

  50. Imatinib 400 mg versus 800 mgEORTC 62005 Phase III • 946 patients randomized to 400 mg QD or BID 400 mg 800 mg P value CR 5% 6% PR 45% 48% SD 32% 32% PD 13% 9% 1y 85% 86% 2y 69% 74% PFS 44% 50% .026 Verweij, J, et al. Lancet 2004;364:1127.

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