1 / 35

Incidence of NETs Increasing

Incidence of NETs Increasing. 6.00. 600. All malignant neoplasms. 5.00. 500. 4.00. 400. Incidence per 100,000 - NETs. 3.00. 300. Incidence per 100,000 - All malignant neoplasms. 2.00. 200. 1.00. 100. Neuroendocrine tumors. 0.00. 0. 1982. 1983. 1984. 1985. 1986. 1987. 1988.

finn
Download Presentation

Incidence of NETs Increasing

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. NETs — Second Most Prevalent Gastrointestinal Tumor NET Prevalence in the United States, 2004 1200 103,312 cases(35/100,000) 1100 Cases (thousands) 100 0 Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary 29-year limited duration prevalence analysis based on SEER [Surveillance, Epidemiology, and End Results]. Yao JC, et al. J ClinOncol. 2008;26:3063-3072.

  3. Many NETs Are Diagnosed When Metastatic Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

  4. Diagnostic Challenges in NET

  5. Classification of NET TNM: tumor, lymph nodes, metastasis; AJCC: American Joint Committee on Cancer; ENETS: European Neuroendocrine Tumor Society

  6. Classification of NET (cont) HPF: high-power fields; MEN: multiple endocrine neoplasia; VHL: Von Hippel-Lindau disease

  7. Grading Proposal for NETs of Ileum, Appendix, Colon, and Rectum *10 HPF: 2 mm2, at least 40 fields (at 40× magnification) evaluated in areas of highest mitotic density. †Ki-67, MIB1 antibody; % of 2000 tumor cells in areas of highest nuclear labeling. HPF: high-power field Rindi G, et al. Virchows Arch. 2007;451:757-762.

  8. NET Survival by Histology 1.0 0.8 0.6 Survival Probability 0.4 0.2 0 12 24 36 48 60 72 84 96 108 120 Time (months) Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

  9. Assessment of NET: Factors to Consider CT: computed tomography; PET: positive electron tomography; SPECT: single-photon emission computed tomography; SSR: somatostatin receptor

  10. Treatment Goals in NET

  11. Factors in Treatment Decisions in NETs • Treatment decisions require discussion by a multidisciplinary team • Options may depend on: • Type of NET • TNM stage • Tumor grade • Extent of disease, including liver disease • Functional status of tumor • Patient: organ function, ECOG PS, comorbidity • Access to various options ECOG: Eastern Cooperative Oncology Group; PS: performance status

  12. Treatment Options in NET PRRT: peptide receptor radionuclide therapy

  13. Surgical Options in NET

  14. Radical Surgery in NET: Consider Likelihood of Malignancy In absence of liver metastases or nearby structure invasion

  15. Debulking Procedures in NET RFTA: radiofrequency thermal ablation; TACE: transarterial (chemo) embolization

  16. Prognosis and Clinical Course of Patients With Liver Metastatic Midgut NETs: A Retrospective European Study Survival of patients with bowel bypass vs failed resection, no resection, or resection 1.0 Log rank (Mantel-Cox) P < .000 0.8 Primary removed Bowel bypass (n = 12) 0.6 Failed resection (n = 17) Cumulative Survival No resection (n = 80) 0.4 Resected (n = 210) 0.2 0.0 0 Yrs 5 Yrs 10 Yrs 15 Yrs 20 Yrs 25 Yrs 30 Yrs Duration of follow up from date of diagnosis Ahmed A, et al. Endocr Relat Cancer. 2009;16:885-894.

  17. Challenges in Treatment of Metastatic NETs [a]Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

  18. Symptoms of patients with metastatic NETs include:[a] Diarrhea, flushing, bronchoconstriction, cardiac disease, hypoglycemia, gastric ulcer, skin rash 80% to 90% of patients with NETs express somatostatin receptors, which can be targeted[b] Somatostatin analogues effective in reducing hormonal secretion and controlling symptoms of NETs[a] Most common adverse events: diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis Symptomatic Treatment of NETs [a]Moertel CG. J Clin Oncol. 1987;5:1502–1522. [b]de Herder WW, et al. Endocr Related Cancer. 2003;10:451–458.

  19. Complete or Partial Symptom Control With Octreotide LAR in NET Flushing 89% n = 53 57% > 50% improvement Diarrhea 74% n = 49 Complete improvement 25% Urinary 5-HIAA 68% n = 57 5% 0 50 100 Patients with improvement (%) 5-HIAA: 5-hydroxyindoleacetic acid; LAR: long-acting release Moertel CG. J Clin Oncol. 1987;5:1502–1522.

  20. PROMID: Phase 3 Randomized, Double-Blind, Placebo-Controlled Study in Midgut NETs • Primary endpoint: TTP • Secondary endpoints: Objective response rate, OS, quality of life, safety • Patients with midgutNETs • Treatment naive • Histologically confirmed • Locally inoperable or metastatic • Well differentiated • Measurable (CT/MRI) • Functioning or nonfunctioning Octreotide LAR 30 mg IM every 28 days Treatment until CT/MRI documented tumor progression or death RANDOMIZATION (1:1) Placebo IM every 28 days CT: computed tomography; IM: intramuscular; MRI: magnetic resonance imaging; OS: overall survival; PROMID: Placebo-controlled prospective Randomized study on the antiproliferative efficacy of Octreotide LAR in patients with metastatic neuroendocrine MIDgut tumors; TTP: time to progression Rinke A, et al. J Clin Oncol. 2009;27:4656-4663.

  21. 1 Octreotide LAR (n = 42) Median 14.3 months Placebo (n = 43) Median 6.0 months 0.75 Proportion without progression 0.5 0.25 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (months) PROMID: Octreotide LAR Slows Disease Progression in Midgut NETs TTP in Midgut NET Octreotide LAR vs placebo P < .001 HR: 0.34 (95% CI: 0.20–0.59) Based on conservative ITT analysis HR: hazard ratio; ITT: intent-to-treat Rinke A, et al. J Clin Oncol. 2009;27:4656-4663.

  22. Systemic radiotherapy targeting somatostatin receptors Compounds vary by isotope and carrier molecule Most common isotopes used are 90Y-DOTATOC and 177Lu-DOTATATE Positive somatostatin receptor scan required prior to treatment Promising results with Yttrium-90 edotreotide[1] and 177Lu DOTATATE[2] in single-arm phase 2 trials No randomized controlled trials to date Peptide-Guided Radio Receptor Therapy (PRRT) [a] Bushnell DL, et al. J Clin Oncol. 2010;28:1652-1659 [b] Kwekkeboom DJ, et al. J Clin Oncol. 2008;26:2124-2130.

  23. Systemic Chemotherapy in Pancreatic NET: Streptozocin and Temozolomide • Have shown ability to control symptoms and proliferation in G1/2 pancreatic NETs • Considered second-line agents because of more side effects than first-line SSAs • Combinations studied to date include: • Streptozocin + 5-FU and/or doxorubicin • Temzolomide + thalidomide, bevacizumab, or capecitabine • Some combinations show promising RRs, but quality of existing data do not allow registration FU: fluorouracil; G1/2: grade 1/2; RR: response rate; SSA: somatostatin analogue

  24. Poorly Differentiated Neuroendocrine Carcinoma (NEC): Cisplatin + Etoposide • Tumors mainly in upper GI and colon • Must be considered separately from other tumors • Treated similarly to SCLC • Small studies (N = 18 to 41) with cisplatin + etoposide:[1,2] • Objective response similar to that in SCLC (42% to 54%) • Median survival also low (15 to 19 mo) SCLC: small-cell lung cancer [a]Moertel CG, et al. Cancer. 1991;68:227-232. [b]Mitry E, et al. Br J Cancer. 1999;81:1351-1355.

  25. Rationale for the Use of Angiogenesis Inhibitors in NETs VEGF: vascular endothelial growth factor Terris B, et al. Histopathology. 1998;32:133-138; Papouchado B, et al. Mod Pathol. 2005;18:1329-1335; Pavel M, et al. Clin Endocrinol. 2005;62:434-443; Welin S, et al. Neuroendocrinology. 2006;84:42-48; Zhang J, et al. Cancer. 2007;109:1478-1486.

  26. Efficacy and Tolerability of Angiogenesis Inhibition in NETs *PNET; †GI NETs HTN: hypertension; MR: minor response; ND: not determined; PDGFR: platelet-derived growth factor receptor; PR: partial response; SD: stable disease; SSTR: somatostatin receptor; VEGFR: vascular endothelial growth factor receptor 1. Pavel ME, et al. J Clin Oncol. 2008;26(May 20 suppl):14684. 2. Varker KA, et al. Cancer Chemother Pharmacol. 2008;61:661-668. 3. Kulke MH, et al. Clin Oncol. 2006;24:3555-3561. 4. Hobday TJ, et al. J Clin Oncol. 2007;25(June 20 suppl):4504. 5. Raymond E, et al. Presented at 2010 ASCO GI: Abstr 127. 6. Yao JC, et al. J Clin Oncol. 2008;26:1316-1323.

  27. Oral mTOR inhibitor with broad antitumor activity and antiangiogenic activity[a-d] Daily dosing with everolimus 5-10 mg resulted in continuous inhibition of mTOR activity[d,e] Everolimus (RAD001): An Oral mTOR Pathway Inhibitor mTOR: mammalian target of rapamycin [a]Beuvink I, et al. Proc Am Assoc Cancer Res. 2001;42:366. Abstract 1972; [b]O’Reilly T, et al. Proc Am Assoc Cancer Res. 2002;43:71. Abstract 359; [c]O’Donnell A, et al. J Clin Oncol. 2008;26:1588-1595; [d]Tabernero J, et al. J Clin Oncol. 2008;26:1603-1610; [e]Tanaka C, et al. J Clin Oncol. 2008;26:1596-1602.

  28. RADIANT-1: RAD001 +/- Octreotide LAR in Pancreatic NET: Open-Label Phase 2 Study PFS by Central Review Everolimus + octreotide LAR 33.0% grade 3-4 AEs Everolimus 37.2% grade 3-4 AEs 100 100 n: 115 80 n: 45 80 60 60 Probability (%) Probability (%) 40 40 20 20 Median PFS: 16.7 mo Median PFS: 9.7 mo 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (mo) Time (mo) Patientsat risk Patientsat risk 115 111 81 58 54 36 25 15 12 5 3 3 1 0 45 39 32 22 21 19 14 10 8 3 3 1 0 Yao JC, et al. J Clin Oncol. 2010;28:69-76.

  29. RADIANT 3: BSC + Everolimus or Placebo in Progressive AdvancedpNET Primary endpoint: PFS 100 Kaplan-Meier median PFS Everolimus: 11.04 mo Placebo: 4.60mo HR: 0.35 (95% CI 0.27 to 0.45)P < .0001 80 60 % of patients with progression 40 20 Censoring times Everolimus (n/N = 109/207) Placebo (n/N = 165/203) 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mo) Number of patients “at risk” Everolimus Placebo 207 203 189 177 153 98 126 59 114 52 80 24 49 16 36 7 28 4 21 3 10 2 6 1 2 1 0 1 0 1 0 0 • P value obtained from stratified one-sided log-rank test • HR obtained from stratified unadjusted Cox model Yao J, et al. Ann Oncol. 2010;21(suppl 6): Abstract O-0028.

  30. Phase 3 Trial: Sunitinib vs Placebo in Advanced pNET Study halted prior to complete accrual due to treatment benefit Unplanned Kaplan-Meier PFS analysis 1.0 0.8 0.6 0.4 0.2 0 P < .001; HR: 0.397 (95% CI: 0.243 to 0.649) Sunitinib: PFS 11.1 mo Survival probability Placebo: PFS 5.5 mo Sunitinib Placebo 0 5 10 15 20 Efficacy endpoint variable value (mo) Placebo, n 79 25 6 1 0 Sunitinib, n 74 32 14 2 0 Raymond E, et al. Presented at ESMO-GI 2009: Abstract 0013.

  31. Medical Therapy in NETs: Summary • Numerous agents now available • Streptozocin and temozolomide have shown response in NETs • Lack strong evidence base • Good data with everolimus, octreotide LAR, and sunitinib • Options for poorly differentiated tumors: • Oxaliplatin • Cisplatin + etoposide

  32. Future Directions • Biomarkers and molecular imaging for evaluation of therapeutic response • Personalized treatment based on molecular genetics and tumor biology • WHO and TNM classification • Molecularly targeted treatment will be the future: • Targeted agents • PRRT • Combinations of traditional cytotoxics with targeted agents • Combinations of targeted agents

  33. Take-Home Messages Role of Pathology in NET Management • Critical to appropriate management decisions in NETs • Includes staging, grading, differentiation, site of origin, Ki-67 status, histologic characteristics • Drives therapeutic strategy When to Consider Surgery • Radical surgery should take priority when feasible • Surgeon must coordinate with oncologist in advanced disease

  34. Take-Home Messages (cont) When and How to Initiate Treatment in NETs Multidisciplinary decision-making process including pathologist Factors to consider include: Where is primary site? Progressive or stable disease? Stage of disease?

  35. Conclusions • Precise pathology is crucial in management of NETs • Surgical intervention is a key step in NET management, even when not curative • Multidisciplinary team approach • Introduce treatment at appropriate time • Customize treatment based on patient and disease factors

More Related