Phase II Study of Temozolomide and Thalidomide in

1. Phase II Study of Temozolomide and Thalidomide in Patients With Metastatic NeuroendocrineTumors J ClinOncol. 2006 Jan 20;24(3):401-6. Vs 劉俊煌 CR 周益聖 財團法人台灣癌症臨床研究發展基金會

2. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

5. Endocr Relat Cancer. 2004 Mar;11(1):1-18.

6. Endocr Relat Cancer. 2004 Mar;11(1):1-18.

7. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

8. Cancer Chemother Pharmacol (2009) 64:647–655

9. Cancer Chemother Pharmacol (2009) 64:647–655

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12. The Oncologist 2007;12:1114–1123

13. The Oncologist 2007;12:1114–1123

14. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

15. Inclusion (1)‏ • Histologically confirmed, locally unresectable or metastatic neuroendocrine tumors • Prior treatment with chemotherapy, other than DTIC, temozolomide, or thalidomide, was permitted • ECOG performance status of 0, 1, or 2 • Life expectancy > 12 weeks • Adequate renal function (serum creatinine < 1.5 * the upper limit of normal [ULN])‏

16. Inclusion (2)‏ • Adequate hepatic function (total and direct bilirubin < 2 * the ULN)‏ • ALT and AST < 5 * the ULN, and alkaline phosphatase < 2 * the ULN or < 5 * the ULN in the setting of liver metastases • Adequate bone marrow function (absolute neutrophil count >1,500/mm3, platelets > 100,000/mm3, hemoglobin >9 g/dL)‏

17. Exclusion • Clinically apparent CNS metastases or carcinomatous meningitis • History of myocardial infarction 6 months before protocol treatment • History of major surgery within 2 weeks before treatment initiation • HIV infection or AIDS-related illness • Other serious medical or psychiatric illness • Insufficient recovery from toxicities of prior therapies • Pregnant or lactating.

18. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

19. Treatment Program • Temozolomide • 150 mg/m2 days 1 to 7 and days 15 to 21 • Thalidomide • daily • starting dose of 200 mg • Every 28 days

20. Temozolomide adjustment • Hold if • ANC less than 1,000/mm3 • Plt less than 50,000/mm3 • all nonhematologic toxicities with National Cancer Institute Common Toxicity Criteria grade 2 or higher • Not resumed until full hematologic recovery • On recovery, dose reduction of 50 mg/m2 • Discontineud if • Unable to resume therapy within 3 weeks • Unacceptable toxicity levels

21. Thalidomide adjustment • Increased weekly by 100 mg until a maximum dose of 400 mg • Before escalation • Toxicity >> reduced by 100 mg/d • No improvement within 7days >> further reduced by 50 mg • Not tolerate 50 mg/d >> removed from study • After escalation • Toxicity >> decreased by 100 mg • not resolved to grade 1 within 7 days >> further reduced by 100 mg • P't at a dose of 100 mg >> reduction to 50 mg daily

22. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

23. Response assessment • Every 8 weeks after initiation of treatment • Computed tomography scan • P't with complete [CR] or partial response [PR] or stable disease remained on treatment until progression • CR • disappearance of all target lesions • at least 4 weeks

24. Response assessment • PR • decrease of more than 30% in the sum of the largest perpendicular diameters of all measurable lesions • at least 4 weeks • without progression of any nonmeasurable sites • Without new lesions. • Progressive disease • increase of 20% or more in the sum of longest diameters of target lesions • one or more new lesions

25. Response assessment • Stable disease: • Neither PR, nor progressive disease • Biochemical response • secondary end point • PR:decrease in chromogranin A by 50% or more • Stable: <50 % decrease or <25% increase

26. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

28. Duration of Treatment • 29 patients received treatment for a median of 7.3 months (range, 1 to 23 months)‏ • 1 patient required dose reduction of temozolomide due to thrombocytopenia • 16patients required dose reductions for thalidomide-related toxicities • 14 required dose reduction to 100 mg • 2 required dose reductions to 50 mg daily • 9 patients continued thalidomide at their starting dose of 200 mg • 4 patients able to undergo dose escalation to 400 mg • Median thalidomide dose 100 mg/d

29. Treatment-related toxicities resulting in discontinuation: neuropathy (11 patients,38%, 6 pt's persist > 3 wks), infection (four patients), thrombocytopenia (four patients), neutropenia (one patient), rash (one patient). Infections included: Pneumocystis carinii pneumonia (one patient), disseminated varicella zoster virus (one patient), staphylococcal sepsis (one patient), cutaneous herpes zoster (one patient)‏

30. Median time to treatment discontinuation for toxicity :8.4 months (range, 1.5 to 7.5 months)‏

32. Median duration of response was 13.5 months (range, 2 to 31 months)‏

33. Progression-free survival Overall survival 1-year survival rate: 79% 2-year survival rate: 61%

34. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

35. Discussion • Overall objective radiologic response rate of 25%(CR+PR)‏ • Biochemical response rate of 40% • 2-year survival rate of 61% • Unique toxicities:neuropathy(38%) and selective lymphopenia(69%)‏

36. Carcinoid tumor • Objective response rates of streptozocin-based regimens: 16% to 33% • J Clin Oncol 2:1255-1259, 1984 • Cancer Clin Trials2:327-334, 1979 • J Clin Oncol 23:4897-4904, 2005 • Pancreatic endocrine tumors • Combined biochemical and radiologic response rate of . Streptozocin and doxorubicin : 69% • N Engl J Med 326:519-523, 1992 • Overall response rate of retrospective study of streptozocin, fluorouracil, and doxorubicin:39% • J Clin Oncol 22:4762-4771, 2004 • Cancer 86:944-948, 1999 • Am JClin Oncol 27:485-488, 2004

37. CR+PR • Carcinoid tumor • 1/15 (7%)‏ • Pancreatic endocrine tumors • 5/11(45%) • Pheochromocytoma • 1/3 (33%)‏

38. high proportion (55%) removed for toxicity • Median time to treatment discontinuation for treatment-related toxicity:8.4 months • 4 patients experienced progressive disease while receiving study therapy • Prophylaxis against P carinii pneumonia and herpes simplex virus should be utilized

39. Outline • Classification and grading of NET • Introduction to temozolomide • Inclusion and exclusion criteria • Regimen dosage and adjustment • Response assessment • Result • Disscusion • Conclusion

40. Conclusion • Combination of temozolomide and thalidomide seems to be an active oral regimen for the treatment of metastatic neuroendocrine tumors and alternative to intravenous regimens • More active in pancreatic endocrine tumors than in carcinoid tumors. • Further studies to more precisely assess the relative efficacy of this regimen in pancreatic endocrine and carcinoid tumors • Also to assess the relative contributions of temozolomide and thalidomide to the antitumoractivity