Phase ii study of temozolomide and thalidomide

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Phase ii study of temozolomide and thalidomide

  1. 1. Phase II Study of Temozolomide and Thalidomide in Patients With Metastatic Neuroendocrine Tumors J Clin Oncol. 2006 Jan 20;24(3):401-6. Vs 劉俊煌 CR 周益聖
  2. 2. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  3. 3. Pancreas 2010;39: 707 - 712)
  4. 4. Pancreas 2010;39: 707 - 712)
  5. 5. Endocr Relat Cancer. 2004 Mar;11(1):1-18.
  6. 6. Endocr Relat Cancer. 2004 Mar;11(1):1-18.
  7. 7. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  8. 8. Cancer Chemother Pharmacol(2009) 64:647–655
  9. 9. Cancer Chemother Pharmacol(2009) 64:647–655
  10. 10. J Clin Oncol 25:4127-4136
  11. 11. Temozolomide dosing regimens for malignant gliomas J Clin Oncol 25:4127-4136
  12. 12. The Oncologist 2007;12:1114–1123
  13. 13. The Oncologist 2007;12:1114–1123
  14. 14. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  15. 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. 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. 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. 18. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  19. 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. 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. 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  Pt at a dose of 100 mg >> reduction to 50 mg daily
  22. 22. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  23. 23. Response assessment Every 8 weeks after initiation of treatment Computed tomography scan Pt 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. 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. 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. 26. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  27. 27. 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 16 patients 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
  28. 28. Treatment-related toxicities resulting in discontinuation:neuropathy (11 patients,38%, 6 pts 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)
  29. 29. Median time to treatmentdiscontinuation for toxicity :8.4months (range, 1.5 to 7.5 months)
  30. 30. Median duration of response was 13.5months (range, 2 to 31 months)
  31. 31. Progression-free survival Overall survival 1-year survival rate: 79% 2-year survival rate: 61%
  32. 32. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  33. 33. 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%)
  34. 34.  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
  35. 35. CR+PR Carcinoid tumor  1/15 (7%) Pancreatic endocrine tumors  5/11(45%) Pheochromocytoma  1/3 (33%)
  36. 36.  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
  37. 37. Outline Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
  38. 38. 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 antitumor activity

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