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

3. Pancreas 2010;39: 707 - 712)

4. Pancreas 2010;39: 707 - 712)

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

10. J Clin Oncol 25:4127-4136

11. Temozolomide dosing regimens for
malignant gliomas
J Clin Oncol
25:4127-4136

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
 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

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 antitumor
activity