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. Pancr eas 2010;39: 707 - 712)

4. Pancr eas 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/
d
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)
m

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 C lin O ncol 2:1 255-1 259, 1 984
•
C ancer C lin Trials2:327-334, 1 979
•
J C lin O ncol 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

41. 
Thanks for your attention!