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Temozolomide and thalidomide for treatment of neuroendocrine tumor
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
7. Outline
Classification and grading of NET
Introduction to temozolomide
Inclusion and exclusion criteria
Regimen dosage and adjustment
Response assessment
Result
Disscusion
Conclusion
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
27.
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
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
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