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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
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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Pancreas 2010;39: 707- 712)
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Pancreas 2010;39: 707- 712)
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Endocr Relat Cancer. 2004 Mar;11(1):1-18.
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Endocr Relat Cancer. 2004 Mar;11(1):1-18.
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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Cancer Chemother Pharmacol (2009) 64:647–655
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Cancer Chemother Pharmacol (2009) 64:647–655
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J Clin Oncol 25:4127-4136
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Temozolomide dosing regimens for malignant gliomas
J Clin Oncol 25:4127-4136
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The Oncologist 2007;12:1114–1123
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The Oncologist 2007;12:1114–1123
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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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])
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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)
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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.
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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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
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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
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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
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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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
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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
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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
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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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
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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)
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Median time to treatment discontinuation for toxicity :8.4 months (range, 1.5 to 7.5 months)
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Median duration of response was 13.5 months (range, 2 to 31 months)
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Progression-free survival
Overall survival
1-year survival rate: 79% 2-year survival rate: 61%
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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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%)
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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
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CR+PR
Carcinoid tumor 1/15 (7%)
Pancreatic endocrine tumors 5/11(45%)
Pheochromocytoma
1/3 (33%)
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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
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Outline
Classification and grading of NET Introduction to temozolomide Inclusion and exclusion criteria Regimen dosage and adjustment Response assessment Result Disscusion Conclusion
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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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Thanks for your attention!