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

Outline

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

Pancreas 2010;39: 707- 712)

Pancreas 2010;39: 707- 712)

Endocr Relat Cancer. 2004 Mar;11(1):1-18.

Endocr Relat Cancer. 2004 Mar;11(1):1-18.

Outline

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

Cancer Chemother Pharmacol (2009) 64:647–655

Cancer Chemother Pharmacol (2009) 64:647–655

J Clin Oncol 25:4127-4136

Temozolomide dosing regimens for malignant gliomas

J Clin Oncol 25:4127-4136

The Oncologist 2007;12:1114–1123

The Oncologist 2007;12:1114–1123

Outline

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

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])

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)

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.

Outline

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

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

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

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

Outline

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

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

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

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

Outline

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

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

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)

Median time to treatment discontinuation for toxicity :8.4 months (range, 1.5 to 7.5 months)

Median duration of response was 13.5 months (range, 2 to 31 months)

Progression-free survival

Overall survival

1-year survival rate: 79% 2-year survival rate: 61%

Outline

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

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%)

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

CR+PR

Carcinoid tumor 1/15 (7%)

Pancreatic endocrine tumors 5/11(45%)

Pheochromocytoma

1/3 (33%)

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

Outline

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

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