Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma

• Published in: Journal of clinical oncology Vol. 26; no. 14; pp. 2299 - 2304
• Main Authors: RIETSCHEL, Petra, WOLCHOK, Jedd D, KROWN, Susan, GERST, Scott, JUNGBLUTH, Achim A, BUSAM, Klaus, SMITH, Katherine, ORLOW, Irene, PANAGEAS, Katherine, CHAPMAN, Paul B
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 10-05-2008; Lippincott Williams & Wilkins
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - adverse effects; Base Sequence; Biological and medical sciences; CD3 Complex - biosynthesis; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Dermatology; DNA Methylation; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Drug Administration Schedule; Female; Humans; Male; Medical sciences; Melanoma - blood; Melanoma - drug therapy; Melanoma - genetics; Melanoma - immunology; Middle Aged; Molecular Sequence Data; Promoter Regions, Genetic; Survival Rate; Tumor Suppressor Proteins - genetics; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Antineoplastic agent; Human; Alkylating agent; Cancerology; Treatment; Phase II trial; Malignant melanoma; Malignant tumor; Temozolomide; Dose; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2007.14.5292

We conducted a phase II trial of extended-dose temozolomide (TMZ) in patients with melanoma to test the hypothesis that the approximately 30% response rate observed in patients treated with extended-dose TMZ with antiangiogenic agents was caused by TMZ alone. We hypothesized that expression of methylguanine methyltransferase (MGMT) in the tumor would correlate with drug resistance to TMZ.
Patients with stage IV or unresectable stage III melanoma were treated with TMZ 75 mg/m(2)/d for 6 weeks followed by a 2-week rest period. Cycles were repeated until progression. Patients were stratified by M1c disease or not. The primary end point was objective response proportion. MGMT expression was assessed by methylation-specific pyrosequencing of the promoter and by immunohistochemistry.
Forty-nine patients (25 with M1c disease) were assessable. Three patients (12.5%) in each cohort experienced partial responses; there were no complete responses. Ten patients (21%) had stable disease lasting more than 24 weeks. Median time to progression was 3.3 months. Median survival was 10.1 months; survival was similar in the two cohorts. The estimated 18-month survival was 27%. There was no correlation between response and either immunohistochemistry staining for MGMT or for MGMT promoter methylation. Seventy-five percent of patients developed CD4(+) lymphopenia after three cycles.
Extended-dose TMZ therapy did not result in a 30% responses rate, which has been observed using extended-dose TMZ with antiangiogenic agents. Response did not correlate with MGMT expression or promoter methylation as a continuous variable, suggesting that other resistance mechanisms are important.