Phase II study of extended-dose temozolomide in patients with melanoma Journal Article


Authors: Rietschel, P.; Wolchok, J. D.; Krown, S.; Gerst, S.; Jungbluth, A. A.; Busam, K.; Smith, K.; Orlow, I.; Panageas, K.; Chapman, P. B.
Article Title: Phase II study of extended-dose temozolomide in patients with melanoma
Abstract: Purpose: 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 and Methods: Patients with stage IV or unresectable stage III melanoma were treated with TMZ 75 mg/m2/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. Results: 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. Conclusion: 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. © 2008 by American Society of Clinical Oncology.
Keywords: immunohistochemistry; adolescent; adult; cancer survival; clinical article; controlled study; protein expression; aged; aged, 80 and over; middle aged; survival rate; methylation; promoter region; genetics; clinical trial; constipation; fatigue; neutropenia; cancer growth; side effect; treatment duration; cancer patient; temozolomide; cancer staging; molecular genetics; anorexia; cd3 antigen; cd8+ t lymphocyte; antigens, cd3; cd8-positive t-lymphocytes; dacarbazine; melanoma; controlled clinical trial; infection; multiple cycle treatment; phase 2 clinical trial; anemia; bleeding; randomized controlled trial; drug administration schedule; alkylating agent; drug effect; dna methylation; hyperglycemia; lymphocytopenia; survival time; blood; biosynthesis; immunology; molecular sequence data; nucleotide sequence; tumor suppressor proteins; cd4+ t lymphocyte; cd4-positive t-lymphocytes; drug response; antineoplastic agents, alkylating; drug derivative; dna repair enzymes; nausea and vomiting; base sequence; hyperbilirubinemia; liver function test; methylated dna protein cysteine methyltransferase; drug administration; dna methyltransferase; mgmt protein, human; polydeoxyribonucleotide synthase; tumor suppressor protein; dna modification methylases; prochlorperazine; musculoskeletal pain; promoter regions (genetics)
Journal Title: Journal of Clinical Oncology
Volume: 26
Issue: 14
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2008-05-10
Start Page: 2299
End Page: 2304
Language: English
DOI: 10.1200/jco.2007.14.5292
PUBMED: 18467721
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 26" - "Export Date: 17 November 2011" - "CODEN: JCOND" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Jedd D Wolchok
    669 Wolchok
  2. Irene Orlow
    192 Orlow
  3. Scott R Gerst
    42 Gerst
  4. Paul Chapman
    252 Chapman
  5. Katherine S Panageas
    331 Panageas
  6. Achim Jungbluth
    341 Jungbluth
  7. Klaus J Busam
    540 Busam
  8. Susan Krown
    87 Krown
  9. Katherine M Smith
    29 Smith