SPECIAL DEPARTMENTS
Authors: Martin H. Cohen, John R. Johnson, Mark R. Middleton
Journal: Journal of Clinical Oncology (2000)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.10.2185 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10811684 Martin H. CohenxMartin H. CohenSearch for articles by this author , John R. JohnsonxJohn R. JohnsonSearch for articles by this author Mark R. MiddletonxMark R. MiddletonSearch for articles by this author Show More United States Food and Drug Administration RockvilleMDChristie Hospital National Health Service Trust ManchesterUnited Kingdom https://doi.org/10.1200/JCO.2000.18.10.2185 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse10052000In Reply:Drs Cohen and Johnson do not disagree with any of the conclusions in our trial report.1 Rather, their letter raises the issue of the efficacy of dacarbazine in the treatment of metastatic malignant melanoma, an indication for which it is approved. They state that the approval of dacarbazine by the United States Food and Drug Administration was based on a 23% response rate, including 6% complete response, that was achieved in 450 melanoma patients enrolled in National Cancer Institute–sponsored trials, not on data showing prolonged survival. Nevertheless, dacarbazine is accepted as the standard of care for treatment of advanced melanoma and has been used as the comparator in many clinical studies. Leaving aside the efficacy of dacarbazine, Cohen and Johnson otherwise conclude that (1) the oral formulation of temozolomide makes it more convenient to administer than dacarbazine, (2) temozolomide has an acceptable safety profile, and (3) the effect of temozolomide on survival is equivalent to dacarbazine. In the existing environment, it is unrealistic to expect a trial of a new agent to be conducted against best supportive care. Differences in overall survival are hard to achieve in circumstances under which a small minority of patients respond to treatment. This is not the only yardstick by which a treatment should be measured, although it was the primary end point of our study of 305 patients with advanced, metastatic melanoma.It is hard to see how, as Cohen and Johnson suggest, earlier and more frequent assessment of response might have improved the study. Patients underwent radiologic assessment every two treatment cycles and were assessed clinically for progression in between. The difference in progression-free survival that we observed could be a consequence of the different cycle lengths of dacarbazine and temozolomide, as we stated in the trial report. Cycle-by-cycle radiologic evaluation of response is not usual even in registration studies and would be an undue burden on patients. Although radiologic response is important, it is only one of several outcome measures that matter to patients.Cohen and Johnson express disquiet at the attrition in completion of quality-of-life questionnaires. In fact, the completion rates were high and similar for the two treatment arms. The decrease in numbers reflects the loss of patients to the study as their disease progressed. This is common in trials of treatment for other resistant malignancies, such as lung cancer. Although this places limitations on the analysis of the data, it does not render it worthless. Indeed, quality-of-life issues are of major importance when treatment is given with palliative intent.In conclusion, temozolomide is well tolerated, convenient to administer, and has demonstrated efficacy equivalent to that of the only drug approved for the treatment of advanced, metastatic melanoma. Given the trial result, oral temozolomide would seem a reasonable alternative to intravenous dacarbazine.2. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18::158,2000-166, Link, Google Scholar