Medical Research Council Adjuvant Trial in High-Grade Gliomas
Authors: Marc C. Chamberlain, Kurt A. Jaeckle, Sally Stenning, David Thomas, Michael Brada
Journal: Journal of Clinical Oncology (2001)

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.2001.19.19.3997 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11579124 Medical Research Council Adjuvant Trial in High-Grade Gliomas Marc C. ChamberlainxMarc C. ChamberlainSearch for articles by this author , Kurt A. JaecklexKurt A. JaeckleSearch for articles by this author Sally StenningxSally StenningSearch for articles by this author , David ThomasxDavid ThomasSearch for articles by this author , Michael BradaxMichael BradaSearch for articles by this author Show More University of Southern California, Los Angeles, CAMayo Clinic, Rochester, MNMedical Research Council Clinical Trials Unit, London, United KingdomInstitute of Neurology, London, United KingdomRoyal Marsden Hospital, Surrey, United Kingdom https://doi.org/10.1200/JCO.2001.19.19.3997 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01102001In Reply:Drs Chamberlain and Jaeckle raise a number of points concerning the Medical Research Council BR5 trial to which we are happy to respond.Their primary concern was that the BR5 trial population differed from previous trials with respect to the prognostic value of factors, such as age and performance status, and the median survival of the anaplastic astrocytoma subgroup. With respect to the first of these, the authors state “there was no statistical correlation of survival with the accepted prognostic variables of age, performance status, histologic grade, or extent of resection by proportional hazards regression analysis.” In fact we did not present any such analyses and believe that this statement comes from a misunderstanding of the hazards ratio plots. These represented the results of the subgroup analyses, which we reported as showing “no evidence of a differential treatment effect across any of these factors.” This does not mean that the factors themselves are not prognostic; certainly tumor grade, age, and performance status are prognostic factors in our trial population. It does mean they are not predictive of response to chemotherapy; ie, they do not define subgroups in which the effect of chemotherapy, as judged by the treatment hazards ratio, is greater or less than in other subgroups defined by the same factor. Thus, for example, younger glioma patients live longer than older patients regardless of whether or not they receive chemotherapy (ie, age is prognostic); however, we have found no evidence that any additional benefit that younger patients might gain through receiving chemotherapy is greater or less than any additional benefit that older patients might gain (ie, age is not predictive).Concerning the outcome of the anaplastic astrocytoma (AA) patients, it is very difficult to compare outcomes across trials without data on the distribution of prognostic factors such as age and performance status within the AA populations. In addition, a more aggressive approach to surgery for both low- and high-grade tumors may well lead to apparently improved survival in each grade subgroup, without any overall change in survival, simply through stage/grade migration. For example, centers with a policy of resection rather than biopsy for tumors that are considered low-grade radiologically are likely to identify a higher proportion of patients with anaplastic elements. These patients are then classified as having AA (and entered onto appropriate trials) but are likely to have a better prognosis than those with a high-grade appearance radiologically, who may comprise the bulk of AA patients in other trials. Such variation is inherent in any cross-trial comparison.One further point we would make is that median survival is an isolated point on the survival curve, and just as one would not compare treatment results by focusing on a single time point but rather by comparing the whole survival curves, so one should apply the same principle here. Thus although our AA and glioblastoma multiforme populations differed by only a few months with respect to median survival, survival rates in the two groups beyond this point (ie, after 1 year) are systematically substantially different as illustrated in Fig 4 of the study report.Regarding trial entry criteria, these were indeed quite broad to reflect practice outside of the trial setting and included all patients in whom there was the possibility that chemotherapy may be beneficial (thus those with comorbid conditions that would have made treating or assessing response to treatment impossible were excluded). Although potentially this may mean that a higher proportion of poorer (or indeed better) prognosis patients entered the trial than might otherwise have been the case, these patients would have been equally distributed across the trial arms by randomization. In addition, the subgroup analyses referred to above indicate that the overall negative result of the trial is not simply explained by poor chemotherapy response in the poorer prognosis patients; we were unable to identify any subgroups in which chemotherapy substantially improved survival.Regarding time from surgery to start of radiotherapy, the median interval was 3 weeks; 90% started within 6 weeks and 95% within 7 weeks; the remaining patients incurred additional short delays for a variety of practical and personal reasons. We found no evidence that chemotherapy was more beneficial in patients with a short interval between surgery and the start of radiotherapy.As reported in the article, the median number of cycles received appears comparable with previous trials, but most trials report insufficient data to compare dose-intensity.With regard to treatment at recurrence, the re-treatment rate was low, although the extent to which overall survival may have been extended had the rate been higher is perhaps debatable. Certainly the consistency of the trial results with respect to progression-free and overall survival suggest that cross-over in the radiotherapy arm did not have a major influence on the overall survival results.Finally, with regard to the number of patients followed-up not to death but to date last known to be alive, these comprised less than 10% of the total randomized population, and the numbers according to treatment arm are given in Fig 1 of the trial report; 29 of the radiotherapy patients and 28 of the patients who received radiotherapy plus procarbazine, lomustine, and vincristine were still alive at the time of the final analysis, with a median follow-up for survivors of approximately 4 years in each group.It is clear that any benefit to chemotherapy is indeed marginal, a statement supported not just by BR5 but by the most recent quantitative summary of the worldwide evidence.1 Equally, it is clearly wholly appropriate that patients and their physicians should make decisions regarding the need for chemotherapy on an individual patient basis and that some will choose to have chemotherapy even in the absence of unequivocal evidence of survival gain. This is entirely compatible with our conclusion that it is currently reasonable and appropriate not to offer routine adjuvant chemotherapy to individual patients outside of clinical trials.REFERENCE1. Stewart LA, Burdett S, Souhami R: Chemotherapy in high-grade glioma: A meta-analysis using individual patient data from randomized clinical trials (RCTs)—The Glioma Meta-Analysis Trialist Group. Proc Am Soc Clin Oncol 19:: 168a,,2000 (abstr 650) Google Scholar