Supratentorial Malignant Gliomas: Risk Patterns and Therapy
Authors: R. S. Kaplan
Journal: JNCI Journal of the National Cancer Institute (1993)

For many oncologists, primary central nervous system tumors remain among the most frustrating of neoplasms to manage and treat. For high grade (supratentorial) malignant gliomas, the role of external beam radiation therapy (RT) in modestly prolonging survival has been clearly demonstrated (7), but the efficacy of chemotherapy or of various refinements of radiation technique (e.g., hyperfractionation, interstitial brachytherapy, stereotactic radiosurgery, and high linear energy transfer beams) is either not clear or apparently confined to minor subsets of patients. Among the factors that may contribute to the absence of treatment breakthroughs thus far are the brain's poor capacity for self-repair, the susceptibility of adjacent brain regions to damage from compression, and the profound incapacity that may accompany neurologic damage. Additional obstacles are limitations on the feasibility of surgical resection (depending on location), restrictions on the dose of radiation that the brain can tolerate, and a very limited armamentarium of active chemotherapeutic agents. In general, clinicians and most clinical trials have viewed highgrade gliomas as a single, extremely grim, prognostic entity. In this issue of the Journal, Curran and colleagues from the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (2) have utilized the statistical technique of recursive partitioning to retrospectively review the survival of 1578 patients. These patients were enrolled in three malignant glioma RTOG radiation and chemotherapy trials carried out in the 1970s and 1980s. The goals of Curran et al. were to determine which demographic, disease, and treatment factors have the most important impact on median survival and how these factors might be used to improve the design of subsequent clinical trials. On one level, it might be argued, there are no surprises here. Probably, it was not expected that even such sophisticated manipulation of data that we have been collecting for years would uncover unsuspected qualitative insights. However, the analysis has yielded important quantitation with regard to such previously recognized pretreatment variables as patient age, tumor grade (anaplastic astrocytoma versus glioblastoma multiforme [GBM]), performance status, neurologic and mental status abnormalities. and duration of symptoms. These parameters divided the overall group into subsets with median survivals ranging from as little as 4.7 months to as long as 58.6 months—a 14-fold difference. Indeed, the only treatment variables that proved to be statistically significant in this model were extent of surgical resection and radiation dose, and even these factors did not account for much of the variation in survival. This analysis should not be construed, however, to demonstrate that RT and chemotherapy had very little impact. All patients in these trials were given RT, though the fractionation and precise dosages differed. Moreover, 84% received nitrosourea chemotherapy. Therefore, the analysis was not very sensitive to possible treatment effects. The remarkable finding is that pretreatment variables (age, grade, and performance status) had such a profound impact, a result that re-emphasizes the significant clinical heterogeneity among supratentorial high-grade gliomas. Of course, this general conclusion is also by no means new. Better outcome in most series has been associated with younger age (below 40 or 50), anaplastic astrocytoma rather than GBM, good performance status, and absence of symptoms or a long history of only seizures (5-5). Despite the inability of surgery to cure high-grade gliomas, the extent of tumor resection is also usually predictive {1,3-6), though often only major tumor removal (i.e., 75% or nearcomplete), is associated with longer survival. Possibly, the benefit is related to kinetic effects on the tumor or to removal of potentially resistant cell populations, or perhaps it is simply a result of the decompression. In the RTOG analysis (2), the extent of surgery was an important partitioning variable only in a subset of older patients with GBM (2,7) in which the discrimination was between those patients with biopsy only (who fared worse) and those with any (either partial or total) resection. Interestingly, one variable that did not prove a useful discriminator in the RTOG experience was tumor location, even though there is certainly a relationship among location, neurologic function or performance status, and the extent of surgical resection that is feasible. It may be that any impact of location was subsumed in the effect of these other factors on the analysis. Alternatively, perhaps it is too difficult to accurately code these deeply infiltrating tumors to a single lobe in the brain. It is also possible, moreover, that even this large retrospective analysis necessarily misses one edge of the spectrum of malignant gliomas. Patients with serious neurological compromise, such as those with large dominant hemisphere or bilateral lesions, are unlikely to be entered into randomized clinical trials. This circumstance must be especially true for older patients. In the three trials that served as the RTOG database, the upper age limit was 70. Since the steepest increase in central nervous system tumor incidence in the United States has been in this older age group (i.e., >60-70 years old) (4,8), the missing cohort, with