One and Done: A Week of Radiotherapy for Glioblastoma.

In the article that accompanies this editorial, Roa et al report the results of an international, phase III clinical trial (E33033) conducted under the aegis of the International Atomic Energy Agency that identified no adverse impact on survival from shortening postoperative radiotherapy duration from 3 weeks to 1 week in a cohort of elderly and frail patients with glioblastoma multiforme. Elderly was defined as age 65 years or older with a Karnofsky performance score (KPS) of 80 to 100; frail as age 50 years or older with KPS of 50 to 70; and elderly and frail as age 65 years or older with KPS of 50 to 70. The study was halted after an interim analysis performed two thirds of the way through accrual, and it is fervently hoped that the statistics that show noninferiority would not have changed with further patient accrual. This trial extends earlier investigations into decreasing radiotherapy duration from 6 weeks to 3 weeks in a cohort of Canadian centers, which found a survival equivalent in patients with glioblastoma age 60 years or older with a KPS of 50 or greater. Those who may raise objections about one or another aspect of this international trial should have their concerns assuaged by Roa et al’s appropriate attention to these critical trial design components: establishing appropriate stratification variables for randomization and central review of enrolling investigators’ ability to plan radiotherapy as per protocol guidelines. Pretreatment audits identified no shortcomings for the central modality tested in this study. Fifty years ago, investigator equipoise about the value of radiotherapy for malignant gliomas led to randomized controlled trials to establish that radiotherapy prolongs survival. The dose fractionation currently regarded as appropriate for malignant glioma radiotherapy in relatively healthy adults was also established with class I data nearly 40 years ago, with an adverse effect on survival for doses less than 60 Gy and no clear benefit for dose escalation beyond 60 Gy. However, elderly and frail patients with glioblastoma often are not treated aggressively. Every important component of multimodality care learned through decades of randomized clinical trials in thousands of patients may be sacrificed because of concern about its appropriateness for individuals with a poor performance status and short anticipated survival. For elderly and frail patients with a newly identified brain tumor, suboptimal surgery may occur when a diagnostic biopsy specimen is all that is essayed for a resectable tumor, and radiotherapy and chemotherapy may be foregone or managed with a hair trigger for discontinuation despite class I data that support their use in this population. Ageism, therapeutic nihilism, concern about prolonging lives with suboptimal quality, difficulties with arranging trips for daily radiotherapy, and appropriate concern about the tolerability of optimal care all may be cited as reasons for nonaggressive treatment in various situations. The completion of a definitive course of radiotherapy in a single week should make this component of therapy a given for elderly and frail patients with glioblastoma. Others tread the path of briefer radiotherapy courses that Roa et al illuminate. In Montreal, 20 fractions of 3 Gy was evaluated and found to provide similar survival to 30 2-Gy fractions. A phase III trial that evaluates this approach with concomitant and adjuvant temozolomide and that will provide class I data on this hypofractionation regimen is under way at the Cross Cancer Institute. A different fractionation regimen that gave 34 Gy in 10 fractions was found to provide superior survival to 60 Gy in 30 fractions for elderly patients with glioblastoma in a phase III Nordic trial. In this same trial, a separate arm gave 5-day courses of temozolomide, repeated monthly, and provided equivalent survival to the 2-week radiotherapy regimen. Investigators at the University of Colorado conducted prospective phase I and II trials in patients with glioblastoma to evaluate hypofractionated intensity-modulated radiation therapy with dose painting to deliver 60 and 30 Gy in 10 fractions to target volumes that represent unresected tumor and contiguous T2-bright infiltrated brain tissue; that is, they gave higher doses to volumes with higher numbers of tumor cells and lower doses to less densely infiltrated contiguous brain tissue. The feasibility of concomitant and sequential temozolomide use with this approach has been shown; survival rates were not improved with the concomitant use of bevacizumab. The optimal dose fractionation for glioblastoma is still far from well established. Contemporary dose escalation trials using conventional fractionation and brachytherapy or radiosurgical boosts have shown little promise to date. The initial NRG Oncology glioblastoma trial (BN001), an important dose escalation trial, currently is comparing overall survival between standard dose and dose-escalated and -intensified photon intensity-modulated radiation therapy or proton beam therapy. Patients in both arms of this phase IIR study will receive concomitant and adjuvant temozolomide. In all clinical settings, whether resource rich or resource poor, the knowledge that a 1-week course of radiotherapy treatment for frail and elderly patients with glioblastoma is as effective in prolonging survival as treatments of 3 to 6 weeks is perhaps the most important conclusion that Roa et al report. This will facilitate the integration of radiation therapy into the management of these patients, and the rapid completion of radiotherapy should permit the rapid introduction of systemic therapy to perhaps avoid potential cytopenias JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 35 DECEMBER 1