On the Merits and Limitations of Whole-Brain Radiation Therapy

Brain metastases are a common event in the progression of many human malignancies. In the article that accompanies this editorial, Soffietti et al present data reporting health-related quality of life (HRQOL)outcomesinpatientsenrolledontoEuropeanOrganisationfor Research and Treatment of Cancer (EORTC) trial 22952-26001. This is the first such analysis in a randomized trial of observation or whole-brain radiation therapy (WBRT) after focal therapy (surgery or stereotactic radiosurgery [SRS]). The primary end point results were reported by Kocher et al in 2011 and eloquently editorialized by Mehta in the same issue of Journal of Clinical Oncology. Few topics in oncology have stirred more controversy and partisanship than the appropriate use and role of WBRT in the modern practice of oncology. Deeply held biases have sometimes been defended with a fervor that cannot be easily justified by the scant available evidence. Nonetheless, recent developments have shed some light on the potential merits and limitations of WBRT. All patients with brain metastases typically receive corticosteroids, which will improve edema and neurologic deficits in approximately 70% of patients. Nonetheless, the median survival with corticosteroids alone is approximately 2 months. WBRT has been the mainstay of therapy for patients with intracranial metastases and is associated with increases in the median survival of these patients to approximately 4 to 6 months. In a pooled recursive partitioning analysis of patients treated with WBRT on Radiation Therapy Oncology Group (RTOG) trials, the median survivals were 7, 4, and 2 months, respectively, for patients in the most favorable, intermediate, and poor prognostic subgroups. A cumulative response rate of approximately 60% can be anticipated with WBRT. The debate over the clinical benefit of WBRT versus the potential risks of treatment have led to interest in identifying a group of patients with limited cranial metastases who can be treated adequately with focal therapies alone (surgery or SRS), withholding WBRT until progression (Table 1). Three randomized trials have examined the incremental benefit of adding WBRT to focal therapy alone in patients with limited cranial metastases. Patchell et al reported improved local control (90% v 54%), elsewhere control (86% v 63%), and cumulative intracranial control (82% v 30%) with WBRT compared with observation after surgical resection of a single brain metastasis. There was no improvement in overall survival, but patients in the WBRT arm were less likely to suffer neurologic death. This study is often misinterpreted as a negative study because of the lack of improvement in survival. However, this trial was designed and powered for intracranial disease control; survival was a secondary end point. From the standpoint of intracranial disease control, this was indeed a positive trial, and the findings are congruent with data from the Japanese Radiation Oncology Study Group (JROSG) 99-1 trial. Aoyama et al reported results for 132 patients with one to four brain metastases, each less than 3 cm, who were randomly assigned to SRS alone or WBRT and SRS. The WBRT arm had superior local control, distant brain control, and total intracranial control. Forty-three percent of patients on the SRS-alone arm required salvage therapy, compared with 15% when WBRT was added. Interestingly, this trial demonstrated improvements in local control of the index lesions with WBRT, presumably because of the higher doses received when WBRT was delivered. This finding seems to undermine the rationale for SRS alone (at least on the