Doh and colleagues are to be commended for summarizing the complex issues inherent in the management of patients with brain metastasis, including those from renal cell carcinoma (RCC). Given the space limitations of this commentary, we are not able to cover all aspects of the topic. However, we will address two major issues that need further examination: the role and efficacy of focal therapies (conventional surgery and stereotactic radiosurgery) in the management of multiple brain metastases and the controversy regarding the use of adjuvant whole-brain radiation therapy (WBRT) in association with surgery and stereotactic radiosurgery.
Efficacy of Focal Therapies for Multiple Brain Metastases
Throughout their review, Doh et al appear to accept the concept that surgery and stereotactic radiosurgery have been shown to be effective in the treatment of multiple brain metastases. Such is not the case. With regard to conventional surgery, there have been no randomized trials addressing the issue, and the retrospective data are contradictory. For stereotactic radiosurgery, the situation is clearer; there have been three randomized trials[1-3] assessing the efficacy of stereotactic radiosurgery in the treatment of multiple metastases.
The first randomized trial was reported by Kondziolka et al. In that study, 27 patients with multiple brain metastases were randomized to treatment with WBRT alone or WBRT plus a stereotactic radiosurgery boost. The study was stopped early because the authors claimed to have found a large difference in recurrence rates in favor of stereotactic radiosurgery. Unfortunately, the study used nonstandard end points to measure recurrence. The investigators used any change in measurement of the lesion rather than the more usual 25% increase in diameter. No attempt was made to control for steroid use, radiation changes, or other factors that might produce small fluctuations in lesion size on magnetic resonance imaging. Also, a study with only 27 patients lacked the statistical power to support any meaningful conclusion, regardless of P values. As a result, this study was uninterpretable.
A second study reported in abstract form by Chougule et al randomized patients with one to three brain metastases to treatment with stereotactic radiosurgery alone, stereotactic radiosurgery plus WBRT, or WBRT alone. This study enrolled 109 patients. There was no statistically significant difference in survival among the three treatment arms. Median survival times for the stereotactic radiosurgery, stereotactic radiosurgery plus WBRT, and WBRT alone-treated groups were 7, 5, and 9 months, respectively. Local control rates in the brain were also not significantly different.
However, this trial suffered from several methodologic problems. The most serious issue was that 51 of the patients had had surgery for at least one symptomatic brain metastasis prior to entry into the study. No attempt was made to stratify for previous surgery or to otherwise ensure that surgical patients were equally distributed among the treatment groups. The inclusion of the surgical patients effectively made this a six-arm trial (the original three subdivided again into surgically treated patients and nonsurgically treated patients), and therefore, the size of this trial was not large enough to support a meaningful analysis. Also, since surgery is in all probability an effective therapy for brain metastases, the nonrandom distribution of surgically treated patients among the treatment arms substantially weakened the trial. Therefore, this study, although ostensibly negative, is uninterpretable.
A third study, reported by Andrews and colleaguesRadiation Therapy Oncology Group (RTOG) 9508was summarized by Doh et al. The primary end point was survival. Overall, there was no significant difference in survival between the two treatment groups (median: 6.5 months for stereotactic radiosurgery plus WBRT and 5.7 months for WBRT alone, P = .1356). The investigators found no survival benefit from stereotactic radiosurgery in patients with multiple metastases (median: 5.8 months for stereotactic radiosurgery plus WBRT and 6.7 months for WBRT alone, P = .9776). However, stereotactic radiosurgery-treated patients with a single metastasis experienced a significant survival advantage (median: 6.5 vs 4.9 months, P = .0393). Lower posttreatment Karnofsky scores and steroid dependence were more common in the WBRT alone group.
Multiple subgroup analyses were performed, and a benefit for stereotactic radiosurgery plus WBRT was found in several subgroups, including patients with single and multiple metastases. These subgroups were recursive partitioning analysis (RPA) class I patients, patients with metastases equal to or larger than 2 cm, and lung cancer patients with squamous cell histology. However, these subset analyses were not prespecified, and the P values needed for significance should have been adjusted for inflation of type I error. When this was done, none of these subgroup analyses showed a positive benefit for stereotactic radiosurgery. So, for multiple brain metastases, this was a completely negative trial with regard to the major end points-prevention of death due to neurologic causes and overall survival.