Comparative effectiveness of stereotactic radiosurgery versus whole‐brain radiation therapy for patients with brain metastases from breast or non–small cell lung cancer

In Cancer, Halasz et al report a multi-institutional, retrospective cohort study of patients undergoing either stereotactic radiosurgery (SRS) or whole-brain radiation therapy (WBRT) for the treatment of brain metastasis. The authors report that compared with WBRT, SRS alone nearly doubled overall survival among patients with fewer than 4 non–small cell lung cancer (NSCLC; hazard ratio, 0.58; P 5 .01) or breast cancer brain metastases (hazard ratio, 0.54; P 5 .02). Although these data are encouraging, we have several concerns regarding the study design and interpretation. Most significantly, the Karnofsky performance status (KPS), a prognosticator incorporated into well-accepted prognostic assessments, was not available at the time of diagnosis of brain metastasis. In an attempt to control for this limitation, the authors assumed that the proportion of patients with a KPS score< 70 who were treated with WBRT was 2.3 times greater than the proportion of patients treated with SRS alone on the basis of a subset analysis; the validity of this assumption is questionable. Then, extrapolating from the recursive partitioning analysis, the authors divided median survival between patients with a KPS score 70 and patients with a KPS score< 70 to arrive at a hazard ratio of 2.13; this unconventional methodology significantly limited the following sensitivity analysis. Our institutional practice is to treat patients who are candidates for SRS with local therapy and to reserve WBRT for patients who present with a poor KPS score, need urgent treatment, or present with many metastases. This paradigm would not yield generalizable hazard ratios across institutions and investigations. Drawing from a population of 787 patients, the authors selected a population of 189 NSCLC patients and 117 breast cancer patients with fewer than 4 metastases. Among these patients with NSCLC and breast cancer, 9% and 28%, respectively, did not undergo magnetic resonance imaging but were nonetheless included. If magnetic resonance imaging utilization was not balanced between the SRS and WBRT cohorts, patients treated with WBRT may have had a greater number of brain metastases than that detected with computed tomography. Chi-square tests were then used to assess balance between the cohorts, but standardized differences were not reported. The authors asserted that “the comparator groups were well matched for all covariates aside from the number of brain metastases, the size of the largest brain metastasis, and the institution. ” Among patients with NSCLC, 69% had a single metastasis and underwent SRS, whereas 46% did in the WBRT cohort (P 5 .001). In the breast cancer cohort, this difference was 48% versus 32% (P 5 .11). Because the number of brain metastases is a well-described prognosticator for survival, this difference may itself be responsible for the observed survival benefit. Moreover, the median size of the largest metastasis was greater in each WBRT cohort; intracranial tumor volume (rather than number alone) has been associated with survival, and this further biased the authors’ findings. One must also consider that P values derived from chi-square tests are not surrogates for cohort balance, particularly in small studies. Although the aforementioned statistically significant differences were noted, several other critical differences were present. These included a greater proportion of extracranial disease in the NSCLC cohort receiving WBRT, more modern patients in both SRS cohorts, and more hormone receptor–positive and human epidermal growth factor receptor 2–amplified patients in the breast cancer cohort receiving SRS. Despite these differences, the authors accepted these cohorts as comparable. Because a complete multivariate propensity score–adjusted model was not reported, it is unclear whether modeling meaningfully accounted for the imbalance. After using standardized mortality ratios to estimate the benefit of SRS in the WBRT cohorts, the authors concluded that SRS would have more than tripled survival in the NSCLC cohort and doubled survival in the breast cancer cohort. Given these differences between the cohorts, we should interpret these provocative results with caution. Although there are data suggesting a survival benefit with the omission of WBRT in select circumstances, this remains controversial. Sahgal et al reported a metaanalysis of 3 phase 3 trials randomizing patients to SRS and WBRT or to SRS alone. A survival benefit was observed among patients who were 50 years old or younger and were treated with SRS alone. As Halasz et al acknowledge, this comparison is incongruent for SRS versus WBRT alone, for which no randomized data are available. In a randomized population, the neurocognitive detriment of WBRT might affect KPS and quality of life and