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November 1, 2006

Radiosurgery Plus Whole-Brain Radiation Therapy for Brain Metastases

Author Affiliations

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2006;296(17):2089-2091. doi:10.1001/jama.296.17.2089

To the Editor: Dr Aoyama and colleagues1 studied stereotactic radiosurgery (SRS) with and without whole-brain radiation therapy (WBRT) for treatment of brain metastases. We think that the appropriate conclusions from this study are different from those drawn by the authors and by Dr Raizer2 in the accompanying Editorial.

In this study, the addition of WBRT to SRS significantly reduced the number of recurrent brain metastases without increasing survival. Omitting WBRT did not produce any difference in neurocognitive functioning. From these data, the authors concluded that WBRT is not necessary and can be safely omitted. However, as noted by the authors, the main reason for omitting WBRT is to avoid the long-term neurotoxic effects. Yet there was no difference between the 2 groups with regard to neurological or neurocognitive functioning, radiation-induced adverse effects, or survival times. Although the rate of deterioration in neurological function was the same in both groups (22/65 in the WBRT group vs 21/67 in the SRS-alone group), the number for whom this was attributable to progression of brain metastases was actually lower in the WBRT group (13/22 [59%]) than in the SRS-alone group (18/21 [86%]) (P = .05). Whole-brain radiation therapy therefore appears to significantly reduce the number of recurrences of brain metastases without demonstrable neurotoxic effects. Therefore, the trial supports the use of WBRT as up-front treatment for brain metastases.

We have more fundamental concerns about the use of survival as the primary end point. Randomized trials for patients with multiple brain metastases have not shown a significant difference in survival based on different treatments. Only patients with single brain metastases have benefited in terms of survival from aggressive local therapy.3,4 To establish whether WBRT could be safely omitted, the trial should have been designed to demonstrate that SRS alone is not inferior to SRS plus WBRT. We estimate that the sample size required for this analysis would be 2250 (assuming the observed survival results of 8.0 months for the SRS-alone group vs 7.5 months for the WBRT group, a clinically significant difference of 1.2 months, and a 1-sided α level of .025 [SAS version 8.2, SAS Institute Inc, Cary, NC]). This study was underpowered and therefore unable to reach any conclusions about treatment equivalence.

We believe that the best currently available class 1 evidence1,35 indicates that most patients with multiple brain metastases should be treated with WBRT alone up front. Patients with single metastases should receive focal treatment with either conventional surgery or SRS, and WBRT should be given as adjuvant therapy in the majority of cases.

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Article Information

Financial Disclosures: None reported.

Aoyama H, Shirato H, Tago M.  et al.  Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for the treatment of brain metastases: a randomized controlled trial.  JAMA. 2006;295:2483-2491PubMedArticle
Raizer J. Radiosurgery and whole-brain radiation therapy for brain metastases: either or both as the optimal treatment.  JAMA. 2006;295:2535-2536PubMedArticle
Vecht CJ, Haaxma-Reiche H, Noordijk EM.  et al.  Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery.  Ann Neurol. 1993;33:583-590PubMedArticle
Andrews DW, Scott CB, Sperduto PW.  et al.  Whole brain radiation therapy with and without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomized trial.  Lancet. 2004;363:1665-1672PubMedArticle
Patchell RA, Tibbs PA, Regine WF.  et al.  Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial.  JAMA. 1998;280:1485-1489PubMedArticle