We read with great interest the recently published Review by Chargari et al. in Nature Reviews Clinical Oncology (Whole-brain radiation therapy in breast cancer patients with brain metastases. Nat. Rev. Clin. Oncol. 7, 632–640).1 The authors discussed the challenges of treating brain metastases, the current strategies of treatment combination, and available radiation therapy techniques that improve efficacy and decrease or prevent neurological toxicity.

The article by Chargari et al.1 focuses on strategies that include whole-brain radiation therapy (WBRT) because many patients with brain metastases from breast cancer are preferentially treated with WBRT.2,3,4 In historical series, WBRT increased median overall survival time by 3–4 months versus 1 month without treatment and 2 months with corticosteroid alone.5 The most common WBRT regimen is 30 Gy delivered in 10 fractions, which is proposed for patients in recursive partitioning analysis stage III (42% of patients with metastatic breast cancer).6 Controversy still exists regarding therapeutic strategies and the impact of WBRT is still unclear. Patchell et al.7 reported that withholding upfront WBRT was associated with a significantly higher risk of cranial distant recurrence. In three randomized controlled trials comparing upfront stereotactic radiation surgery (SRS) with or without WBRT, these results were confirmed and no significant difference was reported in overall survival rates.8,9,10 Nevertheless, in the study conducted by Aoyama,6 although WBRT reduced the brain recurrence rate at 6 months in the high-risk group (extracranial metastases or multiple brain metastases) from 57% to 21%, this difference was no longer observed at 12 months. For the low-risk group (no extracranial metastases and a single brain metastasis) two-thirds of the patients had no regional brain recurrence at 12 months when they are treated by radiosurgery alone.

As underlined by Chargari et al.,1 WBRT induces severe neurotoxicity; however, this toxicity has not been comprehensively evaluated.11 An indication of the severity of this toxicity was determined using mini-mental state examination; no significant difference was reported in neurological status between the two arms in the Aoyama study (SRS with or without WBRT).8 Furthermore, a randomized controlled trial conducted by the MD Anderson Cancer Center assigned cognitive performance as a primary end point.11 In patients with one to three brain metastases, a significant difference in memory decline at 4 months after treatment was reported; a larger proportion of patients who received SRS and upfront WBRT (49%) had a memory decline than those who received SRS alone (20%).11

The protection of organs at risk, such as the hippocampus, temporal lobes and frontal lobes, is one major challenge facing radio-oncologists. In this context, using upfront SRS alone could be proposed to remove the risk of late neurotoxicity from WBRT. In a series of patients with metastatic breast cancer with brain metastases, the median survival time was 17.1 months for the group treated with SRS alone versus 15.9 months for SRS and upfront WBRT. No significant difference was observed in terms of 1-year and 2-year new-brain-metastasis-free survival and median time-to-brain-metastasis-progression after salvage therapy.12 Using a follow-up MRI scan of the brain, up to 80% of brain regional recurrence could be detected before the occurrence of clinical symtoms.8 In this context MRI can be used to indicate the requirement for early treatment using radiosurgery and for delaying WBRT. We believe this point should have been discussed by Chargari et al.,1 in particular with respect to patients in a favorable diagnosis-specific graded prognostic assessment group (median overall survival time 15–18 months).13

Finally, we are totally in agreement with Chargari et al.1 that a multidisciplinary approach to integrate surgery, WBRT and radiosurgery, chemotherapy and targeted therapy offers the best way forward to preserve neurocognitive function and quality of life while maintaining treatment efficacy.