Elsevier

The Lancet Oncology

Volume 18, Issue 8, August 2017, Pages 1049-1060
The Lancet Oncology

Articles
Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(17)30441-2Get rights and content

Summary

Background

Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis.

Methods

In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12–20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774.

Findings

Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1–18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45–5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86–3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35–0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS vs 41 [85%] of 48 evaluable patients assigned to WBRT; difference −33·6% [95% CI −45·3 to −21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7–16·0, 69 deaths) for SRS and 11·6 months (9·9–18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76–1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group vs eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] vs five [5%]). There were no treatment-related deaths.

Interpretation

Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population.

Funding

National Cancer Institute.

Introduction

20–40% of patients with cancer develop brain metastases, and therefore management of this condition has a tremendous impact on health-care systems, patients, and their families.1 Brain metastases are often surgically resected, especially for large lesions with mass effect (ie, a tumour can cause damage by pushing or shifting brain tissue), improving survival in some patient populations.2 However, recurrence in the surgical bed is common following resection alone.

Findings from prospective trials have shown that postoperative, adjuvant, whole brain radiotherapy (WBRT) reduces the risk of recurrence in the surgical bed and also reduces the incidence of new metastases.3, 4 Although adjuvant WBRT improves intracranial control, it has no substantiated survival benefit and has detrimental effects on quality of life and cognitive function.5 To avoid the toxic effects of WBRT, there is a growing practice to treat the surgical bed with stereotactic radiosurgery (SRS): precise delivery of large, highly focused doses of radiation, which is an established and effective treatment for brain metastases although its efficacy compared with WBRT in the postoperative setting is unproven.6 Findings from the only study to directly address comparative efficacy for neurological or cognitive failure did not show non-inferiority of SRS compared with WBRT in the postoperative setting, and showed worse survival in the SRS treatment group than in the WBRT group.7

Research in context

Evidence before this study

Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control after resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the lack of high-level comparative data substantiating efficacy in the postoperative setting. We searched PubMed and the abstracts of major conferences (such as the American Society of Clinical Oncology and American Society for Radiation Oncology) using the terms “brain metastases”, “irradiation (or radiotherapy)”, “radiosurgery”, and “surgery (or resection)”, with no language restrictions, and with no constraints imposed on the timeframe for the search, for randomised evidence to support this practice. We found only one relevant randomised clinical trial. The trial was underpowered and did not demonstrate non-inferiority of SRS compared with WBRT for neurological or cognitive failure in the postoperative setting.

Added value of this study

To our knowledge, this study is the only adequately powered randomised clinical trial directly comparing SRS with WBRT, the standard of care in the postoperative setting. Additionally, this trial assesses both quality of life and cognitive function, which are especially important endpoints in this patient population given the absence of a substantiated given the absence of a substantiated survival advantage with adjuvant radiotherapy.

Implications of all the available evidence

The combined evidence suggests that SRS to the surgical cavity results in no significant difference in survival and improved preservation of quality of life and cognitive outcomes compared with WBRT. Taken in context with other phase 3 trials assessing SRS to the surgical bed, the implication for clinical care is that SRS in the postoperative setting is a viable treatment option to improve surgical bed control and should be considered a standard of care and a less toxic alternative than WBRT. The implication for future research is that continued refinement of the SRS technique, such as fractionated or preoperative radiosurgery, is needed to further improve outcomes such as surgical bed control.

To address these knowledge gaps, we investigated the role of adjuvant SRS compared with WBRT in patients with one resected brain metastasis.

Section snippets

Study design and participants

N107C/CEC·3 was a randomised, controlled, phase 3 trial enrolling patients from 48 institutions in the USA and Canada (appendix p 15). Adult patients (18 years of age or older) with one resected metastatic brain lesion and a resection cavity measuring less than 5·0 cm in maximal extent were eligible for the trial. Up to three unresected metastases (each <3 cm in maximal extent) were allowed. Eligibility criteria included Eastern Cooperative Oncology Group performance status 0–2 and pathology

Results

Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS to the surgical bed (98 patients; five patients did not receive treatment) or WBRT (96 patients; 49 patients received 30 Gy in 10 fractions, 43 received 37·5 Gy in 15 fractions, and four patients did not receive treatment; figure 1). There was one major protocol violation (one patient randomly assigned to the SRS group, whose treatment was switched by the site, received WBRT). Median follow-up was

Discussion

In this multicentre, randomised, controlled, phase 3 study, patients receiving SRS to the surgical cavity had improved cognitive function and quality of life compared with patients receiving WBRT, with no difference in overall survival; intracranial tumour control was better in patients receiving WBRT than SRS. To our knowledge, no large, randomised, controlled trial has compared SRS with WBRT, the standard of care after resection of brain metastases, and simultaneously assessed both quality of

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