Elsevier

The Lancet Oncology

Volume 18, Issue 8, August 2017, Pages 1040-1048
The Lancet Oncology

Articles
Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial

https://doi.org/10.1016/S1470-2045(17)30414-XGet rights and content

Summary

Background

After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone.

Methods

In this randomised, controlled, phase 3 trial, we recruited patients at a single tertiary cancer centre in the USA. Eligible patients were older than 3 years, had a Karnofsky Performance Score of 70 or higher, were able to have an MRI scan, and had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity ≤4 cm). Patients were randomly assigned (1:1) with a block size of four to either SRS of the resection cavity (within 30 days of surgery) or observation. Patients were stratified by histology of the primary tumour, metastatic tumour size, and number of metastases. The primary endpoint was time to local recurrence in the resection cavity, assessed by blinded central review of brain MRI scans by the study neuroradiologist in the modified intention-to-treat population that analysed patients by randomised allocation but excluded patients found ineligible after randomisation. Participants and other members of the treatment team (excluding the neuroradiologist) were not masked to treatment allocation. The trial is registered with ClinicalTrials.gov, number NCT00950001, and is closed to new participants.

Findings

Between Aug 13, 2009, and Feb 16, 2016, 132 patients were randomly assigned to the observation group (n=68) or SRS group (n=64), with 128 patients available for analysis; four patients were ineligible (three from the SRS group and one from the observation group). Median follow-up was 11·1 months (IQR 4·8–20·4). 12-month freedom from local recurrence was 43% (95% CI 31–59) in the observation group and 72% (60–87) in the SRS group (hazard ratio 0·46 [95% CI 0·24–0·88]; p=0·015). There were no adverse events or treatment-related deaths in either group.

Interpretation

SRS of the surgical cavity in patients who have had complete resection of one, two, or three brain metastases significantly lowers local recurrence compared with that noted for observation alone. Thus, the use of SRS after brain metastasis resection could be an alternative to whole-brain radiotherapy.

Funding

National Institutes of Health.

Introduction

Brain metastases are a tremendous health-care burden.1 Surgical resection is a mainstay of treatment for single metastases and has been shown to improve survival compared with that for whole brain radiotherapy (WBRT) alone.2 Surgical resection alone is thought to be insufficient to provide durable local control, and the addition of postoperative WBRT decreases the likelihood of recurrence within the resection cavity (local recurrence).3 Although WBRT is often considered the standard of care after surgical resection of brain metastases to improve time to local recurrence, results from studies have shown an association with cognitive decline.4, 5, 6 Consequently, its routine use has been questioned, and WBRT is now frequently withheld after resection, especially for patients with a low number of brain metastases.7, 8 As an alternative to WBRT, stereotactic radiosurgery (SRS) can be used post-operatively to deliver a high dose of targeted radiation, in one session, to the margins of the resection cavity to minimise local recurrence. Therefore, SRS should decrease local recurrence without the adverse effects of WBRT; however, only retrospective studies have been published that show the feasibility of administering post-operative SRS to the resection cavity, and its efficacy remains unknown.9, 10

Surgical techniques and adjuncts have improved substantially since the original studies of management of brain metastases by Patchell and colleagues,2, 3 with recent studies indicating that local control could be improved through more modern surgical techniques, particularly for smaller tumours.11 Our primary aim was to determine whether administering postoperative SRS to the resection cavity improved time to local recurrence compared with that for surgical resection alone.

Research in context

Evidence before this study

To our knowledge, there have been no completed randomised, controlled trials to assess the efficacy of stereotactic radiosurgery (SRS) to improve local control after surgical resection of brain metastases. Whole brain radiotherapy (WBRT) after surgical resection has been the standard of care but it is associated with cognitive deficits. Many clinicians have advocated the use of SRS after surgical resection to improve local control and avoid the cognitive side-effects of WBRT. We searched PubMed for articles published in English between Jan 1, 1980, and Dec 31, 2016, which reported the use of radiation to improve local tumour control after surgical resection of brain metastases. Search terms included “brain”, “local control”, “metastasis”, “neoplasm”, “radiation”, “surgery”, and “survival”. Numerous retrospective studies have been reported, but these are subject to various limitations. We filtered for randomised, controlled trials and identified 49 articles. We then limited the search results to studies that specifically addressed the use of radiation to increase local tumour control after surgical resection of brain metastases, which yielded three studies. All three studies evaluated the utility of WBRT in the context of surgical resection of brain metastases. No study evaluated the use of SRS after surgical resection. Therefore, level 1 evidence supporting the use of SRS to improve local control after surgical resection of brain metastases is absent. Moreover, the most recent study evaluating the use of radiation after surgical resection (using WBRT) was in 1998. Since that time, surgical techniques have evolved substantially and no recent studies have evaluated local control after surgical resection alone.

Added value of this study

The results of this trial add to the existing evidence for the management of brain metastases by showing a significant improvement in local control when SRS is used after resection of one to three brain metastases compared with that for resection alone. The results also reinforce that surgical resection alone is insufficient to provide durable local control.

Implications of all the available evidence

Our results suggest that SRS might be an alternative to WBRT for patients after surgical resection of one to three brain metastases. Future trials should explore increased radiation doses to improve local control and report outcomes with respect to quality of life.

Section snippets

Study design and participants

In this randomised, controlled, phase 3 trial, done in a single tertiary cancer institution in the USA, we enrolled patients older than 3 years with a Karnofsky Performance Score of 70 or higher who were able to have an MRI scan and who had between one and three resected brain metastases. Complete resection was verified by the study neuroradiologist. The exclusion criteria were age younger than 3 years; previous radiotherapy administered to the brain; previous resection of any brain metastasis

Results

Between Aug 13, 2009, and Feb 16, 2016, we enrolled 132 patients who had undergone resection of at least one brain metastasis between Oct 6, 2009, and Sept 1, 2015. Four patients were declared ineligible after randomisation and were excluded from the analysis: one patient had prior head and neck radiation extending into the brain; one patient's MRI result on the day of SRS revealed a residual tumour, indicating incomplete resection; one patient withdrew from the study; and one patient was

Discussion

In this randomised trial of patients undergoing surgical resection for one, two, or three brain metastases, time to local recurrence was significantly higher after post-operative SRS in the resection cavity than with observation. We also confirmed that surgical resection of brain metastases is insufficient to provide durable local control. In previous studies, the benefit of surgical resection followed by WBRT has been well described, both for improved survival and increased local tumour

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