Elsevier

The Lancet

Volume 393, Issue 10185, 18–24 May 2019, Pages 2051-2058
The Lancet

Articles
Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial

https://doi.org/10.1016/S0140-6736(18)32487-5Get rights and content

Summary

Background

The oligometastatic paradigm suggests that some patients with a limited number of metastases might be cured if all lesions are eradicated. Evidence from randomised controlled trials to support this paradigm is scarce. We aimed to assess the effect of stereotactic ablative radiotherapy (SABR) on survival, oncological outcomes, toxicity, and quality of life in patients with a controlled primary tumour and one to five oligometastatic lesions.

Methods

This randomised, open-label phase 2 study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia. Patients aged 18 or older with a controlled primary tumour and one to five metastatic lesions, Eastern Cooperative Oncology Group score of 0–1, and a life expectancy of at least 6 months were eligible. After stratifying by the number of metastases (1–3 vs 4–5), we randomly assigned patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus SABR to all metastatic lesions (SABR group), using a computer-generated randomisation list with permuted blocks of nine. Neither patients nor physicians were masked to treatment allocation. The primary endpoint was overall survival. We used a randomised phase 2 screening design with a two-sided α of 0·20 (wherein p<0·20 designates a positive trial). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, number NCT01446744.

Findings

99 patients were randomised between Feb 10, 2012, and Aug 30, 2016. Of 99 patients, 33 (33%) were assigned to the control group and 66 (67%) to the SABR group. Two (3%) patients in the SABR group did not receive allocated treatment and withdrew from the trial; two (6%) patients in the control group also withdrew from the trial. Median follow-up was 25 months (IQR 19–54) in the control group versus 26 months (23–37) in the SABR group. Median overall survival was 28 months (95% CI 19–33) in the control group versus 41 months (26–not reached) in the SABR group (hazard ratio 0·57, 95% CI 0·30–1·10; p=0·090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SABR group (p=0·026), an absolute increase of 20% (95% CI 5–34). Treatment-related deaths occurred in three (4·5%) of 66 patients after SABR, compared with none in the control group.

Interpretation

SABR was associated with an improvement in overall survival, meeting the primary endpoint of this trial, but three (4·5%) of 66 patients in the SABR group had treatment-related death. Phase 3 trials are needed to conclusively show an overall survival benefit, and to determine the maximum number of metastatic lesions wherein SABR provides a benefit.

Funding

Ontario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant.

Introduction

Historically, the treatment of patients with metastatic solid tumours has been based on systemic therapies that aim to delay progression and extend life, but not to eradicate the disease completely.1, 2 The oligometastatic paradigm, formally defined in the 1990s3 but anecdotally reported as early as the 1930s,4 suggests that in some patients, metastatic disease is not widespread, but is constrained to develop in only a small number of sites because of anatomical and physiological factors.3 This paradigm suggests that patients with oligometastases should be amenable to a curative treatment approach.3

Clinical evidence to support improved treatment outcomes in the oligometastatic state has generally been limited to non-randomised observational studies.5 Many of these studies, but not all, suggest that the treatment of oligometastatic disease with ablative therapies can lead to better-than-expected survival, compared with a general population of patients with metastatic disease.6, 7 However, these promising results could be due to selection bias, with the inclusion of fit patients with low-burden, indolent cancers.5, 7 Nevertheless, the use of ablative therapies has increased in many jurisdictions worldwide, albeit with substantial geographical variability in practice.8, 9 Interest in treating oligometastatic disease is also increasing because of improvements in systemic therapy, as has been observed with molecular targeted therapies10 and immune checkpoint inhibitors.11

Research in context

Evidence before this study

Several recent systematic reviews examined the effect of ablative therapies in patients with oligometastatic cancers. No previous randomised trials were identified in patients with oligometastases, in which the primary endpoint was a comparison of overall survival between an ablative treatment group (eg, stereotactic ablative radiotherapy [SABR] or surgery) and a group that did not receive ablative therapy. In patients with one to nine hepatic metastases from colorectal cancer, a secondary analysis of a randomised trial assessing systemic therapy with or without radio-frequency ablation showed an overall survival benefit with the use of radio-frequency ablation to all hepatic lesions. Three randomised trials using surrogate endpoints, such as progression-free survival, have shown benefits of ablative therapies in oligometastatic prostate and lung cancers. Findings are based on a search of PubMed from inception to Aug 1, 2018, using search terms related to “oligometastatic” (eg, “limited metastatic”, “solitary metastasis”, and “oligometastatic”), and common cancer types (eg, “breast cancer”, “prostate cancer”, and “lung cancer”), limited to English language randomised trials. A similar search for systematic reviews was undertaken and their reference lists were hand-searched.

Added value of this study

This study found that the use of SABR in patients with controlled primary tumours and one to five oligometastases achieved a 13-month improvement in overall survival, with a doubling of progression-free survival, at the cost of increased risk of toxicity, including a 4·5% risk of grade 5 toxicity. These findings represent the strongest level of evidence, thus far, in support of the existence of an oligometastatic state.

Implications of all the available evidence

Although further trials are needed, the emerging evidence supports the existence of an oligometastatic state, and that patients with a limited number of metastases might be amenable to curative-intent treatment strategies.

Stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiation therapy, is a modern radiation technique that delivers high doses of radiation to small tumour targets with use of highly conformal techniques (appendix p 2).12 SABR is non-invasive, delivered on an outpatient basis, and is used to target lesions in the lungs, brain, liver, adrenals, and bone, among other locations.

To our knowledge, the oligometastatic paradigm has not been directly tested before in a randomised trial; namely, no trial has evaluated whether eradicating oligometastases that have propagated through the systemic circulatory system improves overall survival. In this randomised controlled trial, we aimed to assess standard of care palliative treatments with or without SABR in patients with a controlled primary tumour and up to five metastatic lesions.

Section snippets

Study design and participants

The Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastases (SABR-COMET) trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2 randomised study. Patients were enrolled at ten hospital centres located in Canada, the Netherlands, the UK, and Australia.

Patients were required to be aged 18 years or older, with good performance status (Eastern Cooperative Oncology Group score 0–1), and a life expectancy of at least 6

Results

Between Feb 10, 2012, and Aug 30, 2016, 99 patients were enrolled at ten centres; 33 were randomly assigned to the control group and 66 to the SABR group (figure 1). It was not possible to capture the number of patients assessed for eligibility, because referring physicians were able to discuss cases with participating investigators on an ad-hoc basis without formal referral, and such discussions were not tracked. Baseline characteristics are shown in table 1. The SABR group had a preponderance

Discussion

The use of ablative treatments in patients with oligometastatic cancers has been the subject of substantial debate.5 Although the use of metastasis-directed surgery and stereotactic radiation has increased in the past 10–15 years,8, 9 the reliance on single-arm data of well selected patients without adequate controls has led to suggestions that the use of ablative treatments might be futile.16, 17 The main findings of the present study are that SABR was associated with a 13-month improvement in

Data sharing

The trial protocol did not include a data sharing plan, and therefore data from the trial will not be shared publicly as sharing was not included in the ethical approvals.

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