IN PATIENTS with a controlled primary tumor and up to 5 oligometastatic lesions, delivering stereotactic ablative radiotherapy was associated with a 13-month improvement in overall survival when compared with palliative standard-of-care treatments alone (41 months vs 28 months; P = .09).1
According to the results of the first randomized, phase II clinical trial of its kind, progression-free survival in patients receiving stereotactic ablative radiotherapy in addition to standard-of-care treatment was also doubled vs the standard of care alone (6.0 months vs 12 months; P = .001). Although toxicities were more common in the stereotactic ablative radiotherapy group, with a 4.5% risk of treatment-related death, the investigators reported no decrease in patients’ quality of life.
David Palma, MD, PhD
“To our knowledge, these findings represent the strongest clinical evidence available in support of the oligometastatic state across multiple tumor types,” said David Palma, MD, PhD, a radiation oncologist at the London Health Sciences Centre and a clinician-scientist with the Ontario Institute for Cancer Research, who presented these study results at the 2018 Annual Meeting of the American Society for Radiation Oncology (ASTRO). “To the best of our knowledge, this is a higher level of evidence than exists for any surgical intervention for oligometastatic disease.”
As Dr. Palma explained, the treatment of patients with metastatic solid tumors has historically been based on systemic therapies, which aim to delay disease progression and extend life but not to eradicate the disease completely. Anecdotally reported as early as the 1930s, however, the oligometastatic paradigm suggests that patients with a limited number of metastases should be amenable to a curative treatment approach—if all sites of disease are eradicated with ablative therapies, such as surgery or radiation.
“Despite compelling anecdotal evidence, the oligometastatic paradigm has not been directly tested before in a randomized trial,” said Dr. Palma. “Specifically, there are no completed randomized controlled trials with a primary endpoint comparing overall survival between any ablative approach, whether it’s surgery or stereotactic ablative radiotherapy vs a palliative approach.”
For this phase II study, Dr. Palma and colleagues enrolled patients who had a controlled primary malignancy with 1 to 5 metastatic lesions (all of which were amenable to stereotactic ablative radiotherapy) with a good performance status (Eastern Cooperative Oncology Group 0–1) and a life expectancy of more than 6 months. The researchers stratified patients by the number of metastases (1–3 vs 4–5) and then randomly assigned them to receive either palliative standard-of-care treatments (arm 1) or standard of care plus stereotactic ablative radiotherapy to all metastatic lesions (arm 2). The primary endpoint was overall survival. Secondary endpoints included progression-free survival, toxicity, and quality of life (assessed using the Functional Assessment of Cancer Therapy: General).
Improvement in Survival
A TOTAL of 99 patients were included between February 2012 and August 2016 at centers in Canada, Scotland, the Netherlands, and Australia. The median age was 68, and 59% of patients were men. The most common primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18), and prostate (n = 16); however, the authors noted that the majority of patients with prostate cancer were enrolled in the experimental arm. In addition, although most patients (n = 92) had 1 to 3 metastases, all patients with 5 metastases (n = 3) were treated with stereotactic ablative radiotherapy. The median follow-up was 27 months.
“It’s up to clinicians now to decide whether a clear and definitive progression-free survival benefit is enough to treat, but I’d argue that there is ample precedent in oncology.”— David Palma, MD, PhD
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In patients treated with stereotactic ablative radiotherapy, the median overall survival improved from 28 months to 41 months (P = .09), meeting the primary endpoint of the trial. Progression-free survival also doubled from 6.0 months in the standard-of-care arm to 12.0 months in the experimental arm (P = .001). In addition, progression-free survival beyond 4 years jumped from 0% to 16% in patients receiving stereotactic ablative radiotherapy.
“Progression-free survival in the stereotactic ablative radiotherapy arm is an underestimation of the number of patients who are alive without disease, because eight patients in the experimental arm whose disease progressed received salvage stereotactic ablative radiotherapy after disease progression,” Dr. Palma added.
Nevertheless, side effects occurred more frequently in the stereotactic ablative radiotherapy group, with 30% of patients experiencing grade 2 or higher treatment-related adverse events vs 9% in the standard-of-care arm. The most common grade 2 or higher toxicities in the experimental arm were fatigue (n = 10), dyspnea (n = 9), muscle and joint pain (n = 7), bone pain (n = 6) or pain not otherwise specified (n = 7). There were also three treatment-related deaths in patients undergoing stereotactic ablative radiotherapy. Despite the increased toxicity in the experimental arm, however, researchers observed no differences in quality-of-life measures.
Moreover, Dr. Palma noted several limitations to the study, including the lack of diagnosis-specific data and pragmatic selection of systemic agents. It was impossible to mandate specific systemic therapy, said Dr. Palma, given the multiple disease sites and expected changes in standard of care over time. Moreover, given the phase II trial design, overall survival results are not definitive.
“These outcomes exceeded our expectations, but at 3 years and beyond, there are still a lot of patients alive and at risk who were censored, particularly in the experimental arm,” said Dr. Palma, who noted that the investigators have amended the study to follow patients for 10 years. “It’s up to clinicians now to decide whether a clear and definitive progression-free survival benefit is enough to treat, but I’d argue that there is ample precedent in oncology.”
SABR-COMET 3, a phase III randomized controlled trial for patients with controlled primary tumor and one to three metastatic lesions, is currently being evaluated for funding and confirmation of overall survival benefit study. SABR-COMET 10, a phase III randomized controlled trial for patients with a primary tumor and 4 to 10 metastatic lesions, is expected to open soon.
‘Great Opportunity’ for Radiation Oncology
Robert Timmerman, MD
ROBERT TIMMERMAN, MD, Professor of Radiation Oncology and Neurosurgery at the University of Texas Southwestern Medical Center, in Dallas, expressed excitement about the results of the study but noted that more diagnosis-specific data are needed to confirm that stereotactic ablative radiotherapy is indeed standard of care for patients in the clinic.
“The results of SABR-COMET have provided strong evidence that the oligometastatic state exists and can be affected by local therapy, even though it’s a systemic disease,” said Dr. Timmerman. “This metastatic state constitutes an opportunity to greatly expand the scope of radiotherapy. However, diagnosis-specific randomized clinical trials are desperately needed to convince pragmatic clinicians, who will ultimately send us these patients.”
“For the sake of our patients, I ask you to put more meaningful effort into enrolling patients on these randomized clinical trials, which could transform the field while ensuring competence that we can deliver these treatments safely,” Dr. Timmerman concluded. ■
DISCLOSURE: Drs. Palma and Timmerman reported no conflicts of interest.
REFERENCE
1. Palma DA, Olson RA, Harrow S, et al: Stereotactic ablative radiation therapy for the comprehensive treatment of oligometastatic tumors (SABR-COMET): Results of a randomized trial. 2018 ASTRO Annual Meeting. Abstract 5. Presented October 22, 2018.
