SABR May Provide New Hope for Patients With ‘Incurable’ Metastatic Cancers

metastatic cancers; SABR; ASTRO 2018: metastatic cancers; SABR; ASTRO 2018SAN ANTONIO—New evidence indicates that aggressive high-precision radiotherapy can prolong survival and cancer-free survival in patients with various advanced cancer types once thought to be beyond therapeutic rescue. These findings have come from the first randomized, phase II clinical trial of its kind using stereotactic ablative radiotherapy/stereotactic body radiation therapy (SABR). At a news briefing following a presentation at the plenary session at the American Society for Radiation Oncology (ASTRO) Annual Meeting, the investigator in the open-label phase II SABR-COMET trial at multiple sites across four countries revealed that SABR delivered in just one or several treatment sessions extended survival by a median of 13 months in multiple cancer types and doubled progression-free disease, on average by 1 year (Abstract 5). This compared with a median extended survival rate of only 6 months in patients treated with standard radiotherapy, said David Palma, MD, PhD, Assistant Professor of Radiation Oncology at the Lawson Health Research Institute of London (Ontario) Health Sciences Centre (LHSC), and a clinician-scientist at the Ontario Institute for Cancer Research, which also funded the study. The LHSC is a network of hospitals throughout Ontario and collectively represents one of Canada's largest acute care networks. “We were surprised and quite pleased. We didn't expect the survival benefit to be quite so long for patients with metastatic disease,” Palma said. “Traditionally, when a patient had a cancer that spread to other parts of their body, such as to the bones or brain, they have been considered incurable.” He explained that “oligometastatic theory” hypothesizes that if a patient only has a few small areas of cancer return, these can successfully be killed with radiation or surgery to improve survival. “Now, we've been able to show, for the first time in a randomized trial, that high-dose radiation can effectively treat such limited recurrences.” The trial included 99 patients from Canada, Scotland, the Netherlands, and Australia whose cancer returned after treatment and spread to as many as five different sites. All of the subjects had good performance status, with life expectancies of 6 months or more upon enrollment. Among the subjects, 18 had cancer of the breast or lung, and the same number with cancers of the lung, colon, or rectum, and 16 had prostate cancer. In almost all of the patients, cancer had spread to between one and three new sites. Methodology, Other Findings The subjects were randomized into two treatment arms, at a 1:2 ratio, and underwent treatment between 2012 and 2016. All patients were treated again with a median follow-up of 27 months. The two treatment groups received either current palliative standard-of-care (SOC) radiotherapy, or SOC plus SABR therapy for all metastatic lesions. Their median age was 68 years and ranged from 49 to 89 years. Just over half of the patients were men and there were very few differences in baseline clinical characteristics. For those in the SABR group, median overall survival was 41 months versus 28 months for those in the SOC-alone arm, and progression-free survival was 12 months in the SABR patients compared to 6 months in the SOC radiotherapy group. Six months after treatment, the patients completed the Functional Assessment of Cancer Therapy General (FACT-G) questionnaire. There were very few between-group differences in quality-of-life (QOL) scores, or major differences in functional, emotional, physical, and social outcomes scores. SABR patients had a median QOL score of 82.5, while the average score in the SOC group was 82.6. SABR did however result in more negative severe side effects. While only 9 percent of patients in the SOC arm experienced grade 2 or worse side effects after treatment, serious events occurred in 30 percent of the SABR patients, including three deaths. The most common side effects in the SABR arm were fatigue in 10 patients, dyspnea in nine subjects, six others reported muscle and joint pain, while another seven patients reported unspecified pain. The deaths included one patient who suffered a pulmonary abscess and another from a subdural hemorrhage following surgery to repair a SABR-related perforated gastric ulcer. The third died from treatment-related radiation pneumonitis. Although these are also possible after treatment with SOC radiotherapy, Palma said that such occurrences are, in general, considered rare. SABR needs to be delivered “carefully and by an experienced team,” he emphasized. “Although the overall risk of very serious adverse events is small, for patients whose cancers have spread to several sites and who are not expected to survive, the overall survival benefit of SABR appears to outweigh these risks.” Some patients developed additional lesions during the trial and, when this occurred, these new tumors could sometimes be successfully ablated, he reported. However, because these involved a greater number of sites, the investigators are now planning a follow-up study—called SABR-COMET-10—that will enroll patients with up to 10 metastatic lesions. The upper limit of how many tumors can be safely treated with SABR is unknown, Palma noted. “The concern is the amount of radiation exposure a patient can tolerate. We don't know yet what the safe boundaries are. We've been very conservative, as this is a new technology.” Despite the adverse events that occurred in this study, 46 percent of subjects in the SABR arm were still alive after 5 years, compared to 24 percent in the control group. Palma noted that because such risks are relatively small, more physicians should consider offering SABR as an option for their patients who develop metastatic tumors after initial treatment. Next Step Robert Olson, MD, Associate Professor and Division Head of Radiation Oncology in the Department of Surgery at the University of British Columbia, also explained the findings and said that prior to SABR-COMET-10 there will be another trial. It is important, he noted, that patient accrual in the SABR-COMET trial was broad and not simply limited to only the fittest patients. Olsen is also department head at BC Cancer–Prince George. “In fact, the first patient accrued in BC was treated at the relatively small BC Cancer–Centre for the North,” he said. “The inclusion of patients with a variety of cancer types and treatments of different sizes increases our ability to generalize, or apply the findings, to a broad set of patients in the future,” Olson noted. “I believe that SABR should continue to be delivered in the setting of clinical trials. The primary purpose of this phase II trial is to provide evidence to proceed to a larger randomized phase III trial, which will ultimately provide definitive evidence for the use of SABR in the metastatic setting.” Olson is leading the first follow-up trial titled SABR-COMET-3, which will include patients with cancers that have spread to three sites. The trial will be ready to open in spring or summer 2019, and will initially open in BC and expanded shortly thereafter to several international sites. Commentary In an email to Oncology Times, James B. Yu, MD, Associate Professor of Therapeutic Radiology at Yale School of Medicine and Director of Prostate and Genitourinary Cancer Radiotherapy at the Yale Cancer Center, both in New Haven, Conn., commented on the findings. He said the SBAR-COMET provides “some very exciting implications for patients with metastatic disease, especially if they have only spread to a limited number of sites. “I can envision a future where ever more sophisticated molecularly targeted therapies and immunotherapies, combined with precisely targeted and non-invasive radiosurgery, might lead to the cure of many metastatic disease sites that have until now been considered untreatable in so many patients. “There will always be a role for locally directed therapy, and as radiosurgery gets ever more precise, together with better patient tracking and tumor visualization, and easier to plan and deliver using artificial intelligence-improvements in radiation treatment planning, I believe treatment of multiple lesions will become commonplace.” Kurt Samson is a contributing writer.

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