Two separate randomized trials presented at the 58th Annual Meeting of the American Society of Radiation Oncology (ASTRO) affirmed the value of stereotactic radiosurgery as an option for postoperative treatment of the surgical cavity of resected brain metastases, potentially avoiding the cognitive toxicity associated with the standard of care, whole-brain radiotherapy.1,2 Neither trial showed an improvement in survival for stereotactic radiosurgery or whole-brain radiotherapy. The main advantage of stereotactic radiosurgery appears to be better cognitive function and quality of life compared to the historic standard of whole-brain radiotherapy.
Stereotactic Radiosurgery vs Whole-Brain Radiotherapy
The first study was a phase III trial that compared postoperative stereotactic radiosurgery and whole-brain radiotherapy.1 Stereotactic radiosurgery achieved comparable survival rates to those with whole-brain radiotherapy but had less cognitive toxicity and improved quality of life.
Radiosurgery to the surgical cavity after resection of brain metastases should be considered a standard of care and a less toxic alternative than the historic standard of care, whole-brain radiotherapy.— Paul D. Brown, MD
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In retrospective studies, stereotactic radiosurgery achieved local control rates of 80% to 90%. Stereotactic radiosurgery technology is widely available, and its use to the surgical cavity is growing, but there has been no level I efficacy data in the postoperative setting, explained lead author Paul D. Brown, MD, of the Mayo Clinic, Rochester, Minnesota.
“Stereotactic radiosurgery to the surgical cavity is widely used despite the lack of clinical trials to substantiate its effectiveness. Our multi-institutional trial is the first to demonstrate clearly the efficacy of stereotactic radiosurgery compared to whole-brain radiotherapy in a postoperative setting,” said Dr. Brown.
The trial was conducted from 2011 to 2015 at 48 institutions in North America and included 194 patients with 1 resected brain metastasis and up to 3 unresected brain metastases. Patients were randomized to receive either stereotactic radiosurgery to the surgical bed or whole-brain radiotherapy after surgical resection of one lesion. Unresected brain metastases were treated with radiosurgery. Patients were randomized to receive either stereotactic radiosurgery or whole-brain radiotherapy after surgical resection of one lesion. A total of 77% of patients had a single brain metastasis, and lung cancer was the most common primary site of cancer (59% of patients). The mean age was 61 years, and both arms were well balanced for demographic and clinical characteristics.
At a median follow-up of 18.7 months, overall survival rates were not significantly different in the two treatment arms: 11.3 months with stereotactic radiosurgery and 11.8 months with whole-brain radiotherapy.
On the plus side, stereotactic radiosurgery allowed patients to enjoy a significantly longer time without cognitive decline, as measured by cognitive deterioration–free survival: Median cognitive deterioration–free survival was 3.2 months for stereotactic radiosurgery and 2.8 months for whole-brain radiotherapy (P < .0001).
Cognitive deterioration persisted over time in patients treated with whole-brain radiotherapy. At 6 months, the rate of cognitive deterioration–free survival was 5.4% with whole-brain radiotherapy vs 22.9% with stereotactic radiosurgery (P = .0012). A higher percentage of those receiving whole-brain radiotherapy experienced worse immediate recall, memory, and attention compared with those treated with stereotactic radiosurgery.
Intracranial tumor control rates were improved with whole-brain radiotherapy: At 3 months, the intracranial tumor control rate was 89.4% with whole-brain radiotherapy vs 72.5% with stereotactic radiosurgery, and 6-month control rates were 78.3% with whole-brain radiotherapy vs 53.6% with stereotactic radiosurgery (P < .01). Surgical bed relapse–free survival was similar in the two treatment arms, but long-term outcomes favored whole-brain radiotherapy.
“These results should be balanced with better quality of life in the stereotactic radiosurgery group,” Dr. Brown explained. At 3 months, the stereotactic radiosurgery group experienced smaller decrements in quality of life and physical well-being from baseline compared with whole-brain radiotherapy (P = .002). Physical well-being remained significantly better for stereotactic radiosurgery patients at 6 months as well (–3.1 vs –15.1 for whole-brain radiotherapy, P = .014).
“Our results confirm that radiosurgery to the surgical cavity is a viable treatment option to improve local control with less impact on cognitive function and quality of life compared to whole-brain radiotherapy. There is no significant difference in survival between stereotactic radiosurgery and whole-brain radiotherapy, and radiosurgery avoids the well-known toxicities of whole-brain radiotherapy. Further, due to less time commitment and a quicker recovery after stereotactic radiosurgery, patients can restart systemic therapies more rapidly. Radiosurgery to the surgical cavity after resection of brain metastases should be considered a standard of care and a less toxic alternative than the historic standard of care, whole-brain radiotherapy,” Dr. Brown stated.
Stereotactic Radiosurgery vs Observation Alone
At this time, the lack of a benefit in survival or distant brain metastases limits our ability to conclude there is an obvious clinical benefit [from postoperative stereotactic radiosurgery].— Anita Mahajan, MD
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The second study compared stereotactic radiosurgery to the postoperative surgical cavity with surgical resection alone (observation). “The idea was to delay or avoid whole-brain radiotherapy and its deleterious effects on cognition, as well as other disturbing side effects,” explained lead author Anita Mahajan, MD, of MD Anderson Cancer Center, Houston. The most disturbing adverse events of whole-brain radiotherapy for patients are cognitive deterioration and hair loss, she added.
“Stereotactic radiosurgery allows delivering a single fraction of precise, high-dose radiation while preserving surrounding brain tissue. Over the past few years, radiation to the surgical bed of the resected lesion only has become an area of interest. Although this technique has great potential, we have limited prospective data on efficacy,” admitted Dr. Mahajan.
The prospective study enrolled 132 patients (128 evaluable) with 1 to 3 brain metastases who wished to avoid or delay whole-brain radiotherapy following complete surgical resection of at least 1 metastasis. The median age was 59 years, and demographic characteristics were well balanced between the two arms. Patients were randomized to receive stereotactic radiosurgery to the surgical cavity (or cavities for patients with more than one resected lesion) or observation alone and were stratified by the number of metastasis (one vs two or three), the primary cancer type (melanoma vs other histology), and the preoperative tumor size (≤ or > 3 cm).
Local control was significantly superior in the stereotactic radiosurgery arm: At 12 months, the rate of local control was 72% vs 45% in observation arm (P = .01). Median time to local recurrence was not reached in the stereotactic radiosurgery arm at the time of the ASTRO meeting but was 7.6 months in the observation arm.
Stereotactic Radiosurgery vs Whole-Brain Radiotherapy
- The N107C trial demonstrates the superiority of stereotactic radiosurgery to the surgical bed in patients with resected brain metastases over the standard of care, whole-brain radiotherapy, in preserving cognitive function and improving quality of life. Whole-brain radiotherapy, however, improved intracranial and surgical bed control of relapse.
- A second study in a similar patient population found that stereotactic radiosurgery to the surgical bed improved local tumor control over observation.
- Neither modality improved survival, making it important to discuss the risk/benefit ratio of potential options for resected brain metastases with patients.
However, improved local control did not translate to improved overall survival or distant brain metastasis. At 12 months, 43% of patients who received stereotactic radiosurgery and 33% of observation patients were free of distant metastasis, which was not statistically significant. Median overall survival was 17 and 18 months in the stereotactic radiosurgery and observation arms, respectively.
Patients with smaller tumors (ie, < 2.5 cm) had superior local control (91%) compared with 43% for tumors 2.6 to 3.5 cm (P = .0004) and 46% for tumors > 3.5 cm (P = .004).
Dr. Mahajan and colleagues plan to analyze the data further to determine whether there are specific patient subsets that may derive preferential benefit from postoperative stereotactic radiosurgery.
Whole-brain radiotherapy was given to 24 of 64 patients in the stereotactic radiosurgery group, within an average time frame of 16.1 months, compared with 30 of 67 patients in the observation group, with an average time frame of 15.2 months.
“At this time, the lack of a benefit in survival or distant brain metastases limits our ability to conclude there is an obvious clinical benefit,” Dr. Mahajan told listeners. “In addition, these data suggest that smaller tumors under 2.5 cm may not need postoperative radiosurgery after resection, because the local failure rate was low in this group of patients.”
Additional Commentary
George Rodrigues, MD
George Rodrigues, MD, of London University in Western Ontario, Canada, commented on both studies and moderated a press conference where these data were discussed. “These two studies are linked and important because they confirm the role of radiation in this patient population. The results clarify and affirm that stereotactic radiosurgery is an appropriate option for management of these brain metastases,” he stated.
The importance of surgical bed control is that a recurrence requires treatment, and it is easier to treat upfront than to have to retreat. “Maintaining local control is important in this setting. From a patient perspective, early local failure can mean they will lose any benefit they gained from primary treatment,” Dr. Rodrigues concluded. ■
Disclosure: Drs. Brown, Mahajan, and Rodrigues reported no potential conflicts of interest.
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