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Stereotactic body radiotherapy can safely be used to treat patients with oligometastatic disease with 3 to 4 metastases or 2 metastases in close proximity to each other, according to results from the phase 1 NRG-BR001 trial.
Stereotactic body radiotherapy (SBRT) can safely be used to treat patients with oligometastatic disease with 3 to 4 metastases or 2 metastases in close proximity to each other, according to results from the phase 1 NRG-BR001 trial (NCT02206334) published in JAMA Oncology.1
Among 35 evaluable patients, no protocol-defined dose-limiting toxicities (DLTs) were observed with the approach, and median overall survival (OS) had not yet been reached. Additionally, the treatment was well tolerated, with no treatment-related deaths reported.
“Prior to this trial, little to no evidence was available to support that SBRT is a safe and tolerable treatment option for patients who have multiple metastases,” lead study author Steven J. Chmura, MD, PhD, an associate professor of Radiation and Cellular Oncology at the University of Chicago Comprehensive Cancer Center, stated in a press release.2 “Researchers have hypothesized that SBRT could improve survival outcomes for this patient population; however, it was imperative we determine the safety of this procedure, appropriate dose and scheduling, and how to coordinate across multiple centers the quality assurance of the procedures prior to testing its efficacy.”
Data from prior phase 2 studies have demonstrated the safety and effectiveness of SBRT for patients with limited lung, liver, or spine metastases. Findings from retrospective analyses have also shown the safety of this approach in patients with other single-metastasis locations. SBRT represents a potential alternative to resection for metastasis-directed therapy because it can minimize interruptions in systemic therapy and expand the type and location of metastasis that is responsive to an ablative treatment.
As such, SBRT is increasingly being considered for patients with 3 to 4 metastases or those with 2 metastases in close proximity to one another; however, there is a notable lack of prospective and well-defined techniques, as well as safety data with the approach in this population.
In the phase 1 study, investigators sought to evaluate the safety of administering curative-intent SBRT to patients with 3 to 4 metastases or 2 metastases within close proximity to each other. They hypothesized that through robust treatment planning, identifying delivery parameters, and establishing quality assurance, this approach could be given in 3 to 5 sessions to as many as 4 metastases in a shortened timeframe with acceptable safety.
From August 2014 through March 2018, the trial enrolled patients who were at least 18 years of age; had metastatic breast cancer, prostate cancer, or non–small cell lung cancer (NSCLC); and had either 3 to 4 metastases or 2 metastases within 5 cm of one another.
To be eligible for enrollment, patients needed to have controlled primary tumors, an ECOG performance status of 0 to 2, and acceptable organ and marrow function. Those with brain metastases, severe active comorbid disease, or who had previously received palliative radiation to current metastases were excluded from the study.
After enrollment, metastases were stratified into 1 of 7 different anatomic sites: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal-pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). Six patients were enrolled to each site and treated with different starting doses.
Starting doses were 50 Gy in 5 fractions for CL and MC lymph node locations; 45 Gy in 3 fractions for PL, AP, and L locations; and 30 Gy in 3 fractions BO and SP locations. As such, for each patient, it was possible to receive different doses to multiple metastases. Treating physicians were able to irradiate metastases sequentially or concurrently. However, all treatment had to be completed within 21 days of starting SBRT.
The primary objective of the study was to identify the recommended dose of SBRT for each metastatic location based on 2 potential dose levels: initial and de-escalated doses. To do this, investigators took note of DLTs that occurred within 180 days of the start of treatment. Secondary objectives included identifying the incidence of grade 3 or higher treatment-related adverse effects (TRAEs) within 180 days of treatment start, the incidence of late AEs, and survival.
Among the 35 evaluable patients enrolled to the study, the mean age was 63 years, 57.1% were male (n = 20), 85.7% were White (n = 30), and 68.6% (n = 24) had an ECOG performance status of 0. Additionally, 34.3% (n = 12) of the DLT-evaluable patients had breast cancer, 37.1% (n = 13) had prostate cancer, and 28.6% (n = 10) had NSCLC. A median of 3 metastases were treated per patient and 66.0% (n = 23) had 3 to 4 metastases. Sixty percent of patients (n = 21) had previously received radiation treatment away from the targeted metastases.
SBRT was given per trial protocol or with acceptable variations in all but 1 case, and the median time to completion of the SBRT protocol was 8 days (range, 3-27).
The median follow-up for all surviving patients was 23.9 months (range, 2.1-26). Among 39 eligible patients, 15 patients had died from metastatic disease; this included 38% (n = 5/13) of those with breast cancer, 46% (n = 6/13) of patients with NSCLC, and 30% (n = 4/13) of patients with prostate cancer. The median OS had not yet been reached, but the estimated 2-year OS rate was 57% (95% CI, 38.0%-72.0%).
No protocol-specified DLTs were observed in any of the 7 metastatic locations. These analyses were based on 6 evaluable patients for all but the liver metastatic location, which was based on 5 patients. Based on the study findings, the initial starting dose is the recommended SBRT dose for each metastatic location.
A total of 50 AEs of grade 3 or 4 were observed; 36% (n = 18) were reported by the treating site as potentially being related to treatment. These AEs occurred in 9 patients, with 16 grade 3 events, and 2 grade 4 events. Additionally, all but 6 of these effects happened more than 180 days after the start of treatment, and none met the criteria for DLT. Moreover, the 18-month cumulative incidence of late grade 3 or 4 treatment-related AEs per site reporting was 17% (95% CI, 7%-32%), while the and 2-year cumulative incidence was 20% (95% CI, 9%-35%).
“These are important data from the multicenter study, confirming that complicated SBRT to multiple sites is safe and feasible,” Mitchell Machtay, MD, the interim group chair for NRG Oncology and the associate dean for Clinical Cancer Research at the Penn State College of Medicine, added in therelease. “We eagerly await the results of ongoing, larger randomized trials to demonstrate how effective this is when compared with drug therapy alone for metastatic cancer.”
Late grade 3 toxicities indicate the need for extended follow-up in long-surviving patients with oligometastatic disease, according to the study authors. Moreover, treatment with SBRT in this patients with multiple metastases is under further evaluation in the ongoing randomized phase 2/3 NRG-BR002 (NCT02364557) and NRG-LU002 (NCT03137771) trials.