Evaluation of Safety of Stereotactic Body Radiotherapy for the Treatment of Patients With Multiple Metastases: Findings From the NRG-BR001 Phase 1 Trial

Abstract

Importance: Stereotactic body radiotherapy (SBRT) for oligometastases is hypothesized to improve survival and is increasingly used. Little evidence supports its safe use to treat patients with multiple metastases.

Objective: To establish safety of SBRT dose schedules in patients with 3 to 4 metastases or 2 metastases in close proximity to each other.

Design, setting, and participants: This phase 1 trial opened on August 4, 2014, and closed to accrual on March 20, 2018. Metastases to 7 anatomic locations were included: 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 could be enrolled per anatomic site. The setting was a consortium of North American academic and community practice cancer centers participating in NRG Oncology trials. Patients with breast, prostate, or non-small cell lung cancer with 3 to 4 metastases or 2 metastases in close proximity (≤5 cm) amenable to SBRT were eligible for this phase 1 study. Statistical analyses were performed from December 31, 2017, to September 19, 2019.

Interventions: The starting dose was 50 Gy in 5 fractions (CL, MC), 45 Gy in 3 fractions (PL, AP, L), and 30 Gy in 3 fractions (BO, SP).

Main outcomes and measures: The primary end point was dose-limiting toxicity (DLT) defined by the Common Terminology Criteria for Adverse Events, version 4.0, as specific adverse events (AEs) of grades 3 to 5 (definite or probable per the protocol DLT definition) related to SBRT within 180 days of treatment. Dose levels were considered safe if DLTs were observed in no more than 1 of 6 patients per location; otherwise, the dose at that location would be de-escalated.

Results: A total of 42 patients enrolled, 39 were eligible, and 35 (mean [SD] age, 63.1 [14.2] years; 20 men [57.1%]; 30 White patients [85.7%]) were evaluable for DLT. Twelve patients (34.3%) had breast cancer, 10 (28.6%) had non-small cell lung cancer, and 13 (37.1%) had prostate cancer; there was a median of 3 metastases treated per patient. Median survival was not reached. No protocol-defined DLTs were observed. When examining all AEs, 8 instances of grade 3 AEs, most likely related to protocol therapy, occurred approximately 125 to 556 days from SBRT initiation in 7 patients.

Conclusions and relevance: This phase 1 trial demonstrated the safety of SBRT for patients with 3 to 4 metastases or 2 metastases in close proximity. There were no treatment-related deaths. Late grade 3 AEs demonstrate the need for extended follow-up in long-surviving patients with oligometastatic disease. Treatment with SBRT for multiple metastases has been expanded into multiple ongoing randomized phase 2/3 National Cancer Institute-sponsored trials (NRG-BR002, NRG-LU002).

Trial registration: ClinicalTrials.gov Identifier: NCT02206334.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Winter reported receiving grants from the National Cancer Institute (NCI) NRG Oncology Statistics and Data Management Center during the conduct of the study. Dr Robinson reported receiving grants and personal fees from Varian Medical Systems, grants from Elekta, and equity from Radialogica outside the submitted work. Dr Al-Hallaq reported receiving grants from Varian Medical Systems and royalties from patents licensed through the university from the University of Chicago outside the submitted work. Dr Chmura reported receiving personal fees from RefleXion, a close relative receiving a salary from Astellas Pharma, and grants from Merck, Bristol Myers Squibb, and Emanuel Merck, Darmstadt Serono outside the submitted work. Dr Horton reported that as of October 2018, she moved from Duke University to employment with G1 Therapeutics. Dr Matuszak reported receiving grants and consulting fees from Varian Medical Systems outside the submitted work. Dr Milano reported receiving personal fees from Galera Therapeutics, Wolters Kluwer, and AstraZeneca outside the submitted work. Dr Wong reported receiving grants from Bristol Myers Squibb and AstraZeneca, NexPlasmaGen, and Instadesign, and being a major shareholder of MISO Chip Inc outside the submitted work. Dr Yi reported receiving grants and nonfinancial support from Rowpar Pharmaceuticals outside the submitted work. Dr Yoon reported receiving grants from NCI during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Time to Treatment-Related Grade 3 to Grade 4 Adverse Events (AEs) Occurring Greater Than 180 Days After the Start of Stereotactic Body Radiation Therapy for All Evaluable Patients

Figure 2.. Overall Survival of All Treated Patients

The plus signs indicate censored values.