Evaluating Toxicity and Interaction Outcomes of Systemic Therapy and Stereotactic Ablative Radiation Therapy for Oligometastatic Disease : A Secondary Analysis of the Phase 2 SABR-5 Trial

Abstract

Purpose: Although stereotactic ablative radiation therapy (SABR) is known for low toxicity and safety, its combined use with specific systemic therapies requires further investigation. This study aims to evaluate the toxicity of SABR in combination with various systemic therapies. Materials and Methods: A secondary analysis of the SABR-5 trial evaluated grade 2+ and 3+ toxicities post-SABR in patients who had received high-risk or non-high-risk systemic therapies before SABR at 4 predefined intervals: concurrent with SABR, 1 day to 1 week prior, 1 to 2 weeks prior, or 2 to 12 weeks prior. High-risk systemic therapy was a priori defined as drugs that may increase treatment toxicity when delivered in close proximity to SABR. This category encompasses cytotoxic chemotherapy, multitargeted tyrosine kinase inhibitors, CDK 4/6 inhibitors, EGFR inhibitors, anti-VEGF agents, and anti-CTLA-4 agents. Results: Among 380 patients, grade 2+ toxicity rates were 17.3% (35/202) off systemic therapy, 19.2% (19/99) on non-high-risk therapy, and 42.9% (3/7) on high-risk therapy concurrent with SABR. Grade 3+ rates were 3.5% (7/202), 4.0% (4/99), and 28.6% (2/7), respectively. On multivariable analysis, concurrent use of high-risk systemic therapy was associated with a higher risk of grade 3+ toxic effects (OR, 14.88; P = .009). No significant risk was noted when high-risk drugs were used within 1 week, 2 weeks, or 2 to 12 weeks of SABR or with any non-high-risk drugs. Grade 2+ toxic effects associated with concurrent high-risk systemic therapy were primarily bone/pain related. Increased tumor diameter also elevated grade 2+ toxicity risk (per 1 cm increment; G2+ OR, 1.19; P < .001). Conclusion: Concurrent use of high-risk drugs has demonstrated a potential of increased SABR-related toxicity, warranting caution in their concurrent use with SABR. In contrast, combining non-high-risk drugs (eg, hormonal therapy) with SABR did not increase risk. Further research is essential to identify risks associated with this therapeutic combination. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.