Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy.

Importance: Metastases-directed stereotactic radiotherapy (SRT) is increasingly performed in patients with metastatic or oligometastatic cancer treated with immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), and small-molecule drugs (SMs). However, little is known about potential interactions between SRT and biological cancer therapy (BCT). Objective: To prospectively investigate adverse events associated with SRT combined with concurrent BCT. Design, Setting, and Participants: This international, prospective, multicenter, noninterventional registry cohort study (Toxicity and Efficacy of Combined Stereotactic Radiotherapy and Systemic Targeted or Immune Therapy [TOaSTT]) was conducted between July 2017 and August 2019 with a 24-month follow-up. Patients from 27 centers whose cancer was treated with metastases-directed SRT concurrently with BCT were eligible. Analyses were performed in January 2025. Exposure: Patients treated with SRT for intracranial or extracranial metastases and concurrent (within ≤30 days) BCT. Indication for treatment, decision on the radiotherapy dose and fractionation, as well as interruption of BCT, were left to the discretion of the treating clinician. Main Outcomes and Measures: The primary outcome was severe (at least grade 3) adverse events of combined modality treatment, as graded by the treating physician. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Results: In total, 514 SRTs (271 cranial and 243 extracranial) concurrent with BCT were performed in 433 patients (median [IQR] age, 62 [54-70 years; 275 male [63.5%]). In 315 SRTs (61.3%) patients received ICIs, whereas in 150 SRTs (29.2%), patients received SMs and in 49 SRTs (9.5%) patients received mAbs. In 430 SRTs (83.7%), BCT had been initiated in patients before SRT, while 71 of 392 patients (18.1%) paused BCT during SRT. Severe (≥grade 3) acute adverse events were observed in 27 of 506 treatments (5.3%; 3 patients with grade 5 events), and severe late adverse events were observed in 29 of 459 patients (6.3%; 2 patients with grade 5 events). SRT with uninterrupted BCT was not associated with increased severe acute or late adverse events (odds ratio, 2.32; 95% CI, 0.87-6.22). Interruption of BCT during SRT was not associated with worse PFS and OS after correction for performance status and histologic type (hazard ratio, 0.81; 95% CI, 0.61-1.09; P = .17). Conclusions and Relevance: In this cohort study of 433 patients, severe adverse events after SRT and concurrent BCT were uncommon (<10%), continuing BCT during SRT was not associated with increased risk of severe adverse events, and interrupting BCT was not associated with worse OS when correcting for patients' performance status. These findings suggest a favorable safety profile of metastases-directed SBRT in combined modality treatment settings.