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 (