Stereotactic body radiotherapy combined with immunotherapy: a systematic review focus on timing and toxicity profile

Background: The combination of Stereotactic Body Radiotherapy (SBRT) with immune checkpoint inhibitors (ICIs) has gained increasing interest due to its potential to enhance antitumor immune responses. However, the optimal timing, dose, and safety profile of this combined approach remain unclear, and available clinical evidence is highly heterogeneous. Methods: A systematic review of the literature was conducted in accordance with PRISMA guidelines. PubMed/MEDLINE, Embase, and Cochrane Library databases were searched for clinical studies evaluating the combination of SBRT and ICIs. Studies were included if they reported toxicity outcomes and involved patients with solid tumors treated with SBRT in combination with ICIs. Data on study design, patient characteristics, SBRT dose and fractionation, treatment sequencing, and treatment-related toxicities were extracted and qualitatively analyzed. Results: values spanning approximately 43-113 Gy; detailed dosimetric data were lacking in about 38% of studies. The overall incidence of grade ≥ 3 treatment-related toxicity was comparable between concurrent and sequential approaches (approximately 12-15%). High-grade adverse events were predominantly immune-related, with pneumonitis more frequently reported in concurrent regimens, while gastrointestinal and dermatologic toxicities were slightly more common in sequential strategies. No consistent signal of increased severe toxicity attributable to the addition of SBRT was observed. Conclusions: Current clinical evidence suggests that the combination of SBRT and ICIs is generally feasible and does not appear to systematically increase the risk of severe toxicity compared with immunotherapy alone. However, substantial heterogeneity in study design, SBRT parameters, treatment sequencing, and toxicity reporting limits definitive conclusions regarding safety and efficacy. Future prospective trials with harmonized protocols, standardized toxicity attribution, and integrated translational endpoints are needed to define the optimal therapeutic window for SBRT-ICI combinations across different tumor types.