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: A total of 31 clinical studies met the inclusion criteria, encompassing 2,355 patients across multiple tumor types, including non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, prostate cancer, hepatocellular carcinoma, and pancreatic or biliary malignancies. Fifteen studies employed concurrent SBRT-ICI administration, 13 adopted a sequential approach, and 3 included both strategies. SBRT dose and fractionation were highly variable, ranging from palliative regimens to ablative schedules, with reported BED 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.