The impact of the microbiota on radiation (RT)-induced toxicity and cancer response to radiotherapy is an emerging area of interest. In this review, we summarize the available preclinical and clinical evidence concerning microbiota modulation of RT toxicity and efficacy in the main gastrointestinal (GI) districts. A huge amount of data supports the clinical application of microbiota modulation, particularly through prebiotics and probiotics, to prevent or mitigate radiotherapy-induced toxicity in rectal cancer. Preclinical and clinical studies also support the observation of microbiota modulation to impact the toxicity and efficacy of treatment in esophageal cancer, hepatocellular carcinoma (HCC), and anal squamous cell carcinoma (ASCC). However, insufficient evidence remains to endorse microbiota modulation as a strategy to enhance tumor radiosensitivity in clinical practice. Well-designed studies focusing on prebiotics, probiotics, and fecal microbiota transplantation are needed across all GI sites to evaluate their potential to improve treatment efficacy, as suggested by promising preclinical findings. The impact of pre-treatment microbiota analyses should be addressed in prospective studies to verify the efficacy of patient-level tailored strategies. Additionally, the repurposing of radioprotective agents with innovative delivery systems, such as encapsulated amifostine, holds significant promise for mitigating small bowel toxicity, thereby enabling more effective RT treatment.

Background: One of the challenges in treating pancreatic ductal adenocarcinoma (PDAC) with stereotactic radiotherapy (SRT) is to manage lesions abutted to the duodenum, bowel and stomach. Simultaneous integrated protection (SIP) is one of the proposed approaches to increase plan reproducibility and quality. However, no clinical data are available regarding the dosimetric objectives impacting local control probability. Methods: This is a prospective, single-arm study. Key inclusion criteria were as follows: PDAC histology; tumor abutment with duodenum, stomach, or small bowel; and SRT schedule consisting of 45 Gy in six fractions. Delineation of the PTV overlapped with critical OARs (PTV_SIP) and PTV outside critical OARs (PTV_Dominant) was mandatory. Dose constraints were as follows: (near) maximum dose, D2cc, and D20cc to critical OARs 38 Gy, 32 Gy, and 24 Gy, respectively. This study was designed to prospectively investigate the main clinical and dosimetric parameters impacting freedom from local recurrence (FFLR). Results: From June 2019 to January 2024, 104 patients were enrolled. One-year FFLR was 91.7%. Fifteen events of local failure occurred (17.6%). Mapping of local relapses showed a relapse inside the PTV_SIP area in nine patients and outside the PTV_SIP in six cases (NS). Whole PTV > 69 cc, PTV_SIP > 4 cc, PTV-SIP/whole PTV ratio > 7%, (near) Dmin to PTV_SIP < 25 Gy, mean dose to PTV_SIP < 28 Gy, and (near) Dmin to PTV_Dominant < 29 Gy were associated with worse FFLR. Multivariable analysis showed PTV_SIP absolute volume of more than 4 cc, mean dose to PTV_SIP < 28 Gy and whole PTV > 69 cc were independently related to worse FFLR. One case of acute G4 toxicity and two cases of acute G3 toxicity occurred, with two late toxicity deaths not certainly due to treatment. Conclusions: In this prospective study, SIP planning strategy with six fractions is safe and effective in pancreatic targets with critical contact with critical OARs. Given its potential advantages, SIP planning is a potential innovative strategy that should be compared to standard SRT planning in an ad hoc trial design.