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Objective: The aim of our report was to review the literature concerning the toxicity of radiation therapy in patients treated for high-risk prostate cancer, and to evaluate the differences in toxicity between conventional fractionation and hypofractionated treatments, in view of different techniques used in high-risk prostate cancer patients., Materials and Methods: PubMed database has been explored for studies concerning acute and late urinary/gastrointestinal toxicity in high-risk prostate cancer patients treated with radiotherapy. Prospective studies, concerning potential relationship between acute/late genitourinary (GU)/gastrointestinal (GI) toxicity and prostate radiotherapy in patients with high-risk prostate cancer, were included in the final analysis. Data collected from single arm, phase II non-randomized and randomized studies have been evaluated to perform odds ratio for toxicity risk. Furthermore, meta-analysis randomized prospective trials were considered suitable because they had recruited high-risk prostate cancer patients who didn't undergo surgery, with available data on ≥ G2 toxicity frequency., Results: The initial search provided 606 results, but only 35 manuscripts met all eligibility requirements and were included in this report. In order to perform odds ratio we observed a decrease in late gastrointestinal toxicity for patients treated with hypofractionated schemes compared to CV treated ones. Among patients who underwent conventional treatment, SIB seemed to decrease acute genitourinary side effects; SIB-Hypo treated patients suffered less toxicity than patients treated with hypofractionated- sequential boost schemes. Hypo-SIB schemes would seem less toxic in terms of acute gastrointestinal and late genitourinary side effects than CV-SIB. Therefore, our focus shifted to 6 clinical trials evaluating genitourinary and gastrointestinal toxicity in patients who had been randomized to receive conventional fractionation or hypofractionated treatment, in both cases with IMRT technology. Our meta-analysis of these randomized trials involving patients with high-risk prostate cancer showed a statistically significant increase in late genitourinary toxicity for hypo-treated patients; no difference was observed in acute genitourinary/gastrointestinal toxicity, and in late gastrointestinal toxicity., Conclusions: Our analysis doesn't want to establish a definitive truth; very few trials assessed only high risk-class patients. Our purpose is to stimulate further randomized prospective trials focusing both on the effectiveness and toxicity profile (toxicity/effectiveness ratio), taking into account the use of different technologies and doses.