Simple SummaryRetroperitoneal sarcomas represent a very rare entity. The most common pattern of recurrence and cause of death is local recurrence, and the rates of locoregional recurrences are high even at high-volume centers. In contrast to soft-tissue sarcomas of the extremities, the role of radiotherapy in retroperitoneal sarcoma is not fully established. The aim of the study was to report the results of a prospective single-center trial for preoperative dose-escalated intensity-modulated radiotherapy with an intraoperative boost in patients with retroperitoneal sarcoma after all surviving patients had achieved a follow-up of at least 60 months. The primary endpoint of a 5-year local control of 70% was not met; the local control of the cohort was 59.6%. In those patients who received a dose > 50 Gy and the intraoperative boost, the local control was promising at 64.8%.AbstractBackground: To report the final results of a prospective, one-armed, single-center phase I/II trial (NCT01566123). Methods: Between 2007 and 2017, 37 patients with primary or recurrent (N = 6) retroperitoneal sarcomas were enrolled. Treatment included preoperative IMRT of 45–50 Gy with a simultaneous integrated boost of 50–56 Gy, surgery and IORT. The primary endpoint was local control (LC) at 5 years. The most common histology was dedifferentiated liposarcoma (51%), followed by leiomyosarcoma (24%) and well-differentiated liposarcoma (14%). The majority of lesions were high-grade (FNCLCC G1: 30%, G2: 38%, G3: 27%, two missing). Five patients were excluded from LC analysis per protocol. Results: The minimum follow-up of the survivors was 62 months (median: 109; maximum 162). IORT was performed for 27 patients. Thirty-five patients underwent gross total resection; the pathological resection margin was mostly R+ (80%) and, less often, R0 (20%). We observed 10 local recurrences. The 5-year LC of the whole cohort was 59.6%. Eleven patients received a dose > 50 Gy plus IORT boost; LC was 64.8%; the difference, however, was not significant (p= 0.588). Of 37 patients, 15 were alive and 22 deceased at the time of final analysis. The 5-year OS was 59.5% (68.8% per protocol). Conclusions: The primary endpoint of a 5-year LC of 70% was not met. This might be explained by the inclusion of recurrent disease and the high rate of G3 lesions and leiomyosarcoma, which have been shown to profit less from radiotherapy. Stratification by grading and histology should be considered for future studies.