Local Dose Effects for Late Gastrointestinal Toxicity After Hypofractionated and Conventionally Fractionated Modern Radiotherapy for Prostate Cancer in the HYPRO Trial.

Late gastrointestinal (GI) toxicity after radiotherapy for prostate cancer may have significant impact on the cancer survivor's quality of life. To date, little is known about local dose-effects after modern radiotherapy including hypofractionation. In the current study we related the local spatial distribution of radiation dose in the rectum to late patient-reported gastrointestinal (GI) toxicities for conventionally fractionated (CF) and hypofractionated (HF) modern radiotherapy in the randomized HYPRO trial. Patients treated to 78 Gy in 2 Gy fractions ( = 298) or 64.6 Gy in 3.4 Gy fractions ( = 295) with available late toxicity questionnaires ( ≥ 2 within 1-5 years post-treatment) and available 3D planning data were eligible for this study. The majority received intensity modulated radiotherapy (IMRT). We calculated two types of dose surface maps: (1) the total delineated rectum with its central axis scaled to unity, and (2) the delineated rectum with a length of 7 cm along its central axis aligned on the prostate's half-height point (prostate-half). For each patient-reported GI symptom, dose difference maps were constructed by subtracting average co-registered EQD2 (equivalent dose in 2 Gy) dose maps of patients with and without the symptom of interest, separately for HF and CF. -values were derived from permutation tests. We evaluated patient-reported moderate to severe GI symptoms. Observed incidences of rectal bleeding and increased stool frequency were significantly higher in the HF group. For rectal bleeding ( = 0.016), mucus discharge ( = 0.015), and fecal incontinence ( = 0.001), significant local dose-effects were observed in HF patients but not in CF patients. For rectal pain, similar local dose-effects ( < 0.05) were observed in both groups. No significant local dose-effects were observed for increased stool frequency. Total rectum mapping vs. prostate-half mapping showed similar results. We demonstrated significant local dose-effect relationships for patient-reported late GI toxicity in patients treated with modern RT. HF patients were at higher risk for increased stool frequency and rectal bleeding, and showed the most pronounced local dose-effects in intermediate-high dose regions. These findings suggest that improvement of current treatment optimization protocols could lead to clinical benefit, in particular for HF treatment.