The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study

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Acute gastrointestinal (GI) and genitourinary (GU) toxicity after prostate radiotherapy (RT) has been shown to be associated with late toxicity with 3D conformal RT. However, whether this association is present with modern approaches, such as stereotactic body radiotherapy (SBRT), remains unclear. We analyzed patients treated within the international phase III non-inferiority randomized control trial, PACE-B, to assess the association between acute and late toxicity following SBRT and conventional/moderately hypofractionated radiotherapy (CRT). We hypothesize that acute toxicity is significantly associated with equivalent late toxicity following prostate SBRT and CRT. We analyzed patients with GI and GU Common Terminology Criteria for Adverse Events (CTCAE) measurements in the acute (≤12 weeks post-RT) and late period (6-24 months post-RT). Using logistic regression, we analyze the association between G2+ acute GI and GU toxicities with equivalent late toxicities. Lasso variable selection was used to determine patient, tumor and treatment variables to include in the multivariable model. The area under the receiver operator characteristics curve (AUC) was used to evaluate the model's predictive performance. Of patients included in this analysis (n = 842), 414 were treated with SBRT and 428 with CRT. In univariable analysis (UVA), G2+ acute GU toxicity was significantly associated with developing G2+ late GU toxicity after SBRT (OR 4.63, 95% CI (2.96-7.25), p<0.0001) and CRT (OR 2.83, 95% CI (1.69-4.71), p<0.0001). This association remained significant in multivariable analysis (MVA). The models AUC for predicting G2+ late GU toxicity after SBRT was 0.73 (95% CI, 0.67-0.78) and 0.66 (95% CI, 0.59-0.73) following CRT. In UVA, G2+ acute GI toxicity was associated with developing G2+ late GI toxicity after SBRT (OR 3.67, 95% CI (1.91-7.03), p <0.0001) and CRT (OR 4.4, 95% CI (2.04-9.47), p<0.0001). This association also remained significant in MVA. The models AUC for predicting G2+ late GI toxicity after SBRT was 0.66 (0.95% CI, 0.57-0.75) and 0.64 (95% CI, 0.57-0.72) following CRT. In UVA analysis, G2+ baseline GU symptoms were also associated with developing G2+ late GU toxicity after SBRT (OR 7.59, 95% CI (2.72-21.19, p<0.0001) and CRT (OR 7.98, 95% CI (3.03-20.96), p<0.0001), and this continued to be significant in MVA. Acute toxicity remained associated with persistent late toxicity (≥2 G2+ late events) and late toxicity 12-24 months. Our study demonstrates an independent association between acute and late GU/GI toxicity in patients treated with SBRT and CRT for localized prostate cancer. Recognizing those at risk of late toxicity can provide an opportunity for early intervention to improve outcomes. G2+ acute toxicity should be considered an essential variable for predicting late GI/GU toxicity after prostate RT.