Conventional vs. Hypo-Fractionated, Radiotherapy for High-Risk Prostate Cancer (PCS5), Randomized, Non-Inferiority, Phase 3 Trial: Posthoc Analysis of IMRT vs. 3D-CRT Radiation Therapy Associated Toxicities

Abstract

The Prostate Cancer Study number 5 (PCS5), is a multi-centric non-inferiority, phase 3, randomized controlled trial of high-risk prostate cancer patients of treated with either conventionally fractionated radiotherapy (CFRT) or hypofractionated radiotherapy (HFRT). The 7 years' pre-planned analysis showed that HFRT (68 Gy in 25 fractions) was as effective and well tolerated as CFRT (76 Gy in 38 fractions). In this posthoc analysis we aim to report the genitourinary (GU) and gastrointestinal (GI) toxicities associated with radiation therapy techniques: intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-CRT). PCS5 randomized patients in a 1:1 ratio to receive either CFRT or HFRT. All patients received long term neoadjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. The toxicities were reported as per the Common Terminology Criteria for Adverse Events version 4. Acute toxicities were defined as presenting ≤ 180 days post-RT start and delayed > 180 days. The cumulative acute and delayed GI and GU toxicities were classified in grade groups: grade 1 or higher (G1+), G2+, and G3+. For each grade group, acute and delayed, we performed multivariable logistic regression analyses, adjusting for age, CTV volume, diabetes, fractionation (CRFT or HFRT), hypertension, and stage < T3b or ≥ T3b. For efficacy analyses cox-regression was utilized. A p-value < 0.05 was considered significant. Three hundred twenty of the 329 patients enrolled in the trial were included in this posthoc analyses. The mean age was 71.4 ± 6.1 years, and the mean CTV volume (n = 219) was 47.25 ± 19.9 cc. IMRT was used in 195 (60.6%) patients and 3D-CRT in 125 (39.1%) patients. Multivariable logistic regression showed a significant difference in favor of IMRT for GI G2+ acute toxicity (OR = 0.285 [0.14-0.59]; CI: 95%; p<0.001) and GI G2+ delayed toxicity (OR = 0.202 [0.60-0.69]; CI: 95%; p = 0.01). There were no differences in G3+ GI or GU toxicities and there were no grade 4 toxicities. There were no differences in efficacy at 7 years between the two treatment technics. Outcomes for IMRT vs. 3D-CRT respectively, overall survival (81.5% vs 79.2%; HR: 0.92 [0.55-1.53]; CI: 95%; p-value: 0.74), distant metastasis free survival (90,7% vs 92.8%; HR: 1.4 [0.63-3.1]; CI: 95%; p-value: 0.42), prostate cancer mortality (95.8% vs. 92.2%; HR: 0.93 [0.32-2.67]; CI: 95%; p-value: 0.89), and biochemical failure (85.1% vs 88%; HR: 1.35 [0.72-2.52]; CI: 95%; p-value: 0.35). This is the first phase 3 randomized controlled trial assessing the use of HFRT vs. CFRT, exclusively in high-risk prostate cancer patients. Given that our efficacy data at 7 years follow-up establishes moderate HFRT as a new standard of care and no difference between IMRT and 3D-CRT, we strongly recommend that patients who are treated with EBRT should receive IMRT, given the reduced acute and delayed grade 2 or higher GI toxicities.