Hypofractionated, Dose Escalation Radiotherapy for High-Risk Prostate Cancer: the safety analysis of the Prostate Cancer Study-5 (PCS-5), a GROUQ led phase III trial.

The low α\β ratio of 1.2-2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated (HF) radiation therapy (RT). To date there has been no phase-III randomized clinical-trial comparing moderately HF-RT with standard fractionation (SF) exclusively in high-risk PCa patients. We are reporting the safety of moderately HF-RT in high-risk PCa in an initially non-inferiority designed phase III clinical trial.

From February 2012-March 2015, 329 high-risk PCa patients were randomized to receive either SF or HF-RT. All patients received neo-adjuvant, concurrent, and long-term adjuvant androgen deprivation therapy (ADT). SF-RT consisted of 76Gy in 2Gy per fraction to the prostate, where 46Gy was delivered to the pelvic lymph-nodes. HF-RT included concomitant dose escalation of 68Gy in 2.72Gy per fraction to the prostate, and 45Gy in 1.8Gy per fraction to the pelvic lymph-nodes. The co-primary endpoints were the acute and delayed toxicity at 6 and 24 months, respectively. The trial was originally designed as a non-inferiority with a 5% absolute margin. Given the lower than expected toxicities in both arms, the non-inferiority analysis was completely dropped.

Of the 329 patients, 164 were randomized to the HF arm and 165 to the SF arm. In total, there were more grade 1 or worse acute GI events in the hypofractionated arm, 102 vs 83 events in the HF and SF arm, respectively (p: 0.016). This did not remain significant at 8 weeks of follow up. There were no differences in grade 1 or worse acute GU events in the two arms, 105 vs 99 events in the HF and SF arm, respectively (p:0.3). At 24 months, 12 patients in the SF arm and 15 patients in the HF arm had grade-2 or worse delayed gastrointestinal (GI)-related adverse events (HR: 1.32 [0.62-2.83] 95% CI; P=0.482). There were 11 patients in the SF arm and 3 patients in the HF arm with grade-2 or higher delayed genitourinary (GU) toxicities (HR: 0.26 [0.07-0.94] 95% CI; P=0.037). There were three grade-3 GI and one grade-3 GU delayed toxicities in the HF arm, and three grade-3 GU and no grade-3 GI toxicities in the SF arm. No grade 4-toxicities were reported.

This is the first study of moderate HF dose escalated RT in exclusively high-risk prostate cancer patients treated with long-term ADT and pelvic RT. Although our data was not analyzed as a non-inferiority, our results demonstrate that moderately HF-RT is well-tolerated and similar to SF-RT at 2 years and could be considered as an alternative to SF-RT.

International journal of radiation oncology, biology, physics. 2023 May 22 [Epub ahead of print]

T Niazi, A Nabid, T Malagon, R Bettahar, L Vincent, A G Martin, M Jolicoeur, M Yassa, M Barkati, L Igidbashian, B Bahoric, R Archambault, H Villeneuve, J M Tsui, M Mohiuddin

Jewish General Hospital, McGill University, Quebec, Canada.. Electronic address: ., Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada., McGill University, Montreal, Quebec, Canada. Electronic address: ., Centre Hospitalier Régional de Rimouski-Centre de Cancer, Rimouski, Quebec, Canada., Pavillon Ste-Marie Centre Hospitalier Régional de Trois-Rivières (CHRTR), Trois-Rivières, Quebec, Canada., Centre Hospitalier Universitaire de Québec (CHUQ)-L'Hôtel-Dieu de Québec, Quebec City, Quebec, Canada., Hôpital Charles LeMoyne, Greenfield Park, Quebec, Canada., Hôpital Maisonneuve-Rosemont, Montreal, Quebec, Canada., Centre Hospitalier de l'Université de Montréal (CHUM) (MB), Montreal, Quebec, Canada., Hôpital Cité-de-la-Santé, Laval, Quebec, Canada., Jewish General Hospital, McGill University, Quebec, Canada., Hôpital Gatineau, Gatineau, Quebec, Canada., Hôpital de Chicoutimi, Chicoutimi, Quebec, Canada., McGill University Health Centre, Montreal, Quebec, Canada.. Electronic address: ., Saint John Regional Hospital (MM), Saint John, New Brunswick, Canada.