Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

Abstract

Background: Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.

Methods: CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.

Findings: Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.

Interpretation: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.

Funding: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Figure 1

Trial profile

Figure 2

Biochemical or clinical failure-free survival (A) and overall survival (B) *Number of events reported after 7 years.

Figure 3

Univariable subgroup analyses of biochemical or clinical failure comparing 60 Gy (A) and 57 Gy (B) with conventional radiotherapy *Stratified by risk group; all other analyses are unstratified.

Figure 4

Acute RTOG toxicity by timepoint and randomised treatment group (A) Prevalence of bowel toxicity and (B) prevalence of bladder toxicity. RTOG=Radiation Therapy Oncology Group. Grade 1+=grade 1 or worse adverse event. Grade 2+=grade 2 or worse adverse event. Grade 3+=grade 3 or worse adverse event.

Figure 5

Late bowel and bladder toxicity by timepoint, assessment, and randomised treatment group Grade distribution of (A) bowel adverse events and (B) bladder adverse events measured with RTOG. Cumulative incidence of (C) bowel adverse events measured with RTOG and (E) bowel symptom scores measured with UCLA PCI/EPIC. Cumulative incidence of (D) bladder adverse events measured with RTOG and (F) bladder symptom scores measured with UCLA PCI/EPIC. Late toxicity data have been included in analyses if they were reported within 6 weeks of the 6 month visit, within 3 months of the 12–24 month visit, and within 6 months of the 36–60 month visit. For UCLA/EPIC, before androgen deprivation therapy data were included if they were reported within 3 months before starting androgen deprivation therapy and within 1 month after starting androgen deprivation therapy. Before radiotherapy data are included if they were reported within 3 months before radiotherapy and no more than 7 days after starting radiotherapy. Time-to-event analyses use all data reported from 6 weeks before the 6 month visit onwards. RTOG=Radiation Therapy Oncology Group scale. UCLA PCI=UCLA Prostate Cancer Index. EPIC=Expanded Prostate Cancer Index Composite. Grade 1+=grade 1 or worse adverse event. Grade 2+=grade 2 or worse adverse event. Grade 3+=grade 3 or worse adverse event. Very small+=score of very small, small, moderate, or big bother. Small+=score of small, moderate, or big bother. Moderate+=score of moderate or worse bother.