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

Abstract

SummaryBackgroundProstate 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.MethodsCHHiP 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.FindingsBetween 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.InterpretationHypofractionated 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.FundingCancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

Stereotactic Body Radiation Therapy for Patients with Early-stage Prostate Cancer

“…Four studies reporting outcome data for early stage prostate cancer treated with CF-EBRT with a combined patient cohort of n=1778 were included in this review (27)(28)(29)(30). This cohort consisted of 407 low-risk, 1,111 intermediate-risk and 254 high-risk patients.…”

Challenges in the Analysis of Outcomes for Surgical Compared to Radiotherapy Treatment of Prostate Cancer

“…Thirdly, evolution in therapeutic techniques over the past decade may have had an impact on the relative cost and value of care delivered in the present day, which was not adequately captured in this dataset. Of particular interest is emerging data on hypofractionated radiotherapy whereby a course of radiation is delivered over 2-4 weeks instead of the conventional 8-9 weeks (38,39). While there are certainly limitations to this type of analysis, the volume and detail of data available within an IDFS create advantages not available in other cost models, and we anticipate this analysis will serve as a model for future work.…”

Advances in external beam radiotherapy for prostate cancer

“…Tissues with a lower alpha/beta ratio will undergo greater cell killing by larger doses per fraction of radiotherapy than tissues with a higher ratio (Figure 2 showing that 60Gy delivered over four weeks is non-inferior to 74Gy over sevenand-a-half weeks in terms of prostate cancer progression and is not associated with significant differences in bladder and bowel toxicity. 8,9 This is likely to become the new standard of care for many men with low-or intermediate-risk prostate cancer and will allow considerable savings in resources as well as being more convenient for patients.…”