Prostate cancer and hypofractionation: reflections on recent randomised phase III clinical trial results

Four large randomised controlled trials testing modest hypofractionation for localised prostate cancer have reported efficacy and side effect outcomes within the last year (1-8). The studies were designed using different strategies which need to be considered when interpreting their results. The two largest trials, CHHiP (3,216 patients) (1-3) and PROFIT (1,206 patients) (4), have much in common. Both studies compared standard fractionation radiation therapy (SFRT) schedules using 2.0 Gy daily fractions (total doses CHHiP 74 Gy; PROFIT 78 Gy) with hypofractionated radiotherapy (HFRT) schedules using 3.0 Gy daily fractions (total doses CHHiP 60 and 57 Gy; PROFIT 60 Gy). Both trials tested the hypothesis that modest hypofractionation is non-inferior to standard fractionation in terms of disease control. Intensity modulated radiotherapy methods (IMRT) using either forward or inverse planning with a three part simultaneous integrated boost were used in all patients in the CHHiP trial. Thirty percent of patients had image-guided radiotherapy (IGRT) (Table 1). IMRT/IGRT methods were used in the PROFIT trial. A key difference between the trials was the use of 6 months neoadjuvant androgen deprivation therapy (ADT) in 97% of patients in CHHiP. In contrast, only about 5% patients in the PROFIT trial received ADT. The CHHiP trial showed that efficacy defined by biochemical/clinical failure free outcome was non-inferior for the 60 Gy group compared with the 74 Gy group using a critical hazard ratio of 1.208. Non-inferiority could not be claimed for the 57 Gy group. At 5-year, the failure free proportion was higher in the 60 Gy group at There was no heterogeneity of fractionation effect seen in patients with low (15% of trial population), intermediate (73% of trial population) or high risk (12% of trial population) disease. We estimate that the 60 Gy in 3 Gy fraction group had an approximate equivalence to 76 Gy in 2 Gy fractions. The PROFIT trial included patients with intermediate risk disease and showed that the 60Gy group was non-inferior to the 78 Gy group with identical 21% biochemical/clinical failure at 5 years. The 11% higher biochemical control rate than in CHHiP is probably due to the use of ADT and similar findings have been reported in EORTC Trial 22991 which showed a 13% gain in 5 years PSA control with 6 months of ADT (10). Regarding side effects the two trials also gave complimentary results. In the CHHiP trial acute RTOG bowel (GI) and bladder (GU) symptoms peaked …