Hypofractionation versus conventionally fractionated radiation therapy
The key evidence supporting this protocol is provided by a phase 3 multicentre international randomised non-inferiority trial (PROFIT) involving 1206 patients with intermediate-risk prostate cancer, receiving radiation therapy. PROFIT compared conventionally fractionated radiation therapy (78 Gy in 39 fractions; n = 598) with hypofractionated radiation therapy (60 Gy in 20 fractions; n = 608).r The use of androgen deprivation therapy (ADT) was not permitted in this study. The primary end point was biochemical-clinical failure which was defined as the first occurrence of any of the following outcomes: PSA failure, hormonal intervention, clinical evidence of local or distant failure, or death from prostate cancer. After a median follow up of 6 years, the 5-year biochemical-clinical failure disease-free survival in both arms was 85% (95% CI:82-88%). The hazard ratio (HR) for the hypofractionated versus conventional arm was 0.96 (90% CI:0.77-1.20). The hypofractionated regimen was found to be non-inferior to the conventional regimen. In the hypofractionated arm, 10 deaths as a result of prostate cancer were observed, compared with 12 in the conventional arm (HR = 0.76, 95% CI:0.32-1.82). There was no significant difference for grade ≥3 late genitourinary or gastrointestinal toxicity. The hypofractionated arm observed significantly less late grade ≥2 gastrointestinal toxicity than the conventional arm.
Two other large, well powered, multicentre international non-inferiority randomised controlled trials, CHHiPP and RTOG 0415, have also reported non-inferior efficacy for hypofractionated regimens compared to conventional control arms.rr
The CHHiP trial involved 3216 patients (73% with intermediate-risk prostate cancer and 15% with low-risk) randomly assigned to receive conventionally fractionated radiation therapy (74 Gy in 37 fractions) or one of two hypofractionated regimens (60 Gy in 20 fractions or 57 Gy in 19 fractions).r Men with intermediate or high-risk disease also received 3-6 months of androgen deprivation therapy (ADT) before and during radiation therapy. 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 conventional arm, 90.6% (95% CI:88.5-92.3%) in the hypofractionated 60 Gy arm, and 85.9% (95% CI:83.4-88.0%) in the hypofractionated 57 Gy arm. The hypofractionated 60 Gy regimen (n = 1074) was non-inferior to the conventional 74 Gy regimen (n = 1065) (HR = 0.84, 90% CI:0.68-1.03, pNI = 0.0018). Non-inferiority could not be claimed for the hypofractionated 57 Gy regimen (n = 1077) compared with conventional 74 Gy regimen (HR = 1.20, 90% CI:0.99-1.46, pNI = 0·48). Similar long-term side effects were observed between both the hypofractionated groups and the conventional group.
The RTOG 0415 study randomised 1115 patients with low-risk prostate cancer to receive conventionally fractionated radiation therapy (73.8 Gy in 41 fractions) (n = 542) or hypofractionated radiation therapy (70 Gy in 28 fractions) (n = 550).r The use of ADT was not permitted in this study. After a median follow up of 5.8 years, the 5-year disease-free survival in the conventional arm was 85.3% (95% CI:81.9-88.1%) and 86.3% (95% CI:83.1-89.0%) in the hypofractionated arm. The hazard ratio (HR) for hypofractionated vs conventional fractionation was 0.85 (95% CI:0.64-1.14) with the hypofractionated regimen found to be non-inferior. There were no statistically significant differences in the early gastrointestinal and genitourinary toxicities; however, there was an increase in late grade 2-3 gastrointestinal and genitourinary toxicities observed in the hypofractionated arm (HR = 1.31-1.59).r
The HYPRO trial showed non-superior disease control and a lack of non-inferiority for gastrointestinal and genitourinary toxicities of the hypofractionated regimen.r HYPRO used a significantly higher biologically equivalent dose compared to other studies which potentially explains the increased toxicity.
Further review articles and guidelines have been published.rrrrAll recommend moderate hypofractionation as a treatment option for select, well-informed patients. Although a caveat has been expressed regarding uncertainty of longer term outcomes, recently published data from randomised control trials with longer follow-up suggest the findings reported at 5-6 years do not change significantly at 8-9 years.rrr
Prostate cancer risk category
Some caution should be given to the application of hypofractionated regimens in different risk settings. PROFIT enrolled intermediate risk patients only, RTOG 0415 cautions not to extrapolate results beyond the setting of low-risk prostate disease, and CHHiP enrolled patients with low, intermediate and high-risk disease, however, patients were predominantly in the intermediate-risk category.rrr
IMRT and IGRT
Of the three trials, PROFIT was the only one to mandate IGRT for all patients, and the vast majority of the men in PROFIT received IMRT rather than 3DCRT.r