Hypofractionation vs conventional fractionation radiotherapy
The key evidence supporting this protocol is provided by a phase 3 multicentre international randomised non-inferiority trial (PROFIT) involving 1206 patients comparing conventional fractionation (cfx) radiotherapy (cfx arm – 78Gy/39# n=598) with hypofractionated (hfx) radiotherapy (hfx arm – 60Gy/20# n= 608) in patients with intermediate risk prostate cancer.r The use of androgen deprivation therapy (ADT) was not permitted in this study. The primary end point was biochemical-clinical failure (BCF) 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 BCF disease-free survival in both arms was 85% (95% CI, 82% to 88%). The hazard ratio (HR) for the hfx vs cfx arm was 0.96 (90% CI, 0.77 to 1.20). Compared to the cfx regimen, the hfx regimen was found to be non-inferior. In the hfx arm, 10 deaths as a result of prostate cancer were observed compared with 12 in the cfx arm (HR, 0.76; 95% CI, 0.32 to 1.82). There was no significant difference for grade ≥ 3 late GU and GI toxicity. The hfx arm observed significantly less late grade ≥ 2 GI toxicity than in the cfx arm.
Two other large, well powered, multicentre international non-inferiority randomised controlled trials, CHHiPP and RTOG 0415, have also reported non-inferior efficacy for hfx regimens compared to cfx control arms.rr
The CHHiP trial involved 3216 patients with predominantly intermediate risk prostate cancer randomly assigned to receive cfx radiotherapy (74Gy/37#) or one of two hfx radiotherapy dose regimens (either 60Gy/20# or 57Gy/19#).r Most patients received ADT before and during radiotherapy. 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 cfx fractionated 74 Gy group, 90·6% (95% CI, 88·5–92·3) in the hfx 60Gy group, and 85·9% (95% CI, 83·4–88·0) in the hfx 57Gy group. The hfx 60Gy regime (n= 1074) was non-inferior to the cfx 74Gy regime (n=1065) (HR 0·84 [90% CI, 0·68–1·03], pNI=0·0018). Non-inferiority could not be claimed for the 57Gy hfx regime (n=1077) compared with 74Gy cfx regime (HR 1·20 [0·99–1·46], pNI=0·48). Similar long-term side effects were observed between both hfx groups and the cfx group.
The RTOG 0415 study randomised 1115 patients with low-risk prostate cancer to receive either cfx radiotherapy of 73.8 Gy in 41 fractions (n= 542) or hfx radiotherapy 70 Gy in 28 fractions (n= 550).r The use of androgen deprivation therapy (ADT) was not permitted in this study. After a median follow up of 5.8 years, the 5-year disease-free survival in the cfx arm was 85.3% (95% CI, 81.9 to 88.1) and 86.3% (95% CI, 83.1 to 89.0) in the hfx arm. The hazard ratio (HR) for hfx vs cfx fractionation was 0.85 (95% CI, 0.64 to 1.14) with the hfx regimen found to be non-inferior. There were no statistically significant differences in the early GI and GU toxicity; however, there was increased late grade 2 - 3 GI and GU toxicity observed in the hfx arm (HR, 1.31 to 1.59).
The HYPRO trial showed non-superior disease control and a lack of non-inferiority for GU and GI toxicity of the hfx regimen.r HYPRO used a significantly higher biologically equivalent dose compared to other studies which potentially explains the increased toxicity.
Several review articles and guidelines have been published.rrrrAll recommend moderate hypofractionation as a treatment option for selected, 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 that the findings reported at 5-6 years do not change significantly after 8-9 years.rrr
Prostate cancer risk category
Some caution should be given to the application of these hfx regimes in the different risk settings. The PROFIT trial only enrolled intermediate risk patients, the RTOG 0415 study cautions not to extrapolate these results beyond the setting of low-risk disease, and whilst the CHHiP trial enrolled patients with low, intermediate and high-risk disease, overall the patients predominantly were 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 managed on PROFIT received IMRT rather than 3DCRT.r