Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

Abstract

SummaryBackgroundPatient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.MethodsThe CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b–T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.Findings2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4–64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change...

Quality of life outcomes from a dose-per-fraction escalation trial of hypofractionation in prostate cancer

“…The CHHiP trial [31], which compared 74 Gy in 37 fractions to either 57 or 60 Gy in 19 or 20 fractions, has now reported early PRO data [32]. The included PRO substudy enrolled 2100 patients and included bowel, bladder and sexual QoL instruments, using UCLA-PCI, including Short Form (SF)-36 and either FACT-P) or EPIC and SF-12 quality-of-life questionnaires completed pre-radiotherapy and at 2.5, 6, 12, 18, and 24 months post-radiotherapy.…”

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.…”

Exploiting Gene Expression Kinetics in Conventional Radiotherapy, Hyperfractionation, and Hypofractionation for Targeted Therapy

“…In comparison to ConvRT, HypoRT is the “new kid on the block.” There are currently several ongoing and a few complete randomized clinical trials evaluating patient survival, normal tissue effects (acute and late), and several other endpoints of HypoRT or HyperRT or all of these in comparison with ConvRT (Table 1). Recent Phase III reports by Lee et al 8 and Wilkins et al 9 show that HypoRT is not inferior to ConvRT in localized prostate cancer. Consequently, HypoRT could become the standard treatment for localized prostate cancer, as HypoRT may provide the benefit of shorter, potentially less costly, and more efficient treatment schedules and fewer patient visits.…”

“…5,6 Conventional RT (ConvRT) is administered in 1.8–2.2 Gy single fractions per day, 5 days per week for a total of 3–9 weeks, and maximum dose between 60 and 90 Gy. 7–9 In contrast, hyperfractionated RT (HyperRT) is administered in smaller doses of 0.5–1.8 Gy with multiple fractions per day for 2–4 weeks, and hypofractionated RT (HypoRT) as single daily fractions 3–20 Gy with a small number of fractions usually over a week. Overall, advances in technology such as intensity-modulated RT, image-guided RT, stereotactic body RT, stereotactic radiosurgery, and protons and carbon RT have improved the ability to deliver higher radiation dose more accurately to tumors.…”