Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial

Abstract

Background: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer.

Methods: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing.

Findings: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred.

Interpretation: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity.

Funding: Accuray and National Institute of Health Research.

Figure 1

Trial profile Crossovers between treatment groups were analysed per-protocol for this acute toxicity substudy. Dose fractionation regimens administered within each group are shown. *One patient who received two fractions of stereotactic body radiotherapy then developed grade 3 toxicity (urosepsis) and switched to conventionally fractionated or moderately hypofractionated radiotherapy (further 46 Gy in 23 fractions) was not excluded from the toxicity analysis because he had toxic effects after two fractions of sterotactic body radiotherapy. †One patient who received a single incomplete fraction of stereotactic body radiotherapy (<7·25 Gy, set-up issues) and switched to conventionally fractionated or moderately hypofractionated radiotherapy (further 55 Gy in 20 fractions) was excluded.

Figure 2

Acute Radiation Therapy Oncology Group toxicity for gastrointestinal (A) and genitourinary (B) systems As each group allowed two different treatment durations (CFMHRT 78 Gy in 39 fractions and 62 Gy in 20 fractions; SBRT 36·25 Gy in five fractions over 1 or 2 weeks) it was necessary to interpolate data where assessments did not overlap. Raw data are presented in the appendix (p 17), with all four schedules shown separately. Numbers at risk for each arm are asynchronous because they are shown only at data collection timepoints (which are non-simultaneous relative to the start of radiotherapy). Week 0 is the baseline toxicity score taken before start of radiotherapy. CFMHRT=conventionally fractionated or moderately hypofractionated radiotherapy. SBRT=stereotactic body radiotherapy.

Figure 3

Acute CTCAE toxicity for gastrointestinal (A) and genitourinary systems As each group allowed two different treatment durations (CFMHRT 78 Gy in 39 fractions and 62 Gy in 20 fractions; SBRT 36·25 Gy in five fractions over 1 or 2 weeks) it was necessary to interpolate data. Raw data are presented in the appendix (p 21), with all four schedules presented separately. Numbers at risk for each arm are asynchronous because they are shown only at data collection timepoints (which are non-simultaneous relative to the start of radiotherapy). The initial points for CFMHRT are connected by grey dashed lines to emphasise that there were no CTCAE assessments during radiotherapy delivery. Week 0 is the baseline toxicity score taken before start of radiotherapy. CTCAE=Common Terminology Criteria for Adverse Events. CFMHRT=conventionally fractionated or moderately hypofractionated radiotherapy. SBRT=stereotactic body radiotherapy.

Figure 4

Changes from baseline in expanded prostate cancer index composite (26 question) subdomains Urinary bother is graphed separately, as it does not form part of the urinary incontinence or obstructive subdomain scores. Error bars show 95% CIs for estimates of mean subdomain scores. The time period between baseline scoring and week 4 after radiotherapy follow-up is variable, since the total time of radiotherapy delivery varied (SBRT in 1 or 2 weeks; CFMHRT in 4 or 7·8 weeks). Week 0 is the baseline score taken before start of radiotherapy. Scores are change from baseline, with 0 representing no change. CFMHRT=conventionally fractionated or moderately hypofractionated radiotherapy. SBRT=stereotactic body radiotherapy.