Ian S. Dayes

Purpose Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score ≤ 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason ≤ 6, and PSA ≤ 20 ng/mL; or T1 to 2, Gleason = 7, and PSA ≤ 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio, < 1.32). Results Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade ≥ 3 late genitourinary and GI toxicity. Conclusion The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.

PURPOSE: Conventional radiotherapy (C-RT) treatment schedules for patients with prostate cancer typically require 40 to 45 treatments that take place from > 8 to 9 weeks. Preclinical and clinical research suggest that hypofractionation-fewer treatments but at a higher dose per treatment-may produce similar outcomes. This trial was designed to assess whether the efficacy of a hypofractionated radiotherapy (H-RT) treatment schedule is no worse than a C-RT schedule in men with low-risk prostate cancer. PATIENTS AND METHODS: A total of 1,115 men with low-risk prostate cancer were randomly assigned 1:1 to C-RT (73.8 Gy in 41 fractions over 8.2 weeks) or to H-RT (70 Gy in 28 fractions over 5.6 weeks). This trial was designed to establish (with 90% power and an α of .05) that treatment with H-RT results in 5-year disease-free survival (DFS) that is not worse than C-RT by more than 7.65% (H-RT/C-RT hazard ratio [HR] < 1.52). RESULTS: A total of 1,092 men were protocol eligible and had follow-up information; 542 patients were assigned to C-RT and 550 to H-RT. Median follow-up was 5.8 years. Baseline characteristics were not different according to treatment assignment. The estimated 5-year DFS was 85.3% (95% CI, 81.9 to 88.1) in the C-RT arm and 86.3% (95% CI, 83.1 to 89.0) in the H-RT arm. The DFS HR was 0.85 (95% CI, 0.64 to 1.14), and the predefined noninferiority criterion that required that DFS outcomes be consistent with HR < 1.52 was met (P < .001). Late grade 2 and 3 GI and genitourinary adverse events were increased (HR, 1.31 to 1.59) in patients who were treated with H-RT. CONCLUSION: In men with low-risk prostate cancer, the efficacy of 70 Gy in 28 fractions over 5.6 weeks is not inferior to 73.8 Gy in 41 fractions over 8.2 weeks, although an increase in late GI/genitourinary adverse events was observed in patients treated with H-RT.

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.

PURPOSE: To determine if iridium implant (IM) and external-beam radiation therapy (EBRT) is better than standard EBRT in locally advanced prostate cancer. METHODS: Patients with T2 and T3 prostate cancer with no evidence of metastatic disease were randomly assigned to EBRT of 66 Gy in 33 fractions during 6.5 weeks or to IM of 35 Gy delivered to the prostate during 48 hours plus EBRT of 40 Gy in 20 fractions during 4 weeks. The primary outcome consisted of biochemical or clinical failure (BCF). BCF was defined by biochemical failure, clinical failure, or death as a result of prostate cancer. Secondary outcomes included 2-year postradiation biopsy positivity, toxicity, and survival. RESULTS: Between 1992 and 1997, 51 patients were randomly assigned to receive IM plus EBRT, and 53 patients were randomly assigned to receive EBRT alone. The median follow-up was 8.2 years. In the IM plus EBRT arm, 17 patients (29%) experienced BCF compared with 33 patients (61%) in the EBRT arm (hazard ratio, 0.42; P = .0024). Eighty-seven patients (84%) had a postradiation biopsy; 10 (24%) of 42 in the IM plus EBRT arm had biopsy positivity compared with 23 (51%) of 45 in the EBRT arm (odds ratio, 0.30; P = .015). Overall survival was 94% in the IM plus EBRT arm versus 92% in the EBRT arm. CONCLUSION: The combination of IM plus EBRT was superior to EBRT alone for BCF and postradiation biopsy. This trial provides evidence that higher doses of radiation delivered in a shorter duration result in better local as well as biochemical control in locally advanced prostrate cancer.

BACKGROUND: Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT. METHODS: PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258. FINDINGS: We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe. INTERPRETATION: In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited. FUNDING: Accuray.