Phase 3 Trial of Stereotactic Body Radiotherapy in Localized Prostate Cancer.

BACKGROUND: Whether stereotactic body radiotherapy (SBRT) is noninferior to conventionally or moderately hypofractionated regimens with respect to biochemical or clinical failure in patients with localized prostate cancer is unclear. METHODS: We conducted a phase 3, international, open-label, randomized, controlled trial. Men with stage T1 or T2 prostate cancer, a Gleason score of 3+4 or less, and a prostate-specific antigen (PSA) level of no more than 20 ng per milliliter were randomly assigned (in a 1:1 ratio) to receive SBRT (36.25 Gy in 5 fractions over a period of 1 or 2 weeks) or control radiotherapy (78 Gy in 39 fractions over a period of 7.5 weeks or 62 Gy in 20 fractions over a period of 4 weeks). Androgen-deprivation therapy was not permitted. The primary end point was freedom from biochemical or clinical failure, with a critical hazard ratio for noninferiority of 1.45. The analysis was performed in the intention-to-treat population. RESULTS: A total of 874 patients underwent randomization at 38 centers (433 patients in the SBRT group and 441 in the control radiotherapy group) between August 2012 and January 2018. The median age of the patients was 69.8 years, and the median PSA level was 8.0 ng per milliliter; the National Comprehensive Cancer Network risk category was low for 8.4% of the patients and intermediate for 91.6%. At a median follow-up of 74.0 months, the 5-year incidence of freedom from biochemical or clinical failure was 95.8% (95% confidence interval [CI], 93.3 to 97.4) in the SBRT group and 94.6% (95% CI, 91.9 to 96.4) in the control radiotherapy group (unadjusted hazard ratio for biochemical or clinical failure, 0.73; 90% CI, 0.48 to 1.12; P = 0.004 for noninferiority), which indicated the noninferiority of SBRT. At 5 years, the cumulative incidence of late Radiation Therapy Oncology Group (RTOG) grade 2 or higher genitourinary toxic effects was 26.9% (95% CI, 22.8 to 31.5) with SBRT and 18.3% (95% CI, 14.8 to 22.5) with control radiotherapy (P<0.001), and the cumulative incidence of late RTOG grade 2 or higher gastrointestinal toxic effects was 10.7% (95% CI, 8.1 to 14.2) and 10.2% (95% CI, 7.7 to 13.5), respectively (P = 0.94). CONCLUSIONS: Five-fraction SBRT was noninferior to control radiotherapy with respect to biochemical or clinical failure and may be an efficacious treatment option for patients with low-to-intermediate-risk localized prostate cancer as defined in this trial. (Funded by Accuray and others; PACE-B ClinicalTrials.gov number, NCT01584258.).

Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial.

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.

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.

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.

Radical Prostatectomy Versus Stereotactic Radiotherapy for Clinically Localised Prostate Cancer: Results of the PACE-A Randomised Trial.

BACKGROUND AND OBJECTIVE: Randomised data on patient-reported outcomes (PROs) for stereotactic body radiotherapy (SBRT) and prostatectomy in localised prostate cancer are lacking. PACE-A compared patient-reported health-related quality of life after SBRT with that after prostatectomy. METHODS: PACE is a phase 3 open-label, randomised controlled trial. PACE-A randomised men with low- to intermediate-risk localised prostate cancer to SBRT or prostatectomy (1:1). Androgen deprivation therapy (ADT) was not permitted. The coprimary outcomes were the Expanded Prostate Index Composite (EPIC-26) number of absorbent urinary pads required daily and bowel domain score at 2 yr. The secondary endpoints were clinician-reported toxicity, sexual functioning, and other PROs. KEY FINDINGS AND LIMITATIONS: In total, 123 men were randomised (60 undergoing prostatectomy and 63 SBRT) from August 2012 to February 2022. The median follow-up time was 60.7 mo. The median age was 65.5 yr and the median prostate-specific antigen (PSA) value 7.9 ng/ml; 92% had National Comprehensive Cancer Network (NCCN) intermediate-risk disease. Fifty participants received prostatectomy and 60 received SBRT. At 2 yr, 16/32 (50%) prostatectomy and three of 46 (6.5%) SBRT participants used one or more urinary pads daily (p < 0.001; 15 and two, respectively, used one pad daily); the estimated difference was 43% (95% confidence interval [CI]: 25%, 62%). At 2 yr, bowel scores were better for prostatectomy (median [interquartile range] 100 [100-100]) than for SBRT (87.5 [79.2-100]; p < 0.001), with an estimated mean difference of 8.9 between these (95% CI: 4.2, 13.7); sexual scores were worse for prostatectomy (18 [13.8-40.3]) than for SBRT (62.5 [32.0-87.5]). The limitations were slow recruitment and incomplete 2-yr PRO response rates. CONCLUSIONS AND CLINICAL IMPLICATIONS: SBRT was associated with less patient-reported urinary incontinence and sexual dysfunction, and slightly more bowel bother than prostatectomy. These randomised data should inform treatment decision-making for patients with localised, intermediate-risk prostate cancer.