A phase III, international, open-label, randomised, controlled PACE-B study showed the noninferiority of 5 fraction stereotactic body radiotherapy (SBRT) as compared with hypofractionated image-guided (control) radiotherapy, given that the 5-year incidence of freedom from biochemical or clinical failure was similar in the two groups, 96% with SBRT and 95% with control radiotherapy. It was achieved without androgen deprivation therapy (ADT) and exceeded the expectations of the study design.
The reduction in treatment fractions would alleviate the burden on healthcare systems while yielding favourable cancer control outcomes without the addition of hormonal treatment according to Dr. Nicholas van As of the Royal Marsden Hospital in London, UK and colleagues who published the findings on 16 October 2024 in The New England Journal of Medicine.
Hypofractionation, involving higher doses per treatment session, is appealing because of its potential to maintain the efficacy, but reduce the total number of treatment sessions, which could make the treatment more attractive to patients and healthcare systems. Previous studies have confirmed the noninferiority of moderately hypofractionated radiotherapy as compared with conventionally fractionated radiotherapy, and moderate hypofractionation has been established as a standard-of-care option. SBRT builds on these developments to allow ultrahypofractionated radiotherapy to be delivered with precision.
Prostate Advances in Comparative Evidence (PACE) is a platform trial evaluating 5 fraction SBRT in 3 independently randomised cohorts of patients with localised prostate cancer. PACE-A compares SBRT with surgery. PACE-B and PACE-C recruited patients who were suitable candidates for radical radiotherapy, but who were not suitable candidates for or who were unwilling to undergo radical prostatectomy. PACE-B included patients with low- and intermediate-risk disease, not warranting hormone therapy, and has already shown the safety of 5 fraction SBRT. PACE-C included patients with higher-risk disease receiving ADT.
In the latest article, the study team reports the primary analysis of PACE-B, which assessed the noninferiority of 5 fraction SBRT as compared with conventionally or moderately hypofractionated radiotherapy with respect to biochemical or clinical failure.
Patients with stage T1 or T2 prostate cancer, a Gleason score of 3 plus 4 or less, and a prostate specific antigen (PSA) level of no more than 20 ng per millilitre 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. ADT was not permitted. The primary endpoint was freedom from biochemical or clinical failure, with a critical hazard ratio (HR) for noninferiority of 1.45. The analysis was performed in the intention-to-treat population.
A total of 874 patients underwent randomisation at 38 centres (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 millilitre; the National Comprehensive Cancer Network (NCCN) 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 HR 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 side-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 side-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).
The study team previously found a significant difference in the incidence grade 2 or higher genitourinary side-effects at 2 years after treatment (12% with SBRT versus 7% with control radiotherapy). The updated 5-year toxicity analysis indicates a decrease in the incidence of these symptoms, with no significant differences between the two groups at 5 years, and low overall levels of side-effects.
Patients should be informed of the higher medium-term risk of genitourinary side-effects, especially patients with clinically significant lower urinary tract symptoms at baseline, who may have better outcomes with respect to symptoms with 20 fraction intensity-modulated radiotherapy than with SBRT. Patients with lower urinary tract symptoms at baseline or clinically significant acute side-effects are more likely to have long-term side-effects, facts that should allow for better patient selection for SBRT and that support careful counselling and monitoring of those with acute toxic symptoms.
The authors concluded that high 5-year incidence of biochemical control and the acceptable side-effect profile, coupled with the considerable advancements in radiotherapy delivery, underscore the potential of the use of SBRT in prostate cancer treatment. Radiotherapy for prostate cancer represents a substantial portion of the workload in radiotherapy departments worldwide. Transitioning patients with PACE-B eligibility criteria to a 5-fraction regimen could reduce the number of fractions administered. This regimen also minimises the socioeconomic and psychological burdens of treatment. In addition, patients with NCCN-defined low-risk disease and some patients with favourable intermediate risk disease could be considered for active surveillance.
The study was supported by funding from Accuray to the Royal Marsden NHS Foundation Trust for trial management, international study coordination, and data analysis. The National Institute for Health and Care Research (NIHR) provided support to facilitate trial recruitment at UK sites. Radiotherapy quality assurance was provided by the NIHR-funded National Radiotherapy Trials Quality Assurance Group. The Canadian Cancer Clinical Trials Network and Cure Prostate Cancer Canada provided funding in the form of infrastructure support and per-case funding to eligible clinical trials programmes for Canadian sites. The Institute of Cancer Research Clinical Trials and Statistics Unit receives programmatic grant funding from Cancer Research UK, which supported in part this endorsed trial.
Reference
van As N, Griffin C, Tree A, et al. Phase 3 Trial of Stereotactic Body Radiotherapy in Localized Prostate Cancer. N Engl J Med 2024;391:1413-1425.