RIsk aDapted Stereotactic Radiotherapy vs. standarD of Care Radiotherapy in Patients With Prostate Cancer in the Adjuvant or saLvage sEtting With or Without Lymph Node Irradiation (RIDDLELN) - A Phase III Trial

Prostate cancer is among the most common cancers in men, and for localised disease both radical prostatectomy and radiotherapy are established curative local treatments. After radical prostatectomy, however, a substantial proportion of patients, roughly 30 to 60%, will eventually develop recurrent disease. For men at increased risk of local recurrence (for example those with extraprostatic extension, positive surgical margins, or a rising prostate-specific antigen after surgery), radiotherapy directed at the prostate bed improves oncological outcomes. This may be given as adjuvant treatment shortly after surgery or as salvage treatment when biochemical or macroscopic recurrence becomes apparent. With modern high-sensitivity PSA testing and PSMA-PET/CT imaging, early salvage radiotherapy has been shown to yield oncological results comparable to immediate adjuvant radiotherapy, allowing many patients to avoid or defer treatment until it is clearly needed. Historically, postoperative radiotherapy to the prostate bed has been delivered with conventional fractionation, using approximately 2 Gy per fraction over six to seven weeks. The biological rationale for exploring fewer, larger fractions rests on the radiobiology of prostate cancer, which is characterised by a low estimated α/β ratio of around 1.5 Gy. A low α/β implies that prostate tumour cells are comparatively sensitive to larger doses per fraction, so hypofractionation is expected to preserve, and potentially improve, the therapeutic ratio between tumour control and normal-tissue toxicity, while shortening overall treatment time. Moderate hypofractionation (fraction doses up to about 3 Gy) in the postoperative setting has been evaluated in several analyses and in phase III trials, showing acceptable and broadly similar toxicity compared with conventional fractionation. The large phase III NRG Oncology GU003 trial demonstrated non-inferiority of moderate hypofractionation with respect to patient-reported genitourinary and gastrointestinal quality of life at 24 months, and a subgroup analysis of the RADICALS trial found comparable outcomes between normofractionation and mild hypofractionation. As a result, moderate hypofractionation has been adopted as a standard option in many centres. Ultra-hypofractionated stereotactic body radiotherapy (SBRT), which delivers high doses in five or fewer fractions with steep dose gradients and image guidance, is well established for definitive treatment of the intact prostate in low-risk and intermediate-risk disease, with mature data showing excellent biochemical control and low rates of high-grade toxicity; encouraging results are also emerging in higher-risk disease. In the postoperative prostate bed, however, the evidence for SBRT is more limited, deriving mainly from retrospective series and early-phase studies. Historically there were concerns about extreme hypofractionation in this region, particularly regarding the vesicourethral anastomosis. Reported acute and late genitourinary and gastrointestinal toxicity rates after prostate-bed SBRT nonetheless fall within the ranges observed with mild or moderate hypofractionation, and the highest reported rates have generally been associated with the most dose-escalated regimens. For patients at high risk of nodal involvement, additional irradiation of the pelvic lymphatic drainage may improve oncological outcomes. Phase I and phase II data on ultra-hypofractionated irradiation of the lymphatic drainage in the context of definitive prostate SBRT suggest acceptable toxicity, and supportive evidence for pelvic ultra-hypofractionation also comes from other pelvic tumour entities such as rectal cancer, where short-course radiotherapy to large pelvic volumes is a recognised standard. Nevertheless, there is little data on an ultra-hypofractionated approach in the postoperative setting, and simultaneous treatment of the prostate bed together with the lymphatic drainage using such a schedule has not previously been investigated in a randomised trial. A direct, randomised comparison of SBRT versus mildly hypofractionated standard-of-care radiotherapy to the prostate bed, with or without nodal irradiation, is therefore lacking. RIDDLELN is designed to fill this gap by evaluating whether a risk-adapted, ultra-hypofractionated SBRT approach is non-inferior to the current standard of care in terms of patient-reported quality of life, while offering a substantially shorter overall treatment course. Overall study design RIDDLELN is a prospective, randomised, open-label, two-arm, non-inferiority trial. Eligible participants are allocated in a 1:1 ratio to the experimental arm (SBRT) or the control arm (standard-of-care radiotherapy). A randomised controlled design was chosen to allow an unbiased comparison of the two fractionation approaches in the postoperative setting. Because the two techniques differ visibly in the number of treatment sessions and overall duration, blinding of patients and treating physicians is not feasible. To minimise bias, the trial uses randomisation with a 1:1 allocation ratio, stratification by clinically relevant factors, standardised treatment protocols with predefined dose constraints and centralised delineation guidance, validated patient-reported outcome instruments, standardised follow-up schedules, and uniform adverse-event grading according to CTCAE version 5.0. Before randomisation, participants are stratified by three factors: concomitant androgen deprivation therapy, irradiation of the lymphatic drainage, and planned use of a boost to a macroscopic recurrence. These factors reflect the main sources of heterogeneity in treatment intensity and are balanced across the two arms. Treatment arms In the experimental arm, SBRT is delivered to the prostate bed using 6 Gy per fraction in five fractions on consecutive working days, corresponding to a 2-Gy equivalent dose (EQD2) of 64.3 Gy at an α/β of 1.5. The entire course is completed within approximately one week. Where a macroscopic recurrence is present, an optional simultaneous integrated boost of up to 6.8 Gy per fraction over five fractions may be delivered in accordance with departmental standards. For patients with an indication for treatment of the lymphatic drainage (for example a Roach score above 20% and/or clinical or pathological node-positive disease), a simultaneous integrated boost of 5 Gy per fraction over five fractions is delivered to the lymphatic drainage, and involved lymph nodes may receive up to 6.8 Gy per fraction over five fractions. In the control arm, standard-of-care radiotherapy is delivered to the prostate bed using 2.625 Gy per fraction in twenty fractions (total 52.5 Gy; EQD2 61.95 Gy) on consecutive working days, over approximately four weeks. Where a macroscopic recurrence is present, an optional simultaneous integrated boost of up to 3 Gy per fraction over twenty fractions to a cumulative total of 60 Gy may be delivered. For patients with an indication for treatment of the lymphatic drainage, a simultaneous integrated boost of 2.2 Gy per fraction over twenty fractions is delivered to the lymphatic drainage, and involved lymph nodes may receive up to 3 Gy per fraction over twenty fractions. The dose concepts of both arms were selected to be iso-effective to the historic normofractionated standard of care, using the 2-Gy equivalent dose framework; the control-arm prescription of 52.5 Gy corresponds to established postoperative schedules. Because the optimal fractionation for boosts to a macroscopic recurrence or to positive lymph nodes is less clearly defined, a range was permitted to match departmental standards. The central distinction between the two arms is therefore not the biologically effective tumour dose, which is comparable, but the fractionation and the resulting overall treatment time. Treatment planning and delivery Participants are immobilised in a stable supine position using a device that ensures reproducible set-up and comfort during simulation and treatment, and that permits CT and/or MR imaging without interfering with dose calculation or delivery. Additional devices such as a urinary catheter, rectal balloon, or fiducial markers may be used at the discretion of the treating physician. All participants undergo a treatment-planning CT with a slice width of 2 mm or less, which serves as the primary image platform for target and organ-at-risk delineation; MRI and PSMA-PET/CT may be co-registered to support target definition. Target volumes are defined according to published consensus guidelines. The clinical target volume of the prostate fossa, any macroscopic recurrence, and, where indicated, the nodal target volumes are contoured and expanded by defined margins to generate the corresponding planning target volumes. Organs at risk, including the bladder, rectum, urethra, vesicourethral anastomosis, penile bulb, femoral heads, and bowel, are contoured according to institutional and consensus standards, with predefined dose constraints specified separately for each treatment arm. Dose prescription adheres to ICRU 83 standards, with defined coverage requirements and rules for permissible coverage reductions to respect organ-at-risk constraints; reduction of the prescription dose itself is not permitted. Treatment planning uses at least a type C dose-calculation algorithm with intensity-modulated radiotherapy delivered by static, rotational, or robotic techniques, and on-board cone-beam CT imaging is performed before and after each fraction, where available, to correct set-up errors. Study procedures and follow-up After written informed consent, screening procedures include review of eligibility, review of imaging, medical history, current PSA, performance status, medication, adverse-event assessment, and completion of patient-reported outcome questionnaires. During treatment, performance status, medication, and adverse events are recorded, and patient-reported outcomes are collected. Participants are then followed for up to five years, with assessments at the end of treatment; at 3, 6, 12, 18, and 24 months; and yearly thereafter up to five years. At each follow-up visit, performance status, medication, adverse events (CTCAE v5.0), and patient-reported outcomes are recorded, and PSA and imaging are obtained as clinically indicated from twelve weeks after radiotherapy onwards. Radiological imaging at follow-up is performed when clinically indicated rather than at fixed intervals, and no biological material is collected or stored as part of the trial; only routine PSA determination is used. Statistical methodology The primary analysis population is the intention-to-treat population, comprising all randomised participants; a per-protocol analysis is performed as a sensitivity analysis for the primary endpoints. The analysis of the primary endpoint and a first analysis of the secondary endpoints are performed once all participants have completed their two-year follow-up or are lost to follow-up, and the secondary endpoints are re-evaluated after five years of follow-up. The co-primary quality-of-life outcomes are analysed using analysis of covariance (ANCOVA), with the 24-month score as the outcome, the corresponding baseline score as a covariate, and treatment group together with the stratification factors as further explanatory variables. Non-inferiority is assessed within a pre-specified framework using a one-sided significance level of 0.025 and a targeted conjunctive power of 0.8. Because both null hypotheses (for the urinary and the bowel domain) must be rejected simultaneously for the trial to be considered positive, no adjustment of the type I error rate is required across the two co-primary endpoints; to achieve the stated conjunctive power, the sample size is derived at higher power for each individual endpoint. Secondary endpoints are analysed with methods appropriate to their nature. Toxicity endpoints are compared between groups using a generalized linear model with a negative binomial link function, accompanied by descriptive analysis of the number and types of events. Longitudinal quality-of-life data are analysed using linear mixed models to characterise the evolution of scores over time, complemented by descriptive analysis at each time point. Time-to-event endpoints are analysed using Kaplan-Meier estimates, with treatment arms compared by stratified log-rank tests and hazard ratios obtained from Cox proportional-hazards models. Analyses of secondary endpoints are adjusted for the stratification factors and reported with corresponding confidence intervals. Missing data are handled according to pre-specified rules that consider whether data are missing completely at random, at random, or not at random, with appropriate imputation or model-based handling and sensitivity analyses to assess robustness. Study drop-outs are not replaced, and an anticipated drop-out rate of approximately 10% is incorporated into the sample-size calculation. A total of 206 participants are planned. Analyses are performed in the R statistical environment using a fully scripted, reproducible workflow, with a detailed statistical analysis plan finalised before database lock, and results reported in accordance with the CONSORT guideline. Setting, duration, oversight, and relevance The trial is conducted at the Department of Radiation Oncology of the Cantonal Hospital Winterthur, with the possibility that further centres may participate; recruitment is distributed across participating centres without increasing the total planned sample size. The expected overall study duration is approximately eight years, comprising a recruitment period of up to three years and a follow-up period of up to five years, with an individual participant duration of about five years from the start of radiotherapy. Accrual may be interrupted or the trial stopped early if new scientific data materially change the risk-benefit assessment. The study is conducted in compliance with the study protocol, the current version of the Declaration of Helsinki, ICH-GCP, and applicable Swiss legislation, and is registered in a WHO primary registry as well as in the Swiss registration system. Its purpose is to generate generalisable, clinically relevant evidence on whether a markedly shorter, precision-based postoperative radiotherapy approach can maintain quality of life and disease control relative to the current standard, with potential benefits including reduced treatment burden, fewer hospital visits, and lower indirect costs for patients.