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.