RE-irradiation for Isolated FOCal Recurrence of Prostate Cancer With Ultrahypofracted SBRT (RE-FOCUS)

One of the most common sites of recurrence is locally in the prostate gland in case of radiotherapy (RT) as primary treatment, and in the prostate bed in case of surgery as primary treatment. In case of PSA persistence or recurrence after surgery as primary treatment, international guidelines recommend salvage RT as the treatment of choice[7]. But what does international guidelines suggest in case of a clinically confirmed local recurrence after an RT course (either curative or salvage)? This presents a significant clinical challenge, as locally radiorecurrent prostate cancer has emerged as the fourth most common genitourinary malignancy in men, following primary prostate cancer, bladder cancer, and kidney cancer[8]. International guidelines recommend various approaches-from monitoring to local therapy (e.g., surgery, high-intensity focused ultrasound, cryotherapy, re-irradiation) or lifelong castration with androgen deprivation therapy (ADT), with a negative impact on patients' quality of life (QoL) due to the wide range of associated side effects. While salvage prostatectomy has been the traditional curative approach, its high morbidity has driven exploration of alternatives like re-irradiation (re-RT) to improve control and reduce adverse events.

Stereotactic body RT (SBRT) has emerged as a promising, curative, non-invasive salvage option, offering precise re-RT with minimal adverse events, as international guidelines suggest. Valle et al.[9] meta-analysis reported no significant differences in 5-year recurrence-free survival among RP, high-intensity focused ultrasound, cryotherapy, and re-RT techniques via brachytherapy (BT) and SBRT. However, re-RT with SBRT was associated with significantly lower genitourinary (GU) adverse events compared to RP, suggesting equivalent efficacy but potentially lower adverse events with re-RT. Similarly, a systematic review on re-RT for local failure after a prior RT showed a safe toxicity profile and promising overall mortality and biochemical control rates[10].

Furthermore, emerging data suggest that partial-prostate re-RT, targeting only the visible recurrent lesion rather than the entire prostate gland or prostate bed, may further reduce severe adverse events without compromising oncological efficacy.

Despite these promising developments, re-RT remains a complex therapeutic challenge requiring careful patient selection, meticulous dosimetric planning, and multidisciplinary clinical management. The cumulative radiation dose to organs at risk (OARs) from both the first radiotherapy course and the second must be carefully evaluated to minimize the risk of severe late adverse events, while delivering sufficient dose to achieve tumor control. Several SBRT techniques for ultrahypofractionated RT (UHRT, defined as >6 Gy per fraction) have been explored. From the early acute adverse events findings of the PACE-B trial, significantly lower RTOG grade 2 or worse GU adverse events were reported in the treatment arm with CyberKnife. This favorable adverse events likely reflects CyberKnife's capability for intrafraction motion management with digitally reconstructed radiographs (DRRs) throughout delivery and real-time beam corrections when deviations exceed tolerance thresholds, which enhance dose conformality to the target volume while improving dose falloff to adjacent OARs. These technical advantages, combined with demonstrated tumor control rates, should position CyberKnife as the preferred SBRT therapy for locally recurrent PCa following a prior RT course.