Prostate cancer is the second most commonly diagnosed cancer in men worldwide and the fifth leading cause of cancer-related death in men [1]. In Chile, it is the most frequently diagnosed malignancy among men, with an incidence rate of 56.7 per 100,000 and 8,157 new cases reported in 2020 [1]. Radical prostatectomy (RP) is a standard curative treatment for localized prostate cancer, yet a significant number of patients recur after surgery. Approximately 5%–20% of men have biochemical persistence (detectable prostate-specific antigen [PSA] level post-prostatectomy), indicating residual disease [2]. Additionally, about one-third of men will develop a delayed biochemical recurrence (BCR) within 10 years of surgery [3]. These PSA-defined recurrences can signify local residual disease in the prostate bed and/or occult metastatic spread to regional lymph nodes. Clinical evidence indicates that the prostate bed is a common site of relapse after surgery, and a considerable subset of patients with post-prostatectomy BCR harbor subclinical nodal metastases in the pelvis [4,5]. Such patterns of failure underscore the rationale for postoperative radiotherapy to eradicate residual local-regional disease.

Salvage radiation therapy (SRT) to the prostate bed is a potentially curative intervention for patients with rising PSA after RP, and its use has been shown to improve long-term outcomes. In the absence of adjuvant or salvage radiotherapy, 10-year biochemical failure rates exceed 60% in men with adverse pathological features, whereas the addition of postoperative radiotherapy roughly halves the risk of recurrence [6-8]. Several studies have established that administering SRT early (at low PSA levels) yields superior disease control and lower all-cause mortality compared to delayed intervention, and current guidelines advocate early SRT in men with BCR after RP [9,10]. Moreover, accumulating evidence supports the inclusion of the pelvic lymph nodes within the salvage radiation field. The recent NRG Oncology SPPORT trial demonstrated that, in men with detectable PSA after prostatectomy, adding short-term androgen deprivation therapy (ADT) and whole-pelvic radiotherapy to prostate bed SRT significantly improved progression-free survival compared to prostate bed irradiation alone [11]. Similarly, in the primary definitive setting, the POP-RT Phase III trial showed that prophylactic whole-pelvis irradiation improved biochemical failure-free and disease-free survival in high-risk prostate cancer relative to prostate-only radiation [12]. This data confirms that targeting sites with potential microscopic nodal disease offers clinical benefit and reinforces the rationale for treating the pelvic lymph nodes in the post-prostatectomy setting when there are risk factors for regional relapse.

Moderately hypofractionated radiation therapy to the prostate bed [13] and pelvic lymph nodes [12,14-17] has emerged as a safe, effective, and convenient alternative to conventional fractionation. Multiple studies [12,14-17] suggest that hypofractionated whole-pelvic radiation therapy (WPRT) can provide favorable disease control with an acceptable toxicity profile.

Building on the success of moderate hypofractionation, there is growing interest in exploring ultra-hypofractionated schedules in the postoperative setting. Ultra-hypofractionation, in the form of stereotactic body radiotherapy (SBRT), delivers a highly conformal radiation dose in five fractions. This extreme hypofractionation offers multiple potential advantages. First, by delivering a high biologically effective dose in a shortened overall treatment time, SBRT can improve patient convenience and resource utilization without compromising efficacy [18]. Second, from a radiobiological perspective, prostate cancer is characterized by a low alpha/beta ratio (~1.5 Gy), indicating greater sensitivity to larger doses per fraction [18]. In the definitive (intact prostate) setting, SBRT has already been validated in clinical trials as a safe and effective treatment, with outcomes comparable to longer courses of radiation [19]. Recent data also support the feasibility of SBRT for WPRT, with excellent regional control and a safe toxicity profile [20,21].

The purpose of this study is to evaluate acute toxicity and quality of life (QoL) outcomes in post-prostatectomy patients treated with ultra-hypofractionated radiation to the prostate bed and pelvic lymph nodes. Reporting the safety profile and patient-reported QoL with stereotactic pelvic radiation contributes to the evidence base supporting this salvage treatment approach and informs future comparative trials.

The decision to irradiate both the prostate bed and pelvic lymph nodes in the salvage setting is supported by growing high-level evidence. The NRG SPPORT trial demonstrated that the addition of short-term ADT and whole-pelvis radiotherapy to salvage prostate bed radiation therapy significantly improved progression-free survival in men with BCR after prostatectomy [11]. More recently, the PEACE V–STORM phase 2 trial further validated the benefit of pelvic nodal irradiation in patients with PET-detected oligorecurrent nodal disease. In that study, elective nodal radiotherapy significantly improved 4-year metastasis-free survival by 13% compared to metastasis-directed therapy alone, without increasing high-grade toxicity [14]. These findings reinforce the oncologic rationale for targeting subclinical nodal disease in the pelvis and support our institutional strategy of combining prostate bed and pelvic lymph node radiation therapy in appropriately selected postoperative patients.

In parallel, fractionation strategies in the postoperative setting have progressively evolved from conventionally fractionated radiotherapy to moderate hypofractionation. The randomized NRG-GU003 trial demonstrated that hypofractionated post-prostatectomy radiotherapy was a well-tolerated regimen, with no sustained increase in GU or GI toxicity at longer follow-up [22]. More recently, prospective data suggest that extreme hypofractionation in the postoperative setting is feasible, with short-course salvage radiotherapy delivered over weeks rather than months without a significant worsening of acute patient-reported toxicity [23]. Additionally, an extreme hypofractionation approach using SBRT offers increased efficiency and convenience. Ultra-hypofractionation significantly reduces overall treatment time compared to conventional fractionation. Standard postoperative radiotherapy typically requires 66–70 Gy in 33–35 fractions over 6.5–7 weeks, which is burdensome for patients and resource-intensive for facilities. In contrast, the SBRT regimen completes treatment in approximately 2 to 3 weeks. This shortened schedule reduces strain on radiotherapy equipment and staff and lowers barriers to patient access. Literature increasingly recognizes the value of such regimens for optimizing resource utilization. A multicenter prospective study reported that extended treatment courses require substantial machine time and personnel effort, potentially limiting access and increasing costs. Ultra-hypofractionated approaches have been shown to decrease equipment use, improve patient convenience, and expand access without compromising efficacy [24].

In this context, characterized by the demonstrated tolerability of postoperative hypofractionation and the potential efficiency benefits of ultra-hypofractionated delivery, our decision to prescribe 30 Gy in 5 fractions to the prostate bed was guided by radiobiological considerations and evidence from conventionally fractionated salvage radiotherapy. Assuming a low α/β ratio for prostate cancer of approximately 1.5 Gy, a dose of 30 Gy delivered in five fractions corresponds to an equivalent dose in 2-Gy fractions of approximately 64 Gy, aligning with the conventional-dose arm of the SAKK 09/10 randomized phase III trial. In that study, salvage radiotherapy to 64 Gy in 32 fractions was non-inferior to dose escalation to 70 Gy with respect to biochemical progression-free survival and was associated with lower GI toxicity [25].

PTV margin selection in the postoperative prostate bed SBRT setting requires particular consideration. The prostate bed is subject to substantial inter-fraction variability driven by bladder and rectal filling as well as surgical bed deformation. In CBCT-guided prostate bed SBRT, most prospective protocols—including SCIMITAR and the UCLA phase II experience—have adopted a 5-mm isotropic CTV-to-PTV expansion [26-28]. In CT/CBCT-guided prostate bed SBRT, prospective series have shown that despite pre- and mid-fraction CBCT, the use of 5-mm margins results in adequate CTV coverage (CTV V95 ≥93%) in only approximately 70%–72% of patients or fractions, with loss of coverage primarily related to CTV shape deformation rather than translational setup error [26,27]. Accordingly, a 5-mm isotropic CTV-to-PTV expansion per institutional protocol was applied together with standardized bladder and rectal preparation and daily CBCT soft-tissue matching to account for postoperative geometric uncertainty while maintaining OAR constraints.

Early prospective data support the feasibility and tolerability of ultra-hypofractionated SBRT to the prostate bed in the postoperative setting. The POPART multicenter prospective study evaluated linac-based salvage SBRT delivering 32.5 Gy in five fractions to the prostate bed and reported no acute grade ≥2 GU toxicity, with low rates of late grade ≥2 GU toxicity (7.5%) and minimal GI toxicity at a median follow-up of 19.6 months [24]. No clinically meaningful deterioration in patient-reported outcomes was observed, and biochemical recurrence-free survival rates were 96.3%, 90.0%, and 85.3% at 6, 12, and 18 months, respectively, supporting both tolerability and short-term oncologic control with postoperative SBRT. Similarly, the SCIMITAR phase II trial demonstrated the feasibility of postoperative SBRT using prostate bed doses in the range of 30–34 Gy delivered in five fractions, with acceptable acute toxicity and preservation of QoL. Although a subset of patients received elective pelvic nodal irradiation and higher prostate bed boost doses, overall acute GI and GU toxicity remained low, further supporting the safety of this dose range in the postoperative SBRT context [28]. In addition, the SHORTER randomized phase II trial evaluated extreme hypofractionation for salvage radiotherapy and demonstrated that delivery of postoperative radiation in 5 fractions was not associated with significantly worse acute patient-reported GU or GI toxicity compared with longer hypofractionated schedules, reinforcing the feasibility of short-course postoperative radiotherapy approaches [23].

The rationale for delivering 25 Gy in five fractions to elective pelvic lymph nodes is primarily derived from prospective SBRT experience in patients with intact prostate cancer. Multiple prospective series and consortium-based analyses have evaluated ultra-hypofractionated pelvic nodal irradiation using 25 Gy in five fractions in combination with prostate SBRT, consistently reporting excellent regional pelvic control and acceptable GI and GU toxicity when delivered with contemporary planning and image guidance. A recent systematic review of pelvic nodal SBRT identified 25 Gy in five fractions as the most commonly adopted elective nodal dose, with acute grade ≥2 GI toxicity generally ≤10% and late grade ≥3 toxicity uncommon across studies [29]. In particular, pooled prospective data from the SHARP consortium [21] demonstrated near-universal pelvic nodal control using this regimen, supporting the biological adequacy of 25 Gy in five fractions for elective nodal irradiation in the ultra-hypofractionated setting. In contrast, evidence supporting ultra-hypofractionated pelvic nodal irradiation in the postoperative setting remains limited. Available prospective postoperative SBRT experiences incorporating elective pelvic nodal irradiation have been restricted to small cohorts and heterogeneous treatment paradigms. Among these, the SCIMITAR multicenter phase II trial included elective pelvic nodal SBRT in a subset of post-prostatectomy patients treated with prostate bed SBRT, demonstrating low rates of acute toxicity and feasibility when delivered with modern image-guided techniques [28]. More recently, Montero et al. [30] reported a prospective postoperative SBRT experience delivering 36.25 Gy in five fractions to the prostate bed with concurrent pelvic nodal irradiation to 26 Gy in five fractions, observing acceptable acute and early-late GI and GU toxicity without unexpected adverse events at a median follow-up of approximately 2 years. Taken together, although direct postoperative data evaluating 25 Gy in five fractions to pelvic lymph nodes remain limited, the consistency of intact-prostate SBRT outcomes and emerging postoperative feasibility data support extrapolation of this nodal dose.

Our findings indicate that ultra-hypofractionated postoperative pelvic radiotherapy (SBRT) yields low acute toxicity and favorable QoL outcomes. Acute GU and GI toxicities were predominantly mild, with few grade 2 events and no severe (grade ≥ 3) complications observed. Patient-reported QoL metrics showed low levels of urinary, bowel, and hormonal symptoms, along with intermediate sexual function scores, reflecting an overall acceptable QoL profile in the short term. The consistent adherence to OAR constraints across nearly all patients further supports the safety of the protocol. All evaluable plans (98.4%) met institutional dose objectives. Mean rectal D1cm³ remained well below the 36 Gy threshold (3,000.7 cGy), and bowel and bladder exposure was similarly conservative. This uniformity in dose delivery likely contributed to the low observed rates of acute GI and GU toxicity. These results reinforce the tolerability of delivering a high biological dose in a condensed treatment schedule in the post-prostatectomy setting. Our acute toxicity outcomes are consistent with those reported in contemporary postoperative prostate bed SBRT series. In the SCIMITAR multicenter phase II trial, which prospectively evaluated post-prostatectomy SBRT using CT- and magnetic resonance (MR)–guided platforms, acute grade ≥2 GI and GU toxicity rates were 5% and 9%, respectively, with improved GI toxicity observed in the MR-guided cohort [28]. However, elective pelvic nodal irradiation was delivered in approximately 27% of patients, and prostate bed boost doses of 36.25–40 Gy were used in a similar proportion, factors that may have contributed to lower acute GI toxicity and slightly higher acute GU toxicity compared with our cohort. The POPART study reported very low acute toxicity following postoperative ablative radiotherapy to the prostate bed alone, with no acute grade ≥2 GU toxicity and approximately 5% grade 2 GI toxicity, and no grade ≥3 acute events [24]. The lower GI toxicity observed in POPART is likely, in part, attributable to the absence of elective pelvic nodal irradiation, which limits direct comparability with our treatment volumes. In the intact prostate setting, the SHARP consortium reported low rates of acute toxicity following five-fraction pelvic nodal SBRT in patients with high-risk prostate cancer, with approximately 12% grade 2 GI toxicity and 3% grade 2 GU toxicity, and no grade ≥3 acute events, despite elective nodal irradiation [31]. Although the intact prostate and postoperative settings are not directly comparable, these data provide supportive evidence for the tolerability of pelvic SBRT when delivered with modern planning techniques.

In exploratory dose–outcome analyses, no significant associations were identified between rectal or bladder dose–volume parameters and acute grade ≥2 GI or GU toxicity, suggesting that the applied dose constraints were effective in mitigating early treatment-related toxicity. A single biologically plausible association was observed between higher mean dose to the penile bulb and lower sexual functioning scores. Although exploratory and based on a limited number of evaluable patients, this finding aligns with prior observations regarding the dose sensitivity of erectile structures and supports continued attention to penile bulb dose during treatment planning [32].

Several limitations of this study should be acknowledged. The retrospective design introduces inherent selection biases and relies on the accuracy of medical record documentation. The absence of a prospective trial increases the risk of under-reporting or inconsistencies in toxicity grading and QoL assessment. Regarding baseline GU symptoms, all patients had undergone prostatectomy, and many exhibited pre-existing GU issues such as urinary frequency or incontinence unrelated to radiation. This complicates the distinction between radiation-induced lower urinary tract symptoms and those attributable to the surgical baseline [24]. Consequently, some mild urinary toxicities recorded, such as grade 1 frequency, may reflect ongoing post-surgical dysfunction rather than new treatment-induced symptoms. In addition, the retrospective nature of toxicity reporting precluded precise characterization of symptom onset, peak severity, and duration, as these details were not consistently documented in clinical records. Furthermore, acute toxicity was abstracted from routine clinical documentation rather than prospectively collected at predefined time points, which may have led to underestimation of transient or mild symptoms. It is important to note that QoL was assessed only at the last follow-up, without a pre-treatment baseline for comparison. This limitation restricts the ability to quantify treatment-related changes, and pooling responses introduces heterogeneity in timing. As all patients completed the survey at least 6 months post-treatment, these post-treatment quality-of-life measures can be interpreted in the context of prior prospective studies suggesting that early quality-of-life metrics are broadly reflective of longer-term patient-reported outcomes. In the SATURN trial, which evaluated five-fraction definitive SBRT to the prostate and pelvic lymph nodes, minimal differences in urinary and bowel domain scores were observed between 3 and 24 months post-treatment [33]. A similar trend was observed in the CHHiP QoL substudy [34], which reported little change in patient-reported outcomes between the 6-month and 5-year time points in the intact-prostate setting using moderately hypofractionated radiotherapy. Although the present data are cross-sectional, they provide preliminary support for the tolerability of this approach.

In addition, the widespread use of ADT in this cohort represents a potential confounding factor for patient-reported urinary, hormonal, and sexual outcomes. ADT was administered to 77.0% of patients, with variable duration and timing relative to radiotherapy. ADT is known to independently affect sexual function, hormonal symptoms, and (to a lesser extent) urinary quality-of-life domains, which limits the ability to attribute patient-reported outcomes solely to radiation treatment [35]. Accordingly, quality-of-life results should be interpreted in the context of combined-modality therapy rather than as isolated radiation effects.

Within these limitations, this study provides one of the largest contemporary postoperative experiences combining prostate bed and elective pelvic nodal SBRT. Our results demonstrate that this approach can be delivered with low acute toxicity, acceptable QoL, and consistent adherence to OAR constraints. Together with emerging prospective data, these findings support the tolerability of postoperative pelvic SBRT and provide a robust foundation for our ongoing prospective study, which will further characterize toxicity and quality-of-life outcomes in this patient population.

Ultra-hypofractionated radiotherapy to the prostate bed and pelvic lymph nodes using SBRT appears to be a well-tolerated and feasible salvage strategy in the postoperative setting. In this cohort, acute toxicity was low and short-term QoL outcomes were acceptable, with minimal symptom burden and preserved functional scores. All treatment plans met predefined OAR constraints, underscoring the technical feasibility of safely delivering combined prostate bed and pelvic nodal SBRT using contemporary planning and image guidance. While these findings should be interpreted in the context of the retrospective design and limited follow-up, they contribute meaningful real-world evidence supporting ultra-hypofractionated postoperative pelvic radiotherapy. An ongoing prospective study at our institution incorporating standardized longitudinal toxicity and quality-of-life assessment is currently underway and will further clarify long-term safety, patient-reported outcomes, and oncologic efficacy of this approach.