Baseline vulnerability over dosimetric precision: reframing late urinary toxicity after prostate stereotactic body radiotherapy

Stereotactic body radiotherapy (SBRT) has rapidly evolved from a novel hypofractionated technique to an established standard option for men with low- and intermediate-risk prostate cancer. The phase III PACE-B trial confirmed its noninferior oncologic outcomes compared with conventionally fractionated radiotherapy and demonstrated comparable long-term side effects (1-3). However, a consistent observation has been a modestly higher incidence of early and intermediate-term genitourinary (GU) side effects following SBRT.

In this context, the detailed post hoc analysis of the SBRT arm of PACE-B by Ratnakumaran and colleagues provides important clarification regarding the drivers of late GU side effects (4). Their analysis delivers a compelling and clinically relevant message: baseline urinary function, rather than planned dosimetric exposure to urinary substructures, is the strongest predictor of late grade ≥2 GU side effects at 2 years.

This finding has significant implications for patient selection, counseling, and how radiation oncologists conceptualize risk of side effects in the era of precision radiotherapy.

The most consistent and statistically robust predictor identified in the study was baseline International Prostate Symptom Score (IPSS). Each incremental increase in baseline IPSS was associated with higher odds of grade ≥2 clinician-reported urinary side effects at 2 years. An exploratory receiver operating characteristic analysis suggested that an IPSS threshold of 11 provided optimal risk discrimination. Men with IPSS >11 experienced markedly higher rates of grade ≥2 toxicity compared with those at or below this threshold. This association remained significant after multivariable adjustment using cross-fit partialling-out least absolute shrinkage and selection operator (LASSO) regression techniques.

Baseline urinary medication usage and acute grade ≥2 GU toxicity were also independently associated with late toxicity. These findings reinforce a biologically plausible narrative: patients with pre-existing lower urinary tract vulnerability are more likely to manifest persistent dysfunction after SBRT. Radiotherapy may not necessarily induce de novo pathology in all cases but may instead exacerbate pre-existing subclinical or compensated urinary compromise. Moreover, the predictive role of acute toxicity for subsequent late events has been robustly demonstrated in a recent individual patient data meta-analysis of six randomized trials, confirming a significant interplay between acute and late GU toxicity after prostate radiotherapy, supporting the concept that early radiation-induced tissue injury may act as a precursor and amplifier of late damage rather than as a self-limiting phenomenon (5).

The clinical implications are immediate. IPSS is already widely used in routine prostate cancer evaluation. Unlike advanced imaging-derived metrics or complex dose-volume histogram (DVH) modeling, IPSS requires no additional infrastructure. It can therefore serve as a practical risk stratification tool during shared decision-making. For men with minimal baseline urinary symptoms, SBRT remains an attractive and convenient option. For those with moderate-to-severe baseline symptoms, these data suggest a higher probability of late toxicity, and moderate hypofractionation may warrant consideration.

Perhaps the most provocative aspect of the analysis is the absence of a consistent association between planned urinary substructure dose and late toxicity. Detailed evaluation of surrogate and contoured urethra (when available), bladder trigone, and bladder DVH parameters failed to demonstrate a consistent dose–response relationship for grade ≥2 GU toxicity.

This finding stands in contrast to prior pooled analyses and institutional reports suggesting correlations between urethral maximum dose and urinary toxicity (6-8). Several factors may explain the discrepancy. First, PACE-B employed strict protocol-driven dose guidance and rigorous quality assurance procedures. When dose variability is tightly constrained, the ability to detect a dose–response gradient diminishes. Second, the study relied on planned rather than delivered dose metrics. Interfractional bladder filling variability, trigone displacement, and urethral deformation may lead to a divergence between the planned and biologically effective delivered dose (9,10). Third, it is possible that within contemporary SBRT dose ranges, host biological susceptibility exerts greater influence than incremental dosimetric differences.

Importantly, the absence of a statistically significant association does not imply that substructure sparing lacks value. Rather, it may reflect successful standardization within safe therapeutic windows. If protective dose thresholds exist below those delivered in the trial, they would not be detectable within this dataset.

The association between acute and late GU side effects further supports a consequential late effect model. Patients experiencing grade ≥2 acute urinary side effects were significantly more likely to develop persistent symptoms. This observation aligns with prior radiobiological understanding that early inflammatory response may identify individuals with heightened radiosensitivity or impaired tissue recovery capacity (11). Clinically, this suggests that acute side effects should prompt intensified symptom management and surveillance.

The exploratory findings regarding the SBRT platform and fiducial use warrant careful interpretation. Conventional linear accelerator (LINAC) SBRT without fiducials was associated with lower odds of clinician-reported grade ≥2 side effects compared with conventional LINAC SBRT with fiducials. However, this association was not observed when IPSS-defined toxicity was used as the endpoint. Differences in medication prescribing patterns, grading behavior, and center-level practice variation may confound clinician-reported adverse events rates.

The absence of a parallel signal in patient-reported outcomes underscores the importance of integrating both measures when interpreting comparative data. Notably, these findings do not support a direct causal role of fiducials themselves in driving adverse events, particularly considering that patients treated with CyberKnife who also routinely receive intraprostatic fiducials did not demonstrate increased side effect rates.

The broader lesson emerging from this analysis extends beyond prostate cancer. Radiation oncology increasingly emphasizes technological precision, adaptive workflows, and substructure contouring. While these advances are transformative, this study reminds us that side effects emerge from the interaction between dose and host biology. Millimeter-level planning refinement cannot fully overcome underlying functional vulnerability.

From a practical standpoint, incorporation of baseline urinary function into fractionation discussions represents an accessible form of precision medicine. Rather than relying solely on dosimetric modeling, clinicians can integrate patient-specific functional phenotype into therapeutic decision-making.

Future research should focus on validating baseline IPSS thresholds in independent SBRT cohorts and exploring integration with additional biomarkers. Delivered dose reconstruction using image-guided adaptive techniques may further clarify dose–toxicity relationships. Inclusion of urodynamic measures, prostate volume parameters, and prior benign prostatic hyperplasia interventions may enhance predictive modeling, as larger prostate volumes may contribute to baseline urinary dysfunction and increase the technical complexity of ultrahypofractionated treatment delivery (12).

The PACE-B dosimetric analysis thus reframes the conversation around SBRT-associated urinary side effects. Baseline urinary symptom burden emerges as the dominant determinant of late grade ≥2 GU events within modern protocol-constrained SBRT practice. Planned urinary substructure dose, within established constraints, does not independently predict side effects in this dataset.

In the era of precision radiotherapy, the most powerful predictor of urinary side effects may not be measured in Gray, but in the symptoms present before the first fraction is delivered. These findings challenge the implicit assumption that technological escalation alone will proportionally reduce side effects. Precision in delivery must be matched by equal precision in patient selection.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0192/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0192/coif). The authors have no conflicts of interest to declare.

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