Moderately hypofractionated IMPT with pelvic nodal irradiation for high-risk prostate cancer: an emerging standard or an incremental step?

The management of high-risk prostate cancer continues to evolve with advances in technology and understanding of tumor biology. Traditionally, management has combined external-beam radiotherapy, long-term androgen deprivation therapy, and elective pelvic nodal irradiation (EPNI) to address the risk of microscopic nodal disease. EPNI remains discussed, as potential gains in cancer control must be weighed against the increased risk of toxicity associated with larger radiation volumes (1-4). In this context, intensity-modulated proton therapy (IMPT) may improve target conformality and reduce doses to organs at risk by exploiting the Bragg peak, especially for large treatment volumes. However, its clinical value in this setting remains incompletely evaluated.

Against this background, the prospective phase II trial conducted by Choo et al. (5), examining moderately hypofractionated IMPT with simultaneous treatment of the prostate, seminal vesicles, and pelvic lymph nodes, provides timely and clinically relevant evidence. This is the first study to report long-term outcomes with a 5-year follow-up in a cohort treated with IMPT. The primary endpoint of this trial is to evaluate late gastrointestinal (GI) and genitourinary (GU) effects. Recurrence-free rate (RFR), freedom from prostate-specific antigen (PSA) relapse, and disease-free survival (DFS) were secondary endpoints.

For this study, 55 patients with high-risk [T3–4 or Gleason score (GS) >7, or PSA >20 but <100 ng/mL; 53 patients] or unfavourable intermediate-risk (T1–2, GS 4+3, PSA 10–20 ng/mL; 2 patients) prostate cancer were selected. All patients received ADT (androgen deprivation therapy) for a median of 17.6 months and IMPT with doses of 67.5 Gy in 25 fractions (fx) to the prostate/seminal vesicles (2.7 Gy/fx), delivered concurrently with 45 Gy in 25 fractions to the pelvic lymph nodes (1.8 Gy/fx), guided by intraprostatic fiducials.

With long-term follow-up, late toxicity remained low and clinically manageable. At 5 years, the actuarial incidence of grade ≥2 and grade 3 GI adverse events was 16% and 4%, respectively (most commonly rectal bleeding and proctitis), with no grade 4–5 events. Late GU toxicity ≥ grade 2 occurred in 41% of patients and was driven by grade 2 irritative urinary symptoms, without any grade 3–5 events; importantly, baseline GU symptoms, but not prior TURP (transurethral resection of the prostate), anticoagulant use, or ADT duration, were associated with increased late GU toxicity. Erectile dysfunction worsened after PBT, with normal erectile function decreasing from 29% to 11% and an increase in grade 1–2 dysfunction from 69% to 87%, while grade 3 erectile dysfunction remained stable. Oncologic outcomes were excellent, with 5-year biochemical relapse-free survival of 90%, DFS of 89%, and overall survival of 94%, and no prostate cancer- or treatment-related deaths; only a pre-treatment PSA >20 ng/mL was significantly associated with inferior biochemical control.

Cross-trial comparisons are inherently limited due to the study design, but outcomes and toxicity appear comparable to contemporary photon-based whole-pelvic radiotherapy using similar hypofractionated regimens. Long-term cohorts of photons delivering 20–28 fractions to the prostate and EPNI, 5-year biochemical control rates generally range from approximately 80% to 95%, show late grade ≥3 GI and GU toxicities reported between 1.8–5.8%, and 1.8–10% respectively (3,6-8). In this prospective trial, the GI and GU G3 late effects are 4% and 0% at 5 years, and RFR is 90%.

Nevertheless, this study is limited by its small sample size, resulting in wide confidence intervals and limiting the reliability of toxicity predictors, as well as by the absence of a control arm, precluding meaningful comparisons with photon-based or conventionally fractionated radiotherapy. Although follow-up extends beyond 5 years, late toxicity and disease recurrence may continue to evolve. Additional limitations include the lack of patient-reported quality-of-life data. To date, no phase III trials have directly compared the clinical or oncologic outcomes of IMPT with modern photon-based techniques such as VMAT. Dosimetric studies, although performed only in small cohorts, suggest that IMPT can significantly reduce mean doses to the bladder, rectum, and abdominal cavity (9). A cohort study (10) compared IMPT and VMAT in ten consecutively accrued patients with unfavorable intermediate- or high-risk prostate cancer receiving prostate and EPNI using paired treatment plans. IMPT provided equivalent target coverage to VMAT (≈99% of CTVs receiving the full prescription dose) while significantly reducing (P<0.05) mean doses and clinically relevant dose–volume parameters for the rectum (V47.5Gy), bladder (V37.5Gy), and small (V30Gy) and large bowel (V27.5Gy)—reflecting a mitigation of the low-dose bath characteristic of VMAT—at the cost of higher mean femoral head doses in IMPT.

On the other hand, elective pelvic irradiation in high-risk prostate cancer has long been a subject of debate. Early randomized trials, including RTOG 9413 (1) and GETUG-01 (4), failed to demonstrate a clear benefit of EPNI over prostate-only radiotherapy. More recently, the POP-RT trial (3) refined this paradigm by showing that a benefit emerges when patients are carefully selected based on a high estimated risk of nodal involvement (Roach >35%) and when treatment volumes are extended to the aortic-iliac bifurcation. In parallel, the SPPORT trial (11) suggested a potential role for EPNI in improving relapse-free survival in the salvage radiotherapy setting. Several factors help contextualize these apparently discordant results. Although earlier trials have been criticized for the use of three-dimensional conformal techniques and relatively modest radiation doses, NRG/RTOG 0924 (12) incorporated contemporary IMRT and allowed for brachytherapy boost, yet still failed to demonstrate in preliminary results a significant advantage for elective nodal irradiation in overall survival and metastasis-free survival. Moreover, the superior border of pelvic treatment in NRG/RTOG 0924 extended to the L4–L5 level, mirroring the field design used in POP-RT, suggesting that differences in target volume definition alone are unlikely to account for the divergent outcomes.

The evolving clinical landscape appears to be shaped primarily by advances in patient selection. The increasing use of PET-based staging—particularly PSMA PET/CT—and the adoption of a higher threshold for nodal risk estimation (≥20% according to the Roach formula, compared with 15% in earlier trials) allow for the identification of a subset of patients with a truly elevated burden of occult nodal disease. It is within this carefully selected, very high-risk population, typically with long life expectancy, that elective pelvic irradiation may offer meaningful benefit in overall survival. Consequently, the key clinical question has shifted from whether pelvic nodal irradiation should be delivered routinely to identifying the patients most likely to derive a tangible advantage from its use.

Finally, we would like to remark that proton therapy is particularly sensitive to geometric and dosimetric uncertainties, including robustness evaluation, daily patient positioning, organ motion, and anatomical changes during treatment. Such factors may compromise conformity and increase unintended exposure to critical structures, especially the rectum and bladder. Moreover, the relative biological effectiveness (RBE) of protons, commonly assumed to be 1.1, is not constant and can vary depending on tissue type, dose, and proton energy, introducing additional uncertainty into treatment planning and clinical outcomes (13-15).

In summary, moderate hypofractionated IMPT for whole-pelvis irradiation demonstrates favorable oncologic and toxicity outcomes for patients with high-risk prostate cancer. While dosimetric advantages suggest a potential therapeutic benefit, robust evidence from randomized comparative trials is still lacking. Future studies will be crucial in determining whether IMPT represents a genuine advancement over modern photon-based techniques or an incremental improvement and guiding the identification of patients most likely to derive meaningful benefits from proton therapy. Until such data is available, cautious adoption and continued critical evaluation remain essential.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0052/coif). E.G.S. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Janssen, and support for attending meetings and/or travel from Astellas, IPSEN, Recordati, Grünenthal, Bayer, IPSEN, Astrazeneca, Janssen. F.C. reports consulting fee from Janssen, AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Janssen, Roche Farma, AstraZeneca, Astellas, Recordati; support for attending meetings and/or travel from AstraZeneca, Astellas, Janssen, Roche Farma., Recordati, Ipsen; and participation on a Data Safety Monitoring Board or Advisory Board of Astellas, Bayer, Johnson & Johnson, Ipsen. F.L.C. reports consulting fee, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and support for attending meetings and/or travel from Astellas, Bayer, Recordati, Johnson & Johnson, Ipsen, and participation on a Data Safety Monitoring Board or Advisory Board of Astellas, Bayer, Johnson &Johnson, Ipsen. The other author has no conflicts of interest to declare.

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