Postoperative proton therapy in uterine and cervical cancer: promising evidence but remaining questions

Background

Node-positive (LN+) uterine and cervical cancers represent a clinically challenging subgroup with a high risk of locoregional and distant recurrence (1). Standard management after hysterectomy and lymphadenectomy includes adjuvant pelvic with or without para-aortic radiation therapy, often combined with chemotherapy (2,3). While advances such as intensity-modulated radiation therapy (IMRT) have reduced toxicity compared with three-dimensional conformal radiation therapy (3D-CRT), clinically meaningful acute and late gastrointestinal (GI), genitourinary (GU), and hematologic toxicities persist (4,5). Proton therapy, and specifically pencil beam scanning proton therapy (PBS-PT), offers a potential dosimetric advantage by eliminating exit dose through the Bragg peak effect, thereby reducing irradiation of surrounding normal tissues (6,7). Clinical prospective data on the use of proton therapy in the treatment course of gynecological pelvic malignancies are rare (8). The authors designed this prospective phase 2 study to test whether adjuvant PBS-PT could reduce normal tissue exposure and toxicity while maintaining oncologic efficacy in node-positive uterine and cervical cancer patients.

Summary of the trial results

Russo et al. conducted a single-institution prospective phase II trial evaluating the use of PBS-PT as adjuvant radiation therapy for patients with node-positive uterine or cervical cancer following hysterectomy and lymphadenectomy (9). Between 2013 and 2018, 21 patients completed treatment, including 15 with uterine cancer and 6 with cervical cancer. Patients received PBS-PT to a dose of 45 Gray (Gy) relative biological effectiveness (RBE) in 25 fractions, with pelvic or extended-field irradiation depending on nodal involvement. The majority of patients (81%) were treated with extended-field radiation therapy (EFRT) including para-aortic lymph node regions. Most patients also received a vaginal brachytherapy boost. Chemotherapy was administered according to disease type, with sequential carboplatin and paclitaxel in uterine cancer and concurrent weekly cisplatin in cervical cancer.

The primary endpoints included dosimetric comparisons between PBS-PT and photon-based treatment plans (IMRT and 3D-CRT) as well as assessment of acute and late toxicity. Secondary endpoints included progression-free survival (PFS), overall survival (OS), recurrence patterns, and quality of life (QoL). PBS-PT significantly reduced radiation exposure to organs at risk such as bowel, bone marrow, and kidneys compared with photon techniques while maintaining excellent target coverage. Acute grade 3 GI toxicity occurred in 14% of patients and grade 3 hematologic toxicity in 24%, with no grade 3 GU toxicity reported. Late grade 3 toxicity was rare. At a median follow-up of approximately 5 years, oncologic outcomes were favorable, with 2- and 5-year PFS rates of 81% and 76%, respectively, and 5-year OS of 80%. Importantly, no in-field recurrences were observed. Patient-reported QoL improved significantly over time. Overall, the study demonstrates that adjuvant PBS-PT provides substantial normal-tissue sparing while maintaining excellent local control in patients with node-positive gynecologic malignancies. Notably, there were no in-field recurrences, suggesting excellent locoregional control. Recurrences occurred exclusively outside the radiation field.

The authors conclude that adjuvant PBS-PT for node-positive uterine and cervical cancer significantly reduces radiation exposure to critical normal tissues compared with conventional photon-based techniques, while maintaining excellent locoregional control and long-term survival outcomes. The low incidence of severe acute and late toxicities, combined with sustained improvements in patient-reported QoL, supports the safety and efficacy of PBS-PT in this setting. Although limited by small sample size and lack of randomization, the study provides important prospective evidence suggesting that proton therapy may be particularly advantageous for patients requiring extended-field radiation or those with specific anatomic or clinical considerations. The authors propose that PBS-PT should be considered a potential standard option for selected node-positive gynecological cancer patients, pending further validation.

Commentary

In this trial adjuvant PBS-PT for patients with uterine or cervical cancer resulted in excellent sparing of the organs at risk (OAR) while maintaining a sufficient dose distribution in the target volumes. In this trial heterogenic groups of patients with endometrial and cervical cancer were included. The larger group of patients with endometrial cancer had, defined by the Fédération Internationale de Gynécologie et d’Obstétrique classification (FIGO), stage IIIC disease (12/15 stage IIIC1 with pelvic lymph node involvement only and 3/15 stage IIIC2 with para-aortic lymph node involvement). These patients represented a uniformly high-risk cohort. Most tumors were endometrioid histology, with a minority of papillary serous carcinomas, further supporting aggressive adjuvant management. Preoperative clinical staging for cervical cancer patients was: FIGO stage IB (IB1 in 2/6 patients and IB2 in 4/6 patients). These patients were initially treated surgically because they presented with early-stage cervical cancer. Lymph node metastases were subsequently detected during surgical staging, resulting in postoperative upstaging and the indication for adjuvant chemoradiotherapy. All cervical cancer received surgical pelvic lymph node staging but no paraaortic operative staging. Therefore, the EFRT was mainly used in the endometrial cancer group (17/21 vs. 2/6). EFRT extended superiorly to the T12–L1 vertebral interface, encompassing pelvic and para-aortic nodal regions, whereas pelvic-only radiation extended to L5–S1. The high proportion of EFRT distinguishes this cohort from many prior proton and photon-based studies, which predominantly included pelvic-only fields (10,11). A summary of distinctive criteria and differences of published prospective trials of PBS-PT in in post-hysterectomy gynecologic cancer patients can be found in Table 1. A rectal balloon was used for treatment planning in all patients to reduce rectal filling differences.

The trial compared dose-volume histogram parameters and toxicity between PBS-PT and photon-based treatment plans generated using both IMRT and 3D-CRT. While 3D-CRT served as a historical comparator reflecting earlier radiation techniques, IMRT represents the current standard of care for pelvic radiotherapy in gynecologic malignancies. Therefore, the comparison between PBS-PT and IMRT is clinically most relevant when evaluating the potential advantages of proton therapy. In comparison to the 3D-CRT the PBS-RT was significantly better in almost all aspects of the key dosimetric values [clinical target volume (CTV) 95%, bowel, bone marrow, kidney, bladder] except for the maximum dose at the rectum. The IMRT could keep up with the PBS-PT in some aspects (CTV 95%, bowel V45 and V40, bone marrow V20 and the maximum dose at rectum) but was ultimately significantly worse in sparring the bladder, the bone marrow V10 and the bowel V30 as well as V20. Similar data have been shown by other trials evaluating PBS-PT in the adjuvant treatment of gynecological cancer. For example, Lin et al. reported that the volume of pelvic bone marrow, bladder, and small bowel receiving 10 to 30 Gy was significantly lower with PBS than with intensity modulated radiation therapy. One patient (9%) developed grade 3 acute GI toxicity; no patient developed grade ≥3 GU toxicity (12).

Especially the V10 of the bone marrow (in this trial defined as thoracolumbar spine T12–L5 and pelvic bone girdle using the outer contour of the bone) is a dose distribution advantage for PBS-PT in comparison to IMRT with a difference of 15.5%. Other trials, focusing mainly on the pelvic bone marrow, showed even higher differences of 28% (13) up to 41% (14). Because the bone marrow is especially vulnerable in these patient groups, based on the likely application of chemo- and/or immunotherapy and the comparable voluminous radiation fields (15), patients could benefit from reduced hematological toxicity.

The important question for the patients receiving postoperative radiation treatment is if these dosimetric advantages translate into less toxicity and better QoL in daily clinical practice.

The GI, GU and hematologic toxicity was low, which was expected considering comparable prospective trials using PBS-PT (10,11,16). Nevertheless, 14% of patients experienced grade 3 GI toxicity. The rate is higher compared for example with the APROVE trial, where no grade 3 events occurred. This might be explained by the much higher proportion of patients receiving EFRT in this trial, where much higher volumes of the bowel are exposed to irradiation. Also rates of acute grade 3 hematologic toxicity are comparably high with 24%. In the APROVE trial 32% experienced hepatotoxicity grade 1–2, but no grade 3 toxicity was observed (10). This might also be due to the smaller irradiation fields and to differences in chemotherapy application. The trial by Anderson et al. even evaluated patient-reported outcomes, showing 9% ≥ grade 3 GI toxicity in the Proton group compared to 31% in the IMRT group (11).

QoL, measured by using the Functional Assessment of Cancer Therapy-Cervix (FACT-En/Cx) Version 4 questionnaires, improved significantly over time, with a mean increase exceeding the threshold for a clinically meaningful difference from baseline to 5 years. QoL trajectories did not differ between uterine and cervical cancer patients, indicating a consistent benefit across disease sites. These favorable results are in line with the QoL results reported in the APROVE trial, although results are not easy to compare due to the use of different questionnaires [EORTC QLQ-C30, -CX24 and -EN24 (10)]. Other trials didn’t measure QoL at all (11). While both questionnaires are valid, the EORTC instruments are generally considered superior for capturing a more comprehensive range of symptoms and health-related QoL in cancer populations, as they are more widely validated and internationally used (17). Overall, the results of the trial at hand were more focused on the general increase in QoL over time and the body image and sexual activity, which were key differences in the APROVE trial, were not reported.

Because of the different setups proton therapy centers use data have to be compared with caution. Radiotherapy using protons varies significantly between centers, with differences in techniques and equipment that can affect treatment outcomes (18-20). One key distinction lies in the use of pencil beam scanning (PBS) versus passive beam delivery. PBS is commonly employed in modern proton therapy centers, as it allows for more precise tumor targeting by delivering the proton beam in a finely controlled manner across the treatment area, minimizing damage to surrounding healthy tissues. In contrast, passive beam delivery uses broader beams, which are less precise and can result in more exposure to adjacent normal structures. Centers also differ in their approach to beam angles, with some using multiple entry points to optimize dose distribution, while others prefer single or fewer beam angles to reduce complexity or treatment time. Patient positioning plays a critical role in ensuring accurate treatment delivery, with many centers using advanced immobilization devices to maintain stability throughout the treatment. Some centers incorporate rectal balloons to ensure the rectum remains in a fixed position, reducing movement during treatment and preventing irradiation of critical surrounding organs. Additionally, image guidance is employed differently across proton centers; while most use daily X-ray imaging systems to track patient alignment, others may utilize in-room computed tomography (CT) or on-board cone beam CT (CBCT) imaging and surface guidance for more advanced tracking of organ motion (21,22). These variations in technique, equipment, and patient setup contribute to the diversity of proton therapy practices and may influence the efficacy and side-effect profiles of treatments at different centers.

The application of proton therapy in the definitive cervical cancer setting is interesting as well but is even more challenging. In the adjuvant setting, post-surgical anatomy is stable, but definitive treatment involves dynamic tumor motion, particularly with changes in uterine position due to bladder and bowel filling. While PBS offers excellent precision, it may not fully address these challenges in definitive therapy without further advancements in patient positioning and treatment planning. The variability in uterine position could impact proton therapy’s effectiveness without enhanced tracking systems. To evaluate PBT in the definitive setting there is a non-randomized prospective multicenter phase-II-trial running in the Netherlands (PROTECT trial), comparing clinical outcomes after IMPT or IMRT in the definitive setting. To account for the mentioned anatomical variability the use of a ‘library of plans’ technique with daily selection of the most appropriate treatment plan using CBCT scans or, when available, in-room CT scans is applied (23).

One step even further would be the use of magnetic resonance imaging (MRI)-guided PBT. Integrating MRI for image guidance could offer daily target localization with improved soft tissue contrast, without the additional ionizing radiation exposure associated with X-ray-based imaging techniques (21,24).

Another important aspect when discussing proton therapy is its economic impact (25). Proton therapy is associated with substantially higher upfront treatment costs compared with photon-based techniques (26). However, cost-effectiveness analyses in other disease sites suggest that the economic balance may improve if proton therapy reduces treatment-related toxicity, hospitalizations, or long-term supportive care requirements (27,28). In the context of gynecologic malignancies, patients receiving extended-field irradiation or multimodal systemic therapies may particularly benefit from reduced irradiation of organs at risk such as bowel and bone marrow (29). In such clinical scenarios, reductions in toxicity and improvements in QoL may partially offset the higher treatment costs. Future studies should therefore not only evaluate clinical outcomes but also incorporate health-economic analyses to better define the value of proton therapy in this patient population (25,30).

The trial discussed here was designed as a prospective phase II feasibility study rather than a randomized superiority trial. At the time of trial initiation, clinical data on proton therapy in postoperative gynecologic malignancies were scarce, and conducting randomized trials remains challenging due to limited proton therapy availability, reimbursement barriers, and logistical constraints.

All in all, the trial from Russo et al. is in line with the literature showing promising results of PBT in the treatment of gynecological cancer patients. More research is necessary and future trials should focus on prospective multi-center settings including a two-armed design comparing modern standard-of care IMRT versus modern PBS-PT to quantify the clinical benefits of PBT, which are missing until today.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0122/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0122/coif). N.A. received travel expenses for attending the annual meeting of the German Society of Senology 2023 and speaker honoraria for the workshop “Breast and Gynecological Cancers: Translation from Bench to Bedside and Back/Brust- und Gynäkologische Tumoren 2023”, outside the submitted work. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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