Radiotherapy Still Matters in dMMR Endometrial Cancer, Researchers Warn in the Immunotherapy Era

Immunotherapy has transformed the treatment of endometrial cancer, the most common gynecologic malignancy in high-income countries, but a new Viewpoint published in eClinicalMedicine argues that one of the oldest tools in the oncology arsenal—pelvic radiotherapy—must not be discarded in the rush to embrace the new. Writing from centers in Italy, the authors, led by radiation and gynecologic oncology specialists including Gabriella Macchia and Domenica Lorusso, examine the evidence for adjuvant treatment in patients with FIGO stage III mismatch repair–deficient (dMMR) endometrial cancer, a molecular subgroup defined by defects in the cellular machinery that repairs DNA replication errors. Their conclusion is deliberately provocative in the current climate: no randomized trial has yet shown that immune checkpoint inhibitors can safely replace external-beam radiotherapy (EBRT) in patients whose disease has been completely removed by surgery, and treatment guidelines should not be read as license to drop it.

The stakes are high because the therapeutic landscape has shifted with remarkable speed. Immune checkpoint inhibitors entered first-line systemic treatment for unresectable stage III–IV or recurrent endometrial cancer on the strength of the RUBY and NRG-GY018 trials, which combined drugs such as dostarlimab and pembrolizumab with standard chemotherapy. More recently, the KEYNOTE-B21 trial pushed immunotherapy even earlier, testing pembrolizumab alongside adjuvant chemotherapy, with or without radiotherapy, in patients with completely resected high-risk disease. Across these studies, checkpoint inhibition has shown its most consistent activity precisely in the dMMR/MSI-H subgroup, whose tumors carry a high mutational burden and are therefore more visible to the immune system. The 2025 ESGO-ESTRO-ESP guidelines responded by recommending that patients with FIGO stage IIIm–IVAm dMMR endometrial carcinoma be considered for adjuvant chemotherapy combined with an immune checkpoint inhibitor, with or without external-beam radiotherapy.

It is that final clause—”with or without EBRT”—that worries the authors. They caution that a superficial reading of the guideline wording could lead clinicians to the unintended conclusion that radiotherapy can be omitted in dMMR high-risk disease. The guideline appendix does acknowledge the varying strength of evidence across clinical scenarios, but the Viewpoint insists that the pivotal role of pelvic radiotherapy in achieving durable locoregional control, combined with the absence of robust randomized evidence demonstrating that systemic therapy alone is equivalent, means any suggestion of safe omission warrants careful scrutiny. The only randomized trial to have specifically examined omitting radiotherapy, GOG-258, predates the immunotherapy era entirely, limiting how far its findings can be carried into modern practice.

That trial, along with PORTEC-3, forms the evidentiary backbone of adjuvant decision-making, and the authors dissect both in detail. PORTEC-3 compared adjuvant chemoradiotherapy with pelvic radiotherapy alone in high-risk endometrial cancer and, in its updated 2019 analysis, demonstrated significant improvements in both failure-free survival and overall survival, each with a hazard ratio of 0.70. Crucially, the trial did not test the omission of radiotherapy: pelvic radiotherapy was present in both arms, and isolated vaginal and pelvic recurrences were exceptionally rare, at just 0.3 percent and 0.9 percent respectively, while distant metastases dominated the pattern of failure. The lesson, the authors argue, is that pelvic radiotherapy already delivers durable locoregional control, and future gains are more likely to come from better systemic therapy than from removing EBRT. PORTEC-3 also incorporated rigorous radiotherapy quality assurance and patient-reported outcome assessments, reinforcing the favorable toxicity profile of modern intensity-modulated radiotherapy (IMRT).

GOG-258 tells a different but complementary story. It compared concurrent cisplatin-based chemoradiotherapy followed by four cycles of carboplatin–paclitaxel against six cycles of carboplatin–paclitaxel alone, and found no improvement in relapse-free survival from adding radiotherapy. Yet chemoradiotherapy significantly reduced vaginal and pelvic or para-aortic nodal recurrences, while distant recurrences were more frequent—possibly influenced, the authors note, by the lower systemic treatment intensity in the combined-modality arm. These findings have led some centers to adopt sequential strategies, typically six cycles of carboplatin–paclitaxel followed by pelvic EBRT with or without vaginal brachytherapy, preserving full-dose chemotherapy while retaining the locoregional benefit. Encouraging prospective cohort and retrospective data support this approach, but it has never been prospectively compared with chemotherapy alone or with the GOG-258 regimen, and therefore cannot be considered an evidence-based standard.

Neither trial included immunotherapy, but exploratory, non-prespecified molecular subgroup analyses of both have generated important—and apparently conflicting—insights for the dMMR population. In PORTEC-3, the subgroup analysis suggested that chemotherapy added little benefit when combined with radiotherapy in dMMR tumors, whereas in GOG-258 exploratory analyses numerically favored chemotherapy over chemoradiotherapy, hinting at a limited incremental role for radiotherapy, though with wide confidence intervals. Strikingly, both trials converged on similar two-year recurrence-free survival rates of roughly 75 percent in PORTEC-3 and 73 percent in GOG-258 for stage III dMMR tumors, with no clear long-term advantage for either strategy. The authors’ verdict is that these hypothesis-generating analyses point in different directions regarding the relative contributions of chemotherapy and radiotherapy, yet converge on a single message: neither modality can be declared safely dispensable in stage III dMMR disease, and prospective molecularly stratified trials are needed.

The immunotherapy data themselves, the authors argue, do not fill this gap. The RUBY and NRG-GY018 trials enrolled patients with advanced, metastatic, or recurrent disease and high anticipated event rates—populations well suited to detecting progression-free survival benefits quickly, but very different from a purely adjuvant cohort of patients rendered disease-free by surgery. KEYNOTE-B21 did address the adjuvant setting directly, but radiotherapy was not randomized; it was delivered at investigator discretion, with approximately 73 percent of patients in the preplanned dMMR subgroup receiving adjuvant radiotherapy and about two-thirds receiving EBRT. The observed benefit of pembrolizumab, including two-year disease-free survival approaching 90 percent in the dMMR subgroup, was therefore achieved largely in the context of combined-modality treatment. The trial, the authors conclude, cannot be used either to support or to refute the independent value of radiotherapy, and certainly not to justify abolishing adjuvant chemoradiotherapy, which remains a validated standard of care.

Biology, if anything, points toward integration rather than substitution. Preclinical work summarized in the Viewpoint describes how radiotherapy may synergize with immune checkpoint inhibition by promoting the release of tumor antigens, enhancing MHC class I expression and antigen presentation, and activating innate immune pathways including the cGAS–STING/type I interferon axis, thereby priming antitumor immune responses. On the toxicity side, the authors contend that fears about pelvic radiotherapy largely stem from the era of four-field box techniques, when higher doses to bowel, bladder, and bone marrow were unavoidable. Contemporary IMRT, validated in PORTEC-3 and the RTOG 1203 trial, significantly reduces acute gastrointestinal and genitourinary toxicity, with low rates of long-term grade ≥2 toxicities and favorable patient-reported outcomes. Phase III data from KEYNOTE-A18, although generated in cervical cancer, showed improved survival when pembrolizumab was added to chemoradiotherapy without increased toxicity—and at higher radiotherapy doses than those typically used adjuvantly in endometrial disease—offering indirect reassurance about the safety of the combination.

What about simply withholding radiotherapy and reserving it for a recurrence? The authors reject this as unsupported. Data on outcomes after recurrence in molecularly defined subgroups remain limited; in a multicenter cohort by Siegenthaler and colleagues, treated largely before immunotherapy became routine, median post-recurrence survival for dMMR tumors was 43 months—meaning relapse is not uniformly lethal but remains clinically significant. Long-term PORTEC-3 results show that recurrences in dMMR tumors cluster within the first two to three years, that locoregional relapses are uncommon where upfront pelvic radiotherapy was given, and that distant metastases are the predominant pattern of failure—suggesting the critical window for locoregional intervention is the adjuvant phase itself. Recurrence also carries intrinsic costs: more intensive salvage treatment, greater cumulative toxicity, and a heavier healthcare burden.

The authors’ synthesis is measured but firm. Molecular classification has refined risk stratification, and emerging immunotherapy data in dMMR tumors are genuinely promising, but those data derive from studies in which radiotherapy was either routinely delivered or never evaluated as an independent variable. Combined chemoradiotherapy must therefore remain a foundational standard, with immunotherapy viewed as a potential addition rather than a replacement. Ongoing trials, including NRG-GY020 (NCT04214067) and the RAINBO MMRd-GREEN trial (ENGOT-en14/GREEN, NCT05255653), are expected to define the optimal integration of immunotherapy and adjuvant radiotherapy in molecularly stratified populations, ideally incorporating patterns of failure and patient-reported outcomes alongside survival. Until such evidence arrives, the authors argue, de-escalation should proceed with caution: the real challenge of the immunotherapy era is not replacing pelvic radiotherapy, but optimizing systemic disease control while preserving the durable locoregional control that modern radiotherapy already delivers.

Subject of Research: Adjuvant radiotherapy and chemo-immunotherapy in FIGO stage III mismatch repair–deficient endometrial cancer

Article Title: Adjuvant radiotherapy in FIGO stage III dMMR endometrial cancer: evidence and perspectives in the molecular era

Article References: Macchia, G., Merlotti, A., De Felice, F., Russo, D., Marchetti, C., & Lorusso, D. (2026). Adjuvant radiotherapy in FIGO stage III dMMR endometrial cancer: evidence and perspectives in the molecular era. eClinicalMedicine, 101, Article 104257. https://doi.org/10.1016/j.eclinm.2026.104257

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104257

Keywords: endometrial cancer, dMMR, radiotherapy, immunotherapy, chemoradiotherapy, PORTEC-3, GOG-258, KEYNOTE-B21, pembrolizumab, ESGO-ESTRO-ESP guidelines, locoregional control, molecular classification