Abstract / Summary
Summary: Current guidelines incorporate chemo-immunotherapy for stage III–IV mismatch repair–deficient (dMMR) endometrial cancer, but the evidence supporting omission of adjuvant radiotherapy remains insufficient. Given the pivotal role of pelvic radiotherapy in achieving durable locoregional control in high-risk endometrial cancer, and the lack of robust randomized evidence demonstrating equivalence of systemic therapy alone, the suggestion that EBRT may be safely omitted in the adjuvant treatment of dMMR high-risk disease warrants careful consideration. Importantly, PORTEC-3 ( NCT00411138 ) included radiotherapy in both treatment groups and no immunotherapy, whereas in KEYNOTE-B21 (ENGOT-en11/GOG-3053, NCT04634877 ) radiotherapy was not randomized; neither trial therefore directly tested the safety of radiotherapy omission. In this Viewpoint, we review current evidence and unresolved questions in the adjuvant management of FIGO stage III dMMR endometrial cancer, with particular attention to the role of radiotherapy in the evolving chemo-immunotherapy era. While our discussion is intentionally focused on dMMR disease, many of the broader considerations regarding the interpretation of emerging evidence and the preservation of effective locoregional treatment are not exclusive to this molecular subgroup. 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. Beyond survival, locoregional control, recurrence burden, and quality of life remain clinically meaningful endpoints. Future randomized trials should evaluate radiotherapy as an independent treatment variable within molecularly stratified populations, incorporating not only survival but also patterns of failure and patient-reported outcomes. Until such data become available, treatment de-escalation strategies should be adopted with caution.