Adjuvant chemoradiotherapy versus radiotherapy alone in high-risk endometrial cancer: Updated meta-analysis of randomized trials.

Abstract

e17635 Background: The survival benefit of adjuvant chemoradiotherapy compared with radiotherapy alone in high-risk endometrial cancer (EC) remains debated. With updated PORTEC-3 results and maturation of earlier randomized clinical trials (RCTs), a contemporary quantitative reassessment is warranted. Methods: A PRISMA-compliant systematic review and meta-analysis of RCTs compared adjuvant chemoradiotherapy versus radiotherapy alone after surgery in high-risk EC. Kaplan–Meier curves were digitized using ScanIt, and individual patient data were reconstructed with IPDfromKM, with validation by log-rank test, root mean square error, and Kolmogorov–Smirnov test. Overall survival (OS) and disease-free survival (DFS) were pooled using random-effects models and expressed as hazard ratios (HRs) with 95% CIs. Trial-level weighted meta-regressions explored effect modification by FIGO stage, histologic subtype, tumor grade, and extent of lymphadenectomy. Safety outcomes were summarized using pooled risk ratios (RRs). Results: Six RCTs including 2,105 patients were analyzed, with OS effects ranging from negative in earlier trials to improved survival in contemporary combined-modality studies. In pooled analysis, chemoradiotherapy was associated with a borderline improvement in OS (HR 0.83, 95% CI 0.69–1.01; p=0.06; I²=0%). DFS was consistently improved with chemoradiotherapy across trials, yielding a statistically significant pooled benefit (HR 0.75, 95% CI 0.63–0.91; p<0.01; I²=0%). Trial-specific DFS HRs ranged from approximately 0.60 to 0.85, favoring combined treatment in the majority of comparisons, including PORTEC-3–eligible populations. Meta-regression analyses demonstrated limited explanatory power for OS according to FIGO stage I–III, tumor grade, or non-endometrioid histology, with low coefficients of determination across models (R²≤0.31). In contrast, DFS benefit showed a strong association with extent of lymphadenectomy (R²=0.85), suggesting greater relative benefit in comprehensively staged patients. Chemoradiotherapy increased acute grade ≥3 hematologic and gastrointestinal toxicity compared with radiotherapy alone, while late grade ≥3 adverse events were infrequent and similar between groups. Conclusions: In high-risk EC, adjuvant chemoradiotherapy significantly improves DFS and confers a borderline OS benefit compared with radiotherapy alone, with acceptable long-term toxicity. The magnitude of benefit appears more closely related to surgical staging quality than to histology or tumor grade, supporting combined-modality therapy in selected patients.