# When Standards Meet Reality: An Inverted PORTEC-3 Protocol for High-Risk Endometrial Cancer in Resource-Limited Settings

## TL;DR

This study proposes a chemotherapy-first approach for high-risk endometrial cancer when radiotherapy is delayed, showing good outcomes but increased toxicity.

## Contribution

The study introduces a practical treatment sequence for resource-limited settings by inverting the standard PORTEC-3 protocol.

## Key findings

- Five-year overall survival and disease-free survival rates were 86.1% and 77.5%, respectively.
- Delays in radiotherapy and chemotherapy initiation were linked to reduced disease-free survival.
- Bone marrow dose thresholds were identified to predict and manage hematologic toxicity.

## Abstract

Adjuvant management of high-risk endometrial cancer typically combines chemotherapy and radiotherapy; however, timely access to radiotherapy remains inconsistent in many healthcare systems, resulting in significant treatment delays. In this study, we evaluated a chemotherapy-first sequence, followed by combined chemotherapy and radiotherapy, as a pragmatic alternative when radiotherapy cannot start promptly. Survival outcomes, patterns of failure, and treatment-related toxicity were analyzed in patients treated with this adapted approach. As disease recurrence in this population is predominantly metastatic, it was postulated that early initiation of systemic chemotherapy might actually improve metastasis-free survival by targeting occult disease at an earlier stage. Our findings demonstrated excellent locoregional control and favorable survival outcomes when systemic therapy is delivered early, supporting the feasibility of this strategy in routine clinical practice. However, increased hematologic toxicity was observed, emphasizing the importance of optimized treatment planning. We identified bone marrow dose parameters associated with hematologic toxicity, and formulated practical guidance to improve treatment tolerability in real-world settings with limited radiotherapy access.

Background/Objectives: The combination of chemotherapy and radiotherapy represents a standard adjuvant treatment for patients with high-risk endometrial cancer. However, limited access to radiotherapy in many healthcare systems frequently results in treatment delays, potentially compromising outcomes. The aim of this study was to evaluate the oncologic outcomes and toxicity profile of an inverted treatment sequence consisting of upfront chemotherapy followed by concurrent chemoradiotherapy. Methods: We conducted a retrospective single-center study including patients with non-metastatic high-risk endometrial cancer. Eligible patients had FIGO stage I grade 3 disease with lymphovascular space invasion, stage II–III disease, or non-endometrioid histology. All patients received four cycles of paclitaxel–carboplatin followed by pelvic radiotherapy with concurrent cisplatin. Survival outcomes, including local recurrence-free survival, disease-free survival, metastasis-free survival, and overall survival, were analyzed using the Kaplan–Meier method and Cox proportional hazards models. Acute hematologic toxicity was graded according to CTCAE v5.0. Bone marrow dose–volume parameters were evaluated, and receiver operating characteristic curve analysis was performed to identify thresholds associated with grade ≥ 2 hematologic toxicity. Results: Fifty-two patients were included, with a median follow-up of 31.4 months. Five-year overall survival and disease-free survival rates were 86.1% and 77.5%, respectively. Ten patients relapsed, with distant metastases observed in all cases and synchronous local recurrence in one. Delays between surgery and radiotherapy of 20 weeks or more, as well as delays exceeding 10 weeks before initiation of chemotherapy, were associated with significantly reduced disease-free survival. Grade ≥ 2 hematologic toxicity was frequent, and neutropenia was associated with inferior overall survival. Bone marrow dose–volume thresholds predictive of hematologic toxicity included V40 Gy < 20–25% and V30 Gy < 40%. Conclusions: A chemotherapy-first adjuvant strategy provides favorable oncologic outcomes and excellent locoregional control in high-risk endometrial cancer when radiotherapy is delayed. However, increased hematologic toxicity highlights the importance of optimized bone marrow sparing.