Effect of treatment sequence on mortality in advanced-stage endometrial cancer

Abstract

<h3>Objectives:</h3> The aim of this study was to assess for an association between the sequence of surgical and systemic treatment and overall survival in patients with Stage IV endometrial cancer, as well as to identify prognostic factors for mortality. <h3>Methods:</h3> The National Cancer Database (NCDB) was queried for cases of endometrial cancer diagnosed between 2006 and 2015. These cases were further narrowed to include only International Classification of Diseases for Oncology (ICD-O) histologic codes of adenocarcinoma or endometrioid adenocarcinoma and FIGO stage IV disease. Exclusion criteria were: reference date prior to date of diagnosis; unknown treatment sequence; intraoperative chemotherapy use; and hormonal or immunotherapy as first-line systemic therapy or unknown hormonal or immunotherapy use. Three groups were defined according to sequence of administration of surgery and systemic therapy. Overall survival (OS) was compared by calculating hazard ratios for death via Cox regression analysis. The Incomplete Treatment (IT) group received surgery alone, systemic therapy alone, or no treatment. The Primary Surgery (PS) group received surgery before systemic therapy. The Interval Surgery (IS) group had neoadjuvant systemic therapy followed by surgery, with or without further systemic therapy after surgery. Subanalyses were performed to assess the impact of post-IS systemic therapy, age, ethnicity, insurance status, and Charlson-Deyo score on OS. Analysis was performed using STATA.16. <h3>Results:</h3> A total of 8,520 cases of FIGO Stage IV endometrial adenocarcinoma were identified using the criteria above. Median OS in months for each treatment sequence group was 7.2 for IT, 35.7 for PS, and 30.7 for IS. Regardless of treatment sequence, receiving both surgical and systemic therapy improved OS compared to receiving only one or neither treatment. The hazard ratio (HR) for death for PS compared to IT was 0.38 (95% CI 0.36-0.40) and for IS compared to IT was 0.41 (95% CI 0.36-0.47), p<0.0001 for both. There was no significant difference in survival for IS compared to PS (HR 1.10, 95% CI 0.96-1.24, p=0.18). Stratification of IS cases by administration of further systemic therapy after surgery yielded the same result. Patient groups with worse OS (p<0.0001 for all) included: age >50 years (HR 1.18, 95% CI 1.08-1.30), non-Hispanic Black compared to non-Hispanic White (HR 1.27, 95% CI 1.17-1.37), and presence of medical comorbidities reflected by Charlson-Deyo score of 1 or more. Patients with private insurance had better OS than uninsured patients (HR 0.80, 95% CI 0.71-0.90, p<0.0001) but the same was not true for government insurance. <h3>Conclusions:</h3> This retrospective survival analysis of NCDB data for FIGO Stage IV endometrial adenocarcinoma illustrated a benefit to receiving both systemic and surgical treatment over receiving only one or neither form of therapy. No difference in mortality was identified between primary surgery with adjuvant systemic therapy and neoadjuvant systemic therapy with interval surgery, even when accounting for additional chemotherapy after surgery. The decision whether to begin treatment with surgery or chemotherapy will thus depend on nuanced clinical factors specific to each patient. Patient factors associated with worse mortality included age >50 years, Non-Hispanic Black ethnicity, lack of insurance, and presence of medical comorbidities. These findings indicate a need to address the socioeconomic determinants of health contributing to these disparities in mortality.