Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies

Abstract

Introduction: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.

Methods: Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.

Results: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).

Conclusion: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.

Trial registration: ClinicalTrials.gov NCT00005583.

Figure 1

a: Consort Flowchart NSGO/EORTC-study. b: Consort Flowchart Iliade-study

Figure 1

a: Consort Flowchart NSGO/EORTC-study. b: Consort Flowchart Iliade-study

Figure 2

Progression-free survival in the pooled NSGO-EC-9501/EORTC-5591 and MaNGO studies. (CI: Confidence interval, HR: Hazard ratio, RT: radiotherapy, RT-CT: sequential radiotherapy and chemotherapy).

Figure3

Overall survival in the pooled NSGO-EC-9501/EORTC-5591 and MaNGO studies. (CI: Confidence interval, HR: Hazard ratio, RT: radiotherapy, RT-CT: sequential radiotherapy and chemotherapy)

Figure 4

Forest plots for interaction between prognostic factors and treatment. The analysis was performed on 444 patients with no missing values for all covariates with progression-free survival (PFS) as the end-point. The analysis of lymphadenectomy was performed on 286 patients with information about lymphadenectomy. The upper bar in each diagram depicts the overall hazard ratio (HR), and the two middle bars show the HR by covariate group. The lowest bar shows the ratio of hazard ratios (RHR), which is a measure of interaction; if it crosses the vertical line there is no significant interaction, which is the case for all five covariates. (RT: radiotherapy, RT-CT: sequential radiotherapy and chemotherapy).

Figure 5

Forest plot with progression-free survival (PFS) as end-point illustrating possible heterogeneity depending on study group (NSGO, EORTC, or MaNGO), and original protocol, amendment 1, or 2 in the NSGO/EORTC-trial. (CI: Confidence interval, HR: Hazard ratio, RT: radiotherapy, RT-CT: sequential radiotherapy and chemotherapy).