Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer – Results from two randomised studies

doi:10.1016/j.ejca.2010.06.002

European Journal of Cancer

Volume 46, Issue 13, September 2010, Pages 2422-2431

https://doi.org/10.1016/j.ejca.2010.06.002 Get rights and content

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.

Introduction

Endometrial cancer is the most common gynaecologic cancer in the Western world. It was estimated that worldwide around 200,000 women acquired and 50,000 died of endometrial cancer in 2002.¹ The prognosis for early-stage endometrial cancer is excellent, but subgroups with a high risk for micrometastatic disease have been identified.² Randomised studies demonstrate high loco-regional control in early-stage endometrial cancer with adjuvant pelvic external radiotherapy (RT).3, 4, 5, 6 However, overall survival (OS) remains largely unaffected. It is therefore likely that patients at risk for micrometastatic disease will benefit from systemic adjuvant therapy.

The Nordic Society of Gynaecological Oncology/European Organisation for the Research and Treatment of Cancer (NSOG/EORTC) trial was designed to investigate if the addition of systemic chemotherapy (CT) to pelvic RT would improve progression-free survival (PFS) and OS for patients with endometrial cancer at high risk for micrometastatic disease. After presentation of the preliminary results at the American Society of Clinical Oncology (ASCO) 2007⁷ it was decided to publish the study together with the results from a similar trial (ILIADE-III) performed by the Gynaecological Oncology group at the Mario Negri Institute (MaNGO). The results of the ILIADE-III were not known.

When these studies were planned Thigpen and colleagues had presented their randomised trial of doxorubicin + cisplatin versus doxorubicin at ASCO 1993.⁸ This regimen was chosen in both studies.

We report the results of the NSGO/EORTC and the MaNGO-trials and an analysis of the pooled data.

Section snippets

The NSGO-9501/EORTC-55991 trial

The inclusion criteria were histologically verified endometrial cancer, surgery with total abdominal hysterectomy and bilateral salpingo-oophorectomy (lymphadenectomy (LA) was optional), no residual postoperative macroscopic tumour, International Federation of Obstetrics and Gynaecology (FIGO) 1988 surgical stage I, age ⩽80 years, World Health Organisation performance status <3 and adequate bone marrow, liver and kidney function. The risk assessment was based on FIGO stage, grade and myometrial

Results

Between May 1996 and January 2007, 383 patients were randomised in the NSGO/EORTC study, 320 from 13 NSGO departments and 63 from 12 EORTC departments (Fig. 1a). In the MaNGO-study, 157 patients from 20 departments were randomised between October 1998 and July 2007 (Fig. 1b). The treatment arms were well balanced regarding prognostic factors (Table 1).

Whether LA was performed was registered in EORTC patients and after amendment 2 in the NSGO. Twenty-eight out of 61 patients in the RT-arm (46%)

Discussion

The NSGO/EORTC-trial showed that the sequential addition of CT to RT was associated with a significant 36% reduction in the risk of relapse or death and a significant 49% reduction in the risk of death from endometrial cancer. The results in the MaNGO-trial point in the same direction but are not significant, likely because of the small study population. The NSGO/EORTC- and MaNGO-trials addressed the same question but in slightly different patient groups. The NSGO/EORTC-trial initially included

Conflict of interest statement

None declared.

Acknowledgements

This study was supported by the Nordic Cancer Union (Grant No. 06 0004 to NSGO), Fondazione Mattioli to MaNGO and the National Cancer Institute at Bethesda, MD, USA (Grant Nos. 5U10 CA11488-30 through 5U10 CA011488-39 to EORTC). The funding organisations had no influence on the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

We thank all the women who participated in this trial and the

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Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer – Results from two randomised studies

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Section snippets

The NSGO-9501/EORTC-55991 trial

Results

Discussion

Conflict of interest statement

Acknowledgements

Int J Gynaecol Obstet

Lancet

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Global cancer statistics, 2002

CA Cancer J Clin

Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma

Obstet Gynecol