Adjuvant endocrine treatment with medroxyprogesterone acetate or tamoxifen in stage I and II endometrial cancer—a multicentre, open, controlled, prospectively randomised trial

Abstract

Endometrial cancer is a hormone-dependent disease and therefore an adjuvant hormonal therapy might improve the outcome in the early stages of the disease. Between 1983 and 1989, we conducted a randomised trial of 388 patients who received either medroxyprogesterone acetate (MPA) (n=133) or tamoxifen (n=121) orally for 2 years, or were observed only (n=134) after surgical therapy. The aim was to evaluate whether an adjuvant treatment can improve disease-free and overall survival rates. After a median follow-up period of 56 months (range 3–199 months), we observed no differences in the disease-free and overall survival rates for the tamoxifen group compared with the control or the MPA group. Side-effects were more frequent and severe in the MPA-group than in the tamoxifen group. In patients with early endometrial cancer, adjuvant endocrine treatment did not significantly improve the outcome. However, tamoxifen did have some beneficial effects on coexisting morbidity.

Introduction

Endometrial cancer (EC) is the most common malignant disease of the female genital tract [1]. Although 75% of patients with carcinoma of the endometrium are initially diagnosed with early stage disease, the mortality is still significant. The prognosis of EC is excellent in stage Ia and Ib patients, with 5-year survival rates of 91% and 88%, respectively. The 5-year survival rate of EC dropped to 77–67% in stage II patients [2]. Primary treatment, including surgery and radiation, cannot provide sufficient tumour control, especially in high grade, undifferentiated tumours with deep muscle infiltration. Therefore, in 1983, we considered an adjuvant treatment for endometrial cancer to prevent recurrence and death. Based on the analogy with breast cancer, we considered the use of tamoxifen (30 mg for 2 years). In 1983, the German standard dose and duration of medroxyprogesterone acetate (MPA) in endometrial cancer was between 400 and 600 mg for 1–2 years. This was based on incomplete empirical information. Unfortunately, earlier studies using cytotoxic agents such as cisplatin or doxorubicin in recurrent endometrial cancer had not been very promising. The response rates ranged from 30 to 40%, but the responses lasted for only approximately 6 months [3]. The dose intensity that could be achieved was low because of the patients' pre-existing multimorbidity. However, a phase II study using carboplatin and paclitaxel in advanced or recurrent endometrial cancer demonstrated a response rate of up to 78%. Nevertheless, the median time to progression lasted for 6 months and the overall survival time was only 15 months [4]. Progestins, by contrast, have produced similar results and are better tolerated. Recurrences of well differentiated, steroid receptor-positive tumours, responded better than those of moderately or poorly differentiated, receptor-negative tumours [5]. Additionally, adjuvant therapy with progestonal agents was starting to be investigated in the late 1970s 6, 7. One trial with only 205 patients, demonstrated a survival benefit for the progestin-treated group. However, 30% of the enrolled patients had stage II-III disease [8].

Jordan and colleagues have shown that tamoxifen can block the binding of oestradiol to the oestrogen receptor of endometrial carcinomas and proposed that anti-oestrogen should be used to treat endometrial cancer [9]. Subsequently, numerous clinical trials in recurrent disease have been carried out that showed an overall response rate of 22% for tamoxifen [10]. However, no trial on the adjuvant use of tamoxifen in endometrial cancer has been reported. Based on this knowledge, we started the first clinical trial of tamoxifen as an adjuvant treatment in endometrial cancer. The following are the results of an open, controlled, multicentre co-operative study. The primary objective of the trial was to evaluate whether endocrine treatment can influence disease-free and overall survival rates in risk-adapted, surgically pretreated patients with early endometrial cancer.