Surgically staged high-risk endometrial cancer: Randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy

Abstract

Objective

Our purpose was to establish whether platinum-based chemotherapy combined with standard surgery and radiotherapy will improve overall and disease-free survival and lower the recurrence rate in patients with high-risk endometrial cancer.

Study design

A total of 156 patients with Stage IA–B Grade 3 (n = 28), or Stage IC–IIIA Grade 1–3 (n = 128) were postoperatively randomized to receive radiotherapy (56 Gy) only (Group A, n = 72) or radiotherapy combined with three courses of cisplatin (50 mg/m²), epirubicin (60 mg/m²) and cyclophosphamide (500 mg/m²) (Group B, n = 84).

Results

The disease-specific overall five-year survival was in Group A 84.7% vs. 82.1% in Group B (p = 0.148). The median disease-free survival in A was 18 (range 9–36) months and 25 (range 12–49) months in B (p = 0.134), respectively. During a five-year follow-up 32 patients relapsed. Of the recurrences 5 were local and 20 distant, while 7 were combined. As calculated from the operation, the median time to recurrence was 15 (range 6–37) months in Group A, and 20 (range 8–60) months in Group B, respectively (p = 0.170). Twenty-six patients died of the disease during the five-year follow-up, 11 in A and 15 in B. The patients succumbing in A lived a median 23 (range 15–44) months as compared to 37 (range 13–50) months in B (p = 0.148).

Chemotherapy was associated with an acceptable rate of acute toxicity. Less than 8% of the patients complained of Grade 3/4 nausea. The rate of Grade 3/4 leucopenia was at the highest at 16.6% during the third cycle but only 6.2% of the patients had Grade 3 infection.

A total of 10 patients developed intestinal complications demanding surgery, 2 in Group A (2.7%) and 8 (9.5%) in Group B, respectively.

Conclusion

Adjuvant chemotherapy with cisplatin, epirubicin and cyclophosphamide failed to improve overall survival or lower the recurrence rate in patients operated on and radiated for high-risk endometrial carcinoma. Chemotherapy was associated with a low rate of acute toxicity but appeared to increase the risk of bowel complications.

Introduction

Endometrial carcinoma is the most common gynecologic cancer in Western countries with an annual incidence of 15–18/100,000 women. The majority or 82% of endometrial cancers are diagnosed at stages I and II [1]. Increasing tumor grade, myometrial invasion and the presence of extrauterine disease are associated with an increasing incidence of cervical involvement, adnexal and lymph node metastases, positive peritoneal cytology and hematogenous spread [2], [3], [4], [5]. Adjuvant radiation therapy given in high-risk situations involving e.g. deep myometrial invasion, cervical invasion, grade 3 histology has reduced the rate of pelvic relapses which is offset by a higher rate of distant metastases, thus diminishing the potential survival benefit [6, [7], [8], [9], [10], [11], [12], [13]. The lack of an unequivocal survival benefit has generated the idea of adding chemotherapy to the treatment of high-risk endometrial cancer [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. Reported response rates of recurrent or metastatic endometrial carcinoma to chemotherapy have varied in a range of 20–50% [25], [26], [27], [28], [29], [30], [31].

In Finland, the standard treatment of high-risk endometrial carcinoma has traditionally been a hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy, followed by external pelvic radiation. The purpose of this study was to determine whether adjuvant chemotherapy consisting of cisplatin, epirubicin and cyclophosphamide combined to the standard treatment would reduce the recurrence rate and improve survival.