Intravaginal brachytherapy alone for intermediate-risk endometrial cancer

Purpose: Despite the results of the Gynecologic Oncology Group trial No. 99 (GOG#99), some unanswered questions still remain about the role of adjuvant radiotherapy (RT) for intermediate-risk endometrial cancer. First, can intravaginal brachytherapy (IVRT) alone substitute for external beam RT but without added morbidity? Second, is the high-risk (HR) definition from GOG#99 a useful tool to predict pelvic recurrence specifically? The purpose of this study was to try to answer these questions in a group of patients with Stage IB-IIB endometrial carcinoma treated with high-dose-rate (HDR) IVRT alone.

Methods and Materials: Between November 1987 and December 2002, 382 patients with Stage IB-IIB endometrial carcinoma were treated with simple hysterectomy followed by HDR-IVRT alone at our institution. Comprehensive surgical staging (CSS), defined as pelvic washings and pelvic/paraaortic lymph node sampling, was performed in 20% of patients. The mean age was 60 years (range, 29–92 years). Lymphovascular invasion (LVI) was present in 14% of patients. The median HDR-IVRT dose was 21 Gy (range, 6–21 Gy), given in three fractions. Complications were assessed in terms of late Radiation Therapy Oncology Group (Grade 3 or worse) toxicity of the GI tract, genitourinary GU tract, and vagina.

Results: With a median follow-up of 48 months, the 5-year vaginal/pelvic control rate was 95% (95% confidence interval [CI], 93–98%). On multivariate analysis, a poor vaginal/pelvic control rate correlated with age ≥60 years old (relative risk [RR], 3, 95% CI, 1–12; p = 0.01), International Federation of Gynecology and Obstetrics (FIGO) Grade 3 (RR, 9, 95% CI, 2–35; p = 0.03), and LVI (RR, 4, 95% CI, 1–13; p = 0.051). The depth of myometrial invasion and CSS, however, were not significant. With regard to pelvic control specifically, the presence of GOG#99 HR features did not affect the pelvic control rate. The 5-year rate for HR patients was 96% (95% CI, 90–100%) vs. 96% (95% CI, 94–99%) for those without HR disease (p = 0.48). Even when the CSS effect was taken into account, the influence of HR features on pelvic control was still not significant (p = 0.51). In contrast, pelvic control was significantly influenced when patients were grouped according to CSS and stage/grade substages. For those with Stage IB Grade 3-IIB and no CSS, the 5-year pelvic control rate was 86% compared with 97% for those with Stage IB Grade 3-IIB and CSS, 97% for Stage IB, Grade 1–2 without CSS, and 100% for those with Stage IB, Grade 1–2 and CSS (p = 0.027). The 5-year disease-free survival rate was 93% (95% CI, 90–96%). On multivariate analysis, poor disease-free survival correlated with age ≥60 years (RR, 5; 95% CI, 1–18; p = 0.002), FIGO Grade 3 (RR 5, 95% CI 2–17; p = 0.013), and LVI (RR 3, 95% CI 1–8; p = 0.054). Unlike pelvic control, disease-free survival was significantly affected by GOG#99 HR features, with a 5-year rate of 87% (95% CI, 76–99%) vs. 94% (95% CI, 91–97%) for those without HR features (p = 0.027). The 5-year overall and disease-specific survival rate was 93% and 97%, respectively. The overall 5-year actuarial rate of Grade 3 or worse complications was 1% (95% CI, 0–2%).

Conclusion: Tumor grade, depth of invasion, and the use of CSS were better predictors of pelvic control than the GOG#99 HR factors. IVRT alone seemed to provide adequate tumor control with very low morbidity. Therefore, it seems prudent to consider it for intermediate-risk patients because of its superior therapeutic ratio compared with that for surgery alone or pelvic RT. Additional follow-up, however, with a larger number of patients is needed, especially for those with LVI.

Introduction

In the past 5 years, two major developments have occurred in the management of early-stage endometrial cancer. By far, the most important have been the results of two prospective randomized trials showing no overall survival advantage with the addition of pelvic radiotherapy (RT) to surgery (1, 2). The other parallel development was the increased use of lymph node dissection in most patients with early-stage endometrial cancer. Thus, it is not surprising that the benefit of pelvic RT has been questioned, especially because its morbidity has been significantly greater than that with surgery alone (2, 3). What is concerning however, is the call to abandon all forms of adjuvant RT for early-stage endometrial cancer, even for patients with Stage IC (4, 5).

The Gynecologic Oncology Group trial No. 99 (GOG#99), randomizing patients with Stage IB-IIB endometrial cancer to surgery vs. surgery and pelvic RT, was especially important because it tried to address the role of pelvic RT for patients who had undergone comprehensive surgical staging (CSS). In addition, the authors of GOG#99 divided the patients into high-risk (HR) and low-risk groups. Patients were considered HR if they met a combination of the following criteria: advancing age, Grade 2–3 tumors, lymphovascular invasion (LVI), or outer-third invasion (2). However, despite the results of the GOG#99, some unanswered questions still remain. First, can intravaginal brachytherapy (IVRT) alone substitute for external beam RT? Second, is the HR definition from GOG#99 a useful tool to predict pelvic recurrence per se or is it a predictor of recurrence in general? Answering those two questions is very critical. Perhaps, rather than abandoning adjuvant RT altogether for intermediate-risk endometrial cancer, it would be useful to determine whether IVRT alone can provide equivalent locoregional control to that with external beam RT but without the added toxicity. Furthermore, if the GOG#99 HR factors are not good predictors of pelvic control, we could not reliably use those factors to determine who needs adjuvant RT.

Several reports have been published in the literature about IVRT, but not all of them have been applicable to everyday practice. Most of the reports included patients with Stage IA, Grade 1–2 disease, for whom most authors would not recommend adjuvant RT, thus diluting the results (6, 7). In addition, the use of IVRT in some reports was linked to pelvic and paraaortic lymph node dissection (6, 7, 8). Yet, it could be argued that lymph node dissection is not needed for all subsets of patients with early-stage endometrial cancer (9). Therefore, the purpose of this study was to try to answer those questions in a group of patients with Stage IB-IIB endometrial carcinoma treated with simple hysterectomy with or without CSS followed by high-dose-rate (HDR) IVRT alone.