Phase III Trial: Adjuvant Pelvic Radiation Therapy Versus Vaginal Brachytherapy Plus Paclitaxel/Carboplatin in High-Intermediate and High-Risk Early-Stage Endometrial Cancer

Abstract

PURPOSE The primary objective was to determine if vaginal cuff brachytherapy and chemotherapy (VCB/C) increases recurrence-free survival (RFS) compared with pelvic radiation therapy (RT) in high-intermediate and high-risk early-stage endometrial carcinoma. PATIENTS AND METHODS A randomized phase III trial was performed in eligible patients with endometrial cancer. Eligible patients had International Federation of Gynecology and Obstetrics (2009) stage I endometrioid histology with Gynecologic Oncology Group protocol 33–based high-intermediate–risk criteria, stage II disease, or stage I to II serous or clear cell tumors. Treatment was randomly assigned between RT (45 to 50.4 Gy over 5 weeks) or VCB followed by intravenous paclitaxel 175 mg/m2 (3 hours) plus carboplatin (area under the curve, 6) every 21 days for three cycles. RESULTS The median age of the 601 patients was 63 years, and 74% had stage I disease. Histologies included endometrioid (71%), serous (15%), and clear cell (5%). With a median follow-up of 53 months, the 60-month RFS was 0.76 (95% CI, 0.70 to 0.81) for RT and 0.76 (95% CI, 0.70 to 0.81) for VCB/C (hazard ratio, 0.92; 90% confidence limit, 0.69 to 1.23). The 60-month overall survival was 0.87 (95% CI, 0.83 to 0.91) for RT and 0.85 (95% CI, 0.81 to 0.90) for VCB/C (hazard ratio, 1.04; 90% confidence limit, 0.71 to 1.52). Vaginal and distant recurrence rates were similar between arms. Pelvic or para-aortic nodal recurrences were more common with VCB/C (9% v 4%). There was no heterogeneity of treatment effect with respect to RFS or overall survival among clinical or pathologic variables evaluated. CONCLUSION Superiority of VCB/C compared with pelvic RT was not demonstrated. Acute toxicity was greater with VCB/C; late toxicity was similar. Pelvic RT alone remains an effective, well-tolerated, and appropriate adjuvant treatment in high-risk early-stage endometrial carcinomas of all histologies.

LVSI positive and NX in early endometrial cancer: Surgical restaging (and no further treatment if N0), or adjuvant ERT?

“…The superiority of VCB/chemotherapy arm was not demonstrated compared to EBRT alone. Acute toxicity was greater with VCB and chemotherapy though late toxicity was similar between the arms [28]. Based on this limited data, we do not currently recommend the use of adjuvant chemotherapy for LVSI positive, unstaged early endometrial cancer patients.…”

“…The management of early stage high intermediate risk patients have been informed by results for GOG 249. VCB and 3 cycles of chemotherapy were not superior to pelvic RT with significant increase in non-hematologic grade 3 and > toxicities in the VCB and chemotherapy arm (GOG 249) [28]. It will be important to evaluate this trial for late toxicities, particularly in the external beam arm.…”

“…PORTEC II demonstrated that in high intermediate risk patients, vaginal brachytherapy provides equivalent vaginal control compared with WPRT without any difference in survival. Both trials demonstrated a small improvement in pelvic nodal control, 5.2% and 5.7%, respectively in PORTEC II and GOG 249, without any survival benefit [24,28,31,32]. The utility of chemotherapy in high intermediate risk or high-risk early patients has not been defined nor the optimal number of chemotherapy cycles.…”

“…Harkenrider et al have performed a comprehensive review for the American Brachytherapy Society which demonstrated a very low rate of significant late toxicity with VCB [31]. The early impact of GOG 249 is making many providers reconsider the utility of WPRT in high risk subsets [28].…”

“…LVSI is an independent predictor of lymph node metastases, higher rates of recurrence and decreased OS [5e7,51]. LVSI positivity is associated with rates of pelvic lymph node metastases as high as 25e45% [12,18,28,44,50]. See Table 2.…”