Background Management of high risk, early stage endometrial cancer is controversial. Historically, adjuvant pelvic radiation therapy is standard for

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1 A Phase III Trial of Pelvic Radiation Therapy versus Vaginal Cuff Brachytherapy Followed by Paclitaxel/Carboplatin Chemotherapy in Patients with High-risk, Early-stage Endometrial Cancer: A Gynecology Oncology Group Study M. Randall 1, V. Filiaci 2, D. McMeekin 3, C. M. Yashar 4, R. Mannel 3, R. Salani 5, P. DiSilvestro 6, J. Burke 7, T. Rutherford 8, N. Spirtos 9, J. Cho 10, J. Kim 11, 12, P. Anderson 13, W. Brewster 14, W. Small 15, M. Carney 16, C. Aghajanian 17, and D. S. Miller 18 1 University of Kentucky, Lexington, KY, 2 NRG Oncology Statistics and Data Management Center, Buffalo, NY, 3 University of Oklahoma, Oklahoma City, OK, 4 University of California San Diego, San Diego, CA, 5 The Ohio State University, Columbus, OH, 6 Brown University, Providence, RI, 7 Memorial University, Savannah, GA, 8 Yale Gynecologic Oncology, New Haven, CT, 9 Women's Cancer Center of Nevada, Las Vegas, NV, 10 University of Hawaii, Honolulu, HI, 11 Seoul National University, Seoul, Korea, Republic of (South), 12 Korean Gynecologic Oncology Group, Seoul, Korea, Republic of (South), 13 Fox Chase Cancer Center, Philadelphia, PA, 14 University of North Carolina, Chapel Hill, NC, 15 Loyola University Medical Center, Maywood, IL, 16 University of Hawaii Cancer Center, Honolulu, HI, 17 Memorial Sloan Kettering Cancer Center, New York, NY, 18 University of Texas- Southwestern, Dallas, TX

2 Background Management of high risk, early stage endometrial cancer is controversial. Historically, adjuvant pelvic radiation therapy is standard for patients thought to be at significant risk of local recurrence after surgery. Most recognized local recurrences occur at the vaginal cuff, although metastatic failure occurs in 1 of 5 patients with high risk disease. Combination chemotherapy has demonstrated improved outcomes in more advanced disease, e.g. stage III and IV. Trend toward increased use of vaginal brachytherapy. Data suggests similar excellent ability to limit cuff recurrences compared to external RT. Needed a direct comparison of the standard approach (pelvic RT) to the more experimental treatment of cuff brachytherapy and chemotherapy.

3 Method 1:1 randomized comparison, phase III study. Intent to treat analysis. Designed to test if VCB/C is superior to PXRT (not equivalency study) Primary objective: To determine if treatment with Vaginal Cuff Brachytherapy and Chemotherapy (VCB/C) reduces the rate of recurrence or death (improves Recurrence Free Survival, RFS) compared to Pelvic Radiation Therapy (PXRT) Secondary objectives: Overall Survival (OS), patterns of failure, toxicity/functioning between arms Close follow-up for recurrence (including regular imaging) and toxicity Toxicity grading used NCI Common Terminology Criteria for Adverse Events, version 3

4 Relapse Free Survival by Randomized Treatment Hazard Ratio 90% Hazard Ratio Confidence Limits VBT + Chemotherapy

5 Overall Survival by Randomized Treatment Hazard Ratio 90% Hazard Ratio Confidence Limits VBT + Chemotherapy

6 Results 36 month RFS = 82% for both PXRT and VCB/C 36 months OS = 91% for PXRT and 88% for VCB/C (p = 0.57) No difference in vaginal or distant failure rates Pelvic and Para-aortic nodal failures more common in VCB/C arm (estimated 9% at 5 years, vs 4% in the PXRT arm, Hazard Ratio 0.47) Estimated rate of vaginal and distant recurrences: 2.5% and 18% at 5 years, not different between the arms No significant treatment heterogeneity between the 2 arms with respect to RFS and OS Variables studied include Stage, Histology, Performance Status, LND

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8 Conclusions This large randomized phase III study did not demonstrate superiority of VCB/C over PXRT in a cohort of patients with High Risk, Early Stage Endometrial Carcinoma. RFS and OS were not improved with VCB/C compared to PXRT. This conclusion applies to all subgroups analyzed, including patients with serous and clear cell histology. Analysis of failure patterns showed a significantly lower nodal failure rate in the PXRT arm. Distant failure is the predominant failure pattern in this patient population (18% in both arms).

9 Conclusions Acute toxicity was significantly greater in VCB/C arm, while late toxicity was similar in the 2 arms. Pelvic radiation therapy remains an appropriate (and probably preferable) treatment for high risk, early stage endometrial carcinoma. Better treatment strategies to address the risk of systemic disease will be necessary to further improve outcomes in this patient group.