Research Article| Volume 154, ISSUE 1, P13-21, July 2019

The addition of paclitaxel to doxorubicin and cisplatin and volume-directed radiation does not improve overall survival (OS) or long-term recurrence-free survival (RFS) in advanced endometrial cancer (EC): A randomized phase III NRG/Gynecologic Oncology Group (GOG) study


      • No significant difference in OS in women with advanced-stage endometrial cancer on cisplatin and doxorubicin +/− paclitaxel
      • Despite a slight protective effect on OS and long-term RFS, the addition of paclitaxel comes with increased neurotoxicity.
      • Second malignancies were reported in 36 patients, including 13 breast cancers occurring mostly in the arm with paclitaxel.



      To determine if the addition of paclitaxel (P) to cisplatin and doxorubicin (CD) following surgical debulking and volume-directed radiation therapy improved long-term, recurrence-free survival (RFS) and overall survival (OS) in patients with advanced-stage endometrial cancer (EC).


      Prospective, randomized GOG trial comparing (CD) (50 mg/m2)/(45 mg/m2) +/− (P) (160 mg/m2) following volume-directed radiation and surgery in advanced EC. A Kaplan-Meier (KM) analysis characterized the relationship between treatment arms and the OS outcome, a log-rank test assessed the independence of treatment with the OS outcome, and the treatment effect on estimated OS was determined using a Cox proportional hazards (PH) model stratified by stage. The PH assumption was assessed using a test of interaction between treatment variable and the natural logarithm of survival time. Adverse events, regardless of attribution, were graded.


      Since initial publication, 60 deaths occurred, leaving 311 patients alive with 290 (93.8%) recurrence- free. There was no significant decrease in the risk of recurrence or death associated with the CDP treatment regimen stratified for stage (p = 0.14, one-tail). The exploratory analysis for OS and the corresponding homogeneity tests for different effects across subgroups revealed only EFRT and EFRT & GRD status to have significantly different treatment effects (p = 0.027 and p = 0.017, respectively). Second primary malignancies were identified in 17/253 (6.4%) and 19/263 (7.0%) of patients treated with CD and CDP respectively. Breast (2.4%) followed by colon (1%) were the two cancers most frequently diagnosed in this setting.


      No significant difference between treatment arms was identified. Subgroup analysis both in the initial and current reports demonstrated a trend towards improved RFS and OS in patients treated with CDP and EFRT. This long-term analysis of outcomes also identified the necessity of providing on-going cancer screening to patients enrolled in trials.


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        • Greer B.E.
        • Hamberger A.
        Treatment of intraperitoneal metastatic adenocarcinoma of the endometrium by whole-abdominal moving strip technique and pelvic boost irradiation.
        Gynecol. Oncol. 1983; 16: 365-373
        • Dembo A.J.
        Abdominopelvic radiotherapy in ovarian cancer. A 10-year experience.
        Cancer. 1985; 55: 2285-2290
        • Potish R.A.
        • Twiggs L.B.
        • Adcock L.L.
        • Prem K.A.
        Role of whole abdominal radiation therapy in the management of (EC): prognostic importance of factors indicating peritoneal metastases.
        Gynecol. Oncol. 1985; 21: 80-86
        • Martinez A.
        • Schray M.
        • Podratz K.
        • Stanhope R.
        • Malkasian G.
        Postoperative whole abdomino-pelvic irradiation for patients with high risk (EC).
        Int. J. Radiat. Biol. Phys. 1989; 17: 371-377
        • Gibbons S.
        • Martinez A.
        • Schray M.
        Adjuvant whole abdominal pelvic irradiation for high risk endometrial carcinoma.
        Int. J. Radiat. Oncol. Biol. Phys. 1991; 21: 1019-1025
      1. Sutton G, Axelrod JH, Bundy BN, Roy T, Homesley H, Lee RB, et al. Adjuvant whole abdominal irradiation in clinical stage I and II papillary serous or clear cell carcinoma of the endometrium: a phase II study of the Gynecologic Oncology Group. Gynecol. Oncol. 2006; 100:349–354.

      2. Sutton G, Axelrod JH, Bundy BN, Roy T, Homesley H, Malfetano JH, e al. Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV (EC): a Gynecologic Oncologic Group study. Gynecol. Oncol. 2005; 97:755–763.

      3. Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, et al. Phase III trial of doxorubicin with or without cisplatin in advanced (EC): a Gynecologic Oncology Group study. J. Clin. Oncol. 2004; 22:3902–3908.

      4. Fleming GF, Brunetto, VL, Cella D, Look KY, Reid GC, Munkarah AR, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgastrim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J. Clin. Oncol. 2004; 22: 2159–2166.

        • Lincoln S.
        • Blessing J.A.
        • Lee R.B.
        • Rocereto T.F.
        Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study.
        Gynecol. Oncol. 2003; 88: 271-281
      5. Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J. Clin. Oncol. 2006; 24:36–44.

      6. Homesley HD, Filiaci V, Gibbons SK, Long HJ, Cella D, Spirtos, NM, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Gynecol. Oncol.. 2009: 112:543–552.

        • Arbuck S.G.
        • McClure J.
        • Ivy S.P.
        • Setser A.
        The Common Toxicity Criteria Manual. National Cancer Institute, Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events; CTC v2.0.
        NCI, NIH, DHHS, April 30, 1999
        • Cox J.D.
        • Stetz J.
        • Pajak T.F.
        Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC).
        Int. J. Radiat. Oncol. Biol. Phys. 1995; 1: 1341-1346
        • Kaplan E.L.
        • Meier P.
        Nonparametric estimation from incomplete observations.
        J. Am. Stat. Assoc. 1958; 53: 457-481
        • Mantel N.
        Evaluation of survival data and two new rank order statistics arising from its consideration.
        Cancer Chemother. Rep. 1996; 50: 163-170
        • Cox D.R.
        Regression model and life tables (with discussion).
        J. R. Stat. Assoc. 1958; 53: 457-481
        • Schoenfeld D.A.
        Sample size formula for the proportional hazards regression model.
        Biometrics. 1983; 39: 499-503
      7. Cella D, Huang H, Homesley HD, Montag A, Salani R, DeGeest K, et al. Patient-reported peripheral neuropathy of doxorubicin and cisplatin with and with paclitaxel in the treatment of advanced (EC): results from GOG 184. Gynecol. Oncol. 2010; 119:539–542.

        • Creasman W.T.
        • Morrow C.P.
        • Bundy B.N.
        • Homesley H.D.
        • Graham J.E.
        • Heller P.B.
        Surgical pathologic spread patterns of (EC). A Gynecologic Oncology Group Study.
        Cancer. 1987; 60: 2035-2041
        • Geller M.A.
        • Ivy J.
        • Dusenbery K.E.
        • Ghebre R.
        • Isaksson Vogel R.
        • Argenta P.A.
        A single institution experience using sequential multimodality adjuvant chemotherapy and radiation in the “sandwich” method for high risk endometrial carcinoma.
        Gynecol. Oncol. 2010; 118: 19-23
        • Fields A.L.
        • Einstein M.H.
        • Novetsky A.P.
        • Gebb J.
        • Goldberg G.L.
        Pilot phase II trial of radiation “sandwiched” between combination paclitaxel/platinum chemotherapy in patients with uterine papillary serous carcinoma (UPSC).
        Gynecol. Oncol. 2008; 108: 201-206
      8. Lupe K, D'Souza DP, Kwon JS, Radwan JS, Harle IA, Hammond JA, et al. Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced (EC). Gynecol. Oncol.. 2009; 114: 94–98.

      9. de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018; 19(3):295–309.

      10. Secord AA, Geller MA, Broadwater G, Holloway R, Shuler K, Dao ND, et al. A multi-center evaluation of adjuvant therapy in women with optimally resected stage III (EC). Gynecol. Oncol. 2013; 128:65–70.

      11. Hogberg T, Signorelli M, Freire de Oliveira C, Fossati R, Lissoni AA, Sorbe B et al. Sequential adjuvant chemotherapy and radiotherapy in (EC) - results from two randomized trials. Eur. J. Cancer 2010; 46:2422–2431.

      12. Chan JK, Cheung MK, Huh WK, Osann K, Hussain A, Teng NN, et al. Therapeutic role of lymph node resection in endometrioid corpus cancer: a study of 12,333 patients. Cancer 2006. 107:1823–1830.

      13. Yoon MS, Park W, Huh SJ, Kim HJ, Kim YS, Kim YB, et al. Impact of paraaortic lymphadenectomy for endometrial cancer with positive pelvic lymph nodes: a Korean Radiation Oncology Group study (KROG 13-17). Eur. J. Surg. Oncol. 2016; 42:1497–1505.

      14. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N. Engl. J. Med. 2006; 354:34–43.

        • Fowler J.M.
        • Brady W.E.
        • Grigsby P.W.
        • Cohn D.E.
        • Mannel R.S.
        • Rader J.S.
        Sequential chemotherapy and irradiation in advanced stage (EC): a Gynecologic Oncology Group phase I trial of doxorubicin-cisplatin followed by whole abdomen irradiation.
        Gynecol. Oncol. 2009; 112: 553-557
      15. Randall ME, Barrett RJ, Spirtos NM, Chalas E, Homesley HD, Lentz SL, et al. Chemotherapy, early surgical reassessment, and hyperfractionated abdominal radiotherapy in stage III ovarian cancer: results of a gynecologic oncology group study. Int. J. Radiat. Oncol. Biol. Phys.. 1996; 34:139–147.

        • Lee L.
        • Bu P.
        • Feltmate C.
        • Viswanathan A.N.
        Adjuvant chemotherapy with external beam radiation therapy for high-grade, node positive (EC).
        Int. J. Gynecol. Cancer. 2014; 24: 1441-1448
      16. McMeekin DS, Sill MW, Walker JL, Moore KN, Waggoner SE, Thaker PH, et al. A phase I study of IV doxorubicin plus intraperitoneal (IP) paclitaxel and IV or IP cisplatin in (EC) patients at high risk for peritoneal failure (GOG 9920): and NRG Oncology/Gynecologic Oncology Group study. Gynecol. Oncol. 2015:138; 36–40.

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