Clinical outcomes and the role of adjuvant therapy sequencing in Type II uterine cancer following definitive surgical treatment

Purpose of Investigation: Because of rarity, consensus on adjuvant therapies for Type II endometrial cancers (EC) remains undefined. Reporting their institutional outcomes, the present authors assessed the impact of adjuvant therapies on recurrence and overall survival in women with 2009 FIGO Stage I-III Type II EC. Material and Methods: The authors identified 108 women, treated with definitive surgery between 2000-2013, with pathologically-confirmed Type II EC (non-endometrioid [NEM, n=80] and high grade endometrioid [G3EEC, n=28]) Cox proportional hazard models were used to assess the effect of prognostic variables on disease-free (DFS) and overall survival (OS). Kaplan-Meier method was used to assess survival. Results: Of the 108 women, 83 (77%) were African American (AA). Fifty-nine (55%), 12 (11%), and 37 (34%) were Stage I, II, and III, respectively. Ninety-seven patients received adjuvant therapy: 52 (radiation only), four (chemotherapy only), and 40 (combined). During follow-up (median 41 months), 44 patients (41%) recurred. Five-year DFS was 53% overall (48% [NEM], 80% [G3EEC]). Five-year OS was 75% overall (68% [NEM], 95% [G3EEC]). On multivariate analysis, lower stage and adjuvant radiation improved DFS. Higher stage, NEM, and increasing age were poor prognostic indicators of OS. Conclusion: Representing a large single institutional cohort for Type II EC, the present study’s observed survival rates are consistent with previous studies, despite the relatively high frequency of carcinosarcoma and Stage III/nodal disease. The protective effect on recurrence was not lost when radiation was delayed for chemotherapy. The present results support a multimodal adjuvant approach for treating all stages of invasive NEM EC.

Endometrial neoplasms; Surgical pathology; Chemotherapy; Adjuvant; Radiotherapy; Adjuvant.

[1] Schimp V.L., Ali-Fehmi R., Solomon L.A., Hammoud A., Pansare V., Morris R.T., et al.: “The racial disparity in outcomes in endometrial cancer: could this be explained on a molecular level?“. Gynecol. Oncol., 2006, 102, 440.

[2] Prat J.: “FIGO staging for uterine sarcomas“. Int. J. Gynaecol. Obstet., 2009, 104, 177.

[3] Kiess A.P., Damast S., Makker V., Kollmeier M.A., Gardner G.J., Aghajanian C., et al.: “Five-year outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage III papillary serous endometrial cancer“. Gynecol. Oncol., 2012, 127, 321.

[4] Yechieli R., Rasool N., Robbins J.R., Cogan C.M., Elshaikh M.A.: “Adjuvant radiation therapy for patients with type II endometrial carcinoma: impact on tumor recurrence and survival“. Int. J. Gynecol. Cancer, 2013, 23, 763.

[5] Vance S., Yechieli R., Cogan C., Hanna R., Munkarah A., Elshaikh M.A.: “The prognostic significance of age in surgically staged patients with Type II endometrial carcinoma“. Gynecol. Oncol., 2012, 126, 16.

[6] Voss M.A., Ganesan R., Ludeman L., McCarthy K., Gornall R., Schaller G., et al.: “Should grade 3 endometrioid endometrial carcinoma be considered a type 2 cancer-a clinical and pathological evaluation“. Gynecol. Oncol., 2012, 124, 15.

[7] Zhang C., Hu W., Jia N., Li Q., Hua K., Tao X., et al.: “Uterine carcinosarcoma and high-risk endometrial carcinomas: a clinicopathological comparison“. Int. J. Gynecol. Cancer, 2015, 25, 629.

[8] Hamilton C.A., Cheung M.K., Osann K., Chen L., Teng N.N., Longacre T.A., et al.: “Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers“. Br. J. Cancer, 2006, 94, 642.

[9] Fader A.N., Drake R.D., O’Malley D.M., Gibbons H.E., Huh W.K., Havrilesky L.J., et al.: “Platinum/taxane-based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma“. Cancer, 2009, 115, 2119.

[10] Sutton G., Kauderer J., Carson L.F., Lentz S.S., Whitney C.W., Gallion H., et al.: “Adjuvant ifosfamide and cisplatin in patients with completely resected stage I or II carcinosarcomas (mixed mesodermal tumors) of the uterus: a Gynecologic Oncology Group study“. Gynecol. Oncol., 2005, 96, 630.

[11] Kuoppala T., Maenpaa J., Tomas E., Puistola U., Salmi T., Grenman S., et al.: “Surgically staged high-risk endometrial cancer: randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy“. Gynecol. Oncol., 2008, 110, 190.

[12] Galaal K., Kew F.M., Tam K.F., Lopes A., Meirovitz M., Naik R., et al.: “Evaluation of prognostic factors and treatment outcomes in uterine carcinosarcoma“. Eur. J. Obstet. Gynecol. Reprod. Biol., 2009, 143, 88.

[13] Einstein M.H., Klobocista M., Hou J.Y., Lee S., Mutyala S., Mehta K., et al.: “Phase II trial of adjuvant pelvic radiation ‘sandwiched’ between ifosfamide or ifosfamide plus cisplatin in women with uterine carcinosarcoma“. Gynecol. Oncol., 2012, 124, 26.

[14] Nickleach D., Liu Y., Shrewsberry A., Ogan K., Kim S., Wang Z.: “SAS® Macros to Conduct Common Biostatistical Analyses and Generate Reports“. SESUG 2013: The Proceeding of the SouthEast SAS User Group. Available at: http://analytics.ncsu.edu/sesug/2013/PO-05.pdf

[15] El-Hadaad H.A., Wahba H.A., Gamal A.M., Dawod T.: “Adjuvant Pelvic Radiotherapy vs. Sequential Chemoradiotherapy for High- Risk Stage I-II Endometrial Carcinoma“. Cancer. Biol. Med., 2012, 9, 168.

[16] Einstein M.H., Frimer M., Kuo D.Y., Reimers L.L., Mehta K., Mutyala S., et al.: “Phase II trial of adjuvant pelvic radiation ‘sandwiched’ between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma“. Gynecol. Oncol., 2012, 124, 21.

[17] Vogel T.J., Knickerbocker A., Shah C.A., Schiff M.A., Isacson C., Garcia R.L., et al.: “An analysis of current treatment practice in uterine papillary serous and clear cell carcinoma at two high volume cancer centers“. J. Gynecol. Oncol., 2015, 26, 25.

[18] Jhingran A., Ramondetta L.M., Bodurka D.C., Slomovitz B.M., Brown J., Levy L.B., et al.: “A prospective phase II study of chemoradiation followed by adjuvant chemotherapy for FIGO stage I-IIIA (1988) uterine papillary serous carcinoma of the endometrium“. Gynecol. Oncol., 2013, 129, 304.

[19] Damast S., Higgins S.A., Ratner E., De Leon M.C., Mani S., Silasi D.A., et al.: “High-dose-rate vaginal brachytherapy with chemotherapy for surgically staged localized uterine serous carcinoma“. J. Contemp. Brachytherapy, 2015, 7, 35.

[20] Fader A.N., Nagel C., Axtell A.E., Zanotti K.M., Kelley J.L., Moore K.N., et al.: “Stage II uterine papillary serous carcinoma: Carboplatin/ paclitaxel chemotherapy improves recurrence and survival outcomes“. Gynecol. Oncol., 2009, 112, 558.

[21] Desai N.B., Kiess A.P., Kollmeier M.A., Abu-Rustum N.R., Makker V., Barakat R.R., et al.: “Patterns of relapse in stage I-II uterine papillary serous carcinoma treated with adjuvant intravaginal radiation (IVRT) with or without chemotherapy“. Gynecol. Oncol., 2013, 131, 604.

[22] Viswanathan A.N., Macklin E.A., Berkowitz R., Matulonis U.: “The importance of chemotherapy and radiation in uterine papillary serous carcinoma“. Gynecol. Oncol., 2011, 123, 542.

[23] Beitler J.J., Cooper J.S.: “Seduction by induction?“. J. Clin. Oncol., 2009, 27, 9.

[24] Felix A.S., Stone R.A., Bowser R., Chivukula M., Edwards R.P., Weissfeld J.L., et al.: “Comparison of survival outcomes between patients with malignant mixed mullerian tumors and high-grade endometrioid, clear cell, and papillary serous endometrial cancers“. Int. J. Gynecol. Cancer, 2011, 21, 877.

[25] Kim H.J., Kim T.J., Lee Y.Y., Choi C.H., Lee J.W., Bae D.S., et al.: “A comparison of uterine papillary serous, clear cell carcinomas, and grade 3 endometrioid corpus cancers using 2009 FIGO staging system“. J. Gynecol. Oncol., 2013, 24, 120.

[26] Bansal N., Herzog T.J., Seshan V.E., Schiff P.B., Burke W.M., Cohen C.J., et al.: “Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior“. Obstet. Gynecol., 2008, 112, 64.

[27] Gurumurthy M., Somoye G., Cairns M., Parkin D.E.: “An update on the management of uterine carcinosarcoma“. Obstet. Gynecol. Surv., 2011, 66, 710.

[28] Kelly M.G., O’Malley D., Hui P., McAlpine J., Dziura J., Rutherford T.J., et al.: “Patients with uterine papillary serous cancers may benefit from adjuvant platinum-based chemoradiation“. Gynecol. Oncol., 2004, 95, 469.

[29] Lim P., Al Kushi A., Gilks B., Wong F., Aquino-Parsons C.: “Early -stage uterine papillary serous carcinoma of the endometrium: effect of adjuvant whole abdominal radiotherapy and pathologic parameters on outcome“. Cancer, 2001, 91, 752.

[30] Chang-Halpenny C.N., Natarajan S., Hwang-Graziano J.: “Early stage papillary serous or clear cell carcinoma confined to or involving an endometrial polyp: outcomes with and without adjuvant therapy“. Gynecol. Oncol., 2013, 131, 598.

[31] Hanley K.Z., Fadare O., Fisher K.E., Atkins K.A., Mosunjac M.B.: “Clinical significance of positive pelvic washings in uterine serous papillary carcinoma confined to an endometrial polyp”. Int. J. Gynecol. Pathol., 2016, 35, 249.