Clinical benefit of hormonal therapy in advanced ovarian cancer

Objectives: To evaluate the benefit of hormonal therapy in advanced ovarian carcinoma. Materials and Methods: The present authors reviewed the data of advanced epithelial ovarian cancer patients who underwent hormonal therapy between 2009 and 2016. Primary endpoint was clinical benefit. Secondary endpoints were overall response rate, CA 125 response, overall survival, progression-free survival, and toxicity. Results: The authors identified 47 patients. Median age was 61 years. Serous carcinoma was the main histologic subtype (70%). Hormone receptor expression was positive in 23% of patients. Previous to hormonal therapy, 60% of patients were treated with two or more chemotherapy regimens (range 2-8). Hormonal therapy was initiated in 34% of patients due to disease progression and the remaining as maintenance therapy. No relevant toxicity was reported. Progression-free survival was six months (CI 95% 2.1-9.9) and overall survival was 22 months (CI 95% 13.0-31.0). Based on imaging response criteria, one patient had complete response, 70% had stable disease, and 19% progressed on the first evaluation. Overall clinical benefit was 72%. Discussion: Clinical benefit was superior to the reported in the literature, probably related to its maintenance use between chemotherapy treatments. More prospective studies are needed to determine the real advantage of hormonal therapy in advanced ovarian cancer vs. clinical surveillance, mainly in the maintenance setting, as well as its correlation with hormone receptor expression.

Ovarian cancer; Hormonal therapy; Letrozole; Tamoxifen; Megestrol.

[1] EUCAN Cancer Factsheets: “Ovary”. Available at: http://eco.iarc.fr/ eucan/CancerOne.aspx?Cancer=27&Gender=2

[2] Surveillance End Results Program (SEER). Available at: https://seer. cancer.gov/statfacts/html/ovary.html

[3] McGuire W.P., Hoskins W.J., Brady M.F., Kucera P.R., Partridge E.E., Look K.Y., et al.: “Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer”. N. Engl. J. Med., 1996, 334, 1.

[4] Dunton C.J.: “Management of treatment-related toxicity in advanced ovarian cancer”. Oncologist, 2002, 7, 11.

[5] Fotopoulou C.: “Limitations to the use of carboplatin-based therapy in advanced ovarian cancer”. Eur. J. Cancer Supplements, 2014, 12, 13.

[6] Hanker L.C., Loibl S., Burchardi N., Pfisterer J., Meier W., PujadeLauraine E., et al.: “The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinumbased therapy”. Ann. Oncol., 2012; 23, 2605.

[7] Langdon S.P., Crew A.J., Ritchie A.A., Muir M, Wakeling A., Smyth J.F., et al.: “Growth inhibition of oestrogen receptor-positive human ovarian carcinoma by anti-oestrogens in vitro and in a xenograft model”. Eur. J. Cancer, 1994, 30a, 682.

[8] Simpkins F., Hevia-Paez P., Sun J., Ullmer W., Gilbert C.A., da Silva T., et al.: “Src Inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo”. Clin. Cancer Res., 2012, 18, 5911.

[9] Simpkins F., Garcia-Soto A., Slingerland J.: “New insights on the role of hormonal therapy in ovarian cancer”. Steroids, 2013, 78, 530.

[10] Bowman A., Gabra H., Langdon S.P., Lessells A., Stewart M., Young A., et al.: “CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup”. Clin Cancer Res., 2002, 8, 2233.

[11] del Carmen M.G., Fuller A.F., Matulonis U., Horick N.K., Goodman A., Duska L.R., et al.: “Phase II trial of anastrozole in women with asymptomatic mullerian cancer”. Gynecol. Oncol., 2003, 91, 596.

[12] Hatch K.D., Beecham J.B., Blessing J.A., Creasman W.T.: “Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients”. Cancer, 1991, 68, 269.

[13] Papadimitriou C.A., Markaki S., Siapkaras J., Vlachos G., Efstathiou E., Grimani I., et al.: “Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study”. Oncology, 2004, 66, 112.

[14] Ramirez P.T., Schmeler K.M., Milam M.R., Slomovitz B.M., Smith J.A., Kavanagh J.J., et al.: “Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum”. Gynecol. Oncol., 2008, 110, 56.

[15] Schwartz P.E., Keating G., MacLusky N., Naftolin F., Eisenfeld A.: “Tamoxifen therapy for advanced ovarian cancer”. Obstet. Gynecol., 1982, 59, 583.

[16] Smyth J.F., Gourley C., Walker G., MacKean M.J., Stevenson A., Williams A.R., et al.: “Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients”. Clin. Cancer Res., 2007, 13, 3617.

[17] Weiner S.A., Alberts D.S., Surwit E.A., Davis J., Grosso D.: “Tamoxifen therapy in recurrent epithelial ovarian carcinoma”. Gynecol. Oncol., 1987, 27, 208.

[18] Gershenson D.M., Sun C.C., Iyer R.B., Malpica A.L., Kavanagh J.J., Bodurka D.C., et al.: “Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum”. Gynecol. Oncol., 2012, 125, 661.

[19] Gershenson D.M., Sun C.C., Bodurka D., Coleman R.L., Lu K.H., Sood A.K., et al.: “Recurrent low-grade serous ovarian carcinoma is relatively chemoresistant”. Gynecol. Oncol., 2009, 114, 48.

[20] Grabowski J.P., Harter P., Heitz F., Pujade-Lauraine E., Reuss A., Kristensen G., et al.: “Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase”. Gynecol. Oncol., 2016, 140, 457.

[21] Schmeler K.M., Sun C.C., Bodurka D.C., Deavers M.T., Malpica A., Coleman R.L., et al.: “Neoadjuvant chemotherapy for low-grade serous carcinoma of the ovary or peritoneum”. Gynecol. Oncol., 2008, 108, 510.

[22] Gershenson D.M., Bodurka D.C., Coleman R.L., Lu K.H., Malpica A., Sun C.C.: “Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum”. J Clin Oncol., 2017, 35, 1103.

[23] Williams C., Simera I., Bryant A.: “Tamoxifen for relapse of ovarian cancer”. Cochrane Database Syst. Rev., 2010, 3, CD001034.

[24] Verma S., Alhayki M., Le T., Baines K., Rambout L., Hopkins L., et al.: “Phase II study of exemestane in refractory ovarian cancer”. J. Clin. Oncol., 2006, 24, 5026.

[25] George A., McLachlan J., Tunariu N., Della Pepa C., Migali C., Gore M., et al.: “The role of hormonal therapy in patients with relapsed high-grade ovarian carcinoma: a retrospective series of tamoxifen and letrozole”. BMC Cancer, 2017, 17, 456.

[26] Sikic B.I., Scudder S.A., Ballon S.C., Soriero O.M., Christman J.E., Suey L., et al.: “High-dose megestrol acetate therapy of ovarian carcinoma: a phase II study by the Northern California Oncology Group”. Semin. Oncol., 1986, 13, 26.

[27] Veenhof C., van der Burg M., Nooy M., Aalders J.G., Pecorelli S., Oliveira C.F., et al.: “Phase II study of high-dose megestrol acetate in patients with advanced ovarian carcinoma”. Eur. J. Cancer, 1994, 30, 697.

[28] Wilailak S., Linasmita V., Srisupundit S.: “Phase II study of highdose megestrol acetate in platinum-refractory epithelial ovarian cancer”. Anticancer Drugs, 2001, 127, 19.

[29] Bonaventura A., O’Connell R.L., Mapagu C., Beale P.J., McNally O.M., Mileshkin L.R., et al.: “Paragon (ANZGOG-0903): Phase 2 study of anastrozole in women with estrogen or progesterone receptor-positive platinum-resistant or -refractory recurrent ovarian cancer. Int. J. Gynecol. Cancer, 2017, 27, 900.

[30] Day R..”Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project”. Annals N.Y. Acad. Sci., 2001, 949, 143.

[31] Cuzick J., Forbes J., Edwards R., Baum M., Cawthorn S., Coates A., et al.: “First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial”. Lancet, 2002, 360, 817.

[32] Fisher B., Costantino J.P., Wickerham D.L., Redmond C.K., Kavanah M., Cronin W.M., et al.: “Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study”. J. Natl. Cancer Inst., 1998, 90,1371.

[33] Swerdlow A.J., Jones M.E.: “Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study”. J. Natl. Cancer Inst., 2005, 97, 375.

[34] Howell A, Cuzick J., Baum M., Buzdar A., Dowsett M., Forbes J.F., et al.: “Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer”. Lancet, 2005, 365, 60.

[35] Sehdev S., Martin G., Sideris L., Lam W., Brisson S.: “Safety of adjuvant endocrine therapies in hormone receptor–positive early breast cancer”. Curr. Oncol., 2009, 16, S14.