Standard chemotherapy for endometrial cancer – pro

Lay Summary: Adjuvant chemo is standard for endometrial cancer and has a limited role for metastatic disease. However, chemotherapy may be useful for metastatic cases. There is currently little hope for cure in patients with metastatic endometrial carcinoma. Selected patients will respond to hormonal therapy, particularly progestins; however, for most women with advanced disease, chemotherapy is currently the standard antineoplastic treatment option. Taxanes, anthracyclines, and platinum compounds represent the chemotherapeutic agents with the greatest activity in this disease. Response rates (RRs) for each agent range from 20% to 35%.

Doxorubicin is the most active anticancer agent employed, with useful but temporary responses obtained in as many as 33% of patients with metastatic disease. Paclitaxel also has significant activity.

The combination of doxorubicin plus cisplatin (AP) has produced RRs of 40% to 46%, with reported median progression-free survival (PFS) ranging from 5.2 to 7.2 months in the three most recent Gynecologic Oncology Group (GOG) randomized trials. Most recently, the GOG compared AP with doxorubicin plus paclitaxel 150 mg/m2 as a 24-hour continuous infusion with filgrastim support, and there was no statistically significant improvement in objective RR, PFS, or overall survival (OS) between the regimens. The most recent randomized study found that TAP significantly improves RR, PFS, and OS compared with AP. What this suggested is that riplet therapy is superior to doublets. I elaborate. In 2001, the GOG published the results of a dose-finding trial that combined cisplatin, doxorubicin, and a 3-hour infusion of paclitaxel (TAP) in chemotherapy-naïve patients with advanced endometrial carcinoma and other gynecologic malignancies. In that trial, doxorubicin and cisplatin were administered on day 1, and paclitaxel, on day 2 because of previous reports suggesting that the cardiotoxicity associated with the paclitaxel + doxorubicin combination was decreased when these agents were administered 16 to 24 hours apart.12 Even when low doses of the combination of TAP were used, filgrastim was required for hematopoietic support, and neurotoxicity became the dose-limiting toxicity. The recommended phase II doses were doxorubicin 45 mg/m2, cisplatin 60 mg/m2, and paclitaxel 160 mg/m2 intravenously over 3 hours, with filgrastim 5 µg/kg given on days 3 to 12. Of 20 patients treated at this dose level, two (10%) developed grade 3 peripheral neuropathy Next GOG did a phase III trial compared cisplatin plus doxorubicin to doxorubicin, cisplatin, and paclitaxel with granulocyte colony-stimulating factor (G-CSF) support. The three-drug arm produced more objective responses than the two-drug arm (57% vs 34%, P < .01). Progression-free survival was extended to 8.3 months compared with 5.3 months in the control arm (P < .01); and overall survival reached a median of 15.3 months compared with 12.3 months (P < .037). Patients who received doxorubicin plus cisplatin on this trial were not likely to receive paclitaxel as first salvage therapy, which might account for the survival advantage for the three-drug combination. As seen in previous trials, increasing efficacy with more chemotherapy also led to increasing toxicity; patients receiving the three-drug combination were more likely to suffer thrombocytopenia and grade 3 and 4 neurotoxicity. The current GOG phase III trial compares the three-drug regimen of cisplatin, doxorubicin, and paclitaxel with G-CSF support to carboplatin combined with paclitaxel. Phase II trials testing the combination of carboplatin and paclitaxel in advanced, recurrent, or metastatic endometrial cancer have shown response rates of 46% to 78%. A Cochrane review recently attempted to address the issue of whether more chemotherapy is better in the case of treating advanced, recurrent, or metastatic endometrial cancer. Eleven randomized clinical trials were identified that included a total of 2,288 patients. A meta-analysis of six trials showed improved progression-free survival with more intensive chemotherapy compared with less intense chemotherapy (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.71–0.90; P = .004) but a comparable overall survival (HR = 0.90, 95% CI = 0.80–1.03; P = .12). Grade 3 and 4 toxicity, particularly in the form of myelosuppression and gastrointestinal toxicity, was higher in patients receiving more intense chemotherapy regimens. The NCCN lists carboplatin, cisplatin and palcitaxel as options for metastatic or advanced endometrial carcinoma, as single agents or combined. For clinical use, carboplatin is interchangeable with cisplatin by general consensus because of their similarity and trial evidence in a a number of cancer sites (although not in all and not in endometrial cancer). NCCN cites a variety of regimens, including ifosfamide/paclitaxel, doxorubicin/cisplatin/paclitaxel, cisplatin/dosorubicin and the single agents: cisplatin, doxorubicin, paclitaxel and ifosfamide. Cisplatin, etoposide, adriamycin is an older regimen that was found in 1995 to be superior to a melphalan based regimen. It is not currently in any trial for endometrial cancer as per

NCCN, Endometrial ENDO-B, 2019

Samarnthai N, Hall K, Yeh IT. Molecular profiling of endometrial malignancies. Obstet Gynecol Int. 2010;2010:162363.

Urick, M.E., Bell, D.W. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer 19, 510–521 (2019)

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Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004;22(11):2159-2166.

Humber CE, Tierney JF, Symonds RP, et al. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol. 2007;18(3):409-420.

Wolf K, Slomovitz BM. Novel biologic therapies for the treatment of endometrial cancer. Int J Gynecol Cancer. 2005;15(2):411.

J. T. Thigpen, M. F. Brady, H. D. Homesley, J. Malfetano, B. DuBeshter, R. A. Burger, and S. Liao Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study J. Clin. Oncol., October 1, 2004; 22(19): 3902 – 3908.

G. F. Fleming, V. L. Filiaci, R. C. Bentley, T. Herzog, J. Sorosky, L. Vaccarello, and H. Gallion Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study Ann. Onc., August 1, 2004; 15(8): 1173 – 1178

Cornelison TL, Baker TR, Piver MS, Driscoll DL..Cisplatin, adriamycin, etoposide, megestrol acetate versus melphalan, 5-fluorouracil, medroxyprogesterone acetate in the treatment of endometrial carcinoma.: Gynecol Oncol. 1995 Nov;59(2):243-8

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