Mullerian endometrial cancers: Chemotherapy for metastatic disease – pro

Mullerian cancer is also called carcinosarcoma. For metastatic mullerian tumors,paclitaxel has activity. A Phase III trial has demonstrated that the combination of paclitaxel with ifosfamide results in improved survival in advanced uterine carcinosarcomas, compared with ifosfamide alone. The median overall survival for the combination regimen was 13.5 months, compared with 8.4 months with single-agent ifosfamide (p = 0.03).

Iit is reasonable to suggest that the combination of carboplatin plus paclitaxel is likely to be equivalent to, and less toxic than, alternative chemo-therapy approaches in this clinical setting (e.g., cisplatin plus ifosfamide; ifosfamide plus paclitaxel).

Doxorubicin in combination with dacarbazine or cyclophosphamide is no more active than doxorubicin alone for advanced disease. Cisplatin has activity as first-line therapy and minimal activity as second-line therapy for patients with carcinosarcomas (mixed mesodermal tumors), but is inactive as first- or second-line therapy of leiomyosarcoma. Patients who present with measurable disease have been treated on a series of Phase II studies by the Gynecologic Oncology Group (GOG). In separate studies of patients previously untreated with chemotherapy, ifosfamide had a 32.2% response rate in mixed mesodermal tumors , a 33% response rate in endometrial stromal cell sarcomas, and a 17.2% partial response rate in leiomyosarcomas. The GOG has also completed a randomized comparison of ifosfamide with or without cisplatin for first-line therapy for patients with measurable advanced or recurrent carcinosarcoma (mixed mesodermal tumor). The study demonstrated a higher response rate and longer progression-free survival on the combination arm. Survival, however, was not improved by the addition of cisplatin, and the authors concluded that use of the combination was not justified because of increased toxic effects. However, about one-third of patients with metastatic gynecological sarcomas may derive some palliative benefit from chemotherapy, espaecially in stromal tumors which appear to respons better.

Use of Doxil and topotecan is not supported by guidelines or literature. Sequential tretment with different regimens is appealing becauu mullerian cancers have both a sarcom and carcinoma compnents. . Forty-four women had either ovarian cancer or primary peritoneal carcinoma with 3 women diagnosed with fallopian tube carcinoma and 2 with papillary serous carcinoma of the uterus. Eighty-four percent of patients had stage IIIc/IV tumors, with 29% having >1 cm residual disease after primary cytoreductive surgery. Thirty-nine of 49 (80%) patients completed therapy. A total of 283 cycles of chemotherapy were delivered with acceptable toxicities. There were no toxic deaths. Five women were withdrawn from trial (3 for Taxol hypersensitivity, 1 for gemcitabine pulmonary hypersensitivity, and 1 for serious line infection). Neutropenia, typically without fever, was relatively frequent in the first doublet. Nausea and thrombocytopenia were the predominant toxicities in doublet 2. Thirty-nine women completed all cycles of treatment. Thirty-six women had restaging results consistent with a clinical complete response (CR) and underwent SLO. The pathologic CR rate of the patients undergoing SLO was 38%. The authors concluded: ” Sequential doublet regimen is feasible with a 38% pathologic CR rate.”
In anotehr study by the same author, after cytoreductive surgery, patients were treated with three sequential doublets including 3 cycles of carboplatin and gemcitabine, and 3 cycles of carboplatin and paclitaxel, and 3 cycles of doxorubicin and topotecan. The conculsions wa
s “Treatment with the modified triple doublet regimen is tolerable with an encouraging pathologic CR rate.”

Holland Frei Cancer Medicine 2009, Volume 8 By Waun Ki Hong, Robert C. Bast, William Hait, Donald W. Kufe, James F. Holland, Raphael E. Pollock, Ralph R. Weichselbaum, p. 1382

Matulonis U, Campos S, Duska L, Fuller A, Berkowitz R, Gore S, Roche M, Colella T, Lee H, Seiden MV; Gynecologic Oncology Research Program at Dana Farber/Partners Cancer Care; Dana Farber-Harvard Cancer Care.A phase II trial of three sequential doublets for the treatment of advanced müllerian malignancies.Gynecol Oncol. 2003 Nov;91(2):293-8.

Matulonis UA, Campos S, Krasner CN, Duska LR, Penson RT, Falke R, Roche M, Smith LM, Lee H, Seiden MV; Dana-Farber/Partners CancerCare and Harvard Vanguard Medical Associates.
Three sequential chemotherapy doublets for the treatment of newly diagnosed advanced müllerian malignancies: the modified triple doublet regimen.Gynecol Oncol. 2006 Nov;103(2):575-80
S. Kanjeeka et al  Metastatic uterine sarcoma: A systematic review of the literature. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 5105

Sindu Kanjeekal, Alexandra Chambers, Michael Fung Kee Fung, Shailendra Verma and Program in Evidence-based Care, Cancer Care Ontario, Canada on behalf of the Cancer Care Ontario Practice Guidelines Initiative Gynecology Cancer Disease Site Group
Systemic therapy for advanced uterine sarcoma: A systematic review of the literature
Gynecologic Oncology, Volume 97, Issue 2, May 2005, Pages 624-637

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