Ifosfamide for recurrent ovarian cancer – pro

Recurrent ovarian cancer is a difficult clincal problem; fortunately, a number of options are available. For patients whose disease is platinum-refractory (i.e., with disease that has progressed while on a platinum regimen or that has recurred shortly after completion of a platinum-containing regimen), treatment with paclitaxel (Taxol) historically provided the first agent with consistent activity in these patients and should be considered. Other options include tamoxifen, Doxil, vinorelbine, gemcitabine, Xeloda, top[otecan, hexamethylamine,methotrexate.

Modest activity has been demonstrated in patients with epithelial ovarian cancer, including disease that is platinum-refractory. A Gynecologic Oncology Group study demonstrated 3 clinical complete responses and 5 partial responses (overall response rate was 20%) in 41 evaluable patients who were either refractory to platinum or who had relapsed following platinum-based chemotherapy. Toxic effects include myelosuppression, nephrotoxicity, hemorrhagic cystitis, and toxic encephalopathy. Other phase II studies confirm the activity of ifosfamide in patients with epithelial ovarian cancer. In one phase II study, 7 objective responses were observed in 52 patients (objective response rate was 13.5%). Of the 7 patients who responded, 5 had tumors that were platinum-refractory.

Since then 7 or 8 phase II trials, singly or in combination have been performed. most f them in the late 1990′s. The drug is mentioned in the reviews of treatment of recurrent ovarian cancer. As an older agent, most of the experience with ifosfamide has been in patients previously treated with a combination of platinum and cyclophosphamide, prior to the incorporation of paclitaxel. It has been suggested that the current second-line activity of ifosfamide might be enhanced as a consequence of a reduction in the use of cyclophosphamide during initial therapy of ovarian cancer. However, a recently reported trial of single-agent ifosfamide in patients refractory to both platinum and paclitaxel has revealed an objective response rate of only 15%, similar to that achieved in patients previously treated with cyclophosphamide.

Ifosfamide has a number of important toxicities to be considered in the ovarian cancer population, including neutropenia, renal dysfunction, injury to the urothelium (hemorrhagic cystitis), and reversible central nervous system dysfunction. Risk for these toxicities is increased in elderly patients with renal dysfunction and low serum albumin, which are common findings in recurrent ovarian cancer. The drug also has the disadvantage of being administered over multiple days, or requiring a 24-h intravenous infusion.

The drug is not FDA approved. This is off-label use. However, it is mentioned by NCCN and NCI-PDQ. It is listed in ACCC but not other compendia. The documents reviewed did not include Plan defintions or language. However, applying general criteria, this treatment would appear to be suffciently justified by multiple phase II studies, listing in standard guidelines and the clinical situation to warrant approval.

V. Linasmita, S. Wilailak, S. Srisupundit, S. Tangtrakul, S. Bullangpoti, N. Israngura (1997) Ifosfamide/mesna plus adriamycin as salvage therapy of advanced epithelial ovarian cancer International Journal of Gynecological Cancer 7 (5), 388–391.

Hogberg T, Glimelius B, Nygren P; SBU-group. Swedish Council of Technology Assessment in Health Care. Systematic overview of chemotherapy effects in ovarian cancer. Acta Oncol. 2001;40(2-3):340-60.

Thomas J Herzog, Bhavana Pothuri
Ovarian cancer: a focus on management of recurrent disease Nature Clinical Practice Oncology (2006) 3, 604-611

Maurie Markman, Michael A. Bookman Second-Line Treatment of Ovarian Cancer The Oncologist, Vol. 5, No. 1, 26-35, February 2000

Sutton GP, Blessing JA, Homesley HD et al. Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1989;7:1672-1676.

Sorensen P, Pfeiffer P, Bertelsen K. A phase 2 trial of ifosfamide/mesna as salvage therapy in patients with ovarian cancer refractory to or relapsing after prior platinum-containing chemotherapy. Gynecol Oncol 1995;56:75-78.

Markman M, Hakes T, Reichman B et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum resistant disease. J Clin Oncol 1991;10:243-248.

Markman M, Kennedy A, Sutton G et al. Phase 2 trial of single agent ifosfamide/mesna in patients with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent. Gynecol Oncol 1998;70:272-274.

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