Ovarian cancer platinum-refractory

In phase II of treatment hepatic failure, renal failure, pancytopenia, and rhabdomyolysis were eommon adverse effects. Pharmacokinetic and pharmacodynamic studies show that biliary function can be served as reference parameter to indicate whether patient receive full dose of trabectedin or not. It is also reported that alkaline phosphatase and bilirubin can be served as a high risk indicator in full dose treatment. Phase II clinical trials show that trabectedin has greater efficacy in patient who suffered from breast and ovarian cancer and refractory soft tissue sarcoma. A search in Pubmed shows that there are several studies reporting the results of clinical trials (phase I, II and III) on the efficacy of trabectedin against ovarian cancer. Ferrandina et al. [38] performed retrospective, multicenter study to determine the potential efficacy of trabectedin as single agent in 98 patients (67 platinum sensitive, and 31 platinum refractory/resistant) who suffered from heavily relapsed ovarian cancer. They found that trabectedin treatment can prolong the survival of patients (18 month for treatment vs. 14 month for SD). They also found that hepatotoxicity and rare cardiotoxicity were the most important adverse effects of trabectedin treatment [38]. 

Gordon AN, Granai CO, Rose PG, et al. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000 18 3093. 

Docetaxel is a semisynthetic taxane derived from the European yew tree. Its mechanism of action, metabolism, and elimination are identical to those of paclitaxel. It is approved for use as second-line therapy in advanced breast cancer and non-small cell lung cancer, and it also has major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer. Its major toxicities are listed in Table 54-4. 

Chemotherapy refers to drug administration with highly serious side effects, such as nausea, hand and foot rashes, mouth sores, and increased risk of infection, easy bruising, and so on. Therefore, liposomal carriers have been used in order to improve the drug s biodistribution and protect the patient from those side effects. The main anticancer drugs used to treat ovarian cancer are carboplatin and cisplatin, paclitaxel, topotecan, and lurtotecan. PEGylated liposomal doxorubicin has been approved as a regimen for patients with metastatic ovarian cancer refractory to both paclitaxel and platinum based-therapy [449],... 

A variety of new molecules either in combination with liposomal doxorubicin or not are in development at the moment [457]. For example, a phase III study will be conducted to test the efficacy and safety of pattupilone versus PEG-liposomal DXR in taxane/platinum refractory/resistant patients with recurrent epithelial ovarian, primary fallopian, or primary peritoneal cancer. A phase III randomized study of Telcyta with Doxil/Caelyx versus Doxil/Caelyx has been planned in patients with platinum-refractory or platinum-resistant ovarian cancer. A phase II study relevant to side effects and best dose of ixabepilone combined with liposomal DXR will be assessed in patients with advanced ovarian epithelial, peritoneal cavity, or fallopian tube cancer or metastatic breast cancer. 

Gemcitabine is a clinically active antineoplastic drug in platinum-refractory ovarian cancer. The efficacy and tolerability of the particular drug in combination with liposomal DXR were investigated in athymic mice bearing cisplatin-resistant human ovarian carcinoma [458]. 

C21-Amino-Epo B [BMS-310705 (23)] is undergoing clinical evaluation in humans, but only hmited biological data are currently available in the literature for this compound. Thus, an IC50 value of 0.8 nM for growth inhibition of the human epidermoid cancer cell line KB.31 has been reported in a patent application (vs 1.2nM for Epo B under comparable experimental conditions" ). More recently, Uyar et al." have demonstrated that 50 nM BMS-310705 induces substantial apoptosis in early passage ovarian cancer cells (OC-2), which were derived from a clinical tumor sample and were refractory to paclitaxel and platinum treatment. A concentration of 50 nM of BMS-310705 (23) is clinically achievable at a dose of 10 mg/m, which is below the phase 1 maximum tolerated dose (MTD) for the compound. " BMS-310705 (23) exhibits improved water-solubility over BMS-247550 (1), which enables the use of chnical formulations not containing Cremophor-EL. ... 

Trimble EL, Adams JD, Vena D, Hawkins MJ, Friedman MA, Fisherman JS, Christian MC, Canetta R, Onetto N, Hayn R, Arbuck S. Pachtaxel for platinum-refractory ovarian cancer results from the first 1,000 patients registered to National Cancer Institnte Treatment Referral Center 9103. J Clin Oncol 1993 11(12) 2405-10. 

Doxil (doxorubicin) an anticancer drug for the treatment of metastatic ovarian cancer in patients with disease that is refractory to both paclitaxel-and platinum-based chemotherapy regimens and for the treatment of AIDS-related Kaposi s sarcoma with disease that has progressed. 

Carboplatin has been used in the treatment of platinum-refractory ovarian cancer. Kavanagh and coUeagnes treated 33 platinum-refractory ovarian cancer patients with disease progression after tax-ane salvage therapy with carboplatin 300 mg/m every 28 days. These investigators noted a 21% partial response rate, a 39% stabilization rate, and a median response duration greater than 7 months. However, aU responding patients had a platinum-free interval of at least 12 months. 

Docetaxel offers an alternative taxane treatment in patients with platinum-refractory ovarian cancer. " Preclinical studies show that docetaxel has more potent in vitro activity than does paclitaxel. " Docetaxel has produced overall response rates of 20% to 40% in patients with platinum-sensitive and platinum-refractory advanced... 

Kavanagh J, Tresukosol D, Edwards C, et al. Carboplatin reinduction aftertaxane inpatients with platinum-refractory epithehal ovarian cancer. J ain Oncol 1995 13 1584-1588. 

Francis P, Schneider J, Hann L, et al. Phase II trial of docetaxel in patients with platinum-refractory advanced ovarian cancer. J Clin Oncol 1994 12 2301-2308. 

Gordon, A. N., Granai, C. O., Rose, P. G., Hainsworth, J., Lopez, A., Weissman, C., Rosales, R. and Sharpington, T., Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer, J. Clin. Oncol, 18(17), 3093, 2000. 

Kavanagh JJ, Kudelka AP, Gonzalez de Leon C, et al. Phase II study of docetaxel in patients with epithehal ovarian carcinoma refractory to platinum. Clin Cancer Research 1996 2 837-842. 

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