Paclitaxel Capecitabine

Two Phase III clinical studies of orally administered capecitabine in over 1,200 patients with untreated metastatic colorectal cancer demonstrated at least equal efficacy and improved tolerability versus the Mayo Clinic regimen of intravenous 5-fluorouracil/leucovorin administration. The overall response rate for patients taking capecitabine orally was 21%, versus 14% for the intravenous 5-FU/leucovorin regimen. A median 53-month follow-up revealed a three-year disease-free survival rate of 66% for capecitabine versus 63% for 5-FU/leucovorin patients. International Phase II trials also demonstrated therapeutic benefits of capecitabine monotherapy for women with metastatic breast cancer that was either resistant to both paclitaxel and anthracycline therapy. Orally administered at the twice-daily 1,250 mg/m2 regimen (cycles of two weeks of therapy followed by a week of rest), the tumor response rate was in the range of 20-25%. In addition, combination of capecitabine with a taxane yielded a unique survival benefit compared to the previous standard of taxane monotherapy for anthracycline-resistant breast cancer.13,14... 

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

Capecitabine is approved by the FDA for the treatment of (1) metastatic breast cancer in patients who have not responded to a regimen of paclitaxel and an anthracycline antibiotic (2) metastatic breast cancer when used in combination with docetaxel in patients who have had a prior anthracycline-containing regimen and (3) metastatic colorectal cancer for patients in whom fluoropyrimidine monotherapy is preferred. The recommended dose is 2500 mg/m daily, given orally in two divided doses with food, for 2 weeks followed by a rest period of 1 week. This cycle is then repeated two more times. 

There are no clinically significant pharmacokinetic interactions between capecitabine and paclitaxel, and probably not between capecitabine and docetaxel. 

Other studies in similar patients also found that capecitabine did not alter the pharmacokinetics of docetaxel and that the concurrent use of paclitaxel and capecitabine did not significantly alter the pharmacokinetics of either drug. ... 

Martin LP, Kozloff MF, Herbst RS, Samuel TA, Kim S, Rosbrook B, Tortorici M, Chen Y, Tarazi J, Olszanski AJ, Rado T, Starr A, Cohen RB (2012) Phase I study of axitinib combined with paclitaxel, docetaxel or capecitabine in patients with advanced solid tumours. Br J Cancer 107 1268—1276... 

In precfinical studies, the combination of Bevacizumab with chemotherapy led to synergistic activity. In xenotransplants, the combination of Bevacizumab with capecitabine inhibited tumor growth more effectively and longer than any other tested substance (Sachsenmaier 2001). It also showed synergistic effects in combination with paclitaxel and Trastuzumab (Herceptin ), a humanized monoclonal antibody that acts on the HER2/neu (erbB2) receptor. In further in-vivo studies, the application of Bevacizumab to animals previously treated with capecitabine, topotecan, or cis-platin showed more successful tumor suppression. Also, repeated application of Bevacizumab proved to be safe and well tolerated. 

Docetaxel is indicated, in combination with doxorubicin and cyclophosphamide, for adjuvant treatment of node-positive breast cancer and, in combination with doxorubicin, for treating locally advanced or metastatic breast cancer. It is also indicated as monotherapy or in combination with capecitabine for the treatment of locally advanced or metastatic breast cancer in patients who have relapsed or progressed after previous anthracycline or alkylating agents. It can be administered concurrently with trastuzumab, with which it is synergistic in vitro [1091], unlike paclitaxel, which appears to have simply an additive effect with trastuzumab [110 ]. 

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