Docetaxel Capecitabine

Docetaxel + capecitabine Docetaxel 75 mg/m2 IV over 1 hour, day 1 Capecitabine 2000-2500 mg/m2 per day orally divided twice daily for 14 days Repeat cycles every 21 days Epirubicin + docetaxel" Epirubicin 70-90 mg/m2 IV bolus Followed by Docetaxel 70-90 mg/m2 IV over 1 hour Repeat cycles every 21 daysv Doxorubicin + docetaxel" Doxorubicin 50 mg/m2 IV bolus, day 1 Followed by Docetaxel 75 mg/m2 IV over 1 hour, day 1 Repeat cycles every 21 days"... 

Docetaxel 75 m m2 IV over 1 hour, day 1 Capecitabine 2,000-2,500 mg/m2 per day orally divided twice daily for 14 days... 

The mechanism by which the cytotoxic agents were approved is of inferest. Many were approved on fhe basis of response rafe as a surrogafe for survival (e.g., via the accelerated approval path). - Of nofe is the development of fhe cytotoxic agents, capecitabine received initial accelerated approval on the basis of fhe surrogafe endpoint of response rate in patients with refractory breast cancer. This was later followed up with a randomized Phase 111 trial of docetaxel wifh or withouf capecifabine in patienfs with refractory breast cancer with this trial demonstrating an improvement in survival for the combination of docetaxel + capecitabine vs. docetaxel alone. ... 

O Shaughnessy, J. et al., Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated paEents with advanced breast cancer phase III trial results, J. Clin. Oncol, 20, 2812-2823, 2002. 

Capecitabine is a pyrimidine analog. It is an oral systemic prodrug that is enzymatically converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-flu-orouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Capecitabine is indicated in the treatment of resistant metastatic breast cancer alone or in combination with docetaxel, and colorectal cancer. 

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. 

A study in patients with advanced solid tumours found that the use of capecitabine with docetaxel, resulted in an almost twofold decrease in the maximum plasma concentration and AUC of fluorouracil. The authors suggest that more study is needed to assess the significance of this finding. Other pharmacokinetic parameters of capecitabine were not affected by docetaxel, and the pharmacokinetics of docetaxel were not significantly affected by capecitabine or its metabolites. ... 

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. ... 

Pronk LC, Vasey P, Sparreboom Reigner B, Planting AST, Gordon RJ, Osterwalder B, Ver-weij J. A i 4ia I and Jiarmacokinetic study of the combinaticm of capecitabine and docetaxel in patients with advanced solid tumours. BrJ Cancer (2000) 83, 22-9. 

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... 

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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