Capecitabine toxicity

A patient died after treatment with capecitabine possibly because the concurrent use of folic acid enhanced capecitabine toxicity. The maximum tolerated dose of capecitabine is decreased by foli-nic acid. 

Capedtabine is the prodrug of 5-FU and comes as oral tablets that are administered with food twice a day. Capedtabine has shown to be active in tumors of the colon, rectum, and breast. The toxicity profile of capecitabine is similar to that of 5-FU and includes diarrhea, mucositis, palmar-plantar erythrodysesthesia,... 

The dose of capecitabine begins at 1250 mg/m2 twice a day when used by itself lower doses are used often when it is given in combination with irinotecan or oxaliplatin or in patients with renal insufficiency. The dose should be taken on a full stomach with breakfast and dinner. Capecitabine administered with warfarin can result in significant increases in the patient s INR and requires close monitoring to prevent bleeding. The convenience of oral administration and an improvement in toxicity make capecitabine a useful alternative to IV 5-FU both by itself and incorporated into other regimens used in colon cancer. 

Patients with partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity as DPD is responsible for detoxification of pyrimidine-based antimetabolite analogs, such as 5-FU and capecitabine. The onset of toxicity occurs, on average, twice as fast in patients with low DPD activity compared with patients with normal DPD activity (13-16). 

This benefit comes at a cost of significant toxicity, particularly neuropathic, and more mature data are necessary to demonstrate the ultimate benefit of adjuvant therapies on improved overall survival. So far irinotecan plus 5-FU based therapy has produced disappointing results in adjuvant treatment. Despite the present lack of data addressing overall survival benefit, oxaliplatin plus 5-FU/leucovorin is widely recommended as the gold standard adjuvant therapy for stage 3 disease. For those whose medical fitness or other contra-indications preclude oxaliplatin based therapy 5-FU/leucovorin on a weekly or monthly schedule is recommended. Oral capecitabine for 6 months has recently been reported to be at least equivalent to 5-FU/leucovorin. 

Carlini EE, Meropol NJ, Bever J et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. Clin Cancer Res 2005 11 1226-1236. 

Besides the direct, dramatic incidence of acute toxicities on the patient s well-being, these side effects impact as well on the overall survival, because the forthcoming drug cycles have to be postponed or cancelled to allow proper recovery, with a subsequent loss of chance of treatment for the patients. Although the clinical consequences of DPD deficiency upon 5-FU therapy are well characterized now, its impact on capecitabine treatment remains unclear. 

The evidence for the role of DPD deficiency in capecitabine-induced toxicities has been demonstrated by some recent clinical reports (20, 29, 38), and has been finally confirmed by the first report of a toxic-death in a patient with DPYD gene polymorphism and severe enzyme deficiency treated in a capecitabine-containing protocol (28). Overall, numerous clinical reports have shown a link between the level of enzyme deficiency and the severity/lethality of the observed toxicities upon fiuoropyrimidines administration (35,39), thus warranting the need for early detection of patients at risk. 

Such determinations can be achieved using simple UV-HPLC (109,112,113,114,115), GC-MS or LC-MS/MS systems (105,106,113). Study of the correlations between U, UH2-U levels, and DPD activities or 5-FU PK parameters have yield conflicting data (16,22,116). However, a clear relationship has been demonstrated between U-UH2 ratio values and the occurrence of severe/lethal toxicities with 5-FU or capecitabine as a clinical endpoint (20,27,28). 

Table 2 Phenotypic/Genotypic Evidences of DPD Down-Regulation in Patients Presenting with Severe/Lethal Toxicities Upon 5-FU/Capecitabine Administration Since 2000 ...

Ciccolini J, Mercier C, Dahan L et al. Implication of DPD deficiency in severe or lethal toxicities after 5-fluorouracil and capecitabine-based chemotherapies. AACR Annual Meeting Proceedings 2004 46. Ciccolini J, Mercier C, Dahan L et al. Toxic death-case after capecitabine + oxaliplatin (XELOX) administration probable implication of dihydropyrimidine deshydrogenase deficiency. Cancer Chemother Pharmacol 2006 58 272-275. 

Salgado J, Zabalegui N, Gil C et al. Polymorphisms in the thymidylate synthase and dihydropyrimidine dehydrogenase genes predict response and toxicity to capecitabine-raltitrexed in colorectal cancer. Oncol Pep 2007 17 325-328. 

In parallel to these studies, carbamate compounds 1 and 11-14 were assessed for their antitumor efficacy in mouse cancer xenograft models.15 When implanted human colon cancer CXF280 xenografts were grown within mice for fourteen days, doses of test compounds were administered orally. After a three-week regimen, excised tumor volumes were measured and the percent inhibition of tumor growth was calculated. From this investigation, capecitabine (1) was found to be the most effective treatment, and was furthermore found not to cause intestinal toxicity.16 All of these preclinical observations contributed to the selection of capecitabine as a candidate for further development. 

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. 

These equations make a number of assumptions and may be used to estimate Mrs RP s renal function this is necessary as toxicity from capecitabine can be increased in individuals with renal impairment (creatinine clearance <50 mL/min). 

Her diarrhoea has almost certainly been caused by her capecitabine treatment. Capecitabine is a prodrug of 5-fluorouracil and as such may cause similar side-effects to it. Cytotoxic drugs can cause gastrointestinal toxicity such as diarrhoea due to their effect on the rapidly dividing cells of the body, including the cells of the gastrointestinal mucosa. 

Capecitabine is an example of a prodrug chemical delivery system that requires a series of enzymatic steps for conversion to the active antitumor drug species. S-fluorouracil (Scheme 5-24). Tumors located in tissues with high levels of the required enzymes. should respond best to treaunent with capecitabine. Esterase activity occurs primarily in the liver, allowing the intact e.ster capecitabine to be the absorbed species following oral administration. The ester hydrolysis product itself shows some specific toxicity towani... 

The toxicity of antimetabolites is, as expected, due to their incorporation into the metabolism of normal cells, which is nearly identical to that of the malignant cells that they were designed to injure. The normal cells injured most severely are the rapidly proliferating cells of the bone marrow, the lymphoid system, and the GI epithelium. Thus, the common toxicities are bone marrow depression, nausea and vomiting, diarrhea, and mucositis. Cytarabine and pentostatin can cause conjunctivitis. Capecitabine and prolonged use of fluorouracil or cytarabine can cause cerebellar ataxia and the hand-foot syndrome, that is, palmar-plantar erythrodysesthesia or acral erythema. Pentostatin and high-dose methotrexate can cause renal toxicity. 

Kramar et al. (70) showed that the maximum likelihood CRM previously described in this chapter may be useful in a two-drug combination Phase 1 study. As for a single agent, the method requires a priori dose-toxicity profiles. Isobolograms can be obtained using these profiles available from the monotherapy Phase 1 studies of each drug separately, as well as from previous monotherapy Phase 2/3 studies. The method has been used by Morita et al. (71) for designing a Phase 1 clinical trial of capecitabine in combination with cyclophosphamide and epirubicin. 

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