Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Standard therapy for advanced or metastatic colorectal cancer consists of 5-fluorouracil plus leucovorin (5-FU/LV) administered intravenously (i.v.). Capecitabine (Xeloda), an oral fluoropyrimidine carbamate which is preferentially activated by thymidine phosphorylase in tumour cells, mimics continuous 5-FU and is a recently developed alternative to i.v. 5-FU/LV. The choice of oral rather than intravenous treatment may affect medical resource use because the two regimens do not require the same intensity of medical intervention for drug administration, and have different toxicity profiles. Here we examine medical resource use in the first-line treatment of colorectal cancer patients with capecitabine compared with those receiving the Mayo Clinic regimen of 5-FU/LV. In a prospective, randomised phase III clinical trial, 602 patients with advanced or metastatic colorectal cancer recruited from 59 centres worldwide were randomised to treatment with either capecitabine or the Mayo regimen of 5-FU/LV. In addition to clinical efficacy and safety endpoints, data were collected on hospital visits required for drug administration, hospital admissions, and drugs and unscheduled consultations with physicians required for the treatment of adverse events. Capecitabine treatment in comparison to 5-FU/LV in advanced colorectal carcinoma resulted in superior response rates (26.6% versus 17.9%, P=0.013) and improved safety including less stomatitis and myelosuppression. Capecitabine patients required substantially fewer hospital visits for drug administration than 5-FU/LV patients. Medical resource use analysis showed that patients treated with capecitabine spent fewer days in hospital for the management of treatment related adverse events than did patients treated with 5-FU/LV. In addition, capecitabine reduced the requirement for expensive drugs, in particular antimicrobials fluconazole and 5-HT3-antagonists to manage adverse events. As anticipated with an oral home-based therapy patients receiving capecitabine needed more frequent unscheduled home, day care, office and telephone consultations with physicians. In the light of clinical results from the phase III trial demonstrating increased efficacy in terms of response rate, equivalent time to progression (TTP) and survival (OS), and a superior safety profile, the results from this medical resource assessment indicate that capecitabine treatment of colorectal cancer patients results in a substantial resource use saving relative to the Mayo Clinic regimen of 5-FU/LV. This benefit is derived principally from the avoidance of hospital visits for i.v. drug administration, less expensive drug therapy for the treatment of toxic side-effects, and fewer treatment-related hospitalisations required during the course of therapy for adverse drug reactions in comparison to patients treated with 5-FU/LV.
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PMID:Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. 1129 Apr 35

Attempts at improving the efficacy of 5-fluorouracil (5-FU) by protracted continuous infusion and/or biochemical modulation have been hindered by the need for indwelling central venous catheters and their associated toxicity. Capecitabine, an oral fluoropyrimidine carbamate, has been rationally synthesized as an inactive precursor that is absorbed intact through the intestinal mucosa and is sequentially converted by an enzymatic cascade involving 3 distinct enzymes to 5'-deoxy-5-fluorocytidine, to 5'-deoxy-5-fluorouridine (5'-DFUR), and finally to 5-FU. Preclinical studies provided evidence of preferential intratumoral conversion of inactive 5'-DFUR to active 5-FU due to the relative overexpression of the final anabolizing enzyme, thymidine phosphorylase, in tumor tissues, with a resultant decrease of 5-FU exposure in normal tissues. The safety of capecitabine and optimal dosing schedules have been explored in phase I/II studies, resulting in the evaluation of the intermittent schedule (1250 mg/m2 twice daily for 14 days, every 3 weeks) in most subsequent clinical trials. Two large randomized phase III studies in patients with metastatic colon cancer established at least equivalent efficacy and improved tolerability with capecitabine compared to the Mayo Clinic bolus 5-FU/leucovorin regimen. The most common treatment-related adverse events are palmar-plantar erythrodysesthesia, diarrhea, and stomatitis, with grade 3/4 events occurring in 17%, 15%, and 2%-8% of patients, respectively. Myelosuppression was minimal. Overall toxicity was easily managed, with a significant reduction in the frequency of hospitalizations and medical resource use. The spectrum of clinical efficacy of capecitabine is expected to encompass other tumor types and administration in the adjuvant setting. As a home-based outpatient regimen, capecitabine represents a safe and effective advance in modern drug development.
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PMID:Capecitabine (Xeloda): from the laboratory to the patient's home. 1245 32

Although the anti-neoplastic activity of 5-Fluorouracil (5-FU) is improved by continuous infusion or biochemical modulation, the need for in-dwelling central venous catheters and toxicity have proved to be major impediments. Capecitabine (Xeloda, N4-pentyloxycarbonyl-5'-deoxy-5-fluoro-cytidine), an oral fluoropyrimidine, has been synthesized in the laboratory as an inactive precursor that passes intact through the intestinal mucosa and is sequentially converted to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR) and finally 5-FU in the liver and tumour tissues selectively. Preclinical studies provided evidence of preferential conversion of inactive 5'-DFUR to active 5-FU in solid tumours due to the relative overexpression of the final anabolising enzyme, thymidine phosphorylase (TP), in neoplastic tissues more than in normal counterparts. Phase I/II studies exploring toxicity and the appropriate dosing resulted in the evaluation of the intermittent schedule (2510 mg/m2/day for 14 days every 3 weeks) in subsequent trials. Two large phase III studies in patients with metastatic colon cancer established at least equivalent efficacy and improved tolerability for capecitabine compared to the Mayo Clinic bolus 5-FU/folinic acid regimen. Phase II studies established remarkable activity in women with heavily pretreated metastatic breast cancer. Moreover the combination with a taxane yielded a unique survival benefit compared to the previous gold standard of taxane monotherapy in a phase III trial of women with anthracycline resistant breast cancer. The commonest side-effects are hand and foot syndrome, diarrhoea and stomatitis with serious adverse events occurring in a minority of patients. Myelosuppression was minimal or absent. Toxic manifestations are easily managed with a significant reduction in the frequency of hospitalizations and medical resource use, as shown in appropriate studies. Capecitabine is expected to find a role in the treatment of other tumour types as well as adjuvant administration. It represents an advance in modern drug development, stressing the current shift towards rational development of new agents and home-based outpatient regimens.
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PMID:The rational development of capecitabine from the laboratory to the clinic. 1255 61

Preclinical data suggest that the anti-tumour activity of capecitabine is enhanced by taxanes and mitomycin C through up-regulation of thymidine phosphorylase (TP). Here, we studied safety and efficacy of the combination of capecitabine with docetaxel and mitomycin C. Two dose levels (DL) were investigated: capecitabine 1000 mg m(-2) b.i.d. on days 1-14, docetaxel 40 mg m(-2) i.v. day 1, mitomycin C 4 or 6 mg m(-2) i.v. day 1 (DL I or II). Cycles were repeated every 3 weeks. The primary aim was to determine the dose-limiting toxicities (DLT) during the first two treatment cycles and the maximum tolerated dose (MTD). A total of 46 patients (pts) refractory to standard therapies were enrolled, of whom the majority had gastrointestinal tumours (n=40). 14 pts had received >/=3 lines of prior chemotherapy. At DL I, one out of six pts experienced DLT. At DL II, two out of six pts had DLT (mucositis grade 3). Thus, DL I was determined as MTD. Among a total of 37 pts treated on DL I the following toxicities were observed during cycles 1 and 2 (number of patients with grade 1/2/3/4 toxicity; NCI-CTC v. 3.0): anaemia 10/8/3/0, leucocytopenia 4/11/1/2, thrombocytopenia 0/1/2/0, diarrhoea 8/1/2/0, stomatitis/mucositis 3/3/1/0, nausea/vomiting 10/2/0/0, and hand-foot skin reaction 5/1/1/0. Of 30 pts who received at least two treatment cycles nine achieved complete or partial remissions, six pts achieved minor remissions, and seven pts had stable disease (tumour control rate 73%). Of note, four out of 10 patients with pancreatic cancer had partial remissions. In conclusion, capecitabine can safely be combined with docetaxel (40 mg m(-2)) and mitomycin C (4 mg m(-2)). The established regimen was well tolerated and the preliminary efficacy data in this heavily pre-treated patients population appears to be promising.
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PMID:Capecitabine in combination with docetaxel and mitomycin C in patients with pre-treated tumours: results of an extended phase-I trial. 1800 May 7