Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Capecitabine (Xeloda) is a novel rationally designed fluoropyrimidine carbamate. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes resulting in preferential release of 5-fluorouracil (5-FU) at the tumor site. Preclinical studies indicated an enhancement of the therapeutic index when capecitabine was combined with leucovorin. This Phase I trial was designed to determine the safety profile, maximal tolerated dose, and pharmacokinetic profile of the combination of capecitabine plus a fixed dose of p.o. leucovorin (60 mg/day) during administration to patients with refractory advanced cancers. The intention was to administer both drugs continuously, but the starting dose of capecitabine was also the maximum tolerated dose (1004 mg/m2/day) in six patients treated with this regimen. A cycle of treatment was then redefined as leucovorin and capecitabine given p.o., twice daily for 2 consecutive weeks followed by a 1-week rest period. Capecitabine doses from 1004 mg/m2/day to 2510 mg/m2/day were evaluated with the intermittent schedule over approximately 80 courses in an additional 25 patients. The dose-limiting toxicities that defined the maximum tolerated dose at 2000 mg/m2/day were diarrhea, nausea, vomiting, and palmar plantar erythrodysesthesia. The recommended Phase II dose using this schedule was 1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day. Plasma concentrations of capecitabine, intermediate metabolites, and 5-FU were measured in 26 patients on days 1 and 14 of therapy. The pharmacokinetics of capecitabine were characterized by rapid GI absorption, with Cmax at 1 h, followed by conversion to active drug. The coadministration of leucovorin had no effect on the pharmacokinetics of capecitabine. Two patients with colorectal cancer, both previously treated with 5-FU, had partial responses. Phase II studies have confirmed the promising antitumor activity of this drug, and capecitabine is currently in Phase III evaluation.
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PMID:A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors. 982 39

To evaluate the therapeutic effects and systemic toxicities of a capecitabine-based home therapy regimen in patients with metastatic renal cell carcinoma, 30 patients were enrolled in a phase II clinical trial. Treatment consisted of oral capecitabine combined with subcutaneous recombinant human interferon-alpha 2a, recombinant human interleukin-2 and oral 13-cis-retinoic acid. There were two (7%) complete responses (CRs) and eight (27%) partial remissions (PRs), for an overall objective response rate of 34% (95% CI 17-53%). Except one, all responses are ongoing, with a median duration of 9+ and 8+ months for CRs and PRs, respectively. Additionally, 12 patients (40%) reached stable disease. Eight patients (27%) showed continued disease progression despite treatment. Therapy was well tolerated and was given in the outpatient setting. Capecitabine-related World Health Organization (WHO) grade 2 and 3 toxicities were observed in five and two patients respectively, and were limited to fatigue, nausea/vomiting, diarrhoea, stomatitis, dermatitis and hand-and-foot syndrome. The substitution of capecitabine for 5-FU in the pre-existing biochemotherapy regimen did not result in a reduced therapeutic efficacy and showed significant anti-tumour activity in patients with advanced renal cell carcinoma.
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PMID:Capecitabine in the treatment of metastatic renal cell carcinoma. 1094 96

Drug development has undergone rapid shifts in methodology and the use of rationally derived agents which either target specific tissues or molecules such as receptors or enzymatic sites. Capecitabine is a rationally derived prodrug of 5-fluorouracil which is based upon the known high concentration of the enzyme thymidine phosphorylase in many human tumors. The first prodrug designed to exploit this biochemical finding was 5-DFUR which allowed cytotoxic 5-fluorouracil to be preferentially concentrated in tumors. Unfortunately, in man this agent was associated with significant gastrointestinal toxicity. Further manipulation of this molecular resulted in capecitabine which is a relatively inert prodrug, undergoes three enzymatic steps, and offers the potential of less gastrointestinal toxicity. Phase I trials have examined several schedules with the divided oral daily x 14 schedule every 3 weeks as the preferred phase II and phase III dosing method. This agent demonstrates significant antitumor effect in diseases known to be responsive to fluoropyrimidines. Further study is needed to determine whether capecitabine has a broader spectrum of action thus affecting other tumor types than 5-fluorouracil. Major dose limiting toxicities have been hand foot syndrome, nausea/vomiting, and diarrhea.
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PMID:Capecitabine. 1108 71

Capecitabine, an oral fluoropyrimidine carbamate, was designed to generate 5-fluorouracil preferentially at the tumour site. This randomised, phase II trial evaluated the efficacy and safety of capecitabine or paclitaxel in patients with anthracycline-pretreated metastatic breast cancer. Outpatients with locally advanced and/or metastatic breast cancer whose disease was unresponsive or resistant to anthracycline therapy were randomised to 3-week cycles of intermittent oral capecitabine (1255 mg m(-2) twice daily, days 1-14, (22 patients)) or a reference arm of i.v. paclitaxel (175 mg m(-2), (20 patients)). Two additional patients were initially randomised to continuous capecitabine 666 mg m(-2) twice daily, but this arm was closed following selection of the intermittent schedule for further development. Overall response rate was 36% (95% CI 17-59%) with capecitabine (including three complete responses) and 26% (95% CI 9-51%) with paclitaxel (no complete responses). Median time to disease progression was similar in the two treatment groups (3.0 months with capecitabine, 3.1 months with paclitaxel), as was overall survival (7.6 and 9.4 months, respectively). Paclitaxel was associated with more alopecia, peripheral neuropathy, myalgia and neutropenia, whereas typical capecitabine-related adverse events were diarrhoea, vomiting and hand-foot syndrome. Twenty-three per cent of capecitabine-treated patients and 16% of paclitaxel-treated patients achieved a > or =10% improvement in Karnofsky Performance Status. Oral capecitabine is active in anthracycline-pretreated advanced/metastatic breast cancer and has a favourable safety profile. Furthermore, capecitabine provides a convenient, patient-orientated therapy.
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PMID:Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. 1198 65

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).
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PMID:Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. 1251 69

The combination of cisplatin and 5-fluorouracil (5-FU) is considered to be the standard treatment in induction chemotherapy for patients with squamous cell carcinoma of the head and neck. Capecitabine (Xeloda) is an oral fluoropyrimidine that is preferentially activated at the tumoral level, exploiting the higher thymidine phosphorylase activity in tumoral tissue. This phase I trial was conducted in patients with locally recurrent or metastatic head and neck carcinoma. The treatment plan included cisplatin on day 1 every 21 days, followed by capecitabine twice daily from day 2 to day 15, with a 1-week rest period. Pharmacokinetic investigations concerned plasma measurement of unchanged capecitabine, 5'-deoxy-5-fluorocytidine, 5'-doxifluridine and 5-FU using an optimized high performance liquid chromatography method, and cisplatin measurement in plasma using a limited sampling procedure. Twenty-one patients were included (mean age 61 years, range 46-76 years). Dose (mg/m(2)) increments for cisplatin and capecitabine (b.i.d.), respectively, were as follows: level 1, 80 and 1000 (three patients); level 2, 100 and 1000 (12 patients); and level 3, 100 and 1125 (five patients). Dose-limiting toxicities occurring during the first cycle (grade >/= 3) were observed on level 2 (one patient with diarrhea, nausea, vomiting, hand-foot syndrome, one toxic death due to renal failure and neutropenia, one patient with neutropenia) and on level 3 (one patient with diarrhea, one patient with hand-foot syndrome and one patient with neutrothrombocytopenia). Due to delayed side-effects, 14 patients (67%) had repeated cycles every 28 days instead of 21 days as initially planned. Objective response was obtained in seven patients (three complete responses and four partial responses). There was no evidence of pharmacokinetic-pharmacodynamic relationships with the drugs and metabolites investigated. Combination of capecitabine and cisplatin is feasible, with a very promising response rate. The recommended doses for further phase II studies are those of level 2 with cisplatin 100 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) b.i.d. on days 1-14, every 28 days.
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PMID:Phase I and pharmacokinetic study of the association of capecitabine-cisplatin in head and neck cancer patients. 1450 61

Combination protocols of 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan or oxaliplatin have demonstrated high activity in metastatic colorectal cancer. Capecitabine, an oral 5-FU prodrug, may replace infusional 5-FU/LV in combination protocols with irinotecan or oxaliplatin. We therefore initiated a phase II study with capecitabine plus either irinotecan or oxaliplatin to determine the efficacy and toxicity of specific combination protocols in patients with advanced gastrointestinal (GI) tumors. Capecitabine 1000 mg/m(2) taken orally twice a day on days 1-14, plus oxaliplatin 70 mg/m(2) on days 1 and 8, or irinotecan 100 mg/m(2) on days 1 and 8; repeated every 3 weeks in an outpatient setting. Patient and tumor characteristics were as follows: median age, 68 years (range, 34-77 years); sex: 10 women, 33 men; tumor types: 35 colorectal cancer; 8 other GI tumors including 5 gastric, 2 pancreatic, and 1 duodenal cancer. All 43 patients treated were evaluable for toxicity (capecitabine/oxaliplatin, 24 patients; capecitabine/irinotecan, 19 patients), and 39 were evaluable for efficacy (capecitabine/oxaliplatin, 22; capecitabine/irinotecan, 17). Grade 3/4 toxicities (National Cancer Institute Common Toxicity Criteria Version 2.0) were limited to diarrhea, 9 patients (capecitabine/irinotecan, n = 5; capecitabine/oxaliplatin, n = 4); hand-foot syndrome, 1 patient (capecitabine/irinotecan); nausea, 2 patients (capecitabine/oxaliplatin); vomiting, 1 patient (capecitabine/oxaliplatin); and peripheral neuropathy, 1 patient (capecitabine/oxaliplatin). No grade 3/4 myelosuppression was noted for either protocol. Capecitabine/irinotecan and capecitabine/oxaliplatin demonstrated significant clinical activity in colorectal cancer and other GI cancers as first-line and salvage therapy. Capecitabine/oxaliplatin and capecitabine/irinotecan show an excellent safety profile and clinical activity in colorectal cancer and other advanced GI tumors. The main toxicity in both arms was manageable diarrhea. This trial served as basis for a randomized multicenter phase II study comparing capecitabine/oxaliplatin and capecitabine/irinotecan as first-line therapy in patients with advanced colorectal cancer.
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PMID:Phase II trial of capecitabine/irinotecan and capecitabine/oxaliplatin in advanced gastrointestinal cancers. 1520 20

The selection of chemotherapeutic regimens is challenging for metastatic breast cancer (MBC) patients whose diseases have failed to respond to anthracyline and taxane. Capecitabine has advantages of oral administration and favorable toxicity profiles. This study was conducted to evaluate the efficacy of capecitabine and to identify the subgroup of patients who would potentially have benefit from capecitabine monotherapy in patients with anthracycline- and taxane-pretreated MBC. Female patients with MBC who had been previously treated with anthracycline and taxane received oral capecitabine 2500 mg/m(2) divided in two doses daily for 2 wk with 1-wk rest period. Between September, 1999, and December, 2002, a total of 38 patients were enrolled. Among the 36 evaluable patients, one patient achieved a complete response (CR), 9 patients had partial responses (PRs), and 13 patients had stable diseases (SDs). Response rate was 26% [95% confidence interval (CI), 12-40%] and the tumor control rate (TCR, CR+PR+SD) was 61% (95% CI, 45-77%). The median follow-up duration was 27.8 mo. The median duration of response was 8.9 mo, the median time to progression was 4.6 mo, and the median overall survival was 18.1 mo. The major toxicities were hand-foot syndrome, diarrhea, and emesis. There was no treatment-related death. The predictors of better overall survival were positivity of hormone receptor, disease-free survival longer than 1 yr, non-refractoriness to anthracycline, and fewer number (<or= 3) of involved organs. Capecitabine monotherapy is effective and well tolerated for MBC patients who had previously been treated with anthracycline and taxane. The TCR could predict overall survival as well as the objective response in this study, suggesting a possible role of TCR as a surrogate marker for survival in MBC patients on salvage chemotherapy. The patients who have relatively slow growing tumor and less tumor burden could have benefit from capecitabine monotherapy following anthracycline- and taxane-based chemotherapy.
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PMID:Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. 1545 49

Capecitabine is a fluoropyrimidine carbamate capable of exploiting the high concentrations of thymidine phosphorylase in tumor tissue to achieve activation preferentially at the tumor site. Thymidine phosphorylase activity is high in renal cell carcinoma tissue. Interferon alfa has been proved to be the agent for standard therapy in metastatic renal cell carcinoma. The purpose of the study was to assess the efficacy and toxicity of combining capecitabine and interferon alfa-2A in patients with advanced renal cell carcinoma. Twenty-five patients with advanced renal cell carcinoma and no prior systemic therapy were treated with the combination of capecitabine at a dose of 1,250 mg/m2 twice daily for 2 weeks after every 21 days and interferon alfa-2A 6 million U three times a week. The overall response rate was 24.0% (95% CI, 9.4-45.1%), from 6 responded patients 5 had partial responses and 1 complete response. Stable disease status was achieved in 9 patients (36.0% with 95% CI 18.0-57.5%). The median survival time was 248 days (95% CI, 173-265 days). The median time to progression was 126 days (95% CI, 49-165 days). Grade 3-4 toxicities occurred in 12 patients and included fatigue (33.3%), nausea, hand-foot syndrome (both 12.5%), anorexia (8.3%), vomiting, anemia and neutropenia (all 4.2%). The capecitabine and interferon alfa-2A combination has clinical activity and an acceptable toxicity profile in patients with metastatic renal cell carcinoma. The importance of adding capecitabine to interferon alfa needs to be confirmed in a randomized trial.
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PMID:Combination therapy with capecitabine and interferon alfa-2A in patients with advanced renal cell carcinoma: a phase II study. 1546 18

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m(-2) twice daily) days 1-14 every 3 weeks and MMC (7 mg m(-2) IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40-77), and 23 patients (78%) were performance status 0-1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6-6.2). Median overall survival was 9.3 months (95% CI: 6.9-11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.
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PMID:Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan. 1649 15


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