Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.

Budman, Daniel R.; Meropol, Neal J.; Reigner, Bruno; Creaven, Patrick J.; Lichtman, Stuart M.; Berghorn, Elmer; Behr, Joanne; Gordon, R. J.; Osterwalder, B; Griffin, Thomas W.

doi:10.1200/jco.1998.16.5.1795

Cited by 226 publications

(119 citation statements)

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“…Moreover, this 7.2% rate of grade 3 or 4 diarrhea was less than that observed in other studies, which reported rates of 15 -22% Baek et al, 2006;Burge et al, 2006). The diarrhea and hand -foot syndrome were doselimiting toxicities in phase I studies using capecitabine (Budman et al, 1998;Mackean et al, 1998). In the present study, nine patients (16.4%) experienced any grade of hand -foot syndrome and only three patients (5.5%) experienced grade 3 hand -foot syndrome.…”

Section: Discussioncontrasting

confidence: 72%

A phase II study of biweekly dose-intensified oral capecitabine plus irinotecan (bXELIRI) for patients with advanced or metastatic gastric cancer

Sur

Sung

et al. 2007

Br J Cancer

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Capecitabine, a prodrug of 5-FU, has been reported to generate maximal tumour activity at tumour sites and/or to improve drug tolerability as compared with 5-FU infusion, and it has also been demonstrated to act synergistically with irinotecan against some solid cancers. A previous study concluded that dose-intensified biweekly capecitabine seems to be more effective at increasing both response rate and progression-free survival time than conventional dose and schedule of capecitabine in colon cancer. We conducted this study to ascertain the efficacy and toxicity of dose-intensified biweekly capecitabine and irinotecan combination chemotherapy in chemotherapy-naïve advanced or metastatic gastric cancer patients. Patients were treated with irinotecan 130 mg m À2 intravenously for 90 min on days 1 and 15. Capecitabine at 3500 mg m À2 day À1 , divided into two sessions per day, was administered for seven consecutive days from days 1 and 15, and followed by a 7-day drug-free period, respectively. Fifty-five eligible patients were enrolled in this study from November 2003 to April 2006. There were 22 women and 33 men: median patient age was 54 years (range: 27 -81). A total of 200 treatment cycles were administered at a median number of four per patient (range: 1 -9). Intent-to-treatment analysis showed that one patient achieved complete response (1.8%), 23 partial response (41.8%), 15 stable disease (27.3%), 10 progressive disease (18.2%) and 6 were non-evaluable (10.9%). The overall response rate was 43.6% (95% confidence interval: 30.2 -56.9). The common grade 3 -4 toxicities were neutropenia in 12 (21.8%), nausea/vomiting in 3 (5.4%) and diarrhea in 4 (7.2%) patients. Median time to progression was 5 months (range: 0.5 -11 months), median survival duration was 11 months (range: 0.5 -45 months) and median response duration was 6 months (range: 0.5 -9 months). Biweekly dose-intensified capecitabine and irinotecan combination chemotherapy was active for the treatment of advanced or metastatic gastric cancers with a tolerable safety profile.

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Section: Discussioncontrasting

confidence: 72%

A phase II study of biweekly dose-intensified oral capecitabine plus irinotecan (bXELIRI) for patients with advanced or metastatic gastric cancer

Sur

Sung

et al. 2007

Br J Cancer

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“…Different schedules of capecitabine emerged from phase I trials (Budman et al, 1998;Mackean et al, 1998). It is worth noting that mathematical methods applied to the definition of the ideal treatment schedule suggested that the optimal duration of treatment with capecitabine is 7 days and predicted that drug delivery beyond 7 days could contribute to toxicity, with diminishing anticancer benefit (Traina et al, 2008).…”

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confidence: 99%

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer

et al. 2009

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The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m À2 and oxaliplatin 85 mg m À2 on day 1 plus capecitabine 2000 mg m À2 per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3 -4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response rate of 67% (95% CI 51.4 -82%). After a median follow-up of 17.7 months, the median progression-free and overall survival were 10.1 and 17.9 months, respectively. The substitution of 5-fluorouracil with capecitabine, in combination with irinotecan and oxaliplatin, is feasible and does not impair the activity of the regimen. However, the XELOXIRI combination is associated with a high incidence of diarrhoea and, therefore, should be considered as a not preferable alternative to FOLFOXIRI. In the past decade, the advent of oxaliplatin and irinotecan has led to changes in the first-line treatment of metastatic colorectal cancer (mCRC; Saunders and Iveson, 2006). In fact, the combination of one of these new cytotoxic drugs with 5-fluorouracil (5-FU) and leucovorin (LV) significantly increases tumour response and prolongs survival of patients with unresectable advanced colorectal cancer over 5-FU/LV alone (Punt, 2004). Moreover, a pooled analysis of seven phase III trials comparing 5-FU/LV plus irinotecan or oxaliplatin containing doublets vs 5-FU alone demonstrated that survival of mCRC patients might be improved administrating all the three active drugs in the course of the disease. However, in a sequential strategy, 20 -50% of patients who progress after first-line chemotherapy cannot receive second-line treatment, mainly because of deterioration of their performance status and liver function (Grothey et al, 2004). Furthermore, another pooled analysis indicated that there is a strong correlation between the response rate to first-line chemotherapy and the possibility of a postchemotherapy radical resection of metastases that may be associated with long-term survival (Folprecht et al, 2005).Keeping these concepts in mind, the GONO group developed in phases I and II trials a triple-drug combination of oxaliplatin, irinotecan and 5-FU/LV named FOLFOXIRI (Falcone et al, 2002;Masi et al, 2004) and compared this combination to a standard doublet combination of 5-FU/LV plus irinotecan (FOLFIRI) in a phase III study on 244 mCRC patients (Falcone et...

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“…Other phase I studies evaluated a continuous schedule (Budman et al, 1998) and the combination of capecitabine with oral LV . A randomised phase II study in colorectal cancer patients comparing these three schedules reported response rates of 24, 21 and 23%, respectively; all three schedules were generally well tolerated (Van Cutsem et al, 2000).…”

Section: Oral Regimens Capecitabinementioning

confidence: 99%

Which endpoints should we use in evaluating the use of novel fluoropyrimidine regimens in colorectal cancer?

Twelves

Cassidy

2002

Br J Cancer

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Although significant advances have been made in the treatment of advanced/metastatic colorectal cancer, 5-fluorouracil (5-FU) still forms the basis of chemotherapy. Recently, new 5-FU schedules and novel fluoropyrimidines have been developed, but there are no trials directly comparing these regimens. The current review describes the mechanisms of action, pre-clinical and phase I/II studies of two oral fluoropyrimidine therapies, capecitabine and uracil with tegafur plus leucovorin. It also compares the phase III studies of these agents with those of the two most popular infusional 5-FU-based regimens: de Gramont and German AIO (The Association of Medical Oncology (AIO) of the German Cancer Society). Both oral and infusional regimens demonstrated similar survival to the Mayo Clinic regimen, a standard treatment for colorectal cancer. Therefore, other endpoints must be examined to decide optimum therapy, including response rates, time to disease progression, tolerability and patients' convenience. All four new therapies demonstrated superior safety profiles compared with the Mayo Clinic regimen. However the uracil with tegafur plus leucovorin regimen was associated with severe diarrhoea and capecitabine with hand -foot syndrome. Patients will not sacrifice efficacy for the convenience of oral therapy alone, therefore the fact that capecitabine achieved superior response rates and equivalent time to disease progression compared with the Mayo Clinic regimen, while uracil with tegafur plus leucovorin produced lower response rates and significantly inferior time to disease progression, is highly relevant in choosing treatment. British Journal of Cancer (2002) Colorectal cancer is the third most common cancer in men and women, accounting for 783 000 new cases and 437 000 deaths worldwide in 1990 Parkin et al, 1999). About 40 -50% of patients develop metastatic disease. The aims of any therapy in patients with advanced colorectal cancer are to control symptoms, maintain or improve quality of life and ultimately to prolong survival. Recent meta-analyses confirmed that chemotherapy prolongs time to disease progression (TTP) and survival in patients with advanced or metastatic colorectal cancer, compared with best supportive care or observation/no chemotherapy (Colorectal Cancer Collaborative Group, 2000;Jonker et al, 2000).The fluoropyrimidine, 5-fluorouracil (5-FU), has formed the basis of chemotherapy for colorectal cancer for over 40 years. Numerous 5-FU-based schedules are used, and extensive efforts have been made to increase their activity, including biomodulation, modification of the dose or schedule and the use of analogues/ prodrugs.The most successful biomodulation of 5-FU has been with leucovorin (LV), a derivative of tetrahydrofolic acid, the reduced form of folic acid. The rationale is that in the presence of reduced folate, fluorodeoxyuridine monophosphate (a metabolite of 5-FU), covalently interacts with thymidylate synthase, which is the source for de novo synthesis of thymidine nucleotides, ultimately di...

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Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.

Abstract: The suggested phase II dose on a continuous 42-day dosing schedule is 1,331 mg/m2/d. Linear pharmacologic parameters of the parent compound and metabolites are demonstrated.

Cited by 226 publications

References 0 publications

A phase II study of biweekly dose-intensified oral capecitabine plus irinotecan (bXELIRI) for patients with advanced or metastatic gastric cancer

A phase II study of biweekly dose-intensified oral capecitabine plus irinotecan (bXELIRI) for patients with advanced or metastatic gastric cancer

A multicenter phase II study of the combination of oxaliplatin, irinotecan and capecitabine in the first-line treatment of metastatic colorectal cancer

Which endpoints should we use in evaluating the use of novel fluoropyrimidine regimens in colorectal cancer?

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