Epoetin-beta treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events.

BACKGROUND: Epoetin-beta is used to treat patients with cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life (QoL). METHODS: This meta-analysis of all 12 randomised, controlled studies of epoetin-beta evaluated the impact of therapy at different Hb-initiation levels and to different target Hb levels on overall survival, tumour progression and thromboembolic events (TEE). An analysis of risk factors pre-disposing patients to TEEs under epoetin-beta therapy was also performed. A total of 2297 patients are included in the analysis. RESULTS: Analyses based on various Hb-initiation levels indicate no detrimental impact on survival (HR 0.99; 95% CI 0.70, 1.40) and a favourable impact on disease progression (HR 0.73; 95% CI 0.57, 0.94) when epoetin-beta was used within its licensed indication (Hb initiation < or = 10 g dl(-1)) or the EORTC recommended level of 11 g dl(-1). An increased risk of TEEs is seen for all Hb-initiation level strata and a detrimental impact on survival is seen when initiating epoetin-beta therapy at Hb levels >11 g dl(-1). We observe no association between high target Hb levels (> or = 13 g dl(-1)) and an increased risk of mortality, disease progression or TEEs with epoetin-beta compared with control. CONCLUSION: The results of this analysis indicate that epoetin-beta therapy has no detrimental impact on survival or tumour progression when initiated at Hb levels up to 11 g dl(-1). Furthermore, there is no evidence to suggest that high Hb values achieved during epoetin-beta therapy are associated with an increased mortality, disease progression or TEE rate.

First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin.

PURPOSE: To evaluate the safety profile of capecitabine using data from a large, well-characterized population of patients with metastatic colorectal cancer treated in two phase II studies. In these trials, capecitabine achieved significantly superior response rates, equivalent time to disease progression and equivalent survival compared with 5-fluorouracil (5-FU)/leucovorin. PATIENTS AND METHODS: Patients (n = 1207) were randomized to either oral capecitabine (1250 mg/m2 twice daily, on days 1-14 every 21 days) or intravenous (i.v.) bolus 5-FU/leucovorin (Mayo Clinic regimen). RESULTS: Capecitabine demonstrated a safety profile superior to that of 5-FU/leucovorin, with a significantly lower incidence of diarrhea, stomatitis, nausea, alopecia and grade 3 or 4 neutropenia leading to significantly fewer neutropenic fever/sepsis cases and fewer hospitalizations. All patients in the capecitabine group received a starting dose of 1250 mg/m2 twice daily and the majority (66%) did not require dose modification for adverse events. In the 5-FU/leucovorin group, 58% of patients did not require dose reduction for toxicities. The capecitabine dose-modification scheme reduced the recurrence of key toxicities without compromising efficacy. In both treatment arms, patients with moderate renal impairment at baseline (estimated creatinine clearance 30-50 ml/min) experienced a higher incidence of grade 3 or 4 toxicities. This increase was more pronounced with 5-FU/leucovorin. CONCLUSIONS: Capecitabine is at least as effective, better tolerated and more convenient than i.v. 5-FU/leucovorin as treatment for patients with metastatic colorectal cancer. Analysis of data from two large phase III trials demonstrates that efficacy is not compromised in patients requiring a dose reduction for adverse events. The phase III data and an additional pharmacokinetic study support a lower starting dose in patients with moderate renal impairment at baseline (calculated creatinine clearance 30-50 ml/min) and a contra-indication in patients with severely impaired creatinine clearance at baseline (<30 ml/min). For patients with normal or mildly impaired renal function at baseline, the standard starting dose is well tolerated. The incidence and severity of adverse events in patients with moderate renal impairment at baseline who were treated with 5-FU/leucovorin was more pronounced, indicating that capecitabine provides a better-tolerated alternative.

Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines.

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.

Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients.

BACKGROUND: Capecitabine is an oral, tumor-targeted fluoropyrimidine carbamate with high activity in metastatic breast carcinoma and in paclitaxel-pretreated metastatic breast carcinoma. METHODS: The current multicenter, Phase II trial assessed the efficacy and safety of intermittent oral capecitabine, 1255 mg/m(2) twice daily (2 weeks of treatment followed by a 1-week rest period), in patients with metastatic breast carcinoma in whom prior taxane therapy had failed. All patients had failed treatment or had disease that was refractory to two or three previous chemotherapy regimens, one of which contained a taxane. Nearly all patients (96%) also had received prior anthracycline chemotherapy. Seventy-five patients were recruited at 5 centers, 74 of whom received treatment. RESULTS: The overall response rate was 26%, with response rates of 27% and 20%, respectively, in the subgroups of patients previously pretreated with paclitaxel (n = 47) or docetaxel (n = 27). The median survival was 12.2 months, the median duration of response was 8.3 months, and the median time to disease progression was 3.2 months. The most common treatment-related adverse events (all grades) were hand-foot syndrome (62%), diarrhea (58%), nausea (55%), emesis (37%), and stomatitis (34%). However, the majority were mild to moderate in intensity and only three patients experienced Grade 4 (according to the National Cancer Institute of Canada Common Toxicity criteria) adverse events. The only Grade 3 treatment-related adverse events reported in > or = 10% of the patients were hand-foot syndrome (22%), diarrhea (16%), and stomatitis (12%). Myelosuppression and alopecia were rare, and there were no reported treatment-related deaths. CONCLUSIONS: The results of the current study demonstrate that capecitabine is an effective and well tolerated treatment in patients with taxane-refractory or taxane-failing metastatic breast carcinoma. In addition, it is a convenient, orally administered drug, which makes it an attractive agent for use in outpatient treatment.

Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study.

PURPOSE: To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil (5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity. RESULTS: The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P <.00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P <.00001). Capecitabine also resulted in lower incidences (P <.00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P <.00001) and uncomplicated grade 3/4 hyperbilirubinemia (P <.0001) were reported more frequently with capecitabine. CONCLUSION: Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.

Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer.

BACKGROUND: Oral capecitabine was evaluated in terms of overall response rate, safety, and tolerability as first-line therapy in women aged > or = 55 years with advanced/metastatic breast cancer. PATIENTS AND METHODS: Ninety-five patients were randomized (2:1) to either intermittent oral capecitabine 1,255 mg/m2 twice daily (two weeks' treatment followed by a one-week rest period) or intravenous CMF (cyclophosphamide. methotrexate, 5-fluorouracil [5-FU]) administered every three weeks. RESULTS: The overall response rate in the capecitabine group was 30% (95% confidence interval (95% CI): 19%-43%), including three complete responses (5%). The response rate observed in the CMF group was 16% (95% CI: 5%-33%), with no complete responses. Median time to disease progression was 4.1 months with capecitabine and 3.0 months with CME. Survival was similar in the two treatment groups (median 19.6 months with capecitabine. 17.2 months with CMF). The safety profiles were different for capecitabine and CMF. However, both regimens were generally well tolerated and treatment interruption and/or dose modification was effective in managing toxicities associated with capecitabine. Alopecia and myelosuppression were rare in patients receiving capecitabine while diarrhea and hand-foot syndrome were more common. Treatment interruption and/or individual dose adjustment of capecitabine was required in 34% of patients and was generally effective in managing adverse events. Treatment was stopped owing to toxicity in 16% of patients in the capecitabine arm. The incidence of deaths during or within 28 days of stopping study treatment was 8% and 6% in the capecitabine and CMF arms, respectively. CONCLUSIONS: An oral, twice-daily regimen of capecitabine is effective and well tolerated when used as first-line chemotherapy in older patients (> or = 55 years) with advanced/metastatic breast cancer, and is suitable for outpatient therapy.

Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma.

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.

Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study.

PURPOSE: To compare the response rate, efficacy parameters, and toxicity profile of oral capecitabine with bolus intravenous (IV) fluorouracil plus leucovorin (5-FU/LV) as first-line treatment in patients with metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 605 patients to treatment with oral capecitabine for 14 days every 3 weeks or 5-FU/LV by rapid IV injection daily for 5 days in 4-week cycles. RESULTS: The overall objective tumor response rate among all randomized patients was significantly higher in the capecitabine group (24.8%) than in the 5-FU/LV group (15.5%; P =.005). In the capecitabine and 5-FU/LV groups, median times to disease progression were 4.3 and 4.7 months (log-rank P =.72), median times to treatment failure were 4.1 and 3.1 months (P =.19), and median overall survival times were 12.5 and 13.3 months (P =.974), respectively. Capecitabine, compared with bolus 5-FU/LV treatment, produced a significantly lower incidence (P <.0002) of diarrhea, stomatitis, nausea, and alopecia. Patients treated with capecitabine also displayed lower incidences of grade 3/4 stomatitis and grade 3/4 neutropenia (P <.0001) leading to significantly less neutropenic fever/sepsis. Grade 3 hand-foot syndrome (P <.00001) and grade 3/4 hyperbilirubinemia were the only toxicities more frequently associated with capecitabine than with 5-FU/LV treatment. CONCLUSION: Oral capecitabine was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5-FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5-FU/LV in terms of tolerability.

Phase I trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer: toxicity and pharmacokinetics.

PURPOSE: The present study was designed to determine the toxicity and maximum tolerated doses of oral intermittent oral capecitabine and subcutaneous (s.c.) rHuIFNalpha2a in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of capecitabine and its metabolites were also investigated. METHODS: A total of 27 patients were treated at four dose levels of capecitabine (825 or 1000 mg/m2 twice daily orally, days 1-14, 22-36) and rHuIFNalpha2a (1.5 or 3.0 MU/m2 s.c. three times weekly). Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chroatography/mass spectrometry in ten patients. RESULTS: The toxicity of combined capecitabine and rHuIFNalpha2a was moderate. Patients experienced mild nausea/vomiting (70%) and diarrhea (63%). The hand-foot syndrome was seen in 67% of patients and was generally mild, as was hematologic toxicity. Dose-limiting toxicity included diarrhea, mucositis, neutropenia and the hand-foot syndrome. The dose level recommended for further trials included capecitabine 1000 mg/m2 twice daily and rHuIFNalpha2a 3.0 MU/m2 three times weekly. One patient had a partial response of a liver lesion (duration > 200 days). Pharmacokinetic parameters of capecitabine and its metabolites (5'-deoxy-5-fluorouridine, 5-fluorouracil and alpha-fluoro-beta-alanine) were similar to those reported by other authors. There was rapid conversion to 5'-deoxyuridine. The peak plasma concentrations of capecitabine occurred between 0.5 and 3.0 h. CONCLUSIONS: The combination of capecitabine and rHuIFNalpha2a was well tolerated. The recommended dose levels for phase II trials are: rHuIFNalpha2a 3.0 MU/m2 s.c. three times weekly and oral capecitabine 1000 mg/m2 twice daily for 2 weeks. No evidence of an effect of rHuIFNalpha2a on the pharmacokinetics of capecitabine or its metabolites was apparent. A phase II trial in untreated patients with metastatic RCC is planned.

[A comparative randomized phase-II study of Xeloda (capecitabine) and paclitaxel in patients with breast cancer progressing after anthracycline antibiotics]. / Sravnitel'noe randomizirovannoe issledovanie po II faze kselody (kapetsitabina) i paklitaksela u bol'nykh rakom molochnoi zhelezy, progressiruiushchikh posle antratsiklinovykh antibiotikov.

A randomized study of the effectiveness of treatment with capecitabine (Xeloda) (22) and paclitaxel (taxol) (19) was carried out in breast cancer patients resistant to anthracycline antibiotic drugs. Capecitabine and paclitaxel showed comparable effectiveness, although the former appeared less toxic, particularly, in hematologic complication situations. Therefore, it may be administered to out-patients who previously received several courses of chemotherapy.

A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours.

Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1-14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m(-2) twice a day and of docetaxel from 75 to 100 mg m(-2). The dose-limiting toxicity (DLT) was asthenia grade 2-3 at a dose of 1000 mg m(-2) bid of capecitabine combined with docetaxel 100 mg m(-2). Neutropenia grade 3-4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m(-2) twice a day plus docetaxel 100 mg m(-2) was tolerable, as was capecitabine 1250 mg m(-2) twice a day plus docetaxel 75 mg m(-2).

Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study.

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m(2)/d bid continuously; arm B, 2,510 mg/m(2)/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m(2)/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.

Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer.

PURPOSE: Capecitabine is a novel, oral, selectively tumor-activated fluoropyrimidine carbamate. This large multicenter phase II trial tested the efficacy and safety of twice-daily oral capecitabine at 2,510 mg/m2/d given for 2 weeks followed by a 1-week rest period and repeated in 3-week cycles, in patients with paclitaxel-refractory metastatic breast cancer. PATIENTS AND METHODS: Patients were to have received at least two but not more than three prior chemotherapeutic regimens, one of which had to have contained paclitaxel given for metastatic disease. One hundred sixty-three patients were entered onto the study at 25 centers, and 162 patients received capecitabine. One hundred thirty-five patients had bidimensionally measurable disease, and 27 patients had assessable disease. RESULTS: The overall response rate was 20% (95% confidence interval, 14% to 28%). All responding patients were resistant to or had failed paclitaxel, and all had received an anthracycline. Three complete responses were seen, with complete response durations of 106, 109, and 194+ days. Median duration of response was 8.1 months, median survival time was 12.8 months, and the median time to disease progression was 93 days. The most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Diarrhea (14%) and hand-foot syndrome (10%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity in more than 10% of patients. CONCLUSION: Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic breast cancer. It has a favorable toxicity profile with the added advantage of being an oral drug administered at home.

A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors.

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.

Phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer.

PURPOSE: Capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes that results in the preferential release of 5-FU at the tumor site. PATIENTS AND METHODS: In this phase I study, capecitabine was administered twice daily as outpatient therapy, each cycle administered for 2 weeks followed by 1 week of rest. Thirty-four patients with solid tumors, all of whom except three patients were pretreated, were treated at dose levels from 502 to 3,514 mg/m2 daily. RESULTS: The median treatment duration was four cycles (85 days; range, 14 to 833+ days). Two patients continue on treatment at 686 and 833+ days. Capecitabine 3,000 mg/m2 daily was not tolerable, with dose-limiting toxicities of diarrhea with hypotension, abdominal pain, and leukopenia. Palmar-plantar erythrodysesthesia (PPE) became evident at higher dose levels after prolonged treatment. Evidence of objective tumor response was reported in four patients at 2,510 mg/m2 daily and greater (one complete response [CR] and three partial responses [PRs]) with subjective minor tumor responses in a further seven patients. Pharmacokinetic studies showed rapid gastrointestinal absorption of capecitabine, followed by extensive conversion into 5'-deoxy-5-fluorouridine (5'-DFUR), with only low systemic 5-FU levels. CONCLUSION: Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.

Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine.

PURPOSE: To evaluate the toxicology and pharmacology of an orally active fluoropyrimidine given as a continuous daily dose divided into two portions for 6 weeks, and to determine the maximal-tolerated daily dose (MTD) and the suggested phase II daily dose. PATIENTS AND METHODS: Solid-tumor patients with a Karnofsky performance status greater than 70 who had normal organ function and resolution of the effects of prior therapy, and who gave informed written consent, were enrolled. Oral capecitabine, as a divided morning and evening dose, was administered to cohorts of a minimum of 3 patients starting at 110 mg/m2 and escalating by means of a modified Fibonacci scheme to 1,657 mg/m2/d. Pharmacologic samples were obtained on days 1 and 15. Toxicity evaluations were performed approximately every 3 days for the first 43 days. Antitumor effect was evaluated at day 42 of therapy. RESULTS: Thirty-three patients entered the study. Few side effects occurred at or below 1,331 mg/m2/d. The MTD was 1,657 mg/m2/d with limiting toxicities of palmar-plantar erythrodysesthesia, nausea, vomiting, vertigo, abdominal pain, diarrhea, and thrombocytopenia. All toxicities were reversible. A mixed response was seen in one breast cancer patient. Pharmacologic studies showed rapid and extensive metabolism of the parent drug into cytotoxic metabolites with a maximum plasma concentration (Cmax) 1 hour after ingestion. Linear increases in the area under the concentration-time curve (AUC) and Cmax were seen with linear increases in administered dose. CONCLUSION: 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.

Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients.

Capecitabine (Ro 09-1978) is a novel oral fluoropyrimidine carbamate that was rationally designed to generate 5-fluorouracil (5-FU) selectively in tumors. The effect of food on the pharmacokinetics of capecitabine and its metabolites was investigated in 11 patients with advanced colorectal cancer using a two-way cross-over design with randomized sequence. Patients received repeated doses of 666 or 1255 mg/m2 of capecitabine twice daily. On study days 1 and 8, drug was administered following an overnight fast or within 30 min after consumption of a standard breakfast, and serial blood samples were collected. Concentrations of capecitabine and its metabolites [5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), 5-FU, dihydro-5-fluorouracil (FUH2), and alpha-fluoro-beta-alanine (FBAL)] in plasma were determined by high-performance liquid chromatography or liquid chromatography/mass spectroscopy. Intake of food prior to the administration of capecitabine resulted in pharmacokinetic changes of all compounds involved. The extent of these changes, however, varied considerably between the various compounds. Maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values were decreased after food, and time until the occurrence of Cmax values were increased. In contrast, the apparent elimination half-life was not affected by food intake. The extent of change in Cmax and AUC was highest for capecitabine and decreased with the order of formation of the metabolites. The "before:after food" ratios of the Cmax values were 2.47 for capecitabine, 1.81 for 5'-DFCR, 1.53 for 5'-DFUR, 1.58 for 5-FU, 1.26 for FUH2, and 1.11 for FBAL. The before: after food ratios of the AUC values were 1.51 for capecitabine, 1.26 for 5'-DFCR, 1.15 for 5'-DFUR, 1.13 for 5-FU, 1.07 for FUH2, and 1.04 for FBAL. The results show that food has a profound effect on the AUC of capecitabine, a moderate effect on the AUC of 5'-DFCR, and only a minor influence on the AUC of the other metabolites in plasma. In addition, a profound influence on Cmax of capecitabine and most of its metabolites was found. Detailed information on the relationship between concentration and safety/efficacy is necessary to evaluate the clinical significance of these pharmacokinetic findings. At present, it is recommended that capecitabine be administered with food as this procedure was used in the clinical trials.

Interleukin 2 and interferon alpha-2a do not improve anti-tumour activity of 5-fluorouracil in advanced colorectal cancer.

Treatment using a combination of 5-fluorouracil (5-FU), interferon-alpha (IFN alpha-2a) and interleukin 2 (IL-2) has been shown to mediate disease regression in selected patients with advanced colorectal cancer. This phase II study was designed to evaluate the anti-tumour activity and toxicity of the combination of IL-2, IFN alpha-2a and 5-FU in patients with advanced colorectal cancer. Forty-four patients with metastatic colorectal cancer were treated, predominantly on an outpatient basis, with subcutaneous IFN alpha-2a and IL-2 three times per week followed by once a week bolus intravenous 5-FU injections. There were six (14%) partial responses among the 43 evaluable patients [95% confidence interval (CI) 5-28%]. Twenty-four patients had stable disease (56%) and 13 patients (30%) showed progressive disease. The median time to progressive disease in 43 patients was 19 weeks (range 2-72 weeks) and in responders 34 weeks (range 24-30 weeks). The median overall survival was 47 weeks (range 2-85 weeks) and in responders 60 weeks (range 35-71 weeks). Treatment-related toxic effects included fatigue, nausea and vomiting. Granulocytopenia was the main reason for the dose reductions or treatment interruptions in 32 out of 44 patients. One patient died of toxicity due to renal failure. Serial assessments of immunophenotyping and cytolytic activities of peripheral blood lymphocytes did not show changes in the numbers of circulating natural killer (NK) cells or in the levels of NK and lymphokine-activated killer (LAK) cytolytic activities. This regimen of IL-2 and IFN alpha-2a with 5-FU has only modest anti-tumour activity in advanced colorectal cancer.