1 CRC Dept of Medical Oncology, 2 Department of Radiology, University of Glasgow, Beatson Oncology Centre, Western Infirmary, Glasgow; 3 Department of Surgery, Gartnavel General Hospital, Glasgow; 4 Department of Medical Oncology, Glasgow Royal Infirmary, Glasgow, UK
Received 12 October 2001; revised 25 February 2002; accepted 26 March 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The purpose of this study was to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose of capecitabine when used in combination with epirubicin and cisplatin (ECC) in patients with oesophageal or gastric adenocarcinoma. Response rate, progression-free survival (PFS) and overall survival were also determined, and the effect of previous oesophago-gastric surgery or concurrent oesophago-gastric cancer on the absorption and metabolism of capecitabine was evaluated.
Patients and methods:
Patients with inoperable oesophago-gastric adenocarcinoma received up to six cycles of epirubicin (50 mg/m2 i.v., 3-weekly), cisplatin (60 mg/m2 i.v., 3-weekly) and capecitabine, the latter administered orally in an intermittent schedule (14 days treatment; 7-day rest period) at 3-weekly intervals. Patients were recruited into one of four escalating dose cohorts (500, 825, 1000 and 1250 mg/m2 bd). Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level, with DLT assessed on the toxicity of the first cycle only. Blood sampling for pharmacokinetic analyses was performed over the first 10 h of day 1 of cycle 1.
Results:
Thirty-two patients, median age 63 years (range 3276 years), ECOG performance status 2 with locally advanced (10) or metastatic (22) disease were recruited and were evaluable for toxicity. Two of five patients experienced DLT at 1250 mg/m2 bd with grade II stomatitis (one patient) and grade III diarrhoea with febrile neutropenia (one patient). Cumulative toxicity for all cycles (n = 140) (worst grade per patient) includes grade IV oesophagitis (one patient), grade III diarrhoea (five), grade IV neutropenia with infection (seven), grade II stomatitis (four) and grade IV thrombocytopenia (one). Of 29 patients with evaluable disease, there was one complete response and six partial responses {24% response rate [95% confidence interval (CI) 10% to 44%]}, a median PFS of 22 weeks (95% CI 1727 weeks) and median overall survival of 34 weeks (95% CI 1949 weeks). Capecitabine was rapidly absorbed after oral administration, with a tmax of 12 h for capecitabine, DFCR (5'-deoxy-5-fluorocytidine) and DFUR (5'-deoxy-5-fluorouridine). The Cmax and AUC0
for capecitabine, DFCR and DFUR were similar to those observed in previous monotherapy studies of capecitabine taken after food.
Conclusion:
A dose of 1000 mg/m2 bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.
Key words: capecitabine, cisplatin, epirubicin, oesophago-gastric cancer
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Combination chemotherapy results in a significant survival advantage in patients with advanced gastric cancer when compared with best supportive care in randomised clinical trials [24]. High response rates may be obtained in these tumours by the use of protracted venous infusional 5-fluorouracil (5-FU) in combination with epirubicin and cisplatin (the ECF regimen) [5]. In an initial study with this regimen, an overall response rate of 71% and a complete response (CR) rate of 12% were observed [5]. These encouraging results were confirmed in two subsequent studies, with overall response rates of 60% and with CRs occurring in
10% of patients [6, 7]. In a multi-centre randomised study, ECF resulted in a significantly better response rate (45%) and median survival (8.9 months), with significantly less toxicity compared with the FAMtx regimen (5-FU, doxorubicin and methotrexate) [8], which was the standard chemotherapy regimen of choice in Europe at that time. Consequently, ECF is considered the treatment regimen of choice for advanced adenocarcinoma of the oesophagus and stomach in the UK. However, it requires continuous venous infusion of 5-FU via a Hickman catheter, which is associated with significant morbidity, particularly venous thromboses and sepsis [5, 9], requiring line removal in up to 15% of patients [8]. Consequently, replacing the continuous infusion of 5-FU in this regimen by an oral fluoropyrimidine could overcome the need for inserting a Hickman catheter with its associated morbidity.
Capecitabine is an orally available tumour-selective fluoropyrimidine carbamate that is bioactivated by a three-enzyme process to provide prolonged high levels of 5-FU within tumour cells. The final step in this bioactivation is the metabolism of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU within the tumour under the action of thymidine phosphorylase (TP). This tumour-specific generation of 5-FU, with a reduction of healthy body tissue exposure to systemic 5-FU, could potentially lead to an improved therapeutic index. Thymidine phosphorylase expression is detected by immunohistochemistry in 24% to 66% of gastric cancer specimens [1012], and is correlated with microvessel density [10, 1218], distant or hepatic metastases [16, 17] with conflicting reports on the association between TP expression and prognosis [10, 13, 16, 1821].
The optimal dose of capecitabine when given as monotherapy is twice-daily 1250 mg/m2 administered on an intermittent schedule (2 weeks of therapy with a 1 week rest period) every 3 weeks, with dose-limiting toxicities (DLTs) of diarrhoea and leukopenia at higher dose levels and plantar-palmar erythrodysesthesia (hand-foot syndrome) after prolonged treatment [22]. Subsequent studies in colorectal cancer have confirmed the preferential activation of capecitabine intratumourally compared with normal tissues [23]. Further trials have also confirmed capecitabines activity in colorectal [24] and breast [25] cancer, with the intermittent schedule preferred for phase III evaluation compared with the continuous administration schedule [24]. Consequently, we have performed a dose-finding study of capecitabine in combination with epirubicin and cisplatin in an attempt to design a regimen for subsequent comparison with ECF, and have included a pharmacokinetic (PK) analysis of capecitabine absorption and metabolism in view of the requirement for an intact gastro-intestinal mucosa for drug absorption.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All patients entered into this study had histologically or cytologically confirmed adenocarcinoma of the stomach, oesophagus or gastro-oesophageal junction. Inoperability was determined on the basis of clinical evaluation, radiological imaging, laparoscopy or at laparotomy with failed resection. Eligibility criteria included estimated life expectancy 12 weeks; adequate renal function (calculated creatinine clearance
60 ml/min by the Cockcroft and Gault formula), adequate hepatic function (serum bilirubin
1.5 x the upper limit of the reference range; transaminases <5 x the upper limit of the reference range) and adequate haematological function (haemoglobin
10 g/dl; neutrophil count
1.5 x 109/l; platelets
100 x 109/l). Patients who had received prior chemotherapy for advanced disease were excluded. Patient performance status was assessed using the Eastern Cooperative Oncology Group (ECOG) criteria, and those patients with performance status
2 were considered eligible. Eligibility also included the ability to reliably tolerate and comply with oral medication, and patients with a lack of physical integrity of the gastro-intestinal tract leading to intestinal obstruction or a malabsorption syndrome were excluded. Similarly, patients were excluded if they had severity of dysphagia such that compliance and tolerance of oral medication would have been compromised. However, it was anticipated that all potential patients would have either a history of oesophago-gastric surgery for carcinoma or have an on-going primary oesophago-gastric or locally recurrent cancer. These patients were considered eligible if the investigator considered that there was no malabsorption syndrome and no gastro-intestinal obstruction that would impair administration of oral therapy. Patient compliance was recorded using chemotherapy diary cards.
Chemotherapy
Cisplatin (60 mg/m2) and epirubicin (50 mg/m2) were administered on day 1 and then every 21 days for up to a maximum of six cycles of treatment. Cisplatin was administered as a short intravenous infusion over 4 h in 1000 ml of 0.9% NaCl with standard pre- and post-hydration protocols, and magnesium and potassium supplementation. Pre-hydration consisted of 1000 ml of 0.9% NaCl administered over 1 h followed by a bolus of frusemide (40 mg i.v.); post-hydration consisted of 100 ml of 20% mannitol over 30 min, 1000 ml of 0.9% NaCl over 2 h and 500 ml of 0.9% NaCl over 1 h. Prophylactic anti-emetics consisted of dexamethasone (8 mg i.v.) and granisetron (3 mg i.v.) prior to chemotherapy, with dexamethasone (2 mg orally tds) and domperidone (20 mg orally qds) for 3 and 5 days, respectively, post-cisplatin. Capecitabine was given as a twice daily oral medication in an intermittent schedule (2 weeks of treatment, 1 week rest period) repeated every 21 days. Capecitabine was commenced on the day of administration of epirubicin and cisplatin and was taken before administration of the epirubicin and cisplatin. Cohorts of six patients were treated at each of four pre-determined dose levels (500, 825, 1000 and 1250 mg/m2 bd) and no intra-patient dose escalation was permitted. Dose escalation was performed after all six patients in the previous dose level had completed at least one cycle of chemotherapy. The total daily dose was rounded-up and given in equally divided twice daily doses. The rounding-up of doses was based on surface area and total daily dose in accordance with the manufacturers recommendations, and is available from the authors on request.
Evaluation of toxicity
Chemotherapy toxicity was graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC). Toxicity, performance status and biochemical profile were assessed prior to each chemotherapy cycle, with full blood count and clinical assessment performed weekly during all treatment cycles. If grade IV neutropenia occurred, the full blood count was repeated daily to determine its duration. Dose escalation and determination of DLT and maximum tolerated dose (MTD) was on the basis of toxicity from the first cycle of chemotherapy only.
DLT was defined as grade IV myelosuppression with neutropenia lasting 5 days or grade IV neutropenia with fever; grade IV thrombocytopenia; complicated grade III haematological toxicity (neutropenia with fever; thrombocytopenia with bleeding requiring platelet transfusion); grade III/IV non-haematological toxicity other than alopecia, nausea or vomiting; or stomatitis grade
II. The MTD was defined as the most dose intensive regimen with acceptable toxicity, i.e. less than two of six cases experiencing a DLT. Once the MTD had been defined, a further cohort of six patients was recruited at the optimal dose level to gain further experience with this regimen. Patients who did not complete 14 days of capecitabine administration during the first cycle of chemotherapy for reasons other than toxicity (e.g. withdrawal of consent) were replaced to determine DLT and MTD. Cumulative toxicity was also recorded for all subsequent chemotherapy cycles at all dose levels in all patients.
Dose modification and delays
Dose modifications were performed on the basis of toxicity. Administration of all three agents was delayed until adequate haematological recovery (neutrophil count 1.5 x 109/l, platelets
100 x 109/l) up to a maximum of 3 weeks. Dose modification of epirubicin was based on haematological parameters at the time that each chemotherapy cycle was due. In the event of clinically significant thrombocytopenia or an episode of neutropenic sepsis, the dose of epirubicin was reduced by 25% for all subsequent cycles of chemotherapy, even if haematological recovery had occurred at the time of treatment. In addition if the serum bilirubin rose to >1.5 x the upper limit of the normal range, and/or the serum transaminases rose to
5 x the upper limit of normal administration of all three agents was delayed for 1 week (up to a maximum of 3 weeks) until recovery of liver function.
Capecitabine administration was interrupted immediately if patients developed NCI CTC grade II diarrhoea, stomatitis or hand-foot syndrome, and interrupted until resolution of the toxicity to grade
I. Doses of capecitabine omitted for toxicity were not replaced or restored, but the patient could resume the planned treatment cycle with appropriate dose modification on resolution of the toxicity to grade
1. Subsequent treatment cycles were also given at the appropriate dose adjustment. No dose reductions or interruptions were performed for anaemia, or for any grade I toxicity. The daily dose of capecitabine was reduced by 25% at the first occurrence of grade III toxicity or the second occurrence of grade II toxicity; the daily dose was reduced by 50% at the first occurrence of grade IV toxicity, the second occurrence of grade III toxicity and the third occurrence of grade II toxicity. Capecitabine was discontinued at the second occurrence of grade IV toxicity, the third occurrence of grade III and the fourth occurrence of grade II toxicity. Similar dose adjustment guidelines were applied for stomatitis. However, if grade II stomatitis occurred during the first cycle of treatment, this was considered to be a DLT, and subsequent courses of chemotherapy were administered for that patient with the dose of capecitabine reduced to that of the previous dose cohort.
Full-dose cisplatin was administered if the glomerular filtration rate (GFR) was 60 ml/min. Full-dose cisplatin was administered as two equally divided doses on two consecutive days if the GFR was 5059 ml/min, and was omitted if the GFR was <50 ml/min. Cisplatin was also discontinued if a patient developed significant (grade >I) ototoxicity (sensory-neuronal deafness).
Evaluation of response and overall survival
Chest X-ray and computed tomography (CT) scan of the abdomen (and of other disease sites as appropriate) were performed prior to starting treatment and repeated after three and six cycles of chemotherapy to assess response. Endoscopy was also performed on completion of chemotherapy in patients with endoscopically evaluable disease. Response was documented using the modified SWOG response criteria for solid tumors [26]. Subsequently, CT scans and endscopy were not routinely performed at regular intervals but at the investigators discretion. Progression-free survival (PFS) was recorded from the start of chemotherapy until documented disease progression or death and the overall duration of survival was determined from the start of chemotherapy until death (all causes). However, as CT scans were repeated at the investigators discretion after completing chemotherapy rather than on a regular basis, the data on PFS should be interpreted with caution. Survival curves were estimated using KaplanMeier techniques. All analyses were on an intention-to-treat basis.
PK analyses
PK studies were performed on the first day of the first cycle of chemotherapy. On the day of PK sampling, patients took the capecitabine 30 min after a set breakfast, with the epirubicin and cisplatin given 1 h later (that is, after completion of pre-hydration). If the patient required further pre-hydration, cisplatin administration was delayed until this occurred and the time of cisplatin administration recorded. Five millilitres of venous blood was collected into glass vacutainers containing EDTA as anticoagulant at 0.5, 1, 2, 3, 4, 5, 7 and 10 h after capecitabine administration. After centrifugation, plasma was removed and 2 ml transferred into plastic tubes and stored immediately at 20°C until analysis. The times of breakfasting, capecitabine administration, administration of epirubicin and cisplatin, and the blood sampling times were recorded. In addition, concomitant medication and the time of any vomiting that occurred during the blood sampling period were also recorded.
Capecitabine, 5'-DFUR and 5'-deoxy-5-fluorocytidine (5'-DFCR) concentrations were measured by high-pressure liquid chromatography (HPLC) and solid phase extraction using a modification of the method described previously [27]. Capecitabine and its metabolites were ex-tracted from plasma samples following the addition of internal standards and precipitation with acetonitrile. The compounds in the supernatant were separated using a (automatic) solid phase extraction system (Bond Elut Column, C18; Varian, Walton-on-Thames, UK). Capecitabine, 5'-DFCR and 5'-DFUR were eluted with methanol, and were separately analysed by reversed-phase HPLC with all samples analysed in triplicate. A Luna C18 [2] column (150 x 4.6 mm, inside diameter 5 µm; Phenomenex, Macclesfield, UK) was used. A step gradient was used that consisted of mobile phase A [20 mM sodium citrate pH 4.0: acetonitrile (95:5 v/v)]. This was switched to mobile phase ß [20 mM sodium citrate pH 4.0: acetonitrile (70:30 v/v)] at 13 min to elute capecitabine. The flow rate was 1 ml/min, and UV detection was at 267 nm. The retention times of capecitabine, 5'-DFCR, 5'-DFUR and tegafur (internal standard) were 25.9, 8.1, 12.5 and 18.6 min, respectively. For capecitabine, 5'-DFCR and 5'-DFUR, the limit of quantification [defined as the lowest concentration with a coefficient of variation (CV) <20%] was 0.05, 0.03 and 0.05 µg/ml, respectively, using a 0.5 ml plasma specimen.
The following parameters were estimated using non-compartmental methods. Maximum plasma concentration (Cmax) and time of their occurrence (tmax) were determined from the observed highest concentration and its occurrence, respectively. Apparent elimination half-life (t) was estimated from log 2/K, where the apparent rate constant of elimination, K, was estimated by linear regression on the logarithm of the plasma concentration versus time data. Area under the plasma concentration time curve from 0 to infinity (AUC0) was estimated from the sum of AUC0t and Ctlast/K. AUC0t is the area under the curve from time 0 to the last sampling time (tlast) at which the concentration could be measured (Ctlast).
Descriptive statistics were used to summarise the PK parameters. Geometric mean and geometric CV are reported for Cmax, AUC0 and t, and median, minimum and maximum values for tmax. Spearman rank correlation was used to determine the relationship between AUC0
and Cmax, with dose. All P values quoted are two-sided. Owing to the small number of patients in this study, subgroup analyses were not performed to determine the variation in PK parameters with site of origin of the cancers. Similarly, PK parameters were not compared between patients with a history of resection of primary tumour with those patients with no history of prior surgery, as the small number of patients would not permit reliable conclusions to be drawn.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Seven patients were included in cohort 3 (1000 mg/m2 bd). One patient had prolonged grade IV neutropenia (5 days) with a low-grade fever (maximum recorded temperature of 37.5°C), but was a major protocol violation as he had continued to take capecitabine until day 18 when he was admitted with fever and neutropenia. Consequently, the patients total capecitabine dose was higher than would be administered in cohort 4 (1250 mg/m2 bd) and so he was considered unevaluable for DLT due to significant capecitabine overdose and was replaced. However, this patient was included in all other analyses. Of the remaining six patients, one developed prolonged grade IV neutropenia (
5 days) without fever or sepsis, and this was considered a DLT. A further six patients were included in a confirmatory cohort of six patients at this dose level after the MTD had been established. The first cycle haematological toxicity for all patients treated at this dose level (n = 13) included grade III neutropenia (n = 3), grade IV neutropenia (n = 5), grade III thrombocytopenia without complications (n = 2) and grade IV thrombocytopenia (n = 1). This included one patient in the confirmatory cohort who developed grade IV neutropenia with sepsis, grade IV thrombocytopenia requiring platelet transfusion, and possible meningitis.
In cohort 4 (1250 mg/m2 bd; n = 5), haematological toxicity included grade III neutropenia (three patients), grade IV neutropenia (n = 1) with low grade fever (maximum temperature 37.5°C) and grade III thrombocytopenia (n = 1).
Non-hematological toxicity
Non-haematological toxicity during the first cycle of treatment included: one patient in the first cohort developed grade IV dysphagia and oesophagitis that was considered to be related to the chemotherapy, but there were no cases of grade III diarrhoea. One patient in the second cohort developed grade III diarrhoea (in association with neutropenic sepsis), as did one patient in the confirmatory cohort at dose level 3 (1000 mg/m2 bd), again in association with neutropenic sepsis. In dose cohort 4, grade II stomatitis (one patient) and grade III diarrhoea (one) were observed during the first cycle of treatment.
DLT and MTD
The DLTs were grade III diarrhoea with grade IV neutropenia (one patient) and grade II stomatitis (one patient) during the first cycle at 1250 mg/m2 bd. Consequently, 1000 mg/m2 bd of capecitabine on an intermittent schedule is recommended for use in combination with epirubicin and cisplatin. At this recommended dose level (n = 13), DLTs (first cycle only) were one patient with prolonged (5 days) grade IV neutropenia (without fever), and one patient with grade IV neutropenia with fever (
38.5°C), sepsis and grade III diarrhoea in the confirmatory cohort.
Cumulative toxicity (all cycles)
Haematological toxicity
The worst toxicity (all cycles) per patient is shown in Table 2. Febrile neutropenia, defined as grade IV neutropenia with temperature 38.5°C, occurred in five patients, including one patient (cycle 6) at 500 mg/m2 bd, one patient (cycle 1) at 825 mg/m2 bd and three patients (cycles 1, 4, 5) at 1000 mg/m2 bd. Grade IV neutropenia with low-grade fever (
38.5°C) requiring intravenous antibiotics occurred in three patients in total, including one patient (cycle 2) at 500 mg/m2 bd, one patient (cycle 1) at 1000 mg/m2 bd and one patient (cycle 1) at 1250 mg/m2 bd. Low-grade fever was not considered a DLT in these two patients who developed this during the first cycle of treatment. However, one of these patients (treated at 1000 mg/m2 bd) had prolonged (
5 days) grade IV neutropenia, which would have been a DLT if he had not been a major protocol violation, and the other patient (treated at 1250 mg/m2 bd) had DLT as defined by grade III diarrhoea. Two patients, both at 1000 mg/m2 bd, required platelet transfusion for grade III and grade IV thrombocytopenia during episodes of sepsis (cycle 4 and cycle 1, respectively). Platelet transfusion was indicated for the patient with grade III thrombocytopenia as this occurred during an episode of sepsis (Klebsiella pneumoniae) and anaemia, the latter probably due to bleeding from the primary gastric tumour. However, this was not considered to be DLT as this event occurred during the fourth rather than first cycle of chemotherapy.
|
|
Dose modifications and delays
Chemotherapy was delayed for 1 week in 53 cycles in 21 patients, most commonly due to inadequate recovery of the neutrophil count in 42 cycles, inadequate recovery of the platelet count (two cycles), upper respiratory tract infection (one cycle), diarrhoea (one cycle), low GFR (one cycle), rigors on the day chemotherapy was due (one cycle) and delayed for recovery of other toxicities (five cycles). Furthermore, the epirubicin dose was reduced in 13 cycles in 11 patients due to inadequate recovery of the neutrophil count on the day of treatment in whom the neutrophil count was not sufficiently low to lead to a dose delay, and in one patient (one cycle) because of neutropenic sepsis during the nadir of the previous course. Cisplatin was omitted in cycle 4 for one patient treated at 1000 mg/m2 bd because of a low GFR, but this patient subsequently received full-dose cisplatin on recovery of renal function to normal limits. No other dose modification of cisplatin was necessary.
No dose modifications of capecitabine were required at the 500 and 825 mg/m2 bd dose levels. Capecitabine dose was reduced in three patients at the 1000 mg/m2 bd dose level, due to prolonged grade IV neutropenia (one patient, cycle 2), grade II stomatitis (one patient, cycle 3) and for hand-foot syndrome (one patient, cycle 6). Capecitabine dose was also reduced in two patients at the 1250 mg/m2 bd dose level due to grade II stomatitis and diarrhoea (one patient, cycles 2 and 3) and grade II diarrhoea (one patient, cycle 2). At least one dose of capecitabine was omitted in 20 cycles in 15 patients due to toxicity (12), patient error (three), withdrawal of consent (one) and intercurrent illness (four).
Response and survival
Twenty-four patients had measurable disease and five had evaluable disease at baseline. Six patients received only one cycle of chemotherapy and were withdrawn due to rapid disease progression (two), dose-limiting toxicity (two), CVA (one) and withdrawal of consent (one), with two patients being withdrawn after only two cycles of treatment due to CVA (one) and progression of disease-related symptoms (one). There were no deaths that were attributed to toxicity of the chemotherapy treatment.
The response rate based on all patients evaluable for response at baseline (n = 29) included one CR and six partial responses (PR) for an overall response rate of 24% (seven of 29) [95% confidence interval (CI) 10% to 44%]. The response rate excluding the four patients who were withdrawn after only one treatment cycle for reasons not due to disease progression was 28% (seven of 25) with a 95% CI of 12% to 49%. In addition, a further five patients achieved a PR that was not confirmed by a second imaging procedure. Two patients in the optimal dose cohort of 1000 mg/m2 bd were sufficiently downstaged to enable them to proceed to potentially curative surgical resesctions. At the time of writing, 20 patients had died from disease (18) and CVA (two), with a median follow-up of 32 weeks (range 1946 weeks) for the 12 patients still alive. The median PFS is 22 weeks (95% CI 1727 weeks) and the median survival 34 weeks (95% CI 1949 weeks) (Figure 1).
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There are no previous studies in the published literature of capecitabine monotherapy or combination chemotherapy in oesophago-gastric cancer. However oral doxifluoridine (DFUR) has been evaluated in a phase II study [28] and is comparable to oral 5-FU in a phase III trial as adjuvant therapy after resection of stage II or stage III gastric cancer [29]. However, single-agent capecitabine has demonstrated activity in paclitaxel-refractory metastatic breast cancer [25] and in metastatic colorectal cancer, with a significantly higher response rate and significantly lower incidence of diarrhoea, stomatis, and nausea when compared with intravenous 5-FU and leucovorin as first-line treatment of patients with metastatic colorectal cancer [30], although this did not result in a superior time to disease progression or overall survival. Nevertheless, it would seem reasonable to speculate that capecitabine would not be inferior to single-agent intravenous 5-FU as monotherapy in oesophago-gastric cancer in view of the frequency of TP expression in these tumours [1012] and the fact that the PK studies in this trial have demonstrated absorption and metabolism of capecitabine in patients with previous resection of oesophago-gastric cancer, or locally recurrent or primary oesophago-gastric cancer.
The rapid time to peak plasma concentrations for capecitabine and its metabolites in this study is similar to that observed in the original phase I study [22] and in patients who take capecitabine after food [27], as was the case in this study. This suggests that the presence of a primary or recurrent oesophago-gastric cancer or previous oesophago-gastric resection does not adversely impair capecitabine absorption. The Cmax and AUC of capecitabine and DFCR at the optimal doses are also similar to those observed in previous studies after ingestion of food [22, 27], although the Cmax and AUC of DFUR tended to be lower than those previously observed [22, 27]. There was a significant dose-related increase in the Cmax of DFCR, and the AUC of both DFCR and DFUR, as would be expected in the case of linear kinetics, and this is consistent with results obtained in previous studies. In contrast, there was no dose-related increase in the Cmax and AUC with dose of capecitabine. The likely explanation for this is the large inter-patient variability and small sample size.
The aim of these PK studies was to confirm that the absoption of capecitabine, and its metabolism to DFCR and DFUR, was unaffected by either locally recurrent or primary oesophago-gastric cancer, or previous resection, and this appears to be the case. Consequently, no additional information would have been obtained by analysing 5-FU or FBAL (-fluoro-ß-alanine), which were not performed in this study.
The objective response rate of ECC in this study is less than that reported with the ECF regimen in randomised phase III studies [8], and also less than that of the combination of the oral 5-FU pro-drug UFT (1:4 tegafur:uracil) when used with epirubicin and cisplatin [31], although the latter study also included patients with pancreatic cancer and cancer of the biliary tract. In contrast, this study using the ECC regimen has also documented the absorption and metabolism of the 5-FU pro-drug. Thus the acceptable toxicity profile of this regimen, and the encouraging, but modest, activity and the reassuring PK profile confirming drug absorption and metabolism suggests that this regimen warrants further evaluation in phase III trials in comparison with the ECF regimen.
Although other interesting approaches are being pursued in this disease, including signal transduction inhibitors and modulators of growth promoting factors, it is likely that these will ultimately be used along with, rather than instead of, conventional chemotherapy agents. Consequently, it is appropriate to consider further development of a regimen that may modify the standard ECF regimen used in the UK by reducing the morbidity associated with insertion of indwelling Hickman catheters for the administration of continuous infusion of 5-FU.
![]() |
Acknowledgements |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Murad AM, Santiago FF, Petroianu A et al. Modified therapy with 5-fluorouracil, doxorubicin and methotrexate in advanced gastric cancer. Cancer 1993; 72: 3741.[ISI][Medline]
3. Glimelius B, Hoffman K, Haglund U et al. Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 1994; 5: 189190.[ISI][Medline]
4. Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 1995; 71: 587591.[ISI][Medline]
5. Findlay M, Cunningham D, Normal A et al. A phase II study in advanced gastro-oesophageal cancer using epuribicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol 1994; 5: 609616.[Abstract]
6. Highley MS, Parnis FX, Trotter GA et al. Combination chemotherapy with epirubicin, cisplatin and 5-fluorouracil for the palliation of advanced gastric and oesophageal adenocarcinoma. Br J Surgery 1994; 81: 17631765.[ISI][Medline]
7. Zaniboni A, Barni S, Labianca R et al. Epirubicin, cisplatin and continuous infusion 5-fluorouracil is an active and safe regimen for patients with advanced gastric cancer. An Italian Group for the Study of Digestive Tract Cancer report. Cancer 1995; 76: 16941699.[ISI][Medline]
8. Webb A, Cunningham D, Scarffe JH et al. Randomised trial comparing epuribicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin and methotrexate in advanced oesophagogastric cancer. J Clin Oncol 1997; 15: 261267.[Abstract]
9. Evans TRJ, Lofts FJ, Mansi JL et al. A phase II study of continuous infusion 5-fluorouracil with cisplatin and epirubicin in inoperable pancreatic cancer. Br J Cancer 1996; 73: 12601264.[ISI][Medline]
10. Kikuyama S, Inada T, Shimizu K, Miyakita M. Thymidine phosphorylase expression in gastric cancer in association with proliferative activity and angiogenesis. Anticancer Res 2000; 20: 20812086.[ISI][Medline]
11. Ogawa K, Konno S, Takebayashi Y et al. Clinicopathological and prognostic significance of thymidine phosphorylase expression in gastric carcinoma. Anticancer Res 1999; 19: 43634367.[ISI][Medline]
12. Ikeguchi M, Oka, S, Saito H et al. The expression of thymidine phosphorylase and its correlation with angiogenesis in gastric adenocarcinoma. Anticancer Res 1999; 19: 40014005.[ISI][Medline]
13. Saito H, Tsujitani S, Oka S et al. The expression of thymidine phosphorylase correlates with angiogenesis and the efficacy of chemotherapy using fluorouracil derivatives in advanced gastric carcinoma. Br J Cancer 1999; 81: 484489.[ISI][Medline]
14. Takahashi Y, Bucana CD, Akagi Y et al. Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. Clin Cancer Res 1998; 4: 429434.[Abstract]
15. Maeda K, Kang SM, Ogawa M et al. Combined analysis of vascular endothelial growth factor and platelet-derived endothelial growth factor expression in gastric carcinoma. Int J Cancer 1997; 74: 545550.[ISI][Medline]
16. Tanigawa N, Amaya H, Matsumura M et al. Tumor angiogenesis and expression of thymidine phosphorylase/platelet derived endothelial cell growth factor in human gastric carcinoma. Cancer Lett 1996; 108: 281290.[ISI][Medline]
17. Maeda K, Chung YS, Ogawa Y et al. Thymidine phosphorylase/platelet-derived endothelial cell growth factor expression associated with hepatic metastasis in gastric carcinoma. Br J Cancer 1996; 73: 884888.[ISI][Medline]
18. Takebayashi Y, Miyadera K, Akiyama S et al. Expression of thymidine phosphorylase in human gastric carcinoma. Jpn J Cancer Res 1996; 87: 288295.[ISI][Medline]
19. Koizumi W, Saigenji K, Nakamura N et al. Prediction of response to 5'-deoxy-5-fluorouridine (5'-DFUR) in patients with inoperable advanced gastric cancer by immunostaining of thymidine phosphorylase/platelet-derived endothelial cell growth factor. Oncology 1999; 56: 215222.[ISI][Medline]
20. Suda Y, Kuwashima Y, Shioya T et al. The expression of thymidylate synthase and thymidine phosphorylase in the early-stage of gastric cancer. Jpn J Cancer Chemother 1999; 26: 321327.
21. Shimaoka S, Matsushita S, Nitanda T et al. The role of thymidine phosphorylase expression in the invasiveness of gastric carcinoma. Cancer 2000; 88: 22202227.[ISI][Medline]
22. Mackean M, Planting A, Twelves C et al. Phase I and pharmacodynamic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 1998; 16: 29772985.[Abstract]
23. Schuller J, Cassidy K, Dumont E et al. Preferential activation of capecitabine in tumour following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000; 45: 291297.[ISI][Medline]
24. Van Cutsem E, Findlay M, Osterwalder B et al. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomised phase II study. J Clin Oncol 2000; 18: 13371345.
25. Blum JL, Jones SE, Buzdar AU et al. Multi-center phase II study of capecitabine in paclitaxelrefractory metastatic breast cancer. J Clin Oncol 1999; 17: 485493.
26. Green S, Weiss GR. South West Oncology Group Standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992; 10: 239253.[ISI][Medline]
27. Reigner B, Verweij J, Dirix L et al. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin Cancer Res 1998; 4: 941948.[Abstract]
28. Takahashi Y, Mai M, Taguchi T et al. Prolonged stable disease affects survival in patients with solid gastric tumour: analysis of phase II studies of doxifluridine. Int J Oncol 2000; 17: 285289.[ISI][Medline]
29. Takiguchi N, Nakajima N, Saitoh N et al. A phase III randomised study comparing oral doxifluridine and oral 5-fluorouracil after curative resection of gastric cancer. Int J Oncol 2000; 16: 10211027.[ISI][Medline]
30. Hoff PM, Ansari R, Batist G et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomised phase III study. J Clin Oncol 2001; 19: 22822292.
31. Seymour MT, Dent JT, Papamichael D et al. Epirubicin, cisplatin, and oral UFT with leucovorin (ECU): a phase III study in patients with advanced upper gastrointestinal tract cancer. Ann Oncol 1999; 10: 13291333.[Abstract]