1 Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen; 2 Aventis, Department of Clinical Research, Oncology, Bad Soden, Germany; 3 Hoffmann-La Roche, Nutely, NJ; 4 Department of Molecular Pharmacology and Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY, USA
Received 11 March 2003; revised 3 May 2003; accepted 3 June 2003
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Abstract |
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To define the maximum-tolerated dose (MTD) and to evaluate the dose-limiting toxicities (DLTs) of the combination of capecitabine and irinotecan in patients with metastatic colorectal cancer.
Patients and methods:
Thirty-seven patients with measurable metastatic colorectal cancer with no prior chemotherapy for metastatic disease were treated at three dose levels (DLs). For the first two dose levels, irinotecan (70 mg/m2) was administered once a week for 6 weeks in combination with 2 weeks of capecitabine at 1000 mg/m2 (DL1) or 1250 mg/m2 (DL2) twice daily, starting on days 1 and 22. In the last dose escalation step, the dose of irinotecan was increased to 80 mg/m2 (DL3). One cycle lasted 7 weeks.
Results:
In the subsequent phase I trial, 96 cycles of capecitabine and irinotecan were administered. At DL3, three out of six patients experienced DLTs (diarrhea, neutropenia, asthenia). In order to confirm the safety of the recommended dose, DL2 was extended to 15 patients. Five patients (33%) showed DLTs at this dose level, which was considered too high to embark on further clinical studies. Subsequently, the starting dose (DL1) was extended to a total of 16 patients, with diarrhea being the main toxicity. The overall response rate was 38% [95% confidence interval (CI) 21% to 58%], with a median response duration of 8.7 months (95% CI 6.411.5 months).
Conclusions:
The recommended doses for further studies are irinotecan 70 mg/m2 and capecitabine 1000 mg/m2. The combination of capecitabine and irinotecan appears to have significant therapeutic efficacy with manageable toxicity.
Key words: capecitabine, colorectal cancer, irinotecan, phase I study
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Introduction |
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Clinical studies have established irinotecan as one of the most active cytotoxic drugs in the first- and second-line treatment of colorectal cancer [59]. Two large randomized trials in metastatic colorectal cancer with either bolus 5-FU or infusional 5-FU [biweekly De Gramont or weekly Arbeitsgemeinschaft Internistische Onkologie (AIO) schedule] demonstrated that the addition of irinotecan to 5-FU/leucovorin (LV) significantly improves response rate, median time to disease progression and overall survival in first-line treatment compared with 5-FU/LV alone [10, 11]. This improvement was achieved with manageable toxicities and without compromising overall quality of life in both trials. It is estimated that up to 70% of all patients with metastatic colorectal cancer receive the combination of bolus 5-FU/LV and irinotecan (Saltz regimen) as first-line chemotherapy in the United States [12]. However, increased mortality has recently been reported in subsequent trials of bolus 5-FU and irinotecan, leading to stringent guidelines for dose modifications and monitoring of treatment-related side-effects [12].
Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is an oral precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), with predictable bioavailability and promising efficacy as first-line treatment in colorectal cancer [1316]. Capecitabine is absorbed as an intact molecule through the intestinal mucosa and is then sequentially converted to cytotoxic fluorouracil by three enzymes, as follows: (i) conversion to 5'-deoxy-5-fluorocytidine (5'DFCR) by carboxylesterase in the liver; (ii) 5'-DFCR is metabolized to 5'-DFUR by cytidine deaminase, an enzyme located primarily in the liver and tumor tissue; and (iii) 5'-DFUR is converted to 5-FU by thymidine phosphorylase, which appears to be expressed at higher levels in tumor cells [17]. There is strong evidence that the increased levels of thymidine phosphorylase in tumor cells selectively increase fluoropyrimidine concentrations, resulting in enhanced efficacy and reduction in systemic toxicity.
Capecitabine was compared with bolus 5-FU/LV (Mayo Clinic protocol) as first-line chemotherapy in two large randomized trials in metastatic colorectal cancer [15, 16]. Although no differences in terms of median time to disease progression and overall survival were found in both trials [median time to progression 4.6 and 4.7 months, and overall survival time 12.9 and 12.8 months, respectively (integrated analysis of 1207 patients)], one study showed a significantly higher response rate for capecitabine (26% compared with 12%, P <0.0001) [15, 18].
The most common National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 3 and 4 adverse events with capecitabine were handfoot syndrome (HFS; 17%), diarrhea (13%) and elevation of serum bilirubin (23%) [18]. Severe neutropenia and alopecia were uncommon for treatment with capecitabine. In both studies, adverse events leading to hospitalization were less frequent for patients treated with capecitabine than with bolus 5-FU/LV. Taken together, the results of both studies suggest that oral administration of capecitabine offers a convenient alternative to 5-FU bolus/LV, with a superior safety profile and at least equivalent antitumor efficacy.
Considering the efficacy of irinotecan in combination with 5-FU/LV in the treatment of metastatic colorectal cancer, the substitution of capecitabine for 5-FU/LV appeared to be of significant clinical interest. Irinotecan was administered on a weekly-times-six schedule according to the AIO regimen [10, 19, 20]. Furthermore, preclinical data from our laboratory demonstrated significant synergistic efficacy for the combination of irinotecan and capecitabine in nude mice bearing human colon HCT-8 and HT-29 tumor xenografts, leading subsequently to the design of the present clinical phase I study.
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Patients and methods |
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Pre-treatment evaluation and follow-up
Pre-treatment evaluation consisted of a complete history and physical examination, complete blood cell count (CBCC), serum chemistry including electrolytes, hepatic and renal function tests, electrocardiogram (ECG), chest X-ray, and computed tomography (CT) scans of the abdomen/pelvis and chest (if indicated); all sites of measurable disease were initially documented using CT scans. If indicated, bone scans and X-rays were performed. During the study treatment, patient monitoring included the assessment of clinical toxicities, CBCC, serum chemistry and physical examinations before each weekly administration of the chemotherapy. ECG, chest X-ray and measurement of the target lesion(s) by CT scan were additionally performed before each cycle and at the end of treatment. During the follow-up period patients were evaluated every 2 months after the end of study treatment, including physical examination, CBCC, serum chemistry, ECG, chest X-ray, and CT scans of the measurable lesion(s) in case of tumor response or stable disease until documented disease progression.
Drug administration
Capecitabine was supplied by Hoffmann-La Roche (Basle, Switzerland) as 150 mg and 500 mg film-coated tablets. Capecitabine was administered twice daily (approximately every 12 h) on days 114 and 2236. Daily doses were rounded up to the nearest calculated dose and adjustments were made if indicated. Irinotecan was supplied by Aventis Pharma (Bad Soden, Germany) in 5-ml vials containing 100 mg of the drug, and administered in 250 ml of saline solution 0.9% by i.v. infusion over 3060 min once a week for 6 weeks. Treatment was delayed until full recovery in the case of diarrhea, mucositis or myelosuppression NCI-CTC grade >1 or impaired liver function (serum transaminases >3x UNL, bilirubin >1.5x UNL). Each cycle of chemotherapy consisted of 6 weeks of treatment followed by a 1-week rest period (7 weeks in total). Treatment was routinely given on an outpatient basis. Patients with documented objective response or stable disease continued study treatment for at least one further cycle. In case of dose-limiting toxicities (DLTs), treatment was continued after dose reduction to the next lower dose level. In case of progressive disease, intolerable toxicities or a treatment delay of >4 weeks between cycles, study treatment was discontinued.
All patients received pre-medication with antiemetic drugs (e.g. 5-HT antagonists) before i.v. administration of irinotecan. No other prophylactic treatments were used (e.g. anticholinergic drugs, antibiotics, granulocyte or granulocyte-macrophage colony stimulating factors). Administration of capecitabine was interrupted if diarrhea grade >1 occurred or if grade 1 toxicity persisted for >12 h. Furthermore, all patients were instructed that in case of diarrhea they had to take 4 mg loperamide orally immediately, and to continue with a dose of 2 mg every 2 h for at least 12 h, and up to 12 h after the last liquid stool occurred without exceeding a total treatment duration of 48 h. If diarrhea persisted for >24 h, oral antibiotics (usually ciprofloxacin) were administered in addition.
Dose escalation plan
The starting dose [dose level (DL) 1] was 2x 1000 mg/m2 capecitabine, given daily on days 114 and 2236 in combination with 70 mg/m2 irinotecan given on a weekly-times-six schedule. The dose of capecitabine was then escalated to 2x 1250 mg/m2 with 70 mg/m2 irinotecan (DL2). In the final step, the dose of irinotecan was increased to 80 mg/m2, with the same dose of capecitabine. No intrapatient dose escalation was performed. At each dose level, three patients were initially enrolled and if none of them experienced DLT during the first treatment cycle (defined below), the next cohort of three patients was treated at the next (higher) dose level. If any DLT was observed in one or two out of the first three patients, an additional three patients were enrolled at the same dose level. If three or more patients at the same dose level experienced any DLT, the maximum tolerated dose (MTD) had been reached and the dose level below the MTD was considered to be the recommended dose for further studies.
Evaluation of toxicities and response
Toxicities were evaluated weekly and graded according to the NCI-CTC criteria. The DLTs were defined as neutropenia grade 3 if associated with complications (e.g. neutropenic fever) or grade 4, thrombocytopenia grade 3, or any grade
3 non-hematological toxicity (except alopecia and nausea) during the first cycle. In addition, a toxicity-related discontinuation of capecitabine treatment for >1 week and/or a delay in the administration of irinotecan for >2 weeks were defined as DLT.
Tumor response was assessed by CT scan of the target lesion(s) before each new cycle of chemotherapy (every 7 weeks) and at the end of treatment. Complete remission (CR), partial remission (PR), no change (NC) and progressive disease (PD) were defined according to the standardized response definitions of the WHO. Tumor responses were confirmed by a second evaluation at least 4 weeks apart.
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Results |
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In the first part of the study (dose finding), 17 patients were treated at DL1 to DL3 (Table 1). While one patient experienced grade 4 diarrhea, no other DLTs were observed for the other two patients treated at DL1. Two patients out of eight {25% [95% confidence interval (CI) 3% to 65%]} showed DLTs (diarrhea NCI-CTC grade 4 and neutropenia grade 3 with infection) at DL2. With the escalation of irinotecan to 80 mg/m2 (DL3), the MTD was achieved with DLTs occurring in three out of six patients. The DLTs were diarrhea NCI-CTC grade 3 associated with neutropenia grade 4, diarrhea grade 4 and severe asthenia in one patient each. Based on these data, DL2 with capecitabine 1250 mg/m2 twice daily and irinotecan 70 mg/m2 was defined as the recommended dose.
To evaluate more precisely the safety of the recommended dose, an additional seven patients were entered on DL2. Five out of 15 patients at this dose level showed DLTs during the first cycle, with diarrhea being dose-limiting (Tables 1 and 3). At this dose level, one treatment-related death occurred with neutropenic fever, diarrhea grade 4 and septic multiorgan failure. This patient was non-compliant despite his knowledge of the recommendations for the management of side-effects (especially severe diarrhea), and delay in hospitalization may have contributed to the fatal outcome. The incidence of 33% (95% CI 12% to 62%) of DLTs at the recommended dose was considered to be too high to embark on further clinical trials. Furthermore, a non-treatment-related death occurred at this dose level during the first cycle.
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Diarrhea was the main side-effect after multiple courses for all three dose levels, with an incidence of grade 3 and 4 in 31% (95% CI 11% to 59%) of patients at the recommended dose, and 33% (95% CI 12% to 62%) at DL2 and DL3 (95% CI 4% to 78%) (Table 3).
HFS was mild and only occurred in one patient with NCI-CTC grade 2 at the recommended dose, but four (19%) out of 21 patients developed HFS grade 2 after multiple cycles at DL2 and DL3. Other non-hematological toxicities were moderate and consisted of mucositis and vomiting, with a similar incidence for all dose levels. Alopecia did not exceed NCI-CTC grade 1, with the exception of one patient at the MTD. The safety profile of capecitabine and irinotecan in terms of liver toxicity (AST, ALT, serum bilirubin) was assessed weekly for all patients and cycles (96 cycles). The per-patient analyses for multiple cycles revealed that one patient each experienced a NCI-CTC grade 2 increase in serum bilirubin and elevation of transaminases (AST grade 2, ALT grade 3).
Neutropenia NCI-CTC grade 3 and 4 occurred in one [6% (95% CI 0% to 32%)] out of 16 patients at DL1, and in three (14%) out of 21 patients with grade 3 and 4 neutropenia at the other dose levels. Neutropenia was not cumulative after multiple cycles (Table 4). With the exception of one patient with short-lasting thrombocytopenia NCI-CTC grade 3 after multiple cycles, no other grade >1 thrombocytopenia was observed .
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Discussion |
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The favorable benefit:risk ratio of capecitabine compared with bolus 5-FU/LV, the convenience of oral drug administrationespecially if compared with infusional 5-FU/LVtogether with the impressive synergistic efficacy of capecitabine and irinotecan against human colon tumor xenografts led to the evaluation of this combination in patients with metastatic colorectal cancer.
The MTD of capecitabine and irinotecan was defined as capecitabine 1250 mg/m2 twice daily and irinotecan 80 mg/m2; thus the preceding dose level was initially considered as the recommended dose (DL2). The DLTs comprised diarrhea, neutropenia and asthenia. In order to define more precisely the treatment-related toxicity before embarking on further clinical trials, additional patients were treated at the recommended dose. The extension of this dose level to 15 patients showed an incidence of 33% (95% CI 12% to 62%) of DLTs, which was considered too high for further clinical evaluation. Therefore, an additional 13 patients were treated at the starting dose (DL1) and three (19%) out of 16 patients experienced DLTs. Based on these data, the recommended dose for the investigated combination of capecitabine and irinotecan has finally been defined as follows: capecitabine 1000 mg/m2 twice daily and irinotecan 70 mg/m2. The recommended dose was further supported by the safety analysis of multiple cycles, demonstrating an incidence of diarrhea NCI-CTC grade 3 or 4 in 31% (95% CI 11% to 59%) of patients. No other severe non-hematological toxicities were observed at this dose level.
Two (10%) out of 21 patients treated at higher doses (DL2 and DL3) showed NCI-CTC grade 3 HFS (Table 3). HFS is a common side-effect of capecitabine, which has been observed at NCI-CTC grade 3 in 17% of patients treated with capecitabine alone in two large randomized trials [18]. In the present study, HFS was effectively managed with treatment interruption or dose reduction of capecitabine, and did not result in treatment withdrawal. Of importance is the fact that the combination of capecitabine and irinotecan at the doses used rarely led to alopecia and did not exceed grade 1, with the exception of one patient with grade 2 alopecia at the MTD.
Other non-hematological toxicities were moderate and manageable at all dose levels. Hematological toxicities were moderate and neutropenia grade 3 or 4 occurred only in four [11% (95% CI 3% to 25%)] out of 37 patients at all dose levels, with no evidence of cumulative myelosuppression. NCI-CTC grade 3 and 4 hyperbilirubinemia has been reported in 23% of patients treated with capecitabine alone [18]. Since irinotecan mainly undergoes hepatic biotransformation with sequential metabolism and biliary secretion of its metabolites (e.g. SN-38-ß-glucuronide), altered pharmacokinetics of irinotecanespecially at higher dosesshould be considered [4, 26]. However, recent data of a phase I study in patients with gastrointestinal tumors demonstrated no effect of a 2-week schedule of capecitabine on the pharmacokinetic profile of irinotecan, APC and SN-38 [27]. In the present study, no severe alterations in liver function (ALT, AST, S-bilirubin) were found. Furthermore, calculation of the median relative dose densities of capecitabine and irinotecan revealed a high percentage of administration of the initially intended doses for both drugs.
Antitumor activity was not considered a primary objective of this trial, but the present study was conducted as a disease-oriented study, since both capecitabine and irinotecan have significant efficacy in the first-line treatment of advanced colorectal cancer. Therefore, only patients with measurable disease were entered into this trial and the overall response rate of 38% (95% CI 21% to 58%) indicates significant efficacy. Since patient selection (e.g. performance status) may have contributed to the high response rate for the combination of capecitabine and irinotecan, further clinical studies are required to confirm its antitumor activity.
In another phase I study, capecitabine was administered twice daily for 2 weeks in combination with irinotecan on day 1 every 3 weeks [28]. The dose of capecitabine was escalated from 750 to 1250 mg/m2 (twice daily), and irinotecan from 200 to 300 mg/m2. DLTs were neutropenia, diarrhea and fatigue. The recommended dose was 1000 mg/m2 of capecitabine twice daily and 250 mg/m2 of irinotecan. The data on antitumor efficacy were promising. The recent results of a randomized phase III trial of irinotecan dosing regimens demonstrated superiority of the once-every-3-weeks regimen over a weekly administration of irinotecan in terms of lower incidence of severe diarrhea (19% compared with 36% grade 3 and 4 diarrhea; P = 0.002) [29]. Based on these results, the combination of capecitabine with irinotecan given once every 3 weeks may have a superior toxicity profile if compared with the weekly schedule of irinotecan.
In a two-stage, randomized, phase II study, the Istituto Nazionale per lo Studio e la Cura dei Tumori investigated capecitabine at a dose of 1250 mg/m2 twice daily for 14 days in combination with irinotecan either at a dose of 300 mg/m2 on day 1 once every 3 weeks or at a dose of 150 mg/m2 on days 1 and 8 [30]. The main toxicities for both schedules were diarrhea and neutropenia, which were observed at NCI-CTC grade 3 in 36% and 10% of patients for the once-every-3-weeks schedule, and in 15% and 14% of patients for the biweekly schedule, respectively. In order to improve the safety profile for the investigated schedules (second stage), this trial was continued with lower doses of both drugs using capecitabine at a dose of 1000 mg/m2 twice daily in combination with irinotecan, either at a dose of 240 mg/m2 on day 1 or at a dose of 120 mg/m2 on days 1 and 8. The combined efficacy analysis of the intent-to-treat population showed a response rate of 35% for the once-every-3-weeks schedule (62 patients) and 29% for the biweekly schedule (58 patients). Taken together, the data reported herein suggest that the combination of irinotecan and capecitabine is feasible and may have significant antitumor activity.
Although a disproportionate number of deaths occurred in studies involving irinotecan and bolus 5-FU/LV in advanced colorectal cancer, treatment-associated death rates were <1% for irinotecan combined with infusional 5-FU regimes (De Gramont or AIO schedule) [10]. Similar results have recently been reported for ongoing studies in the adjuvant setting with infusional 5-FU/LV/irinotecan (e.g. PETACC-3) [12]. However, the imperative use of central venous access causes complications (e.g. infections, thrombosis) and may have a negative impact on quality of life [31]. Therefore, the replacement of infusional 5-FU/LV with capecitabine in the combination therapy with irinotecan may offer a meaningful alternative in terms of drug administration and convenience for patients.
Capecitabine has also been combined with oxaliplatin in the first-line treatment of advanced colorectal cancer [3234]. Objective responses have been achieved in 49% and 55% of patients [32, 33]: diarrhea NCI-CTC grade 3 and 4 in 35%, and sensory neuropathy in 16% of patients were the main toxicities [32].
Randomized clinical studies comparing the efficacy and safety profile of capecitabine/irinotecan with 5-FU/LV/irinotecan will be initiated in the near future (e.g. EORTC trial 40015) in order to define the therapeutic value as first-line treatment in advanced colorectal cancer.
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Acknowledgements |
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Footnotes |
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This paper was presented in part at the 91st Annual Meeting of the American Association for Cancer Research, New Orleans, LA, 2428 March 2001, and the 37th Annual Meeting of the American Society for Clinical Oncology, San Francisco, CA, 1619 May 2001.
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