Capecitabine (Xeloda®) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors

E. Díaz-Rubio1,+, T. R. J. Evans2, J. Tabernero3, J. Cassidy4, J. Sastre1, M. Eatock2, D. Bisset2, P. Regueiro5 and J. Baselga3

1Department of Oncology, Hospital Clínico Universitario San Carlos, Madrid, Spain; 2CRC Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, UK; 3Medical Oncology Service, Hospital Vall d’Hebron, Barcelona, Spain; 4Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK; 5Productos Roche SA, Madrid, Spain

Received 13 June 2001; revised 18 September 2001; accepted 25 September 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives

This phase I, dose-escalation study was conducted to determine the recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin. Secondary objectives included evaluation of the safety profile and antitumor activity.

Patients and methods

Twenty-three patients with advanced or metastatic solid tumors received a 21-day regimen of oral capecitabine (500, 825, 1000 or 1250 mg/m2 twice daily, days 1–14) in com-bination with oxaliplatin (130 mg/m2, 2-h i.v. infusion, day 1). Dose-limiting toxicities were determined during the first treatment cycle, and safety and efficacy were evaluated throughout treatment.

Results

The recommended dosing schedule is oral capecitabine 1000 mg/m2 twice daily (days 1–14) with i.v. oxaliplatin 130 mg/m2 (day 1) in a 21-day treatment cycle. The principal dose-limiting toxicity was diarrhea. The most frequent treatment-related adverse events occurring during the study were gastrointestinal (nausea/vomiting, diarrhea) and neurological (dysesthesia, paresthesia). The majority of treatment-related adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 15 patients treated at or below the recommended dose. The most common grade 3/4 laboratory abnormalities were lymphocytopenia (52% of patients), thrombocytopenia (22%; grade 3 only), neutropenia (17%) and hyperbilirubinemia (17%). Among patients treated at or below the recommended dose level (n = 15), only two patients experienced grade 3 neutropenia and no patients experienced grade 4 neutropenia. Partial tumor responses occurred in six patients (26%), including five of nine patients (55%) with colorectal cancer. All responding patients were pretreated with 5-fluorouracil and four responders had received prior irinotecan.

Conclusions

Oral capecitabine with i.v. oxaliplatin is a feasible combination regimen that shows promising antitumor activity in patients with colorectal cancer. There is an ongoing, phase II study to further characterize the safety and efficacy of this combination as first-line therapy for metastatic colorectal cancer, using the recommended dose identified in this study.

Key words: capecitabine, colorectal cancer, fluoropyrimidine, oxaliplatin


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The treatment of solid tumors frequently involves 5-fluorouracil (5-FU). Numerous intravenous 5-FU regimens are used in clinical practice, but there is no universally accepted 5-FU schedule. It is well established that the activity of 5-FU can be enhanced by the addition of the biochemical modulator leucovorin [1], and regimens administering 5-FU as a continuous infusion have also proved superior to bolus schedules in terms of response rate, progression-free survival and tolerability [2]. Despite the modest improvements in efficacy achieved with this method of administration, the clinical use of continuous infusion schedules has been limited by the significant inconvenience, cost and complications associated with in-dwelling central venous access lines and pumps. In addition, both bolus and continuous infusion 5-FU schedules are associated with significant toxicity [3]. Therefore, there remains a need for new therapeutic options offering improved efficacy, tolerability and convenience for patients.

Capecitabine (Xeloda®; F. Hoffmann-La Roche, Basel, Switzerland) is a novel oral fluoropyrimidine carbamate that enables prolonged exposure of tumor tissue to 5-FU. Capecitabine generates 5-FU preferentially at the tumor site by exploiting the higher activity of the enzyme thymidine phosphorylase (TP) in tumor tissue compared with healthy tissue [4, 5]. After oral administration, capecitabine is absorbed rapidly and virtually completely through the gastrointestinal mucosa and is first metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase in the liver. 5'-DFCR is then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase in the liver and tumor tissue. Finally, 5'-DFUR is converted to 5-FU by TP, which is significantly more active in malignant tissue than in adjacent healthy tissue [4]. The tumor-selective activation of capecitabine potentially improves tolerability by minimizing systemic exposure to 5-FU. In clinical trials, capecitabine monotherapy has demonstrated a favorable safety profile [611]. The majority of adverse events associated with capecitabine were mild to moderate in severity, with a particularly low incidence of alopecia and myelosuppression. As an oral agent, capecitabine can be administered in the outpatient setting, providing a more convenient treatment for patients and avoiding the complications associated with indwelling devices for protracted i.v. infusion.

Capecitabine is highly active in patients with colorectal cancer [811]. Data from two large phase III trials have demonstrated that as first-line therapy for metastatic colorectal cancer, capecitabine achieves significantly superior response rates (P <0.0002) and equivalent time to disease progression and overall survival compared with i.v. bolus 5-FU–leucovorin (Mayo Clinic regimen) [11].

Oxaliplatin is a third-generation cisplatin analog, with activity and toxicity profiles that differ from those of other platinum derivatives, including cisplatin and carboplatin [12]. Unlike other platinum compounds, oxaliplatin is active in colorectal cancer and has demonstrated synergic activity with 5-FU in preclinical studies [13, 14]. The most common toxicity with oxaliplatin is acute, reversible peripheral sensory neuropathy, including cold-induced dysesthesia and paresthesia, that may progress to less reversible, cumulative symptoms [12]. Currently, the recommended dose for the single-agent administration of oxaliplatin is 130 mg/m2 every 21 days [15]. In combination with 5-FU–leucovorin, a fortnightly schedule with oxaliplatin 85–130 mg/m2 administered on day 1 is also used [16, 17].

Clinical trials have confirmed that oxaliplatin is active in patients with colorectal cancer [18] and can partially overcome clinical resistance to 5-FU [19]. Two randomized phase III trials demonstrated that, compared with 5-FU–leucovorin alone, the addition of oxaliplatin to first-line 5-FU–leucovorin therapy significantly increased objective response rates (P <0.001) and median progression-free survival (P <0.05), with one trial showing a trend towards superior overall survival that did not reach statistical significance [16, 20]. Survival in this trial may have been influenced by the use of effective second-line therapy, as patients in the control arm were permitted to cross over and receive 5-FU–leucovorin with oxaliplatin following disease progression [16]. 5-FU–leucovorin plus oxaliplatin has demonstrated efficacy as second-line therapy in patients with advanced/metastatic colorectal cancer who have experienced disease progression following 5-FU-based chemotherapy [2125], as well as those refractory to or progressing following irinotecan [26].

The improved efficacy achieved with the addition of oxaliplatin to 5-FU–leucovorin in patients with colorectal cancer and the non-overlapping toxicity profiles provided the rationale for a phase I, dose-escalation study evaluating capecitabine in combination with oxaliplatin in patients with advanced and/or metastatic solid tumors. As an oral fluoropyrimidine, capecitabine has the potential to replace i.v. 5-FU and simplify combination therapy. Like 5-FU, capecitabine may also have synergic activity with oxaliplatin, and its tumor-selective activation and favorable safety profile could further improve the efficacy and safety of the combination regimen.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The primary objective of this study was to determine the dose-limiting toxicities (DLTs) and recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin. Secondary objectives included further characterization of the safety profile throughout all treatment cycles and evaluation of the antitumor activity of the combination. The study protocol was reviewed and approved by the research ethics committees at all participating centers.

Inclusion criteria
Patients with histologically confirmed advanced and/or metastatic solid tumors who were unresponsive or untreatable with standard chemotherapy were eligible for this study. Patients had to be aged 18–75 years, with Karnofsky Performance Status (KPS) >70%, and life expectancy >3 months. All patients gave written, informed consent prior to study-specific screening procedures.

Exclusion criteria
The following patients were excluded: pregnant or lactating patients; women of childbearing potential who did not use a reliable contraceptive method; patients with organ allografts; patients with significant cardiac disease; and patients with a history of uncontrolled seizures, central nervous system disorders or psychological disability thought to be clinically significant, preclude informed consent or adversely affect patient compliance. Patients were also excluded if they had serious, uncontrolled infections, malabsorption syndrome or if they lacked physical integrity of the upper gastrointestinal tract. Patients with sensory neuropathy [severity grade >1 according to National Cancer Institute of Canada common toxicity criteria (NCIC CTC)] or with known sensitivity to fluoropyrimidines or platinum derivatives were ineligible, as were patients who had participated in another clinical trial within 4 weeks of the start of treatment.

Patients with hemoglobin <8 g/dl, absolute neutrophil count <1.5 x 109/l, and platelet count <100 x 109/l were excluded, as were patients with creatinine or total bilirubin concentrations >2.5 times the upper limit of normal, calcium concentrations >11.5 mg/dl, or transaminase or alkaline phosphatase concentrations more than five times the upper limit of normal.

Screening assessments
Screening assessments including medical history, physical examination (including vital signs, height, weight and KPS), electrocardiogram (ECG), chest X-ray and tumor measurements, based on the appropriate imaging techniques or physical examination, were conducted within 14 days before treatment initiation. Laboratory data including complete blood count, blood chemistry and urinalysis were also obtained.

During treatment, weekly assessments included vital signs, physical measurements, KPS, complete blood counts and blood chemistry. For patients continuing treatment beyond 18 weeks, these assessments were carried out at 3-weekly intervals. Urinalysis, chest X-ray, ECG and brain computed tomography (CT) scan were performed if clinically indicated.

Treatment schedule
Oral capecitabine was administered twice daily on days 1–14 of a 21-day regimen in combination with a fixed dose of oxaliplatin 130 mg/m2 administered on day 1 as a 2-h i.v. infusion, 4–6 h after the morning dose of capecitabine. The starting dose of capecitabine was 500 mg/m2 twice daily. Capecitabine doses were escalated to 825, 1000 or 1250 mg/m2 twice daily in subsequent cohorts. Total daily dose was calculated as mg/m2 according to surface area and rounded to the nearest 100 mg. The two daily doses of capecitabine were administered 12 ± 2 h apart, within 30 min after a meal (breakfast and evening meal), with approximately 200 ml of water. Anti-emetics could be administered prior to oxaliplatin infusion.

Treatment was continued until disease progression or unacceptable toxicity. Patients achieving a complete or partial response or stable disease could continue treatment for up to 18 weeks. Patients maintaining a response or stable disease after this time could receive further treatment either with the combination or with capecitabine or oxaliplatin monotherapy, if the investigator considered further treatment to be beneficial.

Identification of DLTs
Adverse events were graded according to NCIC CTC (revised May 1991), with the exception of hand-foot syndrome, which was graded 1–3 [6].

The following toxicities were defined as dose-limiting if they occurred during the first cycle of treatment and did not resolve to grade 1 within 2 days of symptomatic treatment: grade 3/4 diarrhea; other grade 3/4 gastrointestinal toxicities, such as vomiting, nausea or mucositis; grade 3 hand-foot syndrome; grade 3 peripheral sensory neuropathy; and any other clinically relevant grade 3/4 toxicity. In addition, prolonged granulocytopenia (grade 4 for >5 days) and granulocytopenia with complications (e.g. grade 3/4 fever, mucositis or diarrhea) were classified as dose limiting.

Dose-escalation scheme
The capecitabine dose was escalated when three patients had completed one treatment cycle without DLTs. If one patient developed a DLT during the first treatment cycle, an additional three patients were recruited to the same dose level. If DLTs occurred in two or more patients in a six-patient cohort, an additional six patients were recruited to the dose level below. The recommended dose was defined as the dose below that causing DLTs in two or more patients in a six-patient cohort during the first cycle of treatment.

Evaluation of safety and efficacy
Adverse events were monitored continuously during treatment and for 28 days after the last intake of capecitabine. Tumors were evaluated using CT scans at baseline, at weeks 9 and 18, and at the time of withdrawal from the study. Tumor responses were evaluated based on WHO criteria. For patients achieving a tumor response, the time to first response was defined as the period between the first day of treatment and the date when a tumor response was first observed. Duration of response in patients achieving a complete response was defined as the interval from the date a complete tumor response was observed to the date that disease progression was first observed. In patients achieving a partial response, only the duration of overall response was recorded, defined as the interval from the first day of treatment to the date that progressive disease was first observed.

Dose adjustments
Treatment was continued at the same dose (without interruption or dose reduction) in the case of toxicities considered unlikely to become serious or life threatening, or for grade 1 toxicities. No dose reductions were required for anemia. For all other treatment-related adverse events of grade 2 or higher intensity, the standard capecitabine dose modification scheme was implemented [6]. Capecitabine dose reduction was not required following the first appearance of any grade 2 toxicity, although treatment was interrupted until the toxicity had resolved to grade 0 or 1. Treatment was interrupted and the capecitabine dose was reduced by 25% in patients who experienced a second occurrence of a given grade 2 toxicity or any grade 3 toxicity, and by 50% for patients who experienced a third occurrence of a given grade 2 toxicity or the second occurrence of a given grade 3 toxicity. Treatment was discontinued if a toxicity occurred at grade 4 or if, despite dose reduction, a given toxicity occurred for a fourth time at grade 2 or a third time at grade 3. Following treatment interruption, missed capecitabine doses were considered to be lost treatment days and were not to be taken. If the capecitabine dose was reduced owing to toxicity, it was not to be increased at a later time.

Oxaliplatin dose modification was implemented if patients developed grade 2 neurosensory toxicity, which was defined as paresthesiae and/or dysesthesiae with pain, or paresthesiae and/or dysesthesiae for >21 days. Treatment was interrupted until toxicity had resolved to grade 0 or 1, and the oxaliplatin dose was reduced to 100 mg/m2. In patients who experienced a second occurrence of grade 2 neurosensory toxicity, treatment was interrupted and the oxaliplatin dose was reduced to 75 mg/m2. Treatment was discontinued if patients experienced a recurrence of grade 2 neurosensory toxicity after two oxaliplatin dose reductions, if oxaliplatin therapy had to be delayed for >2 weeks owing to toxicity, or if patients developed grade 3 neurosensory toxicity (paresthesiae and/or dysesthesiae causing functional impairment). If patients developed acute, laryngopharyngeal dysesthesiae, the subsequent doses of oxaliplatin were administered as a 6-h infusion.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between February 1999 and April 2000, 23 patients with advanced and/or metastatic solid tumors were enrolled at four centers and received at least one course of study treatment. All patients were Caucasian and the majority had KPS >=90%. A summary of patient characteristics is given in Table 1. The predominant tumor type was colorectal cancer (nine patients). Other tumor types represented included gall bladder, renal and lung cancer (two patients each).


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Table 1. Patient demographics (n = 23)
 
Fifteen patients, including all nine patients with colorectal cancer, had previously received a 5-FU-containing chemotherapy regimen in the neo-adjuvant, adjuvant or metastatic setting. Four patients had also previously received treatment with irinotecan monotherapy for metastatic colorectal cancer. An additional two patients, one with nasopharyngeal carcinoma and the other with endometrial adenocarcinoma, had previously received combination treatment with irinotecan plus 5-FU in the metastatic setting. Three patients had received no prior cytotoxic chemotherapy (one patient with an adenocarcinoma of the gall bladder and two with a renal cell carcinoma).

DLTs and recommended dose level
The principal DLT when capecitabine was administered in combination with a fixed dose of oxaliplatin was diarrhea (Table 2). No DLTs occurred in patients treated with capecitabine 500 or 825 mg/m2 twice daily. Dose-limiting diarrhea occurred in one of nine patients treated at the capecitabine 1000 mg/m2 dose level. Two of six patients treated with capecitabine 1250 mg/m2 twice daily experienced dose-limiting diarrhea, which was accompanied by grade 3 thrombocytopenia in one patient and grade 4 neutropenia in the other. Therefore, a regimen of intermittent capecitabine 1000 mg/m2 twice daily (14 days’ treatment followed by a 7-day rest period) with oxaliplatin 130 mg/m2 administered as a 2-h infusion on day 1 of each 21-day cycle was identified as the recommended dose for further development.


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Table 2. Incidence of DLTs during capecitabine dose escalation
 
Safety profile
During the study, 105 treatment cycles of capecitabine plus oxaliplatin were administered, with a mean of 4.6 treatment cycles (range 1–15 cycles) administered per patient. Table 3 lists the treatment-related clinical adverse events experienced by patients treated at each dose level during all treatment cycles. The most frequent treatment-related adverse events (all grades, >=20% of patients) were nausea (70%), paresthesia (70%), vomiting (65%), dysesthesia (57%), diarrhea (48%), stomatitis/mucositis (39%), asthenia (26%), constipation (26%), hand-foot syndrome (22%) and anorexia (22%). The majority of these were mild to moderate in intensity (Figure 1). The only grade 4 treatment-related adverse event occurring during the study was diarrhea, which occurred in two patients (9% of patients overall) treated at the capecitabine 1250 mg/m2 dose level, during the first treatment cycle in one patient and the second treatment cycle in the other. The most common (>=10% of patients) treatment-related grade 3 adverse events were diarrhea (17%) and paresthesia (13%). Grade 3 diarrhea occurred in treatment cycles 1 (two patients), 2 (one patient) and 3 (one patient), and grade 3 paresthesia occurred during treatment cycles 4 (one patient), 6 (one patient) and 7 (one patient).


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Table 3. Incidence of treatment-related, clinical adverse events during all treatment cycles (all grades)
 


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Figure 1. Most common (>=20% of patients) treatment-related, clinical adverse events (all treatment cycles).

 
Table 4 lists the grade 3/4 laboratory abnormalities occurring in patients throughout the study period. The most common grade 3/4 laboratory abnormalities were lymphocytopenia (52%), thrombocytopenia (22%; grade 3 only), neutropenia (17%) and hyperbilirubinemia (17%). Among patients treated at or below the recommended dose level (n = 15), only two patients experienced grade 3 neutropenia and no patients experienced grade 4 neutropenia.


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Table 4. Incidence of grade 3/4 laboratory abnormalities during all treatment cycles
 
Efficacy
All efficacy analyses were conducted using the intention-to-treat population (n = 23). Overall, partial tumor responses were achieved in six of 23 patients, giving an overall objective tumor response rate of 26%. In addition, disease was stabilized in a further six patients (26%). All of the responding patients had previously received a 5-FU-containing chemotherapy regimen. The combination demonstrated encouraging activity in the subgroup of nine patients with colorectal cancer. Five of these patients (55%) achieved partial tumor responses, with responses confirmed after 9 weeks in four patients, and a further three patients achieved disease stabilization (Table 5). Four of the five responding patients with colorectal cancer had previously experienced tumor progression during or following irinotecan monotherapy administered in the metastatic setting. A partial tumor response (not confirmed) was also achieved in one patient with a carcinoma of the gall bladder.


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Table 5. Antitumor activity of capecitabine–oxaliplatin combination therapy in patients with colorectal cancer
 
Overall, the median time to response [± standard deviation (SD)], defined as the interval from the start of treatment to the date when a tumor response was first observed, was 2.8 ± 1.2 months (range 2.1–4.8 months). The median duration of response (± SD), defined as the interval from the start of treatment to the date when disease progression was first observed, was 4.9 ± 1.6 months (range 4.4–8.3 months).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study has demonstrated that administration of capecitabine in combination with oxaliplatin is a promising new treatment option for patients with solid tumors, particularly colorectal cancer. The recommended dosing schedule was identified as a 21-day treatment cycle of oral capecitabine 1000 mg/m2 twice daily, days 1–14, plus oxaliplatin 130 mg/m2 administered on day 1 as a 2-h i.v. infusion.

The principal DLT associated with this combination was diarrhea. Overall, the safety profile of the combination treatment was favorable and consistent with previous studies investigating oxaliplatin in combination with fluoropyrimidines. Grade 3/4 treatment-related gastrointestinal toxicities occurred early in the treatment course, during cycles 1–3. In contrast, three patients experienced grade 3 paresthesia, in treatment cycles 4, 6 and 7, following mild, recurrent grade 1 paresthesia that developed during the first treatment cycle. This pattern is consistent with previous studies showing that oxaliplatin, administered as monotherapy or in combination with 5-FU–leucovorin, is associated with cumulative sensory neuropathy [16, 27]. This is generally reversible, resolving in the majority of patients following the discontinuation of treatment.

While the safety profile of the combination regimen was favorable, measures must be implemented for the management of side effects. Anti-emetics (dexamethasone and 5HT3 antagonists are recommended) should be routinely administered prior to oxaliplatin infusion to avoid severe nausea/vomiting. In addition, patients need to have anti-emetics (chlorpromazine with, possibly, an oral 5HT3 antagonist as a back-up) readily available at home. Patients should be carefully monitored for the concomitant development of diarrhea with neutropenia, which can lead to serious complications. As oral capecitabine is administered in the outpatient setting, patients should be educated to recognize side effects and their severity. It is important that patients interrupt treatment at the first appearance of a moderate or more severe toxicity and seek further advice from their oncology team (doctor, nurse or pharmacist). Patients should be advised to contact their oncology team immediately upon the development of fever.

The safety profile of another oral fluoropyrimidine, uracil/tegafur (UFT), administered in combination with leucovorin and oxaliplatin has been assessed as first-line therapy in a phase II study [28]. Oral UFT (daily in two divided doses, days 1–14) was administered in a 28-day treatment cycle with leucovorin (250 mg/m2 as a 2-h i.v. infusion on day 1, and 7.5 mg/m2 twice daily orally on days 1–14) and i.v. oxaliplatin (100 mg/m2 on days 1 and 15) to 66 patients with advanced colorectal cancer. With UFT 390 mg/m2 daily, severe/life-threatening (grade 3/4) diarrhea and nausea/vomiting occurred in 56% and 18% of patients, respectively. This unacceptable toxicity required reduction of the daily dose of UFT to 300 mg/m2. At this reduced dose, grade 3/4 diarrhea and nausea/vomiting occurred in 21% and 10% of patients, respectively. Neurotoxicity was observed in 84% of patients, with grade 3 neurotoxicity occurring in 4%.

The toxicity profile of capecitabine–oxaliplatin observed in the present study is consistent with the toxicity profiles established for i.v. 5-FU–leucovorin–oxaliplatin combination regimens evaluated in phase III trials. Among 100 patients treated with oxaliplatin plus chronomodulated 5-FU–leucovorin as first-line therapy for metastatic colorectal cancer, 43% experienced grade 3/4 diarrhea and 45% experienced peripheral sensory neuropathy consisting of long-lasting paresthesiae [20]. In patients with advanced colorectal cancer receiving oxaliplatin in combination with a bimonthly schedule of leucovorin and bolus-plus-continuous infusion 5-FU, the most common toxicities were grade 3/4 neutropenia (42%), grade 3/4 diarrhea (12%) and grade 3 neurosensory toxicity (18%) [16]. The administration of capecitabine in combination with oxaliplatin could potentially provide improved tolerability compared with these regimens and replace 48-h infusion schedules, thus avoiding the complications associated with indwelling devices for protracted i.v. infusion. Capecitabine monotherapy has demonstrated a superior safety profile compared with i.v. bolus 5-FU–leucovorin (Mayo Clinic regimen) as first-line therapy for metastatic colorectal cancer: in two randomized, phase III trials, capecitabine caused significantly less diarrhea, stomatitis, nausea, alopecia, grade 3/4 stomatitis and grade 3/4 neutropenia, leading to significantly less neutropenic fever/sepsis [11].

With the capecitabine–oxaliplatin combination regimen, only one clinic visit every 3 weeks is required for administration of oxaliplatin (2-h i.v. infusion). The simplified, bimonthly 5-FU–leucovorin/oxaliplatin regimen involves 2-h infusion of leucovorin and oxaliplatin, with bolus administration of i.v. 5-FU followed by a 22-h 5-FU infusion on days 1 and 2 [16, 25]. This treatment regimen is repeated every 2 weeks. The chronomodulated schedule, which demonstrated improved tolerability over other 5-FU regimens that have been investigated with oxaliplatin, involves a 5-day chronomodulated infusion of 5-FU and leucovorin, with oxaliplatin administered as a 6-h infusion on day 1 and treatment repeated at 2-weekly intervals [20].

Capecitabine–oxaliplatin combination treatment demonstrated encouraging antitumor activity, with objective tumor responses observed in five of nine patients with colorectal cancer and one patient with a carcinoma of the gall bladder. Disease stabilization occurred in a further three patients with colorectal cancer and three additional patients with other tumor types. This activity is particularly impressive, as all of the responding patients had previously received a 5-FU-containing chemotherapy regimen and four of the five responders with colorectal cancer had experienced disease progression during or following therapy with irinotecan.

This phase I study has demonstrated that oral capecitabine in combination with i.v. oxaliplatin is feasible and shows promising antitumor activity in colorectal cancer patients. There is an ongoing phase II study to further characterize the safety and efficacy of this combination as first-line therapy for patients with metastatic colorectal cancer, using the recommended dose identified in this study.


    Footnotes
 
+ Correspondence to: Dr E. Díaz-Rubio, Department of Oncology, Hospital Clínico Universitario San Carlos, C/Martin Lagos s/n, 28040 Madrid, Spain. Tel: +34-91-330-3546; Fax: +34-91-330-3546; E-mail: ediaz@ene.es Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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