Phase II study of capecitabine and oxaliplatin as first-line treatment in advanced colorectal cancer

M. Zeuli1,+, C. Nardoni1, M. S. Pino1, T. Gamucci2, A. Gabriele2, V. Ferraresi1, D. Giannarelli3 and F. Cognetti1

1 Department of Medical Oncology A, Regina Elena Cancer Institute, Roma; 2 Unit of Medical Oncology, Umberto I Hospital, Frosinone; 3 Unit of Biostatistic and Trial Data, Regina Elena Cancer Institute, Roma, Italy

Received 28 January 2003; revised 4 April 2003; accepted 14 April 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer. The aim of this phase II study is to determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced non-pretreated colorectal cancer.

Patients and methods:

Forty-three chemotherapy-naïve patients were enrolled. Capecitabine 2500 mg/m2/day was administered orally twice a day continuously for 14 days and oxaliplatin 120 mg/m2 was administered as a 2-h infusion on day 1, repeated every 3 weeks.

Results:

Forty-three patients were assessable for toxicity and 39 for clinical activity: the main toxicity was grade 3 or 4 diarrhea, which occurred in 28% of the patients. The response rates were 44% [95% confidence interval (CI), 29.3% to 59.0%] and 48.7% (95% CI 33.0% to 64.4%) (intention-to-treat and per protocol analysis, respectively). The median overall survival was 20 months (95% CI 12–28).

Conclusions:

Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer; therefore, the capecitabine dose we utilized is probably too high. The main toxicity is diarrhea, which is manageable with appropriate dose reductions.This combination may be preferable compared to a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy. Thus, phase III trials are needed to clarify its role in the treatment of chemotherapy-naïve advanced colorectal cancer patients.

Key words: advanced colerectal cancer, capecitabine, first-line chemotherapy, oxaliplatin


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Capecitabine is a rationally designed, oral tumor-selective fluoropyrimidine that is converted to fluorouracil preferentially in tumor tissue by the enzyme thymidine phosphorylase [1]. The recommended dose and schedule of capecitabine is 2500 mg/m2 for 14 days every 21 days and the most adverse events and dose-limiting toxicities (DLTs) were hand–foot syndrome (HFS), nausea/vomiting, diarrhea, fatigue, anorexia and stomatitis.

Two large randomized studies have shown higher tumor response rates and at least equivalent time to disease progression and overall survival (OS) with the oral treatment compared with intravenous (i.v.) bolus fluorouracil/leucovorin [2, 3]. Most importantly in view of the indirect costs caused by the treatment, hospitalization was significantly reduced with capecitabine in comparison with i.v. fluorouracil/leucovorin.

Oxaliplatin is a new third-generation cisplatin analog. In combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) in randomized phase III trials, it has shown a high antitumoral activity in advanced colorectal cancer patients [4, 5].

Combining oxaliplatin with oral capecitabine instead of infusional fluorouracil is an interesting alternative in view of the practicability of the treatment and the lack of major overlapping toxicities of the two drugs. This is confirmed by the results of two dose-finding studies: Diaz-Rubio et al. [6] achieved the maximum tolerated dose (MTD) of capecitabine (2500 mg/m2/day) on days 1–14 in combination with a fixed dose of oxaliplatin (130 mg/m2) on day 1 in a 21-day treatment cycle in chemotherapy-pretreated patients with various solid tumors. The DLTs in the eight patients on the highest dose level were one case each of diarrhea grade 3 with thrombocytopenia and diarrhea grade 4 with neutropenia. Thus, the capecitabine dose recommended by the authors for further studies with this combination was 2000 mg/m2/day. Furthermore, 25 pretreated advanced colorectal cancer patients were treated in our institution in a dose-escalation setting: DLTs were diarrhea (grade >=3: 27%) and stomatitis (grade >=3: 9%) at dose level 6 (capecitabine 2500 mg/m2/day and oxaliplatin 130 mg/m2). Dose level 5 (capecitabine 2500 mg/m2/day and oxaliplatin 120 mg/m2) was found to be the MTD. Hematological toxicity was minimal; overall neurotoxicity (grade 1–4) was 27% with 1% grade 3–4. The global response rate was 17% [95% confidence interval (CI) 2% to 32%] and the median OS was 12 months [7]. In our experience the recommended dose for further phase II studies should be capecitabine 2500 mg/m2/day with intermittent schedule and oxaliplatin 120 mg/m2 every 3 weeks.

We report the results of a phase II study in which chemotherapy-naïve advanced colorectal cancer patients were treated with capecitabine 2500 mg/m2/day in combination with oxaliplatin 120 mg/m2 to better characterize the efficacy and tolerability of the combination at this dose level which corresponds to the recommended single-agent dose for both drugs.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with histologically proven advanced adenocarcinoma of the colon or rectum were eligible for this study. They had to be not pretreated with chemotherapy for advanced disease and had to have completed adjuvant chemotherapy 6 months before study entry. Measurable disease according to the RECIST criteria was required [8]. All patients were required to have World Health Organization performance status (PS) <2, aged between 18 and 75 years, life expectancy >12 weeks, white blood cell count 4 x 109 cells/l, absolute neutrophil count 2 x 109 neutrophils/l, platelet count 100 x 109 platelets/l, hemoglobin level 10 g/dl, serum creatinine level within normal values, total bilirubin level 1.5 x the upper limit of normal (ULN), alkaline phosphatases <5 x ULN, aspartate aminotransferase and alanine aminotransferase 1.5 x ULN (or <5 x ULN if hepatic metastases were present). Exclusion criteria were: other malignancies (except excised in situ cervical carcinoma or basal/squamous cell skin carcinoma); peripheral neuropathy of National Cancer Institute (NCI) grade 2; symptomatic brain metastases and concurrent treatment with other experimental drugs or participation in another clinical trial within 30 days prior to study screening. Written informed consent was required for each patient. The study procedures were approved by our institutional ethic committee and were carried out in accordance with national guidelines.

Pretreatment evaluation included a complete clinical history, physical examination, neurological status, electrocardiogram, chest X-ray, and computed tomography scan or ultrasound of assessable target lesions. Complete blood cell counts and differential blood chemistry were obtained at baseline and were repeated every chemotherapy cycle. Toxicities were graded using the NCI common toxicity criteria.

Objective response was the primary end point and was recorded according to the RECIST response criteria [8]. Assessment of response was performed every three chemotherapy cycles and the scans were reviewed blind in our institution. The number of cycles was not limited. Treatment was continued until disease progression, unacceptable adverse effects or withdrawal of consent by the patient.

Capecitabine was supplied as film-coated tablets in two dose strengths (150 and 500 mg) and was delivered daily for 2 weeks followed by 1 week of rest. It was self-administered in the patients’ homes as two separated doses ~12 h apart, taken within 30 min after ingestion of food.

Capecitabine intake was interrupted in the case of grade 3 non-hematological toxicity and was not resumed until the adverse effect improved to grade 1. Capecitabine doses were reduced by 25% in subsequent treatment cycles in the case of grade 3 or 4 non-hematological toxicity in the previous cycle.

Oxaliplatin was administered over a 2-h infusion on day 1 of treatment. This treatment cycle was repeated every 21 days. Before chemotherapy, patients were systematically given i.v. ondansetron or granisetron plus steroids before chemotherapy to prevent emesis. Patients were warned to avoid exposure to cold and cold drinks after therapy with oxaliplatin to reduce related neuropathy episodes or their exacerbation. Oxaliplatin infusion duration was further lengthened to 4 or 6 h if the patients had neurotoxicity superior to grade 2. In the case of grade 3 non-hematological or grade 4 hematological toxicity in the previous cycle, the oxaliplatin dose was reduced by 25% in the subsequent cycles.

Statistical analysis
An optimal two-stage design as described by Simon [9] was used. In the first stage, a total of 13 patients were included and at least four responses (both complete and partial responses) were required to continue to the second stage. In the second stage, 30 additional patients were included to a total sample size of 43. Thirteen responses were needed to conclude with a 95% confidence that the response rate was >40%. Overall survival time was measured from start of treatment and analyzed by the Kaplan–Meier method. Statistical analyses were performed using SPSS version 11 packages for Windows.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Forty-three patients were enrolled and all patients were treated in an outpatient setting. Twenty-nine patients had primary colon and 14 had rectal cancer. A total of 211 cycles of chemotherapy was delivered with a median of five cycles per patient (range 1–11). Patient characteristics are listed in Table 1. Twenty-five patients (58%) had a PS of 0 and 18 patients (42%) had a PS of 1. Eighteen patients received adjuvant chemotherapy, 11 with a bolus FU/FA regimen, three with the de Gramont regimen and four received concomitant chemo-radiotherapy with infusional 5-FU. The majority of patients had liver (53%) or lung (37%) metastases. Twenty-five patients (58%) had only one site of disease, 13 (30%) had two sites and five (12%) had three or more. The dose intensity for capecitabine and oxaliplatin in the first four treatment cycles is summarized in Table 2.


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Table 1. Patient characteristics
 

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Table 2. Cycle number and mean dose intensity per cycle (median cycle number five, range 1–11)
 
Toxicity
The incidence of non-hematological toxicity is summarized in Table 3. To examine the temporal pattern of the occurrence of adverse events, the distribution of the toxicity grades per cycle was analyzed. Table 3 shows that toxicity peaked in the first three cycles and was then reduced in the following cycles because of dose adaptations. The main toxicity was grade 3 or 4 diarrhea, which occurred in 28% of the patients. Its incidence was cycle-dependent, 13 out of 19 cases of severe diarrhea being observed during the first three cycles. Grade 3 or 4 nausea and vomiting occurred in 5% and severe sensory neuropathy in 7% of patients. Neurotoxicity was observed most frequently after three cycles of treatment, probably due to an oxaliplatin cumulative dose. Laryngospasm during the oxaliplatin infusion was observed in two patients and was prevented in the following treatment cycles by prolonging the oxaliplatin infusion duration. Stomatitis was mild and rarely observed with this treatment combination. HFS was noted in one patient (2%).


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Table 3. Non-hematological study-related adverse events, any grade, per patient and per cycle (43 evaluable patients, 211 evaluable cycles)
 
Hematological toxicity was moderate (Table 4). Grade 3 neutropenia occurred in two patients, but one case of life-threatening febrile neutropenia was reported. One patient had uncomplicated thrombocytopenia grade 4. Mild anemia occurred in 12 patients.


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Table 4. Hematological study-related adverse events, any grade, per patient and per cycle (43 evaluable patients, 43 evaluable cycles)
 
Dose modification due to toxic events was required in 21% of cycles administered (27% of patients). The reasons for dose reduction were severe diarrhea (seven patients), severe vomiting (one patient), persistent grade 2 thrombocytopenia and neutropenia at recycle (two and one patient, respectively) and hypertransaminasemia (one patient). No rises in bilirubin were observed. Three patients discontinued treatment after the second cycle due to severe (grade 4) diarrhea despite dose adaptations.

During the whole treatment period there were only six hospitalizations because of prolonged refractory diarrhea (four patients) and tumor progression (two patients).

Two patients died while receiving treatment. One was hospitalized in another institution because of severe febrile neutropenia and probably died due to diffuse septicemia, and one patient died of myocardial infarction probably unrelated to treatment.

Clinical activity
The results of the response evaluation are summarized in Table 5 according to intention-to-treat (ITT) and per protocol (PP) analysis. The response rates were 44.2% (95% CI 29.3% to 59.0%) and 48.7% (95% CI 33.0% to 64.4%) for ITT and PP analysis, respectively. Non-assessable patients in PP analysis received only one treatment cycle (n = 4) due to early death (two patients) and refusal of treatment (two patients).


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Table 5. Clinical activity [per protocol (PP) and intention-to-treat (ITT) analysis]
 
One patient pretreated with the bolus FU/FA regimen in adjuvant setting, achieved a complete response (CR) on multiple liver and lung metastases with a progression-free survival (PFS) of 49 weeks, and another patient had a CR on multiple liver metastases lasting 36 weeks. Seventeen patients had a partial clinical response with a median PFS of 24 weeks (range 13–48 weeks). In 10 patients (25.6%) stable disease was observed and 10 patients (25.6%) had progressive disease.

Because dose intensity has been related to tumor response [10], we examined whether patients requiring dose reductions were less likely to respond to treatment. There was no significant association between dose modifications due to toxicity and partial or complete tumor remissions.

The median follow-up time for all patients was 6 months. The Kaplan–Meier curve for median survival is depicted in Figure 1. The estimated median OS was 20 months (95% CI 12–28). The median time to treatment failure was 8.2 months (95% CI 6.6–9.8). The activity of this combination regimen in terms of time to treatment failure and OS needs to be confirmed with longer follow-up.



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Figure 1. Overall survival.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
5-FU remains one of the most important drugs in the treatment of advanced colorectal cancer. Several studies have confirmed that continuous infusion of 5-FU is superior to bolus i.v. injection, with improved anticancer activity as well as reduced toxicity. However, continuous infusion requires an indwelling central venous catheter with the associated increased risk of infection and thrombosis. Continuous infusion increases the cost of this palliative treatment and probably decreases the quality of life of the patients. The development of effective oral fluoropirimidine is a desirable goal in advanced colorectal cancer. In fact, oxaliplatin administration does not vary substantially among the combination schedules most commonly used in current practice, so the question of convenience will be decided on grounds of differences in the administration of the fluoropyrimidine. An important argument for the choice of the oral regimen was the fact that this treatment could be taken at home in a self-determined environment.

Therefore, oral capecitabine offers an advantage over infusional fluorouracil/leucovorin in terms of convenience, practicability and cost of health care.

The results of this phase II study establish the feasibility and efficacy of combining capecitabine with oxaliplatin in advanced colorectal cancer. The 48% response rate in non-pretreated patients compared well with the 50.7–53% objective responses observed with oxaliplatin plus continuous infusion fluorouracil/leucovorin in first-line treatment [4, 5, 11, 12].

Besides efficacy, toxicity is a critical end point with which to assess the utility of a new treatment combination. In our study no unexpected adverse event occurred, and the most common toxicities observed were those of each drug: main toxicities consisted of diarrhea, sensory neuropathy and vomiting, and only one case of severe neutropenia and thrombocytopenia occurred. It is noteworthy that the doses of each drug in this combination regimen were as high as that recommended for single-agent therapy. Thus, the toxicity of our treatment regimen in non-pretreated patients seems to be higher compared with the results of the studies using infusional fluorouracil instead of oral capecitabine in combination with oxaliplatin. This is probably due to the dose of capecitabine we utilized, which was higher than that reported in a recent large phase II trial in which the tolerability of treatment seems to be more acceptable [13]. In conclusion, combining oxaliplatin with capecitabine may be preferable compared with a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy and toxicity.

This recommendation is supported by the results of a recently completed phase II study with this combination in which the authors report similar conclusions [14].

Phase III trials are needed to clarify the role of combination capecitabine/oxaliplatin in the treatment of chemotherapy-naïve advanced colorectal cancer patients.


    Acknowledgements
 
The authors thank P. Franke for technical assistance.


    Footnotes
 
+ Correspondence to: Dr M. Zeuli, Oncologia Medica A, Istituto Regina Elena, Polo Oncologico, Via Elio Chianesi n. 53, 00144 Rome, Italy. Tel: +39-6-52666237 or +39-06-52666919; Fax: +39-06-52665637; E-mail: massimozeuli{at}tin.it Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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