Phase II Study of Capecitabine and Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer

Abstract & Commentary

Synopsis: Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer; therefore, the capecitabine dose we used 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-naive advanced colorectal cancer patients.

Source: Zeuli M, et al. Ann Oncol. 2003;14:1378-1382.

There is a need for more effective and less toxic therapy for patients with metastatic colorectal cancer. 5-fluorouracil is still one of the most important drugs in the treatment of both adjuvant and metastatic disease. Continuous infusion has been shown to be superior to intravenous bolus injection. The limitation of the infusion has been the cost, inconvenience, discomfort, and potential risks of the need for an indwelling central venous catheter. Oxaliplatin has entered clinical practice with the demonstration of its efficacy with a number of infusional regimens.1 It has already been demonstrated that capecitabine is superior to bolus 5-fluorouracil/leucovorin in the treatment of metastatic colorectal cancer.2 It has been incorporated in the regimens with oxaliplatin as a substitute for the infusional 5-fluorouracil component.3 The present study expands this experience and the search for the optimal dose of this combination.

Comment by Stuart M. Lichtman, MD, FACP

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. All patients were required to have World Health Organization performance status (PS) < 2, aged between 18 and 75 years, life expectancy > 12 weeks. The regimen consisted of capecitabine 2500 mg/m2/d in combination with oxaliplatin 120 mg/m2. Twenty-nine patients had primary colon, and 14 had rectal cancer. A total of 211 cycles of chemotherapy was delivered with a median of 5 cycles per patient (range, 1-11). 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 5-fluorouracil/leucovorin regimen and 3 with the de Gramont regimen and 4 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 1 site of disease, 13 (30%) had 2 sites and 5 (12%) had 3 or more. The toxicity of the regimen peaked in the first three cycles and was then reduced in the following cycles because of dose modifications. 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 3 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 3 cycles of treatment. Laryngospasm during the oxaliplatin infusion was observed in 2 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. Hematological toxicity was moderate. Grade 3 neutropenia occurred in 2 patients, but 1 case of life-threatening febrile neutropenia was reported. One patient had uncomplicated thrombocytopenia grade 4. Mild anemia occurred in 12 patients. The response rates were 44% and 48.7% (95% CI, 33.0-64.4%) (intention-to-treat and per protocol analysis, respectively). The median overall survival was 20 months.

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 nonpretreated patients compares well with the 50.7-53% objective responses observed with oxaliplatin plus continuous infusion fluorouracil/leucovorin in first-line treatment. Besides efficacy, toxicity is a critical end point with which to assess the benefit of a new treatment combination. In this study, Zeuli and colleagues attempted to use the drugs in combinations in the same doses that are recommended for single-agent therapy. This may have been too high, particularly for the capecitabine. 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. A recent trial has been reported with dosing recommendations of capecitabine in combination with oxaliplatin 130 mg/m2 at an initial dose of 1250 mg/m2 2 times daily in untreated patients and at a dose of 1000 mg/m2 2 times daily in pretreated patients.4 In elderly patients, similar efficacy was seen with lower doses of oxaliplatin (85-100 mg/m2) and capecitabine 1000 mg/m2 2 times daily.5 Phase III trials are needed to clarify the role of the combination of capecitabine and oxaliplatin in the treatment of patients with advanced colorectal cancer. The dose of both oxaliplatin and capecitabine need to be further clarified. Studies are particularly important in previously treated patients, the elderly and those with a poor performance status.

Dr. Lichtman, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.


1. de Gramont A, et al. J Clin Oncol. 2000;18:2938-2947.

2. Hoff PM, et al. J Clin Oncol. 2001;19:2282-2292.

3. Diaz-Rubio E, et al. Ann Oncol. 2002;13:558-565.

4. Borner MM, et al. J Clin Oncol. 2002;20:1759-1766.

5. Carreca I, et al. Proc Annu Meet Am Soc Clin Oncol. 2003:2939a.