Trials Suggest Capecitabine Might Be Simpler Substitute for 5-FU in Colorectal Cancer Regimens

GLASGOW, Scotland—"Development of capecitabine (Xeloda) was inspired by the fact that what is wanted is an oral tablet that will mimic infusional fluorouracil (5-FU) and will have tumor-selective activation. Clearly, about 90% of patients prefer oral therapy, but they do not want to sacrifice efficacy for convenience," Christopher Twelves, MD, stated. A number of recent clinical trials suggest that capecitabine might be a simpler substitute for 5-FU in colorectal cancer regimens and Dr. Twelves, a consultant in medical oncology at Cancer Research UK, Glasgow, Scotland, discussed this possibility at the First International Colorectal Cancer Congress in Palm Beach, Florida.

A phase III study compared single-agent capecitabine to the Mayo Clinic bolus 5-FU-based regimen in patients with metastatic colorectal cancer. Capecitabine was given at 1,255 mg/m² bid for 2 weeks on and 1 week off. The trial was powered to demonstrate equivalence, meaning that capecitabine was not any worse than standard therapy. The overall response rate (complete and partial response) was 26% with capecitabine vs 17% with 5-FU/leucovorin (P < .0002). "Response was also achieved earlier with capecitabine," Dr. Twelves said.

Toxicity analysis showed that 5-FU/leucovorin caused more stomatitis, and capecitabine caused more hand-foot syndrome (HFS). However, capecitabine was associated with a much lower need for hospitalization. The number of hospitalizations was 40 with capecitabine vs 49 with 5-FU/leucovorin (a decrease of 18.4%). The number of patients requiring hospitalization was 35/297 with capecitabine vs 47/295 with 5-FU/leucovorin, a decrease of 25.5%.

Capecitabine has been approved for first-line treatment of metastatic disease. Dr. Twelves said that it has high efficacy, superior response rate, improved overall survival, is better tolerated than previous regimens, and yields cost savings.

Combined With Oxaliplatin

Investigators next began to ask whether capecitabine might completely replace 5-FU in the treatment of colorectal cancer and whether capecitabine might be combined with oxaliplatin (Eloxatin), because each agent is active in this setting and there is no overlap in toxicities.

A capecitabine/oxaliplatin combination was tried as first-line treatment for metastatic colorectal cancer in a nonrandomized multicenter phase II trial of 96 patients. Overall response rate was 55% (95% CI 46%-95%). "There was a consistent response rate above 50% in all patient subgroups, including those with prior adjuvant chemotherapy and those with liver or lung metastases," Dr. Twelves said.

Median progression-free survival (PFS) is currently 7.6 months and 13 patients (14%) are still progression-free 12 months after the conclusion of the study. Overall survival at 1 year was 72%. Median survival has not yet been reached but is at least 16 months. (See updated results in the report on Dr. Edward Chu’s presentation.)

Compared to 5-FU-based regimens, capecitabine/oxaliplatin produced less neutropenia, more nausea and vomiting, more grade 3/4 HFS and about the same degree of diarrhea and stomatitis. "The rate of HFS was 3% in this trial, which was a decrease from the 16% seen in previous trials. That was probably due to the education of doctors and nurses regarding the importance of stopping therapy at the first sign of HFS and re-starting later after HFS resolves," Dr. Twelves said.

Other Combinations

Capecitabine and irinotecan (CPT-11, Camptosar) are also being studied in phase II trials as combination therapy for advanced colorectal cancer. These drugs have different mechanisms but some overlap in toxicities, particularly diarrhea. "The initial dose of irinotecan was 100 mg/m2, but this had to be reduced," Dr. Twelves said. "You really have to quite careful with doses in capecitabine/irinotecan combinations."

Capecitabine also shows promise for combination with radiotherapy. "Radiation induces thymidine phosphorylase, which might increase the activity of capecitabine at the tumor site," Dr. Twelves said. "A number of Phase I studies have been done with this combination, and it is promising. Patients like it because it is much simpler than receiving infusional 5-FU."

There is no definitive answer yet in regard to the question of whether capecitabine might generally replace 5-FU in colon cancer regimens, Dr. Twelves said. For metastatic colorectal cancer, he noted that randomized trial data show that monotherapy with capecitabine is as effective as bolus 5-FU, and preliminary data suggest that it might be as effective as 5-FU in combination with irinotecan, oxaliplatin, or radiotherapy.