Capecitabine (Xeloda ®) an Alternative in Post-Surgery Treatment of Stage III Colon CancerKey Words
Colon cancer, capecitabine (Xeloda®), 5-FU, leucovorin. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
After surgery to remove their tumors, patients with stage III colon cancer who took pills containing the drug capecitabine (Xeloda®) survived about as long without relapse, and with more tolerable side effects, as those treated with a bolus injection of chemotherapy consisting of fluorouracil (5-FU) plus leucovorin. These results suggest that capecitabine, delivered at the doses given in this study, is an effective alternative for some patients.
Source
New England Journal of Medicine, June 30, 2005 (see the journal abstract).
Background
In 2005, more than 56,000 people are expected to die from colorectal cancer. However, if caught early enough – before it has had a chance to spread from the bowels, surgery will cure about half of all patients with colon cancer. If the cancer has spread to nearby lymph nodes but no further (stage III), surgery is followed by adjuvant chemotherapy to prevent recurrence.
The antimetabolite fluoropyrimidine drug called fluorouracil (5-FU is the most common form) has long been a primary agent in colorectal cancer management. In recent years, doctors have added leucovorin to 5-FU in order to increase its antitumor effects. Other agents combined with this 5-FU plus leucovorin regimen are proving even more beneficial. Recurrence is often the ultimate cause of death, though advances in chemotherapy that include the addition of oxaliplatin to intravenous (by injection) infusional 5-FU and leucovorin have pushed the four-year overall survival rate to nearly 80 percent.
Because patients differ in what they can tolerate, another important variable is how the drugs are administered. Three alternatives are: by mouth, in pill form; by an infusional pump that dispenses the medicine continuously over as much as 48 hours; or by a bolus infusion, where a single dose may be injected into a blood vessel within about an hour.
Like 5-FU, capecitabine is also an antimetabolite fluoropyrimidine, but it can be given as a pill. It was approved by the U.S. Food and Drug Administration in 2001 as an initial treatment for metastatic colorectal cancer when treatment with fluoropyrimidine therapy alone is preferred.
The Study
Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) is a phase III randomized trial to determine whether oral capecitabine could achieve equivalent disease-free survival rates to bolus 5-FU plus leucovorin, and also to assess the side effects in patients with stage III colon cancer.
Researchers from an international team enrolled 1,987 patients from 164 centers worldwide between 1998 and 2001. Patients joined after surgery for stage III colon cancer; they were excluded if they had any evidence of disease spread (metastasis) and included if they were expected to live at least five years. Patients were randomly assigned to receive either capecitabine or bolus 5-FU and leucovorin for a total of 24 weeks, and then followed to get a measure of their “disease-free survival,” defined as any disease recurrence, a second primary colon cancer (that is, a new colon tumor unrelated to the first one), or death. Severe (grade 3 or 4) and lesser side effects were also recorded.
The study’s lead author is Chris Twelves, M.D., from the University of Glasgow, United Kingdom. The trial was sponsored by the drug’s manufacturer, Hoffmann-La Roche, Inc.
Results
At a median follow-up of 3.8 years, 348 of 1,004 patients who took capecitabine experienced a recurrence of their disease, compared to 380 of 983 who took 5-FU plus leucovorin. Also, 27 fewer people in the capecitabine group died. The results were not statistically strong enough to prove capecitabine was superior in terms of disease-free survival, but they did show that the pill was at least as good as this particular regimen of 5-FU plus leucovorin.
The capecitabine group also had significantly fewer adverse events in most categories, especially diarrhea, nausea, mouth sores, and low white blood cell counts. They had significantly more severe occurrences of hand-foot syndrome, where pain, swelling, numbness and tingling occur; and also hyperbilirubinemia, where jaundice can develop when too many red blood cells are destroyed.
Limitations
The bolus 5-FU plus leucovorin regimen used in this trial was an appropriate standard at the time this trial was started, said Margaret Mooney, M.D., a surgical oncologist with the National Cancer Institute’s Cancer Therapy Evaluation Program. However, recent results from other adjuvant colon cancer trials, she said, have shown that “the addition of oxaliplatin to either an infusional or bolus intravenous regimen of 5-FU plus leucovorin significantly prolongs disease-free survival compared to 5-FU plus leucovorin alone.” It is not yet known whether capecitabine can replace 5-FU plus leucovorin in the newer multiagent regimens that include oxaliplatin.
While in this trial, capecitabine’s side effects were generally less severe compared to 5-FU plus leucovorin, the starting dose of capecitabine that was tested in the trial (1250 mg per square meter of body-surface area, twice a day) appears not to be well tolerated by patients in the United States. The reasons for this “are not entirely clear,” said Mooney, “and the outcome of this trial may not apply to other doses since the same results might not be seen if lower starting doses are used.”
Comments
In an accompanying editorial, Carmen Allegra, M.D., and Daniel J. Sargent, Ph.D., wrote that it is not known whether capecitabine should replace intravenous 5-FU plus leucovorin in multiagent regimens commonly used in the United States that include oxaliplatin. Nonetheless, capecitabine “is an excellent choice when single-agent therapy is desired, provided that the treating physician is comfortable using the starting dose reported in the present investigation.”
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