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Capecitabine Has Unique Qualities That May Make It A Suitable Substitute for 5-FU

Capecitabine Has Unique Qualities That May Make It A Suitable Substitute for 5-FU

CHICAGO-The pharmacology of capecitabine (Xeloda) exhibits similarities to fluorouracil (5-FU) that make it a suitable substitute to 5-FU infusion, but capecitabine also has unique qualities that make it a distinct drug. These attributes include several pharmacologic effects, such as a selective effect that results in a higher concentration of 5-FU at the tumor, a potential for more effective interaction with several chemotherapy agents and radiation, and advantageous effects on genes involved in apoptosis and DNA repair. Furthermore, when capecitabine and radiation are combined, a relatively dramatic synergistic effect is achieved compared with the use of either alone. No such effect is observed with a combination of radiation and 5-FU. These conclusions were reported by Robert Diasio, MD, of the University of Alabama, Birmingham, at a symposium sponsored by Roche on integrating capecitabine in the management of colorectal cancer. Dr. Diasio listed several properties of capecitabine that distinguish it from 5-FU. "The compound has excellent bioavailability: it crosses the intestinal membrane and then is converted through a three-step activation process (see Figure 1). The third step involves thymidine phosphorylase (TP), which is present more in tumor than in normal tissue, and accounts for much of the selectivity of this drug," Dr. Diasio said. The goal in developing capecitabine was to create an agent that would work specifically at the tumor site, and thereby maximize antitumor activity and improve tolerability. "The oral drug capecitabine has many potential advantages. These benefits include generating 5-FU in both plasma and cells for a longer duration than IV bolus. Many of the complications associated with IV administration can be avoided when an oral drug is used; and oral drug administration is more convenient." When the mean ratio of 5-FU concentrations following capecitabine administration are assessed, results indicate a significant localization of 5-FU within the tumor compared with concentrations in healthy colon or rectal tissues or in plasma. "This indicates that capecitabine really gets to the point where you want it to be maximally present-within the tumor itself," Dr. Diasio said. "It is worth noting that the very important processes of apoptosis and DNA repair are affected by capecitabine," Dr. Diasio added. "One of capecitabine's most important attributes is that the activation of the drug can be upregulated by some of the other therapies that we use. A number of drugs have the ability to induce TP, and when they are used in combination with capecitabine, we achieve a selective effect in terms of upregulation." Rationale for XELOX Dr. Diasio also outlined the rationale for developing the XELOX regimen (capecitabine plus oxaliplatin [Eloxatin]) and some aspects that make this a desirable combination:

  • These two drugs have different molecular mechanisms of action.
  • A superior response rate and time to progression are observed with the addition of oxaliplatin to 5-FU/leucovorin
  • There are no overlaps in key toxicities.
  • There is evidence of synergistic activity beyond additive effects.
"Looking at xenograft studies, capecitabine alone or oxaliplatin alone has a similar effect, but both taken together (at two-thirds of the maximum tolerated dose) actually results in an effect that is beyond an additive effect alone-it is a super-additive effect," Dr. Diasio said. Combined With Radiation Radiation can also upregulate TP in tumor tissue and not in adjacent normal tissue, and it works specifically at the last selective enzymatic step in the activation process. "If we look at the effect of radiation on TP levels in the tumor, there is a dose-related effect even from a single dose of radiation therapy,"Dr. Diasio said. "This presents the possibility of minimizing radiation damage while increasing the chemotherapy effect. When we combine capecitabine and radiation therapy, we get a relatively dramatic effect compared with either one used alone. After 35 days, this achieves a level of change that is beyond super-additive; it is synergistic. There is not such an effect seen with radiation therapy and 5-FU." Dr. Diasio also notes that unlike 5-FU, capecitabine has a selective effect in terms of apoptosis. It inhibits Bcl2, a gene that blocks tumor cell death induced by the radiation and chemotherapy agents. Also, capecitabine has a greater effect than 5-FU in terms of inhibiting ERCC1, an important DNA repair gene that also blocks the effect of radiation and oxaliplatin. Investigating Properties Trials designed to further investigate the properties of capecitabine, particularly in combination regimens in the treatment of colorectal cancer were described by Leonard Saltz, MD, of Memorial Sloan- Kettering Cancer Center. He pointed out that phase I and II studies of capecitabinebased combinations in colorectal cancer show encouraging activity and a tolerable safety profile. However, at present there is no randomized phase III data regarding the use of capecitabine in combination with irinotecan (CPT-11, Camptosar), oxaliplatin (Eloxatin), or radiation therapy, and no phase III comparisons of capecitabine vs an infusional 5-FU regimen have been reported. CapOx vs FOLFOX Dr. Saltz discussed two studies comparing capecitabine/oxaliplatin (CapOx) to one of the FOLFOX regimens (fluorouracil/ leucovorin/oxaliplatin) as firstline therapy for colorectal cancer. A study supported by Roche is evaluating CapOx vs FOLFOX-4 among 1,000 patients. The primary objective is time to progression, and the secondary end points are overall survival, response rate, time to treatment failure, duration of response, tolerability, medical care use, and convenience. "This study will be looking at biomarkers and pharmacokinetics, and, to the degree that it can be obtained, pharmacogenetic analysis as well," Dr. Saltz said. A study from the Southwest Oncology Group (SWOG) will assess CapOx vs modified FOLFOX-6 (with 85 mg/m2 oxaliplatin). The study will involve a larger patient population (with an accrual goal of 1,730). The primary end point of the SWOG trial is overall survival. In addition, the two studies together will indirectly provide a comparison between FOLFOX-4 and the modified FOLFOX-6. The studies will be conducted in the United States, Europe, and elsewhere. FOLFIRI vs IFL vs CapIri A three-arm study is comparing FOLFIRI (fluorouracil, oxaliplatin, irinotecan) vs IFL on a 2-weeks on, 1-week off schedule vs CapIri (capecitabine, irinotecan). This study will look at whether giving IFL on a 2-week on, 1-week off basis will improve the tolerability of the regimen, and provide adequate efficacy. "The rationale is that if there is lower toxicity, patients may stay on the drug longer and then perhaps they will do better," Dr. Saltz said. "The 2-week on, 1-week off regimen will probably be easier on the patient. Whether it will also be easier on the tumor is something this trial will address." The X-ACT Study Other studies are investigating whether capecitabine should replace 5-FU/leucovorin in the adjuvant treatment of colon cancer. The X-ACT study is an open-label, multicenter, phase III trial evaluating capecitabine vs the Mayo Clinic bolus 5-FU/leucovorin schedule. Disease- free survival is the primary end point, and a primary objective is to demonstrate at least equivalence. Secondary end points include overall survival, safety, quality of life, health economics, and biochemical markers. This study opened in 1998 and reached its targeted recruitment goal with 1,987 patients in 164 centers in 25 countries. Safety data were presented at this year's American Society of Clinical Oncology annual meeting and efficacy data will be presented at next year's meeting. Capecitabine + Radiation for Treating Rectal Cancer Another study, the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 schema, is addressing the question of whether capecitabine should replace 5-FU/leucovorin in conjunction with radiation for rectal cancer. Patients with T3-4 operable rectal cancers will be stratified for various risk factors and will receive radiation therapy either with capecitabine or infusional protracted 5-FU. "What is a little disquieting," Dr. Saltz noted, "is that the dose limiting toxicity when the capecitabine was combined with radiation was hand-foot syndrome. This 'must give us pause.' The wrong thing to do is to adopt it routinely. The right thing to do is to conduct the trial." In summarizing, Dr. Saltz said, "There is extensive ongoing phase III testing of capecitabine-based combinations in colorectal cancer. Trials are going to be widely available. There won't be many people without access to the trials. And entrance to the trials should be strongly encouraged."
 
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