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Response to Fixed-Dose Capecitabine in Advanced Colorectal Cancer Is Comparable to Body Surface Area Calculated Dosing

Response to Fixed-Dose Capecitabine in Advanced Colorectal Cancer Is Comparable to Body Surface Area Calculated Dosing

SYDNEY, Australia-Fixed-dose capecitabine (Xeloda) in advanced colorectal cancer patients allows ease of dosing with an acceptable toxicity profile and a response rate comparable to body surface area dosing. Furthermore, an assessment of serum thymidine and folate concentrations as predictors of toxicity determined that a high pretreatment concentration of serum folate is predictive of greater toxicity according to Rohini Sharma, MD, of Sydney Cancer Centre, Australia (ASCO abstract 573). The recommended dose of capecitabine (1,250 mg/m2 bid for 14 days of a 21 day cycle) produces an overall response rate of 25.7% in metastatic colorectal cancer, compared to a response rate of 16.7% for fluorouracil 425 mg/m2 plus leucovorin 20 mg/m2 days 1 to 5 every 4 weeks. As Dr. Sharma pointed out, however, "There is a lack of evidence for dose selection of capecitabine according to body surface area. Therefore, we studied the activity and toxicity profile of capecitabine given as a fixed dose of 2,000 mg bid. We also assessed potential predictors of toxicity." Pretreatment folate status correlates to the development of toxicity in patients treated with antifolates, but Dr. Sharma said that it is unknown whether this relationship also holds for capecitabine. The investigators evaluated the correlation between folate status and cytotoxicity and also assessed homocysteine and methylmalonic acid (MMA), sensitive surrogate markers for folate and B12 status. Lower Median Dose Eligibility criteria for the study included locally advanced or metastatic colorectal cancer with measurable or evaluable disease, Karnofsky performance status 0 to 2, fewer than two prior chemotherapy regimens, and a life expectancy greater than 12 weeks. Patients were treated with capecitabine 2,000 mg bid for 14 days followed by a 1-week break. Dose reduction by 1,000 mg per day was planned for any grade 2 or 3 toxicities. At the time of analysis, patients had completed a median number of five cycles of capecitabine for a median duration of therapy of 80.4 days. The median body surface area calculated dose was 63,000 mg. Therefore, patients received a median dose that was 11% lower than the body surface area calculated dose. Of the 51 patients enrolled in the study, 13 were excluded because they had been dosed in a standard fashion. An objective tumor response was seen in seven of the 33 patients (21%) assessable for response. Fixed-Dose Well Tolerated Dr. Sharma said, "Fixed-dose capecitabine was tolerated well with no grade 3/4 nonhematologic or hematologic toxicities recorded." A single dose reduction because of toxicity was required in 10 patients (26%). Multiple reductions were required in one patient (3%). Toxicity resulted in treatment delays in 13 patients (34%). Two patients (5%) ceased treatment because of toxicity. In terms of the assessment of possible predictors of toxicity, a high pretreatment serum folate was associated with increased toxicity (P = .004). No significant association was found between serum homocysteine or thymidine levels and toxicity. 'Particularly Attractive' "Fixed dosing is particularly attractive because it is difficult to split tablets. In addition, a BSA-calculated dose is difficult to precisely determine, and there is little evidence supporting such an approach," Dr. Sharma summarized. "Our study confirmed that fixed dosing has a comparable response rate to BSA dosing in patients with metastatic colorectal cancer and, importantly, this type of dosing was well tolerated. Fixed-dose capecitabine allows ease of dosing with an acceptable toxicity profile and a response rate similar to that found in phase III trials," she continued. "The second part of our study considered the role of serum markers as predictors for toxicity. A nonsustained fall in thymidine was noted during treatment, indicative of thymidylate synthase (TS) inhibition. A high pretreatment concentration of serum folate is predictive of greater toxicity. This finding has not been previously reported and we can only hypothesize that the basis for this may be increased suppression of TS and therefore increased toxicity," she added. "Finally," Dr. Sharma said, "our study addresses the role of TS genotype in a Caucasian and Chinese population and studies whether differences in toxicity can be predicted by differences in TS genotype. The results of this question are still pending and are awaited with great interest."

 
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