COLUMBUS, Ohio-The combination of capecitabine(Drug information on capecitabine) (Xeloda) and weekly docetaxel(Drug information on docetaxel) (Taxotere) is well tolerated and appears to produce higher response rates in previously treated non- small-cell lung cancer (NSCLC) patients than docetaxel alone. Progression-free survival using this combination regimen appears similar to the docetaxel regimen. Moreover, a preliminary finding that merits further investigation suggests that immunohistochemistry studies may predict response to treatment. "These results encourage further evaluation of this regimen as a first-line treatment in NSCLC," stated Tamila L. Kindwall- Keller, DO, of Ohio State University, Columbus, who reported these findings (ASCO abstract 2601). Capecitabine is a fluoropyrimidine that is converted to its active metabolite fluorouracil(Drug information on fluorouracil) (5-FU) by a three-step enzymatic process. The final step of this process requires thymidine phosphorylase (TP), a potent tumor-associated, angiogenesis factor. TP is expressed at higher levels in tumors than in normal tissue, allowing for the preferential conversion of capecitabine in neoplastic tissues. "Given the prominent role of TP in the therapeutic index of capecitabine-based treatment, maximizing [tumor] TP activity would result in an enhanced therapeutic index," Dr. Kindwall-Keller explained. Earlier Phase I Study Shows Efficacy and Safety "Based on the preclinical observation that TP is upregulated by docetaxel, we conducted a phase I study of docetaxel in combination with capecitabine," Dr. Kindwall-Keller said. "The high and predictable bioavailability of oral capecitabine and the preferential conversion of this tumor-targeted drug to 5-FU in neoplastic tissues render capecitabine one of the most interesting fluoropyrimidines in clinical use." According to the study's investigators, TP is upregulated in cancer xenografts after treatment with docetaxel, which explains the prominent antitumor activity recently observed for the combination of docetaxel and capecitabine. The phase I study pursued the hypothesis that weekly administration of docetaxel, as well as capecitabine administration at times of maximum TP upregulation, would enhance the therapeutic index of this combination. "In view of a preliminary finding of efficacy and a good safety profile in the phase I study, we decided to further evaluate this regimen in previously treated patients with NSCLC in the phase II study," Dr. Kindwall-Keller said. Outpatient Setting In the phase II trial, treatment was administered in an outpatient setting. Docetaxel 36 mg/m2 was administered intravenously weekly for 3 weeks (days 1, 8, and 15) of each 4-week period. Capecitabine 625 mg/m2 orally twice daily was started on day 5 of every cycle and continued for 14 days. Patients were instructed to take 8 mg of oral dexamethasone(Drug information on dexamethasone) 12 hours prior to the docetaxel infusion, immediately prior to the docetaxel infusion, and again 12 hours after the docetaxel infusion on treatment weeks. Prophylactic growth factor therapy (G-CSF, GMCSF, and erythropoietic agents) was not permitted. Of the 39 eligible patients who enrolled in the study, 36 were evaluable. All patients had relapsed or refractory NSCLC and had been previously treated with at least one but not more than two platinum- based or paclitaxel(Drug information on paclitaxel)-based chemotherapy regimens. To be eligible, patients were required to have pathologically or cytologically confirmed advanced NSCLC, and could not have received cytotoxic chemotherapy for at least 28 days prior to starting this chemotherapy regimen. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 and a predicted life expectancy of at least 12 weeks. Patients had to have adequate organ function and no serious active infections, and be free of another malignancy for more than 5 years, with the exception of basal cell or squamous cell skin cancer or carcinoma in situ of the cervix. Patients were excluded if they were pregnant or were lactating, were less than 18 years of age, or had a known brain or leptomeningeal disease, unless those lesions had no associated clinical symptoms and had been previously irradiated. Patients who had an acute myocardial infarction within 6 months, congestive heart failure requiring therapy, unstable angina, uncontrolled diabetes mellitus defined as a random blood sugar greater than 250 mg/dL, or a baseline corrected serum calcium greater than 11.5 mg/dL were also excluded. Overall Response 25% A total of 39 patients (20 female, 19 male) were enrolled in the study. The median age was 61. Twenty-five patients (64%) had received one prior regimen, and 14 (36%) had received two prior regimens. Time to progression ranged from 1 to 13+ months. None of the 36 evaluable patients experienced a complete response, but 25% had partial responses, 3% had minor responses, and 17% had stable disease. The overall response rate was 25% and the progression-free survival rate at 6 months was 19%. Median time to disease progression was 53.5 days. Disease progression was experienced by 56%. Frequent grade 3/4 toxicity included fatigue (22%), mucositis (17%), neutropenia (14%), and thrombotic episodes (9%). Eight patients required dose reductions of capecitabine (one), docetaxel (one), or both (six). Dr. Kindwall-Keller concludes from the study that the combination of docetaxel and capecitabine appears to be well tolerated with relatively little toxicity, which is easily managed with dose modifications and supportive care. The 6- month progression-free survival rate with the combination appears to be similar to the rate seen with every 3-week dosing of docetaxel. "The relatively high response rate observed in this group of patients, the majority of whom had received prior taxanes, is encouraging and warrants evaluation of this regimen as first-line treatment in NSCLC," says Dr. Kindwall- Keller. The immunohistochemistry studies suggest the possibility that thymidine phosphorylase tumor/normal ratios by cellular compartment may predict response to treatment. Additional patients are required to further investigate these preliminary findings.