Capecitabine in Combination With Weekly Docetaxel Appears to Produce Higher Response Rates Than Docetaxel Alone

Oncology NEWS International Vol 12 No 8, Volume 12, Issue 8

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

COLUMBUS, Ohio-The combinationof capecitabine (Xeloda) andweekly docetaxel (Taxotere) is well toleratedand appears to produce higher responserates in previously treated non-small-cell lung cancer (NSCLC) patientsthan docetaxel alone. Progression-freesurvival using this combination regimenappears similar to the docetaxel regimen.Moreover, a preliminary finding thatmerits further investigation suggests thatimmunohistochemistry studies may predictresponse to treatment."These results encourage further evaluationof this regimen as a first-line treatmentin 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(5-FU) by a three-step enzymaticprocess. The final step of this process requiresthymidine phosphorylase (TP), apotent tumor-associated, angiogenesisfactor. TP is expressed at higher levels in tumors than in normal tissue, allowingfor the preferential conversion of capecitabinein neoplastic tissues. "Given theprominent role of TP in the therapeuticindex of capecitabine-based treatment,maximizing [tumor] TP activity wouldresult in an enhanced therapeutic index," Dr. Kindwall-Keller explained.Earlier Phase I Study ShowsEfficacy and Safety"Based on the preclinical observationthat TP is upregulated by docetaxel, weconducted a phase I study of docetaxel incombination with capecitabine," Dr.Kindwall-Keller said. "The high and predictablebioavailability of oral capecitabineand the preferential conversion ofthis tumor-targeted drug to 5-FU in neoplastictissues render capecitabine one ofthe most interesting fluoropyrimidines inclinical use."According to the study's investigators,TP is upregulated in cancer xenograftsafter treatment with docetaxel, which explainsthe prominent antitumor activity recently observed for the combination ofdocetaxel and capecitabine. The phase Istudy pursued the hypothesis that weeklyadministration of docetaxel, as well ascapecitabine administration at times ofmaximum TP upregulation, would enhancethe therapeutic index of this combination."In view of a preliminary finding ofefficacy and a good safety profile in thephase I study, we decided to further evaluatethis regimen in previously treatedpatients with NSCLC in the phase IIstudy," Dr. Kindwall-Keller said.Outpatient SettingIn the phase II trial, treatment wasadministered in an outpatient setting.Docetaxel 36 mg/m2 was administeredintravenously weekly for 3 weeks (days 1,8, and 15) of each 4-week period. Capecitabine625 mg/m2 orally twice daily wasstarted on day 5 of every cycle and continuedfor 14 days. Patients were instructedto take 8 mg of oral dexamethasone 12hours prior to the docetaxel infusion, immediatelyprior to the docetaxel infusion,and again 12 hours after the docetaxelinfusion on treatment weeks. Prophylacticgrowth factor therapy (G-CSF, GMCSF,and erythropoietic agents) was notpermitted.Of the 39 eligible patients who enrolledin the study, 36 were evaluable. Allpatients had relapsed or refractory NSCLCand had been previously treated with atleast one but not more than two platinum-based or paclitaxel-based chemotherapyregimens. To be eligible, patientswere required to have pathologically orcytologically confirmed advanced NSCLC,and could not have received cytotoxicchemotherapy for at least 28 days prior tostarting this chemotherapy regimen. Patientswere also required to have an EasternCooperative Oncology Group(ECOG) performance status of 0, 1, or 2and a predicted life expectancy of at least12 weeks. Patients had to have adequateorgan function and no serious active infections,and be free of another malignancyfor more than 5 years, with the exceptionof basal cell or squamous cell skincancer or carcinoma in situ of the cervix.Patients were excluded if they werepregnant or were lactating, were less than18 years of age, or had a known brain orleptomeningeal disease, unless those lesions had no associated clinical symptomsand had been previously irradiated.Patients who had an acute myocardialinfarction within 6 months, congestiveheart failure requiring therapy, unstableangina, uncontrolled diabetes mellitus definedas a random blood sugar greaterthan 250 mg/dL, or a baseline correctedserum calcium greater than 11.5 mg/dLwere also excluded. Overall Response 25%A total of 39 patients (20 female, 19male) were enrolled in the study. Themedian age was 61. Twenty-five patients(64%) had received one prior regimen,and 14 (36%) had received two prior regimens.Time to progression ranged from1 to 13+ months. None of the 36 evaluablepatients experienced a complete response,but 25% had partial responses, 3% hadminor responses, and 17% had stabledisease. The overall response rate was 25%and the progression-free survival rate at6 months was 19%. Median time to diseaseprogression was 53.5 days. Diseaseprogression was experienced by 56%.Frequent grade 3/4 toxicity includedfatigue (22%), mucositis (17%), neutropenia(14%), and thrombotic episodes(9%). Eight patients required dose reductionsof capecitabine (one), docetaxel(one), or both (six).Dr. Kindwall-Keller concludes fromthe study that the combination of docetaxeland capecitabine appears to be welltolerated with relatively little toxicity,which is easily managed with dose modificationsand supportive care. The 6-month progression-free survival rate withthe combination appears to be similar tothe rate seen with every 3-week dosing ofdocetaxel. "The relatively high responserate observed in this group of patients,the majority of whom had received priortaxanes, is encouraging and warrants evaluationof this regimen as first-line treatmentin NSCLC," says Dr. Kindwall-Keller.The immunohistochemistry studiessuggest the possibility that thymidinephosphorylase tumor/normal ratios bycellular compartment may predict responseto treatment. Additional patientsare required to further investigate thesepreliminary findings.