Asian Study Suggests Combination of Docetaxel/Capecitabine Active in Chemonaive Patients With Advanced Non–Small-Cell Lung Cancer

GOYANG, Korea-Docetaxel(Taxotere) and capecitabine (Xeloda)combination therapy is active in chemonaivepatients with advanced non-smallcelllung cancer (NSCLC). The regimen,however, was frequently associated withsignificant nonhematologic toxicities, suggestinga clinical synergism in terms ofboth efficacy and toxicity. Ji-Youn Han,MD, PhD, Center for Lung Cancer, NationalCancer Center, Goyang, Korea, reportedthese findings (ASCO abstract2691)."Cisplatin-based chemotherapy is currentlyconsidered the standard treatmentfor advanced NSCLC. However, cisplatincauses considerable toxicities, which hasgenerated interest in identifying a chemotherapyregimen that is less toxic," Dr.Han said in explaining the rationale forconducting the phase II study. "Recently,a number of combinations of new agentsactive in NSCLC were introduced and theyyield a better efficacy-toxicity ratio."Capecitabine is an oral fluoropyrimidinecarbamate, which was rationally designedto generate fluorouracil (5-FU)preferentially in tumor tissue by thymidinephosphorylase (TP). High expressionof TP is frequently observed in manymalignancies including NSCLC."Although the antitumor activity ofcapecitabine has not been evaluated inNSCLC, the relatively high expression ofTP in NSCLC provides a rationale for theuse of capecitabine in NSCLC patients,"Dr. Han said.Synergistic Interaction"Furthermore, preclinical studies ofhuman breast and colon cancer xenograftmodels demonstrated that docetaxel wasmore active in combination with capecitabinethan with 5-FU or UFT (uracil andtegafur). This in vivo synergistic activitywas dependent on docetaxel-induced upregulationof TP."Recently a phase III study demonstratedthat capecitabine/docetaxel combinationtherapy was more effective thansingle-agent docetaxel in anthracyclinepretreatedpatients with advanced breastcancer. The significantly superior time toprogression and median survival wasachieved with the addition of capecitabineto docetaxel; however, toxicity was considerable."The more favorable toxicity profile ofweekly docetaxel and the time-dependentcharacter of docetaxel-mediated upregulationof TP provide the rationale for thecombination of weekly docetaxel andcapecitabine," Dr. Han noted. She addedthat the results of the phase I study of a weekly docetaxel and capecitabine combinationin patients with advanced NSCLC"provide additional supporting data of asynergistic interaction between docetaxeland capecitabine."No Complete ResponsesPatient eligibility for the study requiredstage IIIB or IV NSCLC, bidimensionallymeasurable disease and Eastern Cooperative Oncology Group (ECOG) performancestatus 2. Patients could have noprior chemotherapy or radiation therapy,unless the irradiated area was not the onlysource of measurable disease; an estimatedlife expectancy of at least 12 weeks; andadequate hematologic function.Treatment consisted of docetaxel 36mg/m² IV on day 1 and 8 plus capecitabine1,000 mg/m² po bid on days 1 to 14 ofa 21-day cycle, for a maximum of sixcycles. Premedication with oral dexamethasone8 mg was given 12 hours beforeand again immediately before docetaxel,as well as 12 hours after docetaxel. Of 39 patients enrolled, all were evaluatedfor toxicity and 36 for response. Overallresponse rate was 53%, including 19partial responses, but no complete response.Median duration of response was6.2 months (range 2.1-12.4 months). Atfollow-up (median of 10.3 months), 13patients died. The estimated 1-year survivalrate was 61%, and there were twotreatment-related deaths, one pneumoniaand one sepsis.Hematologic toxicity was mild to moderate,although grade 3/4 neutropenia occurredin 13% of patients. Grade 2/3 nonhematologictoxicities were frequent,including asthenia (51%), stomatitis(33%), hand-foot syndrome (33%), anddiarrhea (29%)."This regimen is attractive because ofits relatively high response rate and itsconvenient outpatient administration,"Dr. Han said. "However, it was frequentlyassociated with moderate to severe nonhematologictoxicities, suggesting clinicalsynergism in terms of not only efficacy,but also of toxicity. Further adjustment ofthe dose-schedule is recommended tomaximize the therapeutic index of thisregimen in chemonaive advanced NSCLCpatients."