Multicenter Phase II Data Support Effectiveness of Capecitabine/Irinotecan in Metastatic Colorectal Cancer

BALTIMORE-"Replacing infusional5-FU with capecitabine in combinationwith irinotecan should be an effective,safe, and particularly convenientoption in the first-line treatment of metastaticcolorectal cancer," according toYehuda Z. Patt, MD. He reported resultsof a US multicenter phase II trial (ASCOabstract 1130) showing that the combinationof oral capecitabine (Xeloda) plusirinotecan (CPT-11, Camptosar), knownas XELIRI, offers chemotherapy-naive patients with metastatic colorectal cancer,efficacy and favorable safety comparableto IFL (irinotecan, fluorouracil, leucovorin)and FOLFIRI (fluorouracil, leucovorin,irinotecan).XELIRI also has the additional advantageof being more convenient to administerthan regimens using infusionalfluorouracil. Dr. Patt is chief of gastrointestinalmedical oncology, Universityof Maryland, Greenebaum Cancer Center,Baltimore.'Most Tolerable Fashion'Capecitabine is an oral fluoropyrimidinecarbamate, which generates 5-FUpreferentially in tumor tissue through exploitationof the increased expression ofthymidine phosphorylase in tumors. Accordingto Dr. Patt, the oral administrationof capecitabine enables chronic dosingschedules that mimic continuousinfusional 5-FU. "Capecitabine is designedto deliver high tumor concentrations of5-FU. Preclinical studies show that coadministrationof capecitabine and irinotecanleads to at least additive efficacy and ishighly curative in xenograft models," Dr.Patt said."This study tried to combine capecitabinewith irinotecan in the most tolerablefashion, trying to avoid the toxicitiesobserved with the IFL combination. Protractedinfusion of 5-FU seemed moreeffective and less toxic than bolus 5-FU,hence the selection of capecitabine," hecontinued. "Administering irinotecanevery 3 weeks as it is given in Europe wasalso less toxic, so that is the schedule thatwas chosen."Two independent phase I trials haveidentified the same recommended doseof XELIRI: irinotecan (250 mg/m² IV infusionon day 1) followed by intermittentoral capecitabine (1,000 mg/m² twice dailyfor 14 days) every 3 weeks, from eveningday 1 to morning day 15. In accord withguidelines recommending a 25% reductionin dose for elderly patients, a reduceddose was given to patients 65 years andolder. These patients received irinotecan200 mg/m² and oral capecitabine 750mg/m² twice daily.Locally Advanced orMetastatic DiseaseEligibility criteria included locally advancedand/or metastatic colorectal cancer;a Karnofsky performance status (KPS)greater than or equal to 70; a life expectancyof 3 months or more; measurable orevaluable disease in at least one nonirradiatedsite; no prior immunotherapy orchemotherapy for metastatic disease; andno adjuvant fluoropyrimidines during theprior 6 months. Patients must be at least18 years of age, and either less than 65years with good renal function, or equalto or greater than 65 years with moderaterenal impairment or better.Of the 52 patients enrolled in the study,the age ranged from 30 years to 79 years,with a median age of 58 years. The medianKPS was 90, with a range from 70 to 100.Thirty-eight patients (84%) had colon cancer,five rectal cancer (11%), and two hadboth (4%). Tumor differentiation was 13%poor, 64% moderate, 11% well, and 11%unknown. Twenty-seven percent of patientshad one site of metastatic disease,while 73% had metastatic disease at morethan one site. The liver was a site of metastasisin 77% of patients, and the lungwas a site of metastasis in 31%.Good Antitumor ActivityThe primary end point of the studywas response rate and the overall responserate was 42%. An additional 29% of patientsachieved stable disease, resulting ina disease control rate of 71%. Tumor assessmentswere at intervals of 6 weeks andat study withdrawal.The duration of treatment was basedon tumor response. For patients with completeor partial response, or stable disease,treatment was continued up to 12 cycles(36 weeks), or it could be longer at theinvestigator's discretion. In cases of progressivedisease, patients were withdrawnfrom the study. According to Dr. Patt, asubgroup analysis showed that XELIRIdemonstrated good antitumor activityeven in patients with a poor prognosis.The median time to disease progressionwas 7.1 months. "The efficacy ofXELIRI compares favorably with that ofIFL and FOLFIRI," Dr. Patt said. Theresponse rates are 42% vs 29% to 39%,respectively; the median time to diseaseprogression is 7.1 months vs 6.5 to 7.0months, respectively.Neutropenia Less CommonDuring the study, the majority of adverseevents were either mild or moderatein intensity. Most patients (80%) requireddose modification for management of adverseevents, but only 12 patients withdrewdue to adverse events. Notably, grade3/4 neutropenia was less common withXELIRI (22%) than with IFL (29%) orFOLFIRI (54%).Dr. Patt summarized the safety data bystating, "XELIRI demonstrated a predictable and manageable safety profile. Themajority of adverse events were grade 1 or2 in intensity, and most of the grade 4events were neutropenia without complications(16%)." There were no treatmentrelateddeaths.Based on the findings of the study, Dr.Patt concluded that "XELIRI is highly activeas a first-line treatment for metastaticcolorectal cancer. It achieved an objectivetumor response in 42% of patients, producedconsiderable activity in high-riskpatient subgroups, and exhibited a timeto disease progression of 7.1 months. It isat least comparable in efficacy and safetyto IFL and FOLFIRI."Important Implicationsfor Liver Tumor ResectionDr. Patt also pointed out, "The mostimportant observation from this study isthat in addition to reasonable toleranceand a relatively high response rate, sevenpatients became eligible for liver tumorresection. This highlights the notion thatwe are now in an era when surgical resectionof colorectal cancer liver metastaseshas to be considered in the multimodalitytreatment of patients with metastatic colorectalcancer."The intensified interest in surgical resectionof colorectal cancer liver metastaseswill be reflected in Dr. Patt's next study."We will investigate the ability of a combinationof capecitabine and oxaliplatin(Eloxatin) to bring about resectability,"he said, "and attempt to determine theoptimal postoperative chemotherapybased on preoperative response. Futuretrials should try to determine the optimalsequence of the combinations of capecitabineand the other two agents, irinotecanand oxaliplatin, either combined separatelyor in triplets."