XELIRI Shows Promise as First-Line Treatment for Advanced Colorectal Ca

March 2, 2005

This special “annual highlights” supplement to Oncology News International (ONI)is a compilation of selected news on important advances in the management ofgastrointestinal cancers over the past year, as reported in ONI. Guest Editor, Dr.James L. Abbruzzese, comments on the reports included herein and discussesdevelopments in the clinical management of GI cancers, with a look at the impactof targeted agents with cytotoxic chemotherapy, first-line and adjuvant therapies foradvanced disease, and the role of statins and COX-2 inhibitors in prevention.

NEW ORLEANS-Capecitabine(Xeloda) in combination withirinotecan (CPT-11, Camptosar) every3 weeks is highly active as first-linetreatment of metastatic colorectal cancer,even in older patients, two multicenterphase II investigations in theUS and in Spain have found.Investigators at the 40th AnnualMeeting of the American Society ofClinical Oncology reported responserates of 37% and 57%, along withmedian overall survival time of 15.9and 16.8 months, in the Spanish andAmerican studies, respectively (abstracts3610 and 3602).The toxicity profile of the regimen,sometimes referred to as XELIRI, wasmanageable and predictable for botholder and younger patients, investigatorssaid. Tolerability was "favorable,"with fewer serious toxicities comparedwith what others have reported foririnotecan-based regimens such as IFL(irinotecan, fluorouracil [5-FU], leucovorin[LV]) and FOLFIRI (5-FU,LV, irinotecan).The American Experience"XELIRI offers benefits to the patientin terms of efficacy, safety, convenience,reduced discomfort, andavoidance of central venous access"compared with infusional 5-FU/LVbasedregimens, said investigators inone study, a multicenter US trial including52 patients with metastaticcolorectal cancer.Development of XELIRI representsa "logical progression" from 5-FUbasedtherapy for metastatic colorectalcancer, according to US researchers,led by principal investigatorYehuda Z. Patt, MD, professor of medicineand chief of the AmbulatoryCenter and of the Gastrointestinal On-cology Program at the University ofMaryland Greenebaum CancerCenter, Baltimore."Twice-daily oral capecitabinemimics 5-FU infusion, and it is replacing5-FU in combination regimens,"said Dr. Patt and colleagues (abstract3602).The US trial evaluated first-lineXELIRI in 52 patients (29 male, medianKarnofsky performance status 90,median age 57.5 years [range, 30 to 79years]). Patients received the regimenin cycles repeated every 21 days for amaximum of 12 cycles. The startinghigher-dose consisted of capecitabine1,000 mg/m2 twice daily on days 1-14,plus irinotecan 250 mg/m2 IV infusionon day 1. Patients over the age of65 years and those exposed to priorirradiation were given capecitabine 750mg/m2 twice daily on days 1-14 plusirinotecan 200 mg/m2.Efficacy was assessed for 49 of 52patients. The overall response rate was57% (54% by intent-to-treat analy-sis). In addition, XELIRI was associatedwith a median time to progressionof 7.8 months (95% confidence interval[CI], 5.6-10) and median overallsurvival time of 16.8 months, the investigatorsreported.Predictable and manageable tolerabilitywas seen, with most adverseevents only grade 1 or 2 in intensity.The most common grade 3-4 eventswere neutropenia and diarrhea, occurringin 26% and 20% of patients,respectively. Grade 4 events representedjust 2.5% of all events, and therewere no treatment-related deaths.Notably, age did not affect the safetyof XELIRI, investigators said. Patientsover 65 years of age actually hadless vomiting compared with theiryounger counterparts, and less handfootsyndrome. (This adverse effectwas seen in less than 10% of patientsunder 65 years of age.) Elderly patientsdid have a higher rate of treatmentdiscontinuation owing to adverseevents (36% vs 11%), but therate of grade 3-4 events, including diarrhea,was similar in older and youngerpatients.A European PerspectiveThe high activity and favorable safetyof XELIRI in older patients wasconfirmed in a study by principal investigatorAlberto Muoz, MD, of theHospital de Cruces, Bilbao, Spain (abstract3610).This second study included 91 patientswith either locally advanced ormetastatic colorectal cancer. The patientpopulation in the Spanish trialwas older (median age, 67 vs 57.5years). However, a substantial proportionof patients in the US trial(27%) was 65 years of age or older."Irinotecan/capecitabine is an ac-tive first-line treatment of locally advancedor metastatic colorectal cancer,with a manageable toxicity profile,even in patients older than 65years," Dr. Muoz and colleagues saidin a poster presentation.Similar to the American study, theSpanish regimen studied consisted ofirinotecan 225 mg/m2 on day 1 andcapecitabine 1,000 mg/m2 twice dailyon days 2-15, every 21 days. Patientsolder than 65 years of age receivedreduced doses of both irinotecan (180mg/m2) and capecitabine (750 mg/m2twice daily). The 91 patients enrolled(median age, 67 years) received a totalof 575 cycles.The objective response rate was37% (95% CI, 27-47). Median progression-free survival time was 10.3months, and median overall survivaltime was 15.9 months. Grade 3-4 neutropeniaoccurred in 20% of patientsunder 65 years of age, and in 25% ofolder patients; grade 3-4 leukopeniaoccurred in 12% and 14% of youngerand older patients, respectively. Grade3-4 diarrhea occurred in 17% ofyounger patients and 31% of olderpatients.These results suggest capecitabine/irinotecan has potential as a replacementfor the irinotecan/5-FU combination,which the investigators describedas standard first-line therapyfor patients with metastatic colorectalcancer. A benefit of capecitabine isthat it "provides continuous fluoropyrimidineexposure without the inconvenienceof an infusional therapy,"they said.