XELIRI Shows Promise as First-Line Treatment for Advanced Colorectal Cancers, US and Spanish Trials Report

September 1, 2004

The 30 reports in this special supplement to Oncology News International represent highlights of ongoing major clinical trials and new research presented at ASCO 2004 regarding state-of-the-art chemotherapeutic management of gastrointestinal and other cancers. Important developments in capecitabine as adjuvant therapy, novel targeted agents, and new combinations are discussed.

NEW ORLEANS-Capecitabine(Xeloda) in combination withirinotecan (CPT-11, Camptosar) every3 weeks is highly active as firstlinetreatment of metastatic colorectalcancer, even in older patients, twomulticenter phase II investigations inthe US and in Spain have found.Investigators 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 asXELIRI, was manageable and predictablefor both older and youngerpatients, investigators said. Tolerabilitywas "favorable," with fewer serioustoxicities compared with whatothers have reported for irinotecanbasedregimens such as IFL (irinotecan,fluorouracil [5-FU], leucovorin[LV]) and FOLFIRI (5-FU, LV, irinotecan)."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.The second study, undertaken byinvestigators in Spain, included 91patients with either locally advancedor metastatic colorectal cancer. Thepatient population 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.The American Experience
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 OncologyProgram at the University ofMaryland Greenebaum Cancer Center,Baltimore."Twice-daily oral capecitabinemimics 5-FU infusion, and it is replacing5-FU in combination regimens,"said Dr. Patt and colleagues in an ASCOposter presentation (abstract 3602).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 analysis).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 Perspective
The high activity and favorable safetyof XELIRI in older patients wasconfirmed in a study by principal investigatorAlberto Muoz, MD, of theHospital de Cruces, Bilbao, Spain(abstract 3610)."Irinotecan/capecitabine is an activefirst-line treatment of locally advancedor metastatic colorectal cancer,with a manageable toxicity profile,even in patients older than 65 years,"Dr. Muoz and colleagues said in aposter presentation.Similar to the American study, theregimen studied consisted of irinotecan225 mg/m2 on day 1 and capecitabine1,000 mg/m2 twice daily on days2-15, every 21 days. Patients older than65 years of age received reduced dosesof both irinotecan (180 mg/m2) andcapecitabine (750 mg/m2 twice daily).The 91 patients enrolled (median age,67 years) received a total of 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% of youngerpatients and 31% of older patients.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.