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

NEW ORLEANS-Capecitabine (Xeloda) in combination with irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) every 3 weeks is highly active as firstline treatment of metastatic colorectal cancer, even in older patients, two multicenter phase II investigations in the US and in Spain have found. Investigators reported response rates of 37% and 57%, along with median overall survival time of 15.9 and 16.8 months, in the Spanish and American studies, respectively (abstracts 3610 and 3602). The toxicity profile of the regimen, sometimes referred to as XELIRI, was manageable and predictable for both older and younger patients, investigators said. Tolerability was "favorable," with fewer serious toxicities compared with what others have reported for irinotecanbased regimens such as IFL (irinotecan, fluorouracil(Drug information on fluorouracil) [5-FU], leucovorin [LV]) and FOLFIRI (5-FU, LV, irinotecan). "XELIRI offers benefits to the patient in terms of efficacy, safety, convenience, reduced discomfort, and avoidance of central venous access" compared with infusional 5-FU/LVbased regimens, said investigators in one study, a multicenter US trial including 52 patients with metastatic colorectal cancer. The second study, undertaken by investigators in Spain, included 91 patients with either locally advanced or metastatic colorectal cancer. The patient population in the Spanish trial was older (median age, 67 vs 57.5 years). However, a substantial proportion of patients in the US trial (27%) was 65 years of age or older. The American Experience
Development of XELIRI represents a "logical progression" from 5-FUbased therapy for metastatic colorectal cancer, according to US researchers, led by principal investigator Yehuda Z. Patt, MD, professor of medicine and chief of the Ambulatory Center and of the Gastrointestinal Oncology Program at the University of Maryland Greenebaum Cancer Center, Baltimore. "Twice-daily oral capecitabine(Drug information on capecitabine) mimics 5-FU infusion, and it is replacing 5-FU in combination regimens," said Dr. Patt and colleagues in an ASCO poster presentation (abstract 3602). The US trial evaluated first-line XELIRI in 52 patients (29 male, median Karnofsky performance status 90, median age 57.5 years [range, 30 to 79 years]). Patients received the regimen in cycles repeated every 21 days for a maximum of 12 cycles. The starting higher-dose consisted of capecitabine 1,000 mg/m² twice daily on days 1-14, plus irinotecan 250 mg/m² IV infusion on day 1. Patients over the age of 65 years and those exposed to prior irradiation were given capecitabine 750 mg/m² twice daily on days 1-14 plus irinotecan 200 mg/m². Efficacy was assessed for 49 of 52 patients. The overall response rate was 57% (54% by intent-to-treat analysis). In addition, XELIRI was associated with a median time to progression of 7.8 months (95% confidence interval [CI], 5.6-10) and median overall survival time of 16.8 months, the investigators reported. Predictable and manageable tolerability was seen, with most adverse events only grade 1 or 2 in intensity. The most common grade 3/4 events were neutropenia and diarrhea, occurring in 26% and 20% of patients, respectively. Grade 4 events represented just 2.5% of all events, and there were no treatment-related deaths. Notably, age did not affect the safety of XELIRI, investigators said. Patients over 65 years of age actually had less vomiting compared with their younger counterparts, and less handfoot syndrome. (This adverse effect was seen in less than 10% of patients under 65 years of age.) Elderly patients did have a higher rate of treatment discontinuation owing to adverse events (36% vs 11%), but the rate of grade 3/4 events, including diarrhea, was similar in older and younger patients. A European Perspective
The high activity and favorable safety of XELIRI in older patients was confirmed in a study by principal investigator Alberto Muñoz, MD, of the Hospital de Cruces, Bilbao, Spain (abstract 3610). "Irinotecan/capecitabine is an active first-line treatment of locally advanced or metastatic colorectal cancer, with a manageable toxicity profile, even in patients older than 65 years," Dr. Muñoz and colleagues said in a poster presentation. Similar to the American study, the regimen studied consisted of irinotecan 225 mg/m² on day 1 and capecitabine 1,000 mg/m² twice daily on days 2-15, every 21 days. Patients older than 65 years of age received reduced doses of both irinotecan (180 mg/m²) and capecitabine (750 mg/m² twice daily). The 91 patients enrolled (median age, 67 years) received a total of 575 cycles. The objective response rate was 37% (95% CI, 27-47). Median progression- free survival time was 10.3 months, and median overall survival time was 15.9 months. Grade 3/4 neutropenia occurred in 20% of patients under 65 years of age, and in 25% of older patients; grade 3/4 leukopenia occurred in 12% and 14% of younger and older patients, respectively. Grade 3/4 diarrhea occurred in 17% of younger patients and 31% of older patients. These results suggest capecitabine/ irinotecan has potential as a replacement for the irinotecan/5-FU combination, which the investigators described as standard first-line therapy for patients with metastatic colorectal cancer. A benefit of capecitabine is that it "provides continuous fluoropyrimidine exposure without the inconvenience of an infusional therapy," they said.