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

BALTIMORE-"Replacing infusional 5-FU with capecitabine(Drug information on capecitabine) in combination with irinotecan(Drug information on irinotecan) should be an effective, safe, and particularly convenient option in the first-line treatment of metastatic colorectal cancer," according to Yehuda Z. Patt, MD. He reported results of a US multicenter phase II trial (ASCO abstract 1130) showing that the combination of oral capecitabine (Xeloda) plus irinotecan (CPT-11, Camptosar), known as XELIRI, offers chemotherapy-naive patients with metastatic colorectal cancer, efficacy and favorable safety comparable to IFL (irinotecan, fluorouracil(Drug information on fluorouracil), leucovorin) and FOLFIRI (fluorouracil, leucovorin, irinotecan). XELIRI also has the additional advantage of being more convenient to administer than regimens using infusional fluorouracil. Dr. Patt is chief of gastrointestinal medical oncology, University of Maryland, Greenebaum Cancer Center, Baltimore. 'Most Tolerable Fashion' Capecitabine is an oral fluoropyrimidine carbamate, which generates 5-FU preferentially in tumor tissue through exploitation of the increased expression of thymidine phosphorylase in tumors. According to Dr. Patt, the oral administration of capecitabine enables chronic dosing schedules that mimic continuous infusional 5-FU. "Capecitabine is designed to deliver high tumor concentrations of 5-FU. Preclinical studies show that coadministration of capecitabine and irinotecan leads to at least additive efficacy and is highly curative in xenograft models," Dr. Patt said. "This study tried to combine capecitabine with irinotecan in the most tolerable fashion, trying to avoid the toxicities observed with the IFL combination. Protracted infusion of 5-FU seemed more effective and less toxic than bolus 5-FU, hence the selection of capecitabine," he continued. "Administering irinotecan every 3 weeks as it is given in Europe was also less toxic, so that is the schedule that was chosen." Two independent phase I trials have identified the same recommended dose of XELIRI: irinotecan (250 mg/m² IV infusion on day 1) followed by intermittent oral capecitabine (1,000 mg/m² twice daily for 14 days) every 3 weeks, from evening day 1 to morning day 15. In accord with guidelines recommending a 25% reduction in dose for elderly patients, a reduced dose was given to patients 65 years and older. These patients received irinotecan 200 mg/m² and oral capecitabine 750 mg/m² twice daily. Locally Advanced or Metastatic Disease Eligibility criteria included locally advanced and/or metastatic colorectal cancer; a Karnofsky performance status (KPS) greater than or equal to 70; a life expectancy of 3 months or more; measurable or evaluable disease in at least one nonirradiated site; no prior immunotherapy or chemotherapy for metastatic disease; and no adjuvant fluoropyrimidines during the prior 6 months. Patients must be at least 18 years of age, and either less than 65 years with good renal function, or equal to or greater than 65 years with moderate renal 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 median KPS was 90, with a range from 70 to 100. Thirty-eight patients (84%) had colon cancer, five rectal cancer (11%), and two had both (4%). Tumor differentiation was 13% poor, 64% moderate, 11% well, and 11% unknown. Twenty-seven percent of patients had one site of metastatic disease, while 73% had metastatic disease at more than one site. The liver was a site of metastasis in 77% of patients, and the lung was a site of metastasis in 31%. Good Antitumor Activity The primary end point of the study was response rate and the overall response rate was 42%. An additional 29% of patients achieved stable disease, resulting in a disease control rate of 71%. Tumor assessments were at intervals of 6 weeks and at study withdrawal. The duration of treatment was based on tumor response. For patients with complete or partial response, or stable disease, treatment was continued up to 12 cycles (36 weeks), or it could be longer at the investigator's discretion. In cases of progressive disease, patients were withdrawn from the study. According to Dr. Patt, a subgroup analysis showed that XELIRI demonstrated good antitumor activity even in patients with a poor prognosis. The median time to disease progression was 7.1 months. "The efficacy of XELIRI compares favorably with that of IFL and FOLFIRI," Dr. Patt said. The response rates are 42% vs 29% to 39%, respectively; the median time to disease progression is 7.1 months vs 6.5 to 7.0 months, respectively. Neutropenia Less Common During the study, the majority of adverse events were either mild or moderate in intensity. Most patients (80%) required dose modification for management of adverse events, but only 12 patients withdrew due to adverse events. Notably, grade 3/4 neutropenia was less common with XELIRI (22%) than with IFL (29%) or FOLFIRI (54%). Dr. Patt summarized the safety data by stating, "XELIRI demonstrated a predictable and manageable safety profile. The majority of adverse events were grade 1 or 2 in intensity, and most of the grade 4 events were neutropenia without complications (16%)." There were no treatmentrelated deaths. Based on the findings of the study, Dr. Patt concluded that "XELIRI is highly active as a first-line treatment for metastatic colorectal cancer. It achieved an objective tumor response in 42% of patients, produced considerable activity in high-risk patient subgroups, and exhibited a time to disease progression of 7.1 months. It is at least comparable in efficacy and safety to IFL and FOLFIRI." Important Implications for Liver Tumor Resection Dr. Patt also pointed out, "The most important observation from this study is that in addition to reasonable tolerance and a relatively high response rate, seven patients became eligible for liver tumor resection. This highlights the notion that we are now in an era when surgical resection of colorectal cancer liver metastases has to be considered in the multimodality treatment of patients with metastatic colorectal cancer." The intensified interest in surgical resection of colorectal cancer liver metastases will be reflected in Dr. Patt's next study. "We will investigate the ability of a combination of capecitabine and oxaliplatin(Drug information on oxaliplatin) (Eloxatin) to bring about resectability," he said, "and attempt to determine the optimal postoperative chemotherapy based on preoperative response. Future trials should try to determine the optimal sequence of the combinations of capecitabine and the other two agents, irinotecan and oxaliplatin, either combined separately or in triplets."