First- or Second-line Oxaliplatin Combinations with Capecitabine

FOLFOX regimens typically require infusional therapy over two days every two weeks, whereas XELOX regimens involve one two-hour infusion every three weeks. There is growing evidence that the oral fluoropyrimidine capecitabine can effectively substitute for bolus or infusional schedules of 5-FU/LV in combination with oxaliplatin in the metastatic setting.

Borner and colleagues reported objective response rates of 49% and 15% in first- and second-line treatment, respectively, and median overall survival rates of 17.5 months and 11.5 months, respectively.³⁹ The main side- effect was grade 3/4 diarrhea (35% in first-line and 50% in second-line treatment),which resulted in 26% and 50% dose reductions, respectively. Of note, this toxicity was largely prevented in cycles two through four through appropriate dose reductions. Scheithauer et al. conducted a study in 89 patients with advanced CRC using a dose- intensified bi-monthly schedule for capecitabine (3,500mg/m2 days one to seven and 14-21) plus oxaliplatin (85mg/m2 days one and 14) every four weeks versus a conventional dose regimen.40 Patients receiving high-dose therapy had a higher response rate (54.5% versus 42.2%) and a significantly longer median progression-free survival time than those receiving the conventional dose (10.5 versus 6.0 months; P=00013). The safety profile was similar to that observed with the lower-intensity regimen – diarrhea was the most frequent side-effect, but in general, it was well controlled.

van Cutsem et al. conducted a large Phase II multicenter international study investigating the XELOX regimen.⁴¹ The dosing regimen of capecitabine 1,000mg/m2 bid (days one to 14), plus 130mg/m2 intravenously (day one) every three weeks, yielded an overall response rate of 55% – similar to that observed with infusional 5-FU/LV plus oxaliplatin. Importantly, median overall survival was compelling at 19.5 months. The adverse events most frequently leading to dose reductions were gastrointestinal side-effects, myelo- suppression, and neurotoxicity. The findings from this study, together with those previously summarized, indicate that the XELOX regimen is effective and well tolerated as first-line treatment for patients with metastatic CRC.

XELOX Versus XELIRI

In a Phase II randomized setting, Grothey et al directly compared XELOX with XELIRI as first- and second- line therapy in patients with advanced CRC.⁴² Preliminary efficacy data presented at ASCO 2003 and updated at ASCO 2004 showed a slightly higher response rate with first-line XELOX than with XELIRI (51.3% versus 42.6%),and progression-free survival of 7.9 months in both arms.In the first phase of the study,an unexpected number of early deaths in the XELIRI arm led to a reduction of the irinotecan dose. However, reduction of the irinotecan dose from 100mg/m2 to 80mg/m² did not impair the clinical efficacy of the XELIRI combination (response rate, 41.7% before and 43.8% after dose reduction).Grade 3/4 hematologic and non-hematologic toxicities were generally similar with XELOX and XELIRI therapy. Diarrhea was the most frequently reported grade 3/4 toxicity in both groups, occurring in 12.7% and 13.6% of XELOX- and XELIRI-treated patients, respectively. Grade 2 alopecia occurred more frequently in XELIRI-treated patients (13.9% versus 7.4%), and grade 2/3 sensory neuropathy occurred more frequently in XELOX-treated patients (6.2% versus 1.3%).As second-line therapy, response rates were slightly higher with XELIRI when compared with XELOX (19% versus 12%).

Novel Targeted Agents in the Treatment of Advanced CRC

The significant advances in molecular oncology have generated tremendous interest in the development of targeted therapies for solid tumors. Such agents are designed to modulate, inhibit, and interfere with the function of specific molecular targets that are essential to the malignancy of tumors. The agents with the greatest interest in CRC are the monoclonal antibodies bevacizumab and cetuximab.