Phase I/II Trial of Dose-Reduced Capecitabine in Elderly Patients with Advanced Colorectal Cancer

Background: Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (aCRC). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. Methods: A multicentre phase I/II trial of reduced-dose capecitabine (2000 mg/m², days 1–14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ECOG) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (LDH) (n = 105), or prior pelvic radiation (n = 54). Based on phase I results, patients with prior pelvic radiation received capecitabine 750 mg/m² twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. Results: Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0–50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand–foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (PFS) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ECOG performance status of 0 (compared with 1 or more) and normal LDH (compared with elevated LDH). Conclusions: Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and PFS appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m², or even 750 mg/m², twice daily is an appropriate dose in elderly or frail patients with aCRC.