Phase I/II trial of dose reduced capecitabine in elderly or frail patients with untreated advanced colorectal cancer.

745 Background: Capecitabine (Cape) was initially assessed at a dose of 2500 mg/m2 in young or robust patients that do not represent the population in which oncologists consider Cape monotherapy in advanced colorectal cancer (aCRC). In practice Cape is frequently given to elderly or frail patients at 2000 mg/m2 but the optimal dosing remains controversial. Methods: A multi-centered phase I/II trial of reduced dose Cape 2000 mg/m2 d1–14 q21d was conducted in 221 patients in one or more of the following subsets: age65 years (167 pts), ECOG PS 1 (139 pts), elevated LDH (105 pts), prior pelvic RT (54 pts). Results: Median age was 72 years. A median 5 and mean 8 cycles were given (range 0 to 50). The phase I portion of the study determined prior pelvic radiation required dose reduction to 1500 mg/m2 for diarrhea. Grade 3/4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). Dose reductions were required in 14% and dose delays in 21%. Response rate is 13.6%, with 69.7% disease control rate. Median PFS was 5.6 months. Post progression 125 patients (67%) received further chemotherapy, 56 received further Cape monotherapy with a median of 4 additional cycles. Median overall survival for all patients is 14.3 months. Median survival was significantly higher for baseline ECOG 0 vs. ≥ 1 and normal vs. elevated LDH. When comparing patients receiving 2000 compared to 1500 mg/m2 the ORR was 19% vs. 17%, and the DCR was 73% vs. 63%. Median PFS was 5.9 vs. 4.7 months, and the OS was equal at 14.3 months. Hand-foot syndrome was more common at the higher dose, 46% vs. 30%, any grade. Conclusions: This report suggests dose reduced Cape has less toxicity compared to full dose, with only a small tradeoff in efficacy seen as a lower ORR. However, its improved tolerability likely leads to an increased number of cycles of therapy, and the PFS seems consistently higher at the lower dose. This trial reduces uncertainty regarding further dose reductions to 1500 mg/m2 for frail patients, in whom quality of life may be paramount. This should be viewed as compelling evidence, in the absence of a head to head clinical trial, that 2000, or even 1500, mg/m2 is an appropriate dose in elderly or frail patients with aCRC.

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