UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study

Abstract

The aim of the study was to investigate the associations between UGT1A1(*)28 genotype and (1) response rates, (2) febrile neutropenia and (3) dose intensity in patients with metastatic colorectal cancer treated with irinotecan. UGT1A1(*)28 genotype was determined in 218 patients receiving irinotecan (either first-line therapy with capecitabine or second-line as monotherapy) for metastatic colorectal cancer. TA(7) homozygotes receiving irinotecan combination therapy had a higher incidence of febrile neutropenia (18.2%) compared to the other genotypes (TA(6)/TA(6) : 1.5%; TA(6)/TA(7) : 6.5%, P=0.031). TA(7) heterozygotes receiving irinotecan monotherapy also suffered more febrile neutropenia (19.4%) compared to TA(6)/TA(6) genotype (2.2%; P=0.015). Response rates among genotypes were not different for both regimens: combination regimen, P=0.537; single-agent, P=0.595. TA(7) homozygotes did not receive a lower median irinotecan dose, number of cycles (P-values >or=0.25) or more frequent dose reductions compared to the other genotypes (P-values for trend; combination therapy: 0.62 and single-agent: 0.45). Reductions were mainly (>80%) owing to grade >or=3 diarrhoea, not (febrile) neutropenia. TA(7)/TA(7) patients have a higher incidence of febrile neutropenia upon irinotecan treatment, but were able to receive similar dose and number of cycles compared to other genotypes. Response rates were not significantly different.

Figure 1

Flowchart of patients in current analysis. Abbreviations: BSA=body surface area; CAPIRI=irinotecan first-line combination therapy (250 mg m⁻² every 3 weeks, with capecitabine); IRI=irinotecan (350 mg m⁻² every 3 weeks) second-line single-agent therapy; PS=performance status; ULN=upper limit of normal.

Figure 2

Mean RDI (%) of irinotecan dose per regimen. Boxplots of mean irinotecan dose intensity per cycle. In patients receiving either irinotecan alone or in combination with capecitabine, no statistally significant differences in relative dose intensity were observed (P=0.45 and P=0.83, respectively). Abbreviations: CAPIRI=irinotecan first-line combination therapy (250 mg m⁻² every 3 weeks, with capecitabine); IRI=irinotecan (350 mg m⁻² every 3 weeks) second-line single-agent therapy; 0 depicts a patient with an extreme dosage of irinotecan per cycle; ^*depicts an outlier.