Abstract
The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22–38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.
Highlights
Taxanes and platinum‐containing agents are key drugs that are used in the chemotherapy for gynecological cancers
A combination of CPT‐11 and mitomycin C (MMC) has been reported to be effective in elderly Japanese patients with gynecological cancers who did not respond to the combination regimen of taxanes and platinum [2]
Genomic DNA was isolated from peripheral blood uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and ATP‐binding cassette sub‐family G member 2 (ABCG2) genotypes and allele frequencies
Summary
Taxanes and platinum‐containing agents are key drugs that are used in the chemotherapy for gynecological cancers. The risk of severe neutropenia is increased in individuals who are homozygous for the *28 allele [3,4,5,7] This association is not observed when CPT‐11 is administered at a low dose for lung or colorectal cancer [9,15,16]. In Japanese patients with colorectal and lung cancer, the *6/*28 and *6/*6 genotypes are significantly correlated with the occurrence of severe neutropenia [7]. A study of the CPT‐11 + CDDP regimen in gynecological conditions demonstrated that the risk of severe neutropenia is higher in patients with the *1/*6 genotype than in patients with the *1/*1 genotype [13]. This study did not clarify the affect of the *6/*28 and *6/*6 genotypes on the risk of developing neutropenia
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