The impact of UGT1A1 single-hetero regarding the toxicity of fixed dose irinotecan therapy for advanced gastric cancer

Abstract

Abstract Background Irinotecan is a key drug for advanced gastric cancer (AGC). We previously reported that patients with UGT1A1 single heterozygous (SH) had significantly high frequency of severe hematological adverse events (AEs) compared to patients with UGT1A1 wild type (WT) in irinotecan monotherapy for AGC. However, the difference of initial dose and relative dose intensity (RDI) of irinotecan between UGT1A1 WT and SH might affect those results. Therefore, we compared between UGT1A1 SH and WT regarding the clinical outcomes of the fixed dose irinotecan monotherapy for AGC. Methods We retrospectively analyzed the clinical data of patients who received initial fixed dose irinotecan (150mg/m2, bi-weekly) in the multi-institutional retrospective study. 106 eligible patients were registered from 8 centers in Japan. Result The number of patients with UGT1A1 WT/SH were 62 and 38, respectively. In WT/SH patients, performance status 0/1/≥2 was 20/40/2 and 11/23/4, treatment line 2nd/3rd or later was 27/35 and 18/20, HER2 positive/negative 17/45 and 8/30, respectively. In WT/SH patients, median PFS was 3.2 and 3.3 months (HR = 1.137, P = 0.543) and median OS was 10.4 and 7.3 months (HR = 0.734, P = 0.184). In WT/SH patients, median treatment cycle was 6 and 4 (P = 0.973), and RDI was 0.85 vs 0.84(P = 0.915), respectively. Hematological AEs were observed in 82.2% and 92.1% (P = 0.138), severe hematological AEs (≥G3) were 35.4% and 63.1%(P = 0.006). Non-hematological AEs were 88.7% and 86.8%(P = 0.507), severe non-hematological AEs (≥G3) were 6.6% and 15.8% (P = 0.122), respectively. Severe AEs in more than 5% patients were leukopenia (11.3% and 15.8%), neutropenia (14.5% and 31.6%), anemia (21.0% and 23.7%), and anorexia (1.6% and 10.5%). Conclusion UGT1A1 SH patients who received initial fixed dose Irinotecan had high frequency of severe hematological AE compared to WT patients. However, there was no significant difference in efficacy of Irinotecan monotherapy in each group.