3.2.3 Effects of combined UGT1A1*6 and UGT1A1*28 genetic polymorphisms with irinotecan induced severe toxicity
Altogether 27 and 20 studies had investigated the combined effects ofUGT1A1*6 and UGT1A1 *28 genetic polymorphisms with irinotecan induced neutropenia and diarrhea, respectively. After pooled estimation, it was found that the patients carried both of theUGT1A1*6 and UGT1A1*28 variants (heterozygous:UGT1A1*1/*6+UGT1A1*1/*28 andhomozygous:UGT1A1*6/*6+UGT1A1*28/*28 ) were significantly associated with increased risk of neutropenia compared to the patients carried wild type genotype i.e. UGT1A1*1/*1 (OR 2.89; 95% CI 1.97–4.23; P <0.00001), as shown in Figure 4A. Patients with homozygous variants had much stronger effects in developing neutropenia (OR 6.23; 95% CI 3.11–12.47; P <0.00001) than the patients with heterozygous variants (OR 2.04; 95% CI 1.28–3.27; P =0.003), Figure 4A.
It was also found that the aggregated risk of diarrhea was significantly higher in cancer patients carried both of the UGT1A1*6 andUGT1A1*28 variants (heterozygous,UGT1A1*1/*6+UGT1A1*1/*28; homozygous,UGT1A1*6/*6+UGT1A1*28/*28 ) compared to the patients with wild type genotype i.e. UGT1A1*1/*1 (OR 2.26; 95% CI 1.71–2.99;P <0.00001), as shown in Figure 4B. Further analysis indicated that the risk of diarrhea was much greater in patients carried homozygous variants i.e. UGT1A1*6/*6+UGT1A1*28/*28 (OR 3.21; 95% CI 2.13–4.85; P <0.00001) compared to the patients with heterozygous variants i.e. UGT1A1*1/*6+UGT1A1*1/*28 (OR 1.83; 95% CI 1.31–2.55; P =0.0004), Figure 4B.
3.2.4 Subgroup analysis for combined effects of UGT1A1*6 and UGT1A1*28 with irinotecan induced severe toxicity
For assessing the effects of the combined UGT1A1*6 andUGT1A1*28 varinats in different ethnicities of Asia, this study undertaken subgroup analysis for the toxicities reported in at least two studies in the respective country. Subgroup analysis revealed that patients carried both of the UGT1A1*6 and UGT1A1*28variants were significantly associated with increased risk of neutropenia in Chinese (OR 2.29; 95% CI 1.20–4.37; P =0.01), Japanese (OR 2.81; 95% CI 1.85–4.28; P <0.00001) and Thai patients (OR 10.51; 95% CI 3.56–31.05;P <0.0001), as shown in Figure 5A.
However, patients carried both of the UGT1A1*6 and UGT1A1*28 genetic variants were associated with significantly increased risk of diarrhea in only Chinese patients (OR 3.34; 95% CI 1.67–6.71; P =0.0007) but not in Japanese patients (OR 1.74; 95% CI 0.85–3.55; P =0.13), Figure 5B.
Since different studues used irinotecan in treating different types of cancer e.g. colorectal, lung, stomach, cervical, ovarian, esophageal, pancreatic, pulmonary neuroendocrine tumor, and sometimes combination of these cancers, current study was undertaken subgroup analysis to investigate the impacts of these cancers on the development of toxicities. In this study, patients were grouped as colorectal cancer versus other cancers where other cancers group included lung, stomach, cervical, ovarian, esophageal, pancreatic, pulmonary neuroendocrine tumor, combination of these cancers. After analysis, it was found that the patients with either colorectal or other cancers carried both of the UGT1A1*6and UGT1A1*28 variants were associated with significantly increased risk of neutropenia (Colorectal cancer: OR 2.85; 95% CI 1.42-5.73; P =0.003; Other cancers: OR 2.86; 95% CI 1.90-4.32;P <0.00001), Figure 6A.
Similar trends were also found in diarrhea (Colorectal cancer: OR 2.47; 95% CI 1.24-4.91; P =0.01; Other cancers: OR 2.71; 95% CI 1.26-5.81; P =0.01), Figure 6B.
Because different irinotecan dosing schedule was applied in treating different types of cancer, current study was also undertaken subgroup analysis to assess whether these dosing schedules affected the development of the toxicities. In this analysis, dose was categorized as low, medium and high corresponded to <150 mg/m2, 150 mg/m2and >150 mg/m2, respectively. It was found that patients carried both of the UGT1A1*6 andUGT1A1*28 variants were associated with significantly increased risk of neutropenia in only high and low doses (High dose: OR 3.21; 95% CI 1.77-5.84; P =0.0001; Low dose: OR 3.35; 95% CI 1.78-6.32;P =0.0002) but not in medium doses (OR 1.34; 95% CI 0.46-3.87;P =0.59), Figure 7A.
However, patients carried both of the UGT1A1*6 andUGT1A1*28 variants were associated with significantly increased risk of diarrhea in only high doses (High dose: OR 2.01; 95% CI 1.19-3.38; P =0.009;) but not in medium and low doses (Medium dose: OR 3.38; 95% CI 0.58-19.74; P =0.18; Low dose: OR 2.50; 95% CI 0.97-6.42; P =0.06), Figure 7B.
3.2.5 Association ofABCC2 c.3972C>T with irinotecan induced severe toxicity
Very small number of studies were found in the literature that had assessed the association of ABCC2 c.3972C>Tgenetic polymorphism with the toxicity of irinotecan. Only three and two studies had assessed the effects of ABCC2c.3972C>T genetic variant with irinotecan induced neutropenia and diarrhea, respectively. After pooled estimation, it was found that patients carried heterozygous and homozygous of theABCC2 c.3972C>T variant were not significantly associated with irinotecan induced neutropenia (OR 1.67; 95% CI 0.98–2.84; P =0.06), as shown in Figure 8A.
It was further revealed that patients harbored heterozygous and homozygous of the ABCC2 c.3972C>T variant were significantly associated with the reduction of irinotecan induced diarrhea (OR 0.31; 95% CI 0.11–0.81; P =0.02), Figure 8B.