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.