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. Author manuscript; available in PMC: 2022 Jan 28.
Published in final edited form as: Pharmacotherapy. 2020 Oct 19;40(11):1108–1129. doi: 10.1002/phar.2463

Table 4.

Literature Summary of UGT1A1 Variant Associations with Severe Toxicity

Study Study design Total n patients Tumor type Regimen UGT1A1 variant Irinotecan dose Main findings of grade > 3 toxicity p value
Páez et al., 201946 Prospective randomized multicenter, European population 82 mCRC FOLFIRI-based *28 Experimental (geno typing):
*1/* 1–300 mg/m2
*1/*28–260 mg/m2
Control (no genotyping):
180 mg/m2 		Toxicity in experimental vs control groups
Neutropenia 15% vs 20.5% NS
Diarrhea 2.5% vs 7.7% NS
Liu et al., 201745 Meta-analysis (58 studies), Asian, white, mixed populations 4898 mCRC, SCLC, mNSCLC Irinotecan-based *28 Multiple dosing protocols Toxicity in *28/*28 and *1/*28 vs WT individuals
Neutropenia (OR = 2.15, 95% CI = 1.71–2.70) < 0.001
Diarrhea (OR = 2.18, 95% CI = 1.68–2.83) < 0.001
Toffoli et al., 201744 Prospective dose escalation multicenter, European, North American populations 48 mCRC FOLFIRI plus BEV *28 Initial to maximum tolerated:
*1/*1, *1/*28:
260–370 mg/m2 		Toxicity according to dose in *1/*28 vs WT individuals
Neutropenia 260 mg/m 1/10 vs 0/10 patients NR
310 mg/m2 2/10 vs 0/10 patients NR
Neutropenic sepsis 370 mg/m2 0/3 vs 1/5 patients NR
Diarrhea 260 mg/m2 0/10 vs 1/10 patients NR
310 mg/m2 1/10 vs 2/10 patients NR
370 mg/m2 1/3 vs 0/4 patients NR
Arrhythmia 260 mg/m2 1/10 vs 0/10 patients NR
Mucositis 310 mg/m2 0/10 vs 1/10 patients NR
N/V 370 mg/m2 0/3 vs 1/4 patients NR
Marcuello et al., 201143 Prospective dose escalation, European population 98 mCRC FOLFIRI *28 Initial to maximum tolerated:
*1/*28:
110–390 mg/m2
*28/*28:
90–150 mg/m2 		Toxicity according to dose in *1/*28 vs WT individuals
Neutropenia 300 mg/m 1/6 vs 0/3 patients NR
390 mg/m2 1/2 vs 0/6 patients NR
Diarrhea 220 mg/m2 0/3 vs 1/6 patients NR
340 mg/m2 1/6 vs 0/6 patients NR
Asthenia 260 mg/m2 0/3 vs 1/12 patients NR
390 mg/m2 1/2 vs 1/6 patients NR
Toxicity according to dose in *28/*28 individuals
Neutropenia 150 mg/m 1/5 patients NR
Diarrhea 90 mg/m2 1/6 patients NR
Asthenia 150 mg/m2 1/5 patients NR
Toffoli et al., 201042 Prospective dose escalation multicenter, European population 59 mCRC FOLFIRI *28 Initial to maximum tolerated:
*1/*1, *1/*28:
215–370 mg/m2 		Toxicity according to dose in *1/*28 vs WT individuals
Neutropenia 370 mg/m2 1/4 vs 0/10 patients NR
Diarrhea 215 mg/m2 1/6 vs 0/4 patients NR
260 mg/m2 0/4 vs 1/12 patients NR
Asthenia 370 mg/m2 1/4 vs 0/10 patients NR
Stomatitis 310 mg/m2 0/10 vs 1/6 patients NR
Hu et al., 201041 Meta-analyses (9 studies), European, North American, Asian populations 1998 Solid, various Irinotecan-based *28 High: ≥ 250 mg/m2
Medium: 150–250 mg/mg2
Low: < 150 mg/m2 		Neutropenia in *28/*28 vs. *1/*28 and WT individuals
High dose (RR = 7.22, 95% CI = 3.10–16.78) 0.003
Medium dose (RR = 2.00, 95% CI = 1.62–2.47) < 0.001
Low dose (RR = 2.43, 95% CI = 1.34–4.39) < 0.001
Neutropenia in *1/*28 vs WT individuals
High dose (RR = 2.65, 95% CI = 0.70–9.94) 0.149
Medium dose (RR = 1.29, 95% CI = 1.04–1.62) 0.023
Low dose (RR = 2.94, 95% CI = 1.36–6.35) 0.006
Hoskins et al., 200740 Meta-analyses (9 studies), European, North American populations 821 Solid, various Irinotecan-based *28 High: > 250 mg/m2
Medium: 150–250 mg/mg2
Low: < 150 mg/m2 		Hematological toxicity in *28/*28 vs *1/*28 and WT individuals
High dose (OR = 27.8, 95% CI = 4.0–195) 0.005
Medium dose (OR = 3.22, 95% CI = 1.52–6.81) 0.008
Low dose (OR = 1.80, 95% CI = 0.37–8.84) 0.41
Diarrhea 10.5% vs 5.1% vs 5.6% 0.648
Zhang et al., 201748 Meta-analyses (12 studies), Asian population 1140 Solid, various Irinotecan-based *6 High: ≥ 150 mg/m2
Low: < 150 mg/m2 		Neutropenia in *28/*28 vs. *1/*28 and WT individuals
High dose (OR = 1.97, 95% CI = 1.47–2.67) < 0.001
Low dose (OR = 2.66, 95% CI = 1.10–6.45) 0.03
Neutropenia in *28/*28 vs. WT individuals
High dose (OR = 2.89, 95% CI = 1.69–4.94) < 0.001
Low dose (OR = 3.17, 95% CI = 1.11–9.04) 0.19
Neutropenia in *1/*28 vs. WT individuals
High dose (OR = 1.65, 95% CI = 1.15–2.35) 0.003
Low dose (OR = 2.36, 95% CI = 1.28–4.35) 0.009
Cheng et al., 201447 Meta-analyses (11 studies), Asian population 1141 Solid, various Irinotecan-based *6 High/medium: ≥ 150 mg/m2a
Low: < 150 mg/m2a 		Toxicity in *28/*28 vs. WT individuals
Neutropenia (OR = 4.44, 95% CI = 2.42–8.14) < 0.001
Diarrhea (OR = 3.51, 95% CI = 1.41–8.73’) 0.007
Toxicity in *1/*28 vs. WT individuals
Neutropenia (OR = 1.98, 95% CI = 1.45–2.71) < 0.001
Diarrhea (OR = 1.44, 95% CI = 0.84–2.49) 0.186
Toxicity in *1/*28 vs. WT individuals
High dose (OR = 1.65, 95% CI = 1.15–2.35) 0.003
Low dose (OR = 2.36, 95% CI = 1.28–4.35) 0.009

BEV = bevacizumab; CI = confidence interval; FOLFIRI = 5-fluorouracil and irinotecan; mCRC = metastatic colorectal cancer; mNSCLC = metastatic non-small cell lung cancer; N/V = nausea/vomiting; NR = not reported; NS = not significant; OR = odds ratio; RR = relative risk; SCLC = small cell lung cancer; UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1; WT = wild-type (*1/*1).

Toxicity defined per Common Terminology Criteria for Adverse Events (CTCAE) guidelines used by primary study authors.

a

Dose comparisons not analyzed in overall findings.