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Abstract

Background: Severe delayed diarrhea and hematological toxicity limit the use of irinotecan. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a critical enzyme in irinotecan metabolism. The study aims to investigate the safety and efficacy of irinotecan under the guidance of the pre-treatment UGT1A1 genotype in the second-line treatment of gastric cancer. Methods: This study involved 110 patients. Irinotecan was injected intravenously every 3 weeks, and the dose of irinotecan was determined by polymorphism of the UGT1A1 gene, which was divided into three groups (125 mg/m²: GG type; 100 mg/m²: GA type; 75 mg/m²: AA type). The primary end point was overall survival (OS), the secondary end points were progression-free survival (PFS) and safety. Results: One hundred and seven patients received irinotecan treatment and three patients with AA type received paclitaxel treatment. Among 107 patients, there were no significant differences in PFS (4.8 m vs 4.9 m vs 4.4 m; p = 0.5249) and OS (9.3 m vs 9.3 m vs NA; p = 0.6821) among patients with GG/GA/AA subtypes after dose adjustment. For the patient with homozygosity mutation, treatment was switched to paclitaxel. There were no significant differences in PFS and OS among patients with different alleles or after dose adjustment (p > 0.05). There was a significant difference in the risk of delayed diarrhea (p = 0.000), leukopenia (p = 0.003) and neutropenia (p = 0.000) in patients with different UGT1A1*6 genotypes, while no difference in patients with different UGT1A1*28 genotypes. Additionally, grade 3/4 diarrhea, neutropenia, and leukopenia were significantly more common in AA genotype patients compared to GG (2%, 19%, 24%) or GA (23%, 31%, 31%) genotype patients. Conclusion: Individual irinotecan treatment shows encouraging survival and tolerability outcomes in patients with GG/GA subtype. Irinotecan may be not suitable for patients with AA subtype.

Keywords

UGT1A1 irinotecan gastric cancer gene polymorphism efficacy toxicity

Introduction

Gastric cancer (GC) is one of the most common tumors of the digestive system. In 2020, it became the fifth most common cancer worldwide and the fourth leading cause of cancer death.¹ The incidence and death rates of GC vary by region, but more than 50% of cases occur in East Asia.² In China, there were 478,508 new cases and 373,789 deaths, the third highest incidence and mortality rate followed by lung cancer and breast cancer. Due to the lack of typical symptoms in early GC, nearly two-thirds of the patients were diagnosed in the late stages of the disease, the 5-year survival rate is unsatisfactory.³

Some phase III studies have shown a survival benefit from irinotecan or docetaxel as second-line chemotherapy.^4–6 Ramucirumab plus paclitaxel also acted as a second-line treatment.⁷ Due to high cost of ramucirumab, only irinotecan or paclitaxel is the standard treatment for patients with metastatic GC in China. However, in clinical practice, irinotecan has often caused serious adverse events (AEs). The most common toxicity, neutropenia and delayed diarrhea limits its widespread use to some extent.⁸

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a polymorphic enzyme, which negatively correlates with gene transcription efficiency and total enzyme activity.⁹ The most common is UGT1A1*28 and UGT1A1*6 polymorphism.¹⁰ It has been suggested that UGT1A1 gene polymorphisms can be used as an indicator to predict the risk of irinotecan adverse reactions.^11,12 Multiple meta-analyses showed that the polymorphisms of UGT1A1*6 and UGT1A1*28 genes were significantly associated with irinotecan-induced severe diarrhea and neutropenia, but this conclusion is still controversial due to the different frequencies of UGT1A1 genotypes in eastern and western countries.^13–16

It is reported that UGT1A1*6, rather than UGT1A1*28 is a predictor of irinotecan-induced toxicity in East Asia.¹⁷ In our center, it is observed that some patients displayed intolerable toxicity to standard dosing of irinotecan due to high incidence of grade 3-4 toxicity, so the dosage of irinotecan had to be reduced in the follow-up treatment. In particular, patients with homozygosity mutant UGT1A1*6 had to discontinue irinotecan because of grade 3 or worse leukopenia and diarrhea. These identify molecular features may help us to predict the toxicity and efficacy to irinotecan. Therefore, in this retrospective study, we aimed to conduct pre-treatment UGT1A1*6 genotyping to investigate the clinical outcomes and AEs of irinotecan in second-line treatment of GC patients.

Materials and Methods

Study Design and Clinical Data Collection

A total of 110 patients with advanced GC admitted to our hospital from January 2018 to December 2020 were enrolled. All patients gave written consent for their treatment in this retrospective study. One hundred and seven patients received irinotecan as second-line chemotherapy. For patients with AA genotype, once severe AEs occur, paclitaxel became the replacement option in time. Paclitaxel was directly administered to 3 additional patients with AA genotype. This study was approved by the Medical Ethics Committee and carried out in accordance with the Declaration of Helsinki Principles. UGT1A1 gene polymorphism was determined by single-gene and multi-gene testing platforms.

The administration of intravenous irinotecan occurred every 3 weeks, with the selection of irinotecan dosage based on the polymorphism of UGT1A1*6 gene. This gene was categorized into 3 groups: UGT1A1*6 wild-type (GG type) with a dosage of 125 mg/m², d1, d8, UGT1A1*6 mutant heterozygosity (GA type) with a dosage of 100 mg/m², d1, d8 and UGT1A1*6 homozygosity mutation (AA type) with a dosage of 75 mg/m², d1, d8 or paclitaxel 125 mg/m², d1, d8. RECIST, version 1.1, was used to evaluate clinical response every two cycles through computed tomography (CT).¹⁸ AEs were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Statistical Analyses

Using the CTCAE, version 5.0, we calculated survival, and we compared survival curves using the log-rank test. In addition to the Cox proportional hazard regression model, survival differences among groups were also evaluated by univariable and multivariate analyses. The hazard ratios (HRs) and 95% confidence intervals (CIs) were presented as the survival ratios. With Fisher's exact test and Student's t-test, the relationship between genotyping and irinotecan toxicity was analyzed using SPSS 21.0 (SPSS Inc, Chicago, IL, USA). Two-sided tests were conducted, and p < 0.05 was considered statistically significant.

Results

Patient Baseline Clinical Features

This study included 110 advanced GC patients who underwent irinotecan monotherapy as second-line therapy. The baseline characteristics were summarized in Table 1. The frequencies of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 and GG, GA, AA genotypes for UGT1A1*6 were 70.9%, 25.5%, 3.6% and 60.9%, 31.8%, 7.3%, respectively (Table 2). Three patients (2.7%) carried double heterozygosity (GA and TA6/TA7). No concurrent homozygous mutations were detected.

Table 1.

Patients’ Baseline Characteristics.

Characteristic	Total (n = 110)
Sex—no. (%)
Male	74 (67.3)
Female	36 (32.7)
Age—yr
≤65	76 (69.0)
>65	34 (31.0)
Primary lesion site—no. (%)
Gastric caidia	45 (40.9)
Gastric antrum	29 (26.4)
Gastric body	28 (25.5)
Others	8 (7.3)
Tumor differentiation—no. (%)
Poorly differentiation	72 (65.5)
Moderately differentiation	24 (21.8)
Well differentiation	1 (0.9)
Others	13 (11.8)
Lauren classification—no. (%)
Intestinal	29 (26.4)
Diffuse	59 (53.6)
Mixed	12 (10.9)
NA	10 (9.1)
HER-2 status—no. (%)
Positive	12 (10.9)
Negative	98 (89.1)
Metastasis sites—no. (%)
Liver	46 (41.8)
Peritoneum	43 (39.1)
Others	41 (37.3)
Prior treatment—no. (%)
Oxaliplatin + S-1	55 (50.0)
Oxaliplatin + capecitabine	17 (15.5)
Oxaliplatin + leucovorin + 5-fluorouracil	5 (4.5)
Taxane + S-1	10 (9.1)
Taxane + oxaliplatin + fluorouracil	9 (8.2)
Surgery
Yes	13 (11.8)
No	97 (88.2)
ECOG performance status
0	15 (13.6)
1	92 (83.6)
2	3 (2.7)

HER-2: human epidermal growth factor receptor 2; ECOG: Eastern Cooperative Oncology Group.

Table 2.

Genotyping of UGT1A1 in GC.

Genotyping	Number (%)
UGT1A128*
TA6/TA6	78 (70.9)
TA6/TA7	28 (25.5)
TA7/TA7	4 (3.6)
UGT1A16*
GG	67 (60.9)
GA	35 (31.8)
AA	8 (7.3)
UGT1A16 & UGT1A128
GG & TA6/TA6	38 (34.5)
GG & TA6/TA7	25 (22.7)
GG & TA7/TA7	4 (3.6)
GA & TA6/TA6	32 (29.1)
GA & TA6/TA7	3 (2.7)
GA & TA7/TA7	0 (0.0)
AA & TA6/TA6	8 (7.3)
AA & TA6/TA7	0 (0.0)
AA & TA7/TA7	0 (0.0)

GC: gastric cancer; UGT1A1: Uridine diphosphate glucuronosyltransferase 1A1; GG: UGT1A1*6 wild-type; GA: UGT1A1*6 mutant heterozygosity; AA: UGT1A1*6 homozygosity mutation; TA6/TA6: UGT1A1*28 wild-type; TA6/TA7: UGT1A1*28 mutant heterozygosity; TA7/TA7: UGT1A1*28 homozygosity mutation.

Toxicity of Irinotecan as Second-Line Therapy

Patients with UGT1A1*6 or UGT1A1*28 genetype showed no significant difference in thrombocytopenia and hemoglobin reduction. In addition, there were no significant differences in diarrhea (p = 0.136), neutropenia (p = 0.991), and leukopenia (p = 0.857) in UGT1A1*28 subgroups. However, diarrhea (p = 0.000), neutropenia (p = 0.000), and leukopenia (p = 0.003) were significantly different among UGT1A1*6 subgroups (Table 3). Additionally, grade 3/4 diarrhea, neutropenia, and leukopenia were significantly more common in AA genotype patients compared to GG (2%, 19%, and 24%) or GA (23%, 31%, and 31%) genotype patients, suggesting that that patients with the AA genotype could not tolerate severe toxicity even with reduced doses of irinotecan.

Table 3.

Adverse Events.

Adverse events	UGT1A16*			p	UGT1A128*			p
Adverse events	GG	GA	AA	p	TA6/6	TA6/7	TA7/7	p
Diarrhea
Grade 0	59 (88%)	14 (40%)	0 (0%)	0.000	55 (74%)	15 (54%)	2 (50%)	0.136
Grade 1-2	7 (10%)	13 (37%)	0 (0%)		12 (16%)	7 (25%)	2 (50%)
Grade 3-4	1 (2%)	8 (23%)	5 (100%)		8 (10%)	6 (21%)	0 (0%)
Leukopenia
Grade 0	45 (67%)	10 (29%)	0 (0%)	0.003	49 (65%)	18 (65%)	3 (75%)	0.857
Grade 1-2	9 (14%)	14 (40%)	0 (0%)		14 (19%)	6 (21%)	1 (25%)
Grade 3-4	13 (19%)	11 (31%)	5 (100%)		12 (16%)	4 (14%)	0 (0%)
Neutropenia
Grade 0	39 (58%)	14 (40%)	0 (0%)	0.000	45 (60%)	17 (61%)	2 (50%)	0.991
Grade 1-2	12 (18%)	10 (29%)	0 (0%)		19 (25%)	7 (25%)	2 (50%)
Grade 3-4	16 (24%)	11 (31%)	5 (100%)		11 (15%)	4 (14%)	0 (0%)
Hemoglobinia
Grade 0	38 (57%)	16 (46%)	3 (60%)	0.477	59 (79%)	17 (61%)	4 (100%)	0.151
Grade 1-2	27 (40%)	16 (46%)	1 (20%)		9 (12%)	10 (35%)	0 (0%)
Grade 3-4	2 (3%)	3 (8%)	1 (20%)		7 (9%)	1 (4%)	0 (0%)
Thrombocytopenia
Grade 0	41 (61%)	20 (58%)	3 (60%)	0.814	48 (64%)	15 (54%)	2 (50%)	0.450
Grade 1-2	23 (35%)	11 (31%)	2 (40%)		23 (31%)	10 (35%)	1 (25%)
Grade 3-4	3 (4%)	4 (11%)	0 (0%)		4 (5%)	3 (11%)	1 (25%)

Efficacy of Irinotecan as Second-Line Therapy

With a median follow-up of 9.0 months (range 6.3-12.5 months), median PFS was 4.4 months in all patients. The median PFS was 4.7 months (95% CI = 4.3-5.3) in the TA6/TA6 group, 5.0 months (95% CI = 4.1-6.2) in the TA6/TA7 group, 5.3 months (95% CI = 2.8-NA) in the TA7/TA7 group, 4.8 months (95% CI = 4.1-5.5) in the GG group, 4.9 months (95% CI = 4.4-5.3) in the GA group, and 4.4 months (95% CI = 3.9-NA) in the AA group (Figure 1A, B). Median overall survival (OS) was 8.7 months in all patients. And the median OS was 9.5 months (95% CI = 8.8-10.2) in the TA6/TA6 group, 9.0 months (95% CI = 8.3-NA) in the TA6/TA7 group, 11.2 months (95% CI = 9.1-NA) in the TA7/TA7 group, 9.3 months (95% CI = 8.8-10.9) in the GG group, 9.3 months (95% CI = 8.7-NA) in the GA group, and NA (95% CI = 8.8-NA) in the AA group, respectively (Figure 1). In this cohort, we can see that the PFS and OS of 5 patients with AA genotype showed no difference from GG or GA genotype after timely changing chemotherapy regimen. In addition, GC with single allele variation or two alleles variation also showed no significant difference in PFS and OS (Figure 2).

Figure 1.

Association between UGT1A1 and survival outcomes. (A, B) Kaplan–Meier survival curves of progression-free survival. (C, D) Kaplan–Meier survival curves of overall survival.

Figure 2.

Association between UGT1A1 single or two alleles variation and survival outcomes.

In the present study, univariable and multivariate analysis revealed no relation between PFS and UGT1A1*6 or UGT1A1*28 (Table 4). However, the univariable analysis showed a significant association between OS and tumor differentiation, Lauren classification, surgery and metastasis sites, while no relation between OS and UGT1A1*6 or UGT1A1*28 (Table 5). In a multivariate model, surgery (p = 0.025) and diffuse Lauren classification (p = 0.010) remained independent prognostic indicators for OS (Table 5).

Table 4.

Univariate and Multivariate Analyses of Progression-Free Survival.

Parameter	Univariate analysis			Multivariate analysis
Parameter	HR	95% CI	P	HR	95% CI	P
Sex Male vs Female	1.130	0.706-1.807	0.611
Age >65 vs ≤65	1.294	0.819-2.046	0.270
Tumor differentiation High + Moderate versus poorly	1.062	0.634-1.779	0.819	1.018	0.528-1.963	0.985
LAUREN Diffuse vs intestinal	0.886	0.573-1.369	0.584	0.965	0.523-1.780	0.910
Tumor location Body vs antrum + caidia	1.039	0.629-1.716	0.880
ECOOG 2 vs 0-1	1.485	0.465-4.747	0.505
HER-2 status Positive vs Negative	1.437	0.735-2.812	0.290
Surgery Yes or No	0.995	0.492-2.012	0.990	1.023	0.494-2.119	0.951
Metastasis sites Liver or peritoneum	1.181	0.763-1.827	0.456	1.198	0.703-2.042	0.507
UGT1A16* AA + GA vs GG	1.290	0.811-2.052	0.283	1.325	0.792-2.219	0.284
UGT1A128* TA7/TA7 + TA6/TA7 vs TA6/TA6	0.855	0.525-1.392	0.528	0.962	0.565-1.637	0.887

Table 5.

Univariate and Multivariate Analyses of Overall Survival.

Parameter	Univariate analysis			Multivariate analysis
Parameter	HR	95% CI	p	HR	95% CI	p
Sex Male vs Female	0.958	0.556-1.650	0.877
Age >65 vs ≤65	0.893	0.523-1.525	0.678
Tumor differentiation High + Moderate vs poorly	0.449	0.233-0.862	0.016	0.833	0.376-1.848	0.654
LAUREN Diffuse vs intestinal	3.374	1.898-6.000	0.000	2.512	1.242-5.083	0.010
Tumor location Body vs antrum + caidia	1.006	0.552-1.833	0.984
ECOG 2 vs 0-1	2.730	0.369-20.205	0.325
HER-2 status Positive vs Negative	1.041	0.494-2.195	0.915
Surgery Yes or No	0.338	0.122-0.936	0.037	0.306	0.108-0.864	0.025
Metastasis sites Liver or peritoneum	0.477	0.277-0.822	0.008	0.549	0.299-1.008	0.053
UGT1A16* AA + GA vs GG	1.016	0.610-1.692	0.951	0.894	0.504-1.588	0.703
UGT1A128* TA7/TA7 + TA6/TA7 vs TA6/TA6	1.108	0.648-1.893	0.708	0.992	0.529-1.861	0.981

Discussion

The traditional approach to the dose of irinotecan has been to use body surface area (BSA).¹⁹ However, studies have found that the pharmacokinetic parameters of irinotecan appear to be independent of BSA, leading to a large number of clinicians questioning the validity of irinotecan dose normalization.²⁰ Large evidences have confirmed that UGT1A1 is the main metabolic enzyme that inactivates SN-38 into SN-38G. Ethnic differences in UGT1A1 gene polymorphism are closely associated with AEs of irinotecan,^21–23 but its efficacy remains uncertain.^15,24,25 Most studies believed that patients with homozygous UGT1A1*28 mutation would have serious toxic reactions, and it was suggested to reduce the dosage of irinotecan.^23,24,26,27 To reduce the toxicity of irinotecan, FDA proposed that patients should be genotyped for UGT1A1*28 polymorphism before treatment with irinotecan. In contrast to the rarity of UGT1A1*28, UGT1A1*6 polymorphism was common in Asian populations.²⁸ A recent study showed that the UGT1A1*6 (C.211g>A) allele was more predictive of neutropenia in Korean cancer patients taking irinotecan.²⁹ In addition, the presence of the homozygous UGT1A1*6 allele was associated with an approximately 3-fold increased risk of grade 4 neutropenia in Chinese patients treated with irinotecan.²⁸

In this study, we calculated irinotecan dose according to UGT1A1*6 gene polymorphism based on BSA. For patients with GG type, irinotecan was used in full dose. For patients with GA type, irinotecan was used by 20% reduction. For patients with AA type, irinotecan was used by 40% reduction. It was found that there was no significant difference in the incidence of AEs in GC patients with different UGT1A1*28 genotypes. The incidence of these grade 3-4 toxicities was not similar to previous studies of irinotecan.^4,6 Irinotecan dose reduction may influence the toxicity of each UGT1A1*28 subgroup. UGT1A1*6 gene polymorphism is significantly related to delayed diarrhea and neutropenia, which is consistent with the existing research conclusions. The incidence of adverse reactions gradually increases in patients with wild-type, mutant heterozygous and mutant homozygous. However, we found that for homozygous mutant patients, even if 40% irinotecan dose reduction, severe toxicity still occurred. Of the 8 patients with UGT1A1*6 AA subtype, 5 had severe toxicity and were subsequently switched to paclitaxel in the following treatment. Three patients received paclitaxel treatment directly.

A recent study believes that irinotecan dose reduction may reduce its toxicity, hospitalization, and even cost, but may not affect survival. It may be explained by SN-38 exposure in mutant patients after irinotecan adjustment, which is similar in wild-type patients with irinotecan normalization. GC patient had a median PFS of 2.3 months and an OS of 8.4 months using irinotecan in second-line chemotherapy.⁴ We had similar results. In this study, it did not affect the PFS (GG type 4.8 m vs GA type 4.9 m vs AA type 4.4 m; p = 0.5249), or OS (GG type 9.3 m vs GA type 9.3 m vs AA type NA; p = 0.6821). It is worth noting that, a lower dosage of irinotecan did not significantly affect PFS or OS. However, 5 had severe AEs in 8 patients with UGT1A1*6 AA subgroup. With consideration of the possibility of reoccurrence of these AEs, paclitaxel was directly administered to 3 additional patients. Based on these findings, irinotecan may be a clinically effective drug for selective patients in non-AA subgroup.

In conclusion, there was no significant difference in clinical efficacy between low dosing irinotecan in patients with heterozygous mutations of UGT1A1*6 gene and irinotecan with standard-dose irinotecan in wild-type patients, while patients with homozygous mutations in the UGT1A1*6 gene achieved the same efficacy after switching to paclitaxel regimen. It proved that individual irinotecan treatment can have a good effect in patients with non-AA subtype under the guidance of UGT1A1*6 gene polymorphism. Irinotecan may be not suitable for patients with AA subtype. There are limitations in this study. The current retrospective study was conducted at a single center with a limited number of patients and therefore a selection bias. There has no control group without UGT1A1 polymorphism tests. Patients with GA subtype had greater toxicity than patients with GG subtype, despite 20% irinotecan dose reduction. These should encourage further prospective study of how to manage these patients treated with irinotecan.

Footnotes

Data Availability Statement

Data are available on request to the authors.

Declaration of Conflicting Interests

Junling Zhang is an employee of Shanghai 3D Medicines Inc. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

This study was approved by the Medical Ethics Committee of Henan Cancer Hospital (Zhengzhou University) (No. 2021-KY-0192-001).

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the 1000 Talents Program of Central Plains (grant number 204200510023), Medical Science and Technique Foundation of Henan Province (grant numbers LHGJ20210186 and SB201901101), State Key Laboratory of Esophageal Cancer Prevention & Treatment (grant number Z2020000X), Science and Technique Foundation of Henan Province (grant number 202102310413).

Informed Consent

All patients signed written informed consents in our study.

ORCID iDs

Xiaobing Chen

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