UGT1A1 Allele Test Not Only Minimizes the Toxicity But Also Maximizes the Therapeutic Effect of Irinotecan in the Treatment of Colorectal Cancer: A Narrative Review.

Background: Irinotecan is a first-line agent in the systematic treatment of colorectal cancer (CRC). Adjusting the dose of irinotecan according to the uridine diphosphate glucuronosyltransferase (UGT) 1A1 genotype reflects the principle of individualized and precision medicine, and may improve the chemotherapy response and survival of CRC.
Methods: To summarize the feasibility, efficacy and safety of high dose irinotecan in CRC patients with UGT1A1 wild-type or heterozygous alleles, PubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials online databases were searched from the date of creation to October 22, 2021.
Results: A total of 1,186 related literatures were searched, and 14 studies were included for review according to the inclusion criteria. The results indicated that the maximum tolerated dose of irinotecan in CRC patients with UGT1A1 wild-type or heterozygous variant was significantly higher than the conventional recommended dose. Chemotherapy based on high dose irinotecan improved the clinical efficacy in mCRC patients with UGT1A1*28 wild-type and heterozygous variant, and the toxicity was tolerated, as reflected in most studies. Conclusions: We are optimistic about the application of high dose irinotecan for mCRC patients with UGT1A1*28 wild-type or heterozygous variant, which will provide a relatively clear direction for future research and certain norms for clinical practice.

Introduction

With high morbidity and mortality, colorectal cancer (CRC) is still one of the major diseases threatening human health (1, 2). In 2020, the global incidence of CRC was about 1.88 million, ranking third in the incidence of common cancer, with more than 900 thousand deaths, making it the second leading cause of cancer deaths (3). In the new diagnosis of CRC, 20% of patients have metastatic disease, and the other 25% of patients with local disease will have metastasis later (4). Irinotecan is one of the first-line agents in the systematic therapy of metastatic colorectal cancer (mCRC) (5), but its high toxicity, including severe neutropenia and diarrhea (6), has become the focus of concern in clinical use.

In recent years, the potential of pharmacogenetics in the treatment of malignant tumors has been fully reflected, which provides strong guidance for the rational application of antitumor drugs (7). Uridine diphosphate glucuronosyltransferase (UGT) 1A1 is a key enzyme for metabolism of the active metabolite SN-38 (8) of irinotecan. Studies have confirmed that UGT1A1 gene polymorphism, with defective alleles *28 and *6 as research hotspots, affects the metabolism of irinotecan and enhances its toxicity (9–11). In clinical practice, it has been agreed to reduce the dose of irinotecan in individuals homozygous and double heterozygous mutations for UGT1A1 *28 or *6 alleles (*28/*28 or *6/*6 or *6/*28) to minimize their toxicity (12), but such treatment may be associated with poorer survival (13, 14).

Compared with patients with UGT1A1 homozygous defect, patients with wild-type or heterozygous alleles are more efficient in metabolizing SN-38, which indicates that they may be able to tolerate the treatment of irinotecan beyond the conventional dose, resulting in better clinical outcomes. However, there seems to be no consensus on the dosage of irinotecan in patients with UGT1A1 wild-type (*1/*1) or heterozygous alleles (such as *1/*28 or *1/*6) (15, 16). In the context of precision and personalized medicine, this is a more reasonable hypothesis. In this study, we systematically reviewed the use of high dose irinotecan in mCRC patients with UGT1A1 wild-type or heterozygous variant to determine whether this was feasible and brought good clinical benefits and acceptable toxicity.

Methods

Search Strategy

We systematically searched PubMed, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) online databases for the period from the time of their inception to October 22, 2021. We targeted studies that selected irinotecan doses in mCRC patients based on UGT1A1 genotype, without restrictions related to region, age or gender. We used Medical Subject Heading (MeSH) terms in PubMed, MEDLINE and CENTRAL, EMTREE terms in EMBASE. We performed keyword searches in the above four databases, and exploded them in EMBASE, MEDLINE, and CENTRAL. The search strategy is provided in the .

Inclusion and Exclusion Criteria

The pieces of literature that met the inclusion criteria were those clinical studies that used higher dose of irinotecan in mCRC patients with UGT1A1 wild-type or heterozygous variant and identified specific doses and outcomes for different genotypes. The exclusion criteria include: 1. Only different genotypes results of UGT1A1 in the population were mentioned, but treatment results were not listed according to genotypes; 2. The sample size of the study was <10; 3. The specific dose of irinotecan in different genotypes of UGT1A1 was not clear or the dose in each genotype was not uniform in the retrospective study; 4. The study only reflected the predictive function of UGT1A1 polymorphism on irinotecan toxicity, and there was no specific dosage record; and 5. The study was on the toxicity or therapeutic responses of conventional doses of irinotecan.

Study Selection and Data Collection

We used the search strategy described above to obtain relevant studies, and then selected pieces of literature based on the inclusion and exclusion criteria. Firstly, we performed a preliminary screening by using the title and abstract of a study to exclude obviously unrelated literature. Then, we downloaded the full text of the candidate papers, and finally the clinical studies of high dose irinotecan in the treatment for mCRC patients with UGT1AI wild-type or heterozygous variant were selected in strict accordance with the screening criteria. Two reviewers independently completed the above screening. For any discrepancy, all reviewers negotiated to reach a consensus.

Two independent reviewers used the data extraction table tested in a pilot study to extract data. If necessary, all reviewers jointly decided whether to include the data. For each included study, the main data extracted were author, year of publication, tumor stage, number of evaluable cases, treatment, recruitment period, duration of follow-up and outcome. The main outcomes included the maximum tolerated dose (MTD) of irinotecan and the therapeutic efficacy and toxicity of high dose irinotecan in mCRC patients with target genotypes. We have excluded data that were not clearly reflected in the papers.

Data Analysis

Detailed meta-analysis was not possible due to the wide variation in the included studies. Therefore, a descriptive approach was used to summarize the data.

Results

From the four databases, we obtained 1,186 relevant literatures. The software excluded 342 duplicates, and we identified 784 apparently unrelated studies by viewing the title and abstract. The full text was reviewed for the remaining 60 pieces of literature, excluding reviews, pieces of literature with repeated contents, and studies with unclear or low dose of irinotecan in mCRC patients with target genotypes. Finally, 14 studies were included for systematic review and summary analysis ( ).

Figure 1

Flow diagram detailing the search strategy and results.

The included studies, from a variety of countries and ethnicities, mainly reflected the MTD of irinotecan in mCRC patients with UGT1A1 wild-type or heterozygous variant, and the chemotherapy response, survival, and toxicity in patients with target genotypes treated with high dose irinotecan.

MTD of Irinotecan in mCRC Patients With UGT1A1 Wild-Type or Heterozygous Variant

Five phase I clinical trials in Asia, Europe and the United States specifically described the MTD of irinotecan in mCRC patients with UGT1A1 wild-type and heterozygous variant ( ) (17–21). UGT1A1 heterozygous variant in two studies from Asian populations included *1/*28 or *1/*6 (19, 20), and the other three studies only included genotype *1/*28 (17, 18, 21). In these five studies, the definition of dose limiting toxicity (DLT) was the same, i.e., hematologic grade 4 toxicity or nonhematologic grade 3 to 4 toxicity, but the definition of MTD generated from DLT was slightly different. The definition of recommended dose in two studies was closer to the conventional definition of MTD (19, 20). Therefore, we proposed to replace MTD with the recommended dose in these two studies.

Table 1

MTD of irinotecan in mCRC patients with UGT1A1 wild-type or heterozygous variant.

Source	Country	Tumor stage	No. of person	Treatment	Judgment criteria	Outcome
Toffoli et al. ( 17 )	Italy and US	mCRC	*1/*1, 35; *1/*28, 24	Dose adjusted irinotecan, day 1; leucovorin, 200 mg/m2, day 1; 5-FU at 400 mg/m2 bolus injection, day 1, followed by 2,400 mg/m2 infusion. Repeat every 2 weeks	DLT was defined as hematologic grade 4 toxicity or nonhematologic grade 3–4 toxicity. MTD was defined as the highest dose at which fewer than 2 of 10 patients experienced DLT	The MTD was 370 mg/m2 for *1/*1 patients and 310 mg/m2 for *1/*28 patients
Marcuello et al. ( 18 )	Spain	White mCRC or a locally advanced recurrence after surgery	*1/*1, 42; *1/*28, 38; *28/*28, 14	Dose adjusted irinotecan, day 1; leucovorin, 200 mg/m2, day 1; 5-FU at 400 mg/m2 bolus injection, day 1, followed by 600 mg/m2/day×2 days infusion. Repeat every 2 weeks	DLT was defined as hematologic grade 4 toxicity or nonhematologic grade 3–4 toxicity. If 2 out of 3 or 2 out of 6 patients experienced DLT, the level below was considered MTD	The MTD was 390 mg/m2 for *1/*1 patients and 340 mg/m2 for *1/*28 patients and 130 mg/m2 for *28/*28 patients
Kim et al. ( 19 )	Korea	mCRC	0 DA group: *1/*1, 23; 1 DA group: *1/*28 or *1/*6, 20; 2 DA group: *28/*28, *6/*6, or *28/*6, 7	Dose adjusted irinotecan plus capecitabine (2,000 mg/m2 days 2–15). Repeat every 3 weeks	DLT was defined as hematologic grade 4 toxicity or nonhematologic grade 3–4 toxicity. MTD was defined as DLT in 2 or more of 6 patients. The recommended dose was defined as the level below this cutoff	The recommended dose was 350 mg/m2, 350 mg/m2 and 200 mg/m2 f for 0, 1, 2 DA group patients, respectively
Kim et al. ( 20 )	Korea	mCRC	0 DA group: *1/*1, 19; 1 DA group: *1/*28 or *1/*6, 20; 2 DA group: *28/*28, *6/*6, or *28/*6, 4	Leucovorin, 200 mg/m2, day 1; 5-FU at 400 mg/m2 bolus injection, day 1, continuous infusion of 2,400 mg/m2 for 46 h, followed by dose adjusted irinotecan. Repeat every 2 weeks	DLT was defined as hematologic grade 4 toxicity or nonhematologic grade 3–4 toxicity. MTD was defined as the dose level at which 2 or more of the 3–6 patients developed DLTs. The recommended dose was defined as 1 dose level under the MTD	The recommended dose was 300, 270, 150 mg/m2 for 0, 1, 2 DA group patients, respectively
Toffoli et al. ( 21 )	US and Italy	Previously untreated mCRC	*1/*1, 25; *1/*28, 23	Dose adjusted irinotecan, day 1; leucovorin, 200 mg/m2, day 1; 5-FU at 400 mg/m2 bolus injection, day 1, followed by 2,400 mg/m2 infusion for 46 h; bevacizumab 5 mg/kg, day 1. Repeat every 2 weeks	DLT was defined as hematologic grade 4 toxicity or nonhematologic grade 3–4 toxicity. MTD was defined as the highest dose at which less than 4 of 10 patients had a DLT	The MTD was 310 mg/m2 for *1/*1 patients and 260 mg/m2 for *1/*28 patients

mCRC, metastatic colorectal cancer; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; DA, defective allele.

In general, in the two-week regime of irinotecan combined with 5-FU and leucovorin (FOLFIRI) (17, 18, 20, 21), the MTD of irinotecan in mCRC patients with UGT1A1 wild-type and heterozygous variant was at least greater than 260 mg/m2, which was significantly higher than the clinical routine dose of 180 mg/m2. In this study, 260 mg/m2 was used as the high dose cutoff value of irinotecan in FOLFIRI. Even the combination of biological agent bevacizumab did not change the pharmacokinetics of irinotecan, and its MTD was not significantly affected in the regimen of FOLFIRI combined with bevacizumab (21). In the three-week regimen combined with capecitabine, it was suggested that the TMD of irinotecan in mCRC patients with UGT1A1 wild-type and heterozygous variant was 350 mg/m2, which was also significantly higher than the clinical routine dose (22).

Outcome of High Dose Irinotecan in mCRC Patients With UGT1A1 Wild-Type or Heterozygous Variant

There were five single-arm (23–27) trials and four double-arm trials (28–31) on the application of FOLFIRI regimen containing high dose irinotecan under the guidance of genotypes in mCRC patients with UGT1A1 *1/*1 or *1/*28. The characteristics and results of these studies are shown in , , respectively. The dose of irinotecan was progressively escalated in some studies, and in others the initial dose was ≥260 mg/m2.

Table 2

Single-arm Trials of High dose Irinotecan based Regimen in mCRC.

Source	Region	Study type	Tumor stage	No. of person	Treatment	Chemotherapy response	Survival time	Toxicity
Hebbar et al. ( 23 )	Europe	Prospective	mCRC with metastases confined to the liver but considered to be unresectable	*1/*1 and *1/*28, 18	HD-FOLFIRI (irinotecan, 260 mg/m2), every 2 weeks. The feasibility of local therapy (surgery and/or radiofrequency) was assessed every 4 cycles of chemotherapy	PR, 8 (44%); SD, 6 (33.3%); DCR, 14, (77.3%); PD, 4 (22%). Local treatment was performed in 6 patients and all were complete clearance	PFS, 15.3 m; OS, 33.7 m	No grade 4 toxicity, and grade 3, 3 times
Lu et al. ( 24 )	Asia	Retrospective	mCRC	Group 1,*1/*1 or *1/*28, 65;Group 2,*28/*28, 5	Bevacizumab plus FOLFIRI, every 2 weeks. Starting dose of irinotecan, 180 mg/m2 for Group 1 and 120 mg/m2 for Group 2. If toxicity ≤grade 3, the dose was escalated by 20 to 30 mg/m2 every 2 cycles. The maximal dose was 260, 240, and 210 mg/m2 for *1/*1, *1/*28 and *28/*28, respectively	Group 1: CR + PR, 50 (76.9%); SD, 11(16.9%); DCR, 61 (93.8%); PD, 4 (6.2%); Group 2: CR + PR, 1 (20%); SD, 1(20%); DCR, 2 (40%); PD, 3 (60%)	PFS was significantly different for the different UGT1A1 genotypes (P = 0.002), and the first Group 1 was longer	Grade 3/4: Group 1, 4 patients; Group 2, 3 patients
Manfredi et al. ( 25 )	Europe	Prospective	mCRC that had not previously been treated	*1/*1, 40; *1/*28, 46	Bevacizumab plus FOLFIRI, and the dose of irinotecan was 260 mg/m². The treatment was stopped in the event of patient withdrawal, disease progression, or unacceptable toxic effects	ORR: *1/*1, 18 (45%); *1/*28, 26 (56.5%)	PFS: *1/*1, 10.7 m; *1/*28, 10.4 m; OS: *1/*1, 25.5 m; *1/*28, 23.9 m	*1/*1, 30 and *1/*28, 37 exhibited at least one grade 3–4 toxicity
Phelip et al. ( 26 )	Europe	Prospective	mCRC with initially borderline-resectable liver metastases, no more than 2 potentially resectable extrahepatic metastases, and KRAS status is wild-type	*1/*1, 9; *1/*28, 14; *28/*28, 3	High dose FOLFIRI (irinotecan 220 mg/m2 for *28/*28, and 260 mg/m2 for *1/*1 and *1/*28) plus cetuximab. Treatment was carried out for 6 cycles in the absence of disease progression or unacceptable toxicity. In cases of objective response and disease that remained unresectable, 2 more cycles were permitted. 23 patients received at least 6 cycles, of which 4 received 8 cycles	The overall cumulative 0RR at 8 cycles was 76.9% (20/26), no PD. Among the 23 patients who received at least 6 cycles, the ORR was 82.6%, metastasectomy, 21 (80.7%)	PFS, 15.8 m, 3-year PFS was 23.3%; OS was not reached and 3-year OS was 66.1%. Among 21 resected patients, 18 (85.7%) had a relapse, with a median relapse-free survival of 15.3 m	Grade 3–4 toxicity: neutropenia (31%), diarrhea (20.8%), anorexia (16.4%). No deaths due to toxicity
Ma et al. ( 27 )	Asia	Prospective	mCRC who were previously treated with FOLFOX, FOLFIRI, anti-VEGFR, or anti-EGFR if KRAS was wild-type	*1/*1, 12; *1/*28, 0; *28/*28, 1	Regorafenib plus FOLFIRI with irinotecan dose escalation (starting dose was 180 mg/m2 for *1/*1 and 120 mg/m2 for *28/*28). The dose was increased by 30 mg/m2 every two cycles until grade ≥3 AEs. The highest prescribed irinotecan dose was 290 mg/m2 for *1/*1 and 120 mg/m2 for *28/*28	PR, 2 (15.4%); SD, 7 (53.8%); DCR, (69.2%); PD, 4 (30.8%)	PFS, 9.5 m (95% CI: 3.0–16.0); OS, 13.0 m (95% CI: 7.2–18.8)	Grade ≥3 AE: hand–foot syndrome, 8; mucositis, 5; neutropenia, 4; diarrhea, 4; fatigue, 3

mCRC, metastatic colorectal cancer; CR, complete response; PR, partial response; ORR, objective response rate; SD, stable disease; DCR, disease control rate; PD, progressive disease; PFS, progression-free survival; OS, overall survival; AE, adverse event; FOLFOX, Oxaliplatin combined with 5-FU and leucovorin; FOLFIRI, irinotecan combined with 5-FU and leucovorin; VEGFR, vascular epithelial growth factor receptor; EGFR, epidermal growth factor receptor; CI, confidence interval.

Table 3

Double-arm Trials of High dose Irinotecan based Regimen in mCRC.

Source	Region	Study type	Tumor stage	No. of person	Treatment	Chemotherapy response	Survival time	Toxicity
Lu et al. ( 28 )	Asia	Retrospective	mCRC	HDG, 79; RDG, 28	Bevacizumab plus FOLFIRI. Starting dose of irinotecan, 180 mg/m2 for *1/*1 and *1/*28, 120 mg/m2 for *28/*28 in HDG. If toxicity ≤grade 3, the dose was escalated by 30 mg/m2. The maximal dose was 260, 240, 210 mg/m2 for *1/*1, *1/*28, and *28/*28, respectively. The dose of RDG was 180 mg/m2	ORR, 55 (69.6%) and 13 (46.4%); SD + PD, 24 (30.4%) and 15 (53.6%) in HDG and RDG, respectively (p = 0.028)	PFS, 12.2 m and 9.4 m in HDG and RDG, respectively (P = 0.025); OS, NA	Grade 3/4 AEs were not significantly different between the 2 groups (P = 0.189)
Páez et al. ( 29 )	Europe	Randomized, multicenter, open-label, non-blinded	mCRC with UGT1A1 *1/*1 or *1/*28, no prior treatment for metastatic disease	HDG, 40; RDG, 39	FOLFIRI. Irinotecan doses for *1/*1 and *1/*28 in HDG were 300 and 260 mg/m2, respectively; and 180 mg/m2 was administered in RDG	ORR, 27 (67.5%) and 17 (43.6%) (p = 0.001); SD, 3 (7.5%) and 17 (43.6%); PD, 10 (25%) and 5 (12.8%); metastasectomy, 9 (22.5%) and 6 (15.4%) in HDG and RDG, respectively	PFS, 8.6 m and 8.2 m (P = 0.46); OS, 26 m and 17.6 m (P = 0.74) in HDG and RDG, respectively	No significant differences in grade 3–4 toxicities between the two groups. No differences in serious AEs, dose reduction, or use of G-CSF
Tsai et al. ( 30 )	Asia	Multicenter, randomized, controlled, open-label	mCRC	HDG: *1/*1, 82; *1/*28, 23; *28/*28, 2; RDG,106	Bevacizumab plus FOLFIRI. Starting dose of irinotecan, 180 mg/m2 for *1/*1 and *1/*28, 120 mg/m2 for *28/*28 in HDG. If toxicity ≤grade 3, the dose was escalated by 30 mg/m2. The maximal dose was 260, 240, 180 mg/m2 for *1/*1, *1/*28, and *28/*28, respectively. The dose of RDG was 180 mg/m2	ORR, 77 (71.9%) and 44 (41.5%) (p <0.001); DCR, 98 (91.6%) and 83 (78.2%) (p = 0.007); PD, 9 (8.4%) and 23 (21.7%); metastasectomy, 34 (31.8%) and 17 (16.1%) (p = 0.007) in HDG and RDG, respectively	PFS, 14.0 m and 10.0 m (P <0.001); OS, 30 m and 22 m (P = 0.02) in HDG and RDG, respectively	Irinotecan-related grade 3/4 AEs, 25 (23.4%) and 25 (23.6%) in HDG and RDG, respectively (P = 0.520)
Hsieh et al. ( 31 )	Asia	Retrospective	mCRC with BRAF mutation, and UGT1A1 *1/*1 or *1/*28	HDG, 8; RDG, 9	Bevacizumab plus FOLFIRI. Starting dose of irinotecan was 180 mg/m2 and the dose was escalated 20–30 mg/m2 until grade 3/4 AEs in HDG. The maximum dose reached 260, 240, 210 mg/m2 in 4, 2 and 2 patients, respectively. The dose of RDG was 180 mg/m2	PR, 1 (12.5%) and 1 (11.1%); SD, 5 (62.5%) and 4 (44.4%); DCR, 75% and 55.6%; PD, 2 (25%) and 4 (44.4%) in HDG and RDG, respectively (p = 0.697)	PFS, 11.5 m and 5.7 m (P = 0.552); OS, 15.8 m and 14.5 m (P = 0.40) in HDG and RDG, respectively	In total, grade 3 toxicity, 2 (11.8%) patients, and no grade 4/5 toxicity

mCRC, metastatic colorectal cancer; HDG, High dose group; RDG, routine dose group; FOLFIRI, irinotecan combined with 5-FU and leucovorin; ORR, objective response rate; SD, stable disease; DCR, disease control rate; PD, progressive disease; PFS, progression-free survival; OS, overall survival; AE, adverse event.

Single-Arm Trials Results

In the single-arm trials, three studies from Europe directly used high dose irinotecan according to the guidance of UGT1A1 genotypes (23, 25, 26), while two studies from Asia used the dose escalation of irinotecan (24, 27).

A prospective study was about high dose FOLFIRI (260 mg/m2) combined with local surgery and radiofrequency ablation for the unresectable liver metastases from CRC patients with UGT1A1 *1/*1 or *1/*28 (23). Due to insufficient recruitment, the trial was terminated early. The evaluable results showed good objective response rate (ORR), disease control rate (DCR), high complete clearance rate, promising survival and excellent safety.

Three studies focused on high dose FOLFIRI in combination with biologics for mCRC. One of these, direct high dose FOLFIRI plus bevacizumab, was prematurely terminated due to the high incidence of overly strict toxicity events specified in the trial protocol, leading to a possible outcome bias (25). The other two studies were dose-escalating FOLFIRI combined with bevacizumab (24) and direct high dose FOLFIRI combined with cetuximab (26) based on UGT1A1 genotypes, including, UGT1A1 homozygous variant (*28/*28). The results suggested that high dose FOLFIRI combined with biological agents can have good chemotherapy response rate, survival and tolerable toxicity in mCRC with UGT1A1 wild-type and heterozygous variant.

Another trial of dose-escalating FOLFIRI in combination with regorafenib based on UGT1A1 genotypes, as a non-first-line treatment for mCRC, also demonstrated a tolerable toxicity associated with irinotecan and an effective clinical outcome that can improve survival (27).

Double-Arm Trials Results

In the double-arm trials, both retrospective and prospective studies demonstrated similar safety and no significant difference in toxicity between high dose and routine dose FOLFIRI based on UGT1A1 genotypes in mCRC.

In the two retrospective studies, the treatment was FOLFIRI combined with bevacizumab. In the high dose group of mCRC with UGT1A1 *1/*1 or *1/*28, the dose of irinotecan was gradually increased to or close to 260 mg/m2, while the dose of irinotecan in the routine dose group remained at 180 mg/m2. One of the studies showed statistically significant improvements in chemotherapy response (p = 0.028) and progression-free survival (PFS) (p = 0.025) in the high dose group over the routine dose group (28). In another small sample study of mCRC with BRAF mutation, although the high dose group showed an advantage in survival, there was no statistically significant difference (31).

A multicenter, open-label randomized trial from Europe (29) showed that in mCRC with UGT1A1 *1/*1 or *1/*28, high dose FOLFIRI group (irinotecan doses was 300 mg/m2 for *1/*1 and 260 mg/m2 for *1/*28) had a significant advantage in chemotherapy response (p = 0.001). The survival was also better than that in the routine dose group, but was not statistically significant.

In a multicenter, open-label randomized controlled trial from Asia (30), the high dose group was treated with dose-escalating FOLFIRI combined with bevacizumab for mCRC and the maximal dose of irinotecan was 260, 240, and 180 mg/m2 for UGT1A1 *1/*1, *1/*28, and *28/*28, respectively. The dose of irinotecan in the routine dose group remained at 180 mg/m2 without UGT1A1 test. Compared with the routine dose group, the high dose group showed significant advantages in chemotherapy response (ORR, P <0.001; DCR, p = 0.007; metastasectomy, p = 0.007) and survival (PFS, P <0.001; OS, P = 0.02).

Discussion

Previous systematic review suggested that for low dose irinotecan, the absolute risk of toxicity in patients with UGT1A1 *28/*28 genotype is similar to the overall risk of all patients. However, moderate and high dose irinotecan increased the absolute risk of toxicity (32, 33), suggesting the tolerance of patients with UGT1A1 wild-type or heterozygous variant to high dose of irinotecan. With conventional dose of irinotecan, the chemotherapy response rate and survival of patients with UGT1A1 *1/*1 was worse than that of patients with UGT1A1 *28/*28 (34–36), which was associated with the higher glucuronidation rate of SN38 (34). Therefore, in order to improve the response rate and even survival of chemotherapy based on irinotecan in patients with UGT1A1 wild-type or heterozygous variant, it is necessary to reasonably increase the dose of irinotecan on the premise of tolerable toxicity. The results of this systematic review basically confirm this hypothesis.

The studies finally included in this system review have been carried out in the past decade, from the exploration of the MTD of irinotecan in CRC patients with UGT1A1 wild-type and heterozygous variant in the early stage, to the single-arm study of the therapeutic effect of high dose irinotecan on target patient groups, and to the randomized controlled double-arm trials carried out in recent years. These studies have shown that the MTD of irinotecan in CRC patients with UGT1A1 wild-type and heterozygous variant was significantly higher than the conventional recommended dose. Chemotherapy based on high dose irinotecan in the treatment of mCRC patients with UGT1A1 *28 wild-type and heterozygous variant can improve the clinical efficacy, and the toxicity was tolerable, which has been reflected in most studies.

In the first-line treatment, high dose FOLFIRI alone has shown a satisfactory chemotherapy response rate (23, 29), with an ORR of 67.5% in the randomized controlled study, although there was no statistical advantage in survival (29). Chemotherapy combined with biologics has shown a survival advantage over chemotherapy alone in first-line treatment of mCRC (37–40). High dose FOLFIRI in combination with bevacizumab or cetuximab in patients with wild-type or heterozygous variant of UGT1A1 *28 have yielded good clinical outcomes (24–26, 28, 30). Survival in the randomized controlled trial (30) is equivalent to that of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) combined with bevacizumab (41, 42). This makes us look forward to the study of high dose FOLFOXIRI combined with anti-vascular endothelial growth factor receptor or anti-epidermal growth factor receptor or immunotherapy in selected target mCRC patients according to UGT1A1 genotypes.

BRAF mutation exists in approximately 10% of CRC (43). The BRAF mutation is related to reduced overall survival and poor treatment response compared with tumors with wild-type BRAF (44, 45). High dose FOLFIRI in mCRC patients with UGT1A1 *28 wild-type or heterozygous variant and BRAF mutant showed a survival advantage (31) and represented statistical difference from the routine dose in the subgroup analysis of a randomized controlled trial (29). In addition, in the small sample trial of non-first-line treatment, the exploration of adjusting the dose of irinotecan in mCRC patients based on UGT1A1 has also achieved positive results (27). These encouraging results suggested a bright application prospect of high dose irinotecan in multi-stages and multi-genotypes of mCRC with UGT1A1 wild-type or heterozygous variant.

In view of the available evidence and the convenience of commercial test (46), we recommend testing UGT1A1 in CRC patients who will undergo irinotecan-based chemotherapy and increasing the dose of irinotecan in patients with UGT1A1 *28 wild-type or heterozygous variant to improve clinical efficacy, which is consistent with the Pan-Asian adapted European Society for Medical Oncology consensus guidelines (47) and the latest comments of Karas et al. (48). It can be applied directly with the recommended MTD or gradually increased from routine dose to MTD by chemotherapy cycle based on safety considerations. For patients with UGT1A1 *28/*28 mutant alleles, initial dose of irinotecan can be reduced by 30% based on safety considerations, although this may lead to poor chemotherapy response and survival (49). However, the dose escalation to standard or higher dose can be considered according to the tolerance of toxicity.

Due to the large heterogeneity of the studies included in this review, such as differences in study types, dose increase methods of irinotecan, treatment methods, types of participants, etc., the outcome could not be quantitatively pooled, but qualitative analysis, which reduced the reliability of evidence. In addition, the included clinical studies of high dose irinotecan for mCRC, whether single-arm or double-arm trials, did not cover the UGT1A1 *6 genotype, which has a greater impact on the Asian population (50–52). These were the obvious major deficiencies of this review, and it is expected that more high-quality randomized controlled studies will be conducted in the future to provide high-level evidence support for the rational application of chemotherapy based on high dose irinotecan in CRC patients with UGT1A1 wild-type or heterozygous.

In conclusion, through the summary of this review, we are optimistic about the application of high dose irinotecan for mCRC patients with UGT1A1 *28 wild-type or heterozygous variant, which will provide a clear direction for future clinical research and certain norms for clinical practice.

Data Availability Statement

The original contributions presented in the study are included in the article/ . Further inquiries can be directed to the corresponding author.

Author Contributions

HZ and BH designed the project. YL, XZ, YX, and LW searched pieces of literature and wrote the manuscript. YL, YZ and MC revised the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Funding

This study was supported by the National Natural Scientific Foundation of China (Nos. 82174463 and 82174465) and the CACMS Innovation Fund (No. CI2021A01804). The funding sources had no role in the design and conduct of the study and collection, management, analysis, and interpretation of the data.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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