A single-arm phase II trial of UGT1A1 genotype–guided high-dose irinotecan rechallenge in refractory metastatic colorectal cancer

A single-arm phase II trial of UGT1A1 genotype–guided high-dose irinotecan rechallenge in refractory metastatic colorectal cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A single-arm phase II trial of UGT1A1 genotype–guided high-dose irinotecan rechallenge in refractory metastatic colorectal cancer Hana Kim, Joohyun Hong, Sun-Young Kong, Moon Ki Choi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7811670/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background There is an unmet need for optimal third- or later-line treatment options for patients with refractory or metastatic colorectal cancer (mCRC). This phase II study evaluated whether high-dose irinotecan rechallenge guided by UGT1A1 genotype could improve the 12-week disease control rate (12-week DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety among patients with refractory mCRC. Methods Patients who had previously received at least two lines of chemotherapy, including 5-fluorouracil, oxaliplatin, and irinotecan, and who had shown a partial or durable response to irinotecan lasting more than 24 weeks were included. Patients without a defective allele of UGT1A1 ( UGT1A1 *1/*1) and one defective allele ( UGT1A1 *1/*6, *1/*28) were treated with intravenous irinotecan at doses of 300 mg/m 2 and 250 mg/m 2 , respectively, every 2 weeks until disease progression or unacceptable toxicity. Results A total of 32 patients were enrolled between October 2020 and March 2023. The primary endpoint, 12-week DCR, was 40.6% (13 of 32 patients). The ORR was 15.6% (5 of 32). The median OS was 9.3 months (95% CI, 5.3 to 13.3) and the median PFS was 2.9 months (95% CI, 2.5 to 3.3). Grade 3 or higher adverse events were observed in 19 patients (59.4%). Dose reduction occurred in 9 (50.0%) of the UGT1A1 wild-type group and 4 (28.6%) of the heterozygous group. Conclusion High-dose irinotecan rechallenge guided by UGT1A1 genotype appeared feasible and achieved disease control as a third- or later-line therapy in patients with mCRC who had previously responded to irinotecan. Trial registration: KCT0005303 (UHD clinical trial, approval date: September 22, 2022) metastatic colorectal cancer UGT1A1 genotype irinotecan rechallenge Figures Figure 1 Figure 2 Introduction Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide ( 1 ), and the 5-year survival rate for metastatic colorectal cancer (mCRC) remains approximately 14% ( 2 ). First- and second-line treatment options for mCRC typically include fluoropyrimidine-based regimens combined with irinotecan or oxaliplatin, along with targeted agents such as anti-vascular endothelial growth factor (anti-VEGF) agent (bevacizumab) or anti-epidermal growth factor receptor (anti-EGFR) agent (cetuximab), particularly in patients with RAS wild-type tumors. These regimens have been shown to improve survival outcomes ( 3 ). Regorafenib or trifluridine/tipiracil hydrochloride (TAS-102) has been approved as third- or later-line treatment options, but their efficacy remains modest, and concerns persist regarding treatment-related adverse events ( 4 , 5 , 6 , 7 , 8 , 9 ). In a study comparing TAS-102 plus bevacizumab with TAS-102 monotherapy, the combination group demonstrated a median progression-free survival (PFS) of 5.6 months and a 12-month overall survival (OS) rate of 43%, while the TAS-102 alone group showed a median PFS of 2.4 months and a 12-month OS rate of 30% ( 10 ). Another study comparing fruquintinib with placebo in metastatic CRC reported an extension of overall survival by 2.6 months ( 11 ). Although both studies showed improved PFS and survival outcomes compared to their respective control groups, the observed benefits were clinically modest. The optimal treatment for patients with refractory mCRC remains uncertain. Consequently, there is an unmet need for more effective and safer third- or later-line therapies for patients with refractory mCRC. The most widely used chemotherapeutic agent for mCRC is 5-fluorouracil (5-FU), a synthetic fluorinated pyrimidine analogue of uracil. It is commonly administered as part of combination regimens such as FOLFOX and FOLFIRI, which include oxaliplatin or irinotecan, respectively, and are often used in conjunction with bevacizumab as frontline treatments for mCRC ( 12 , 13 ). However, resistance to 5-FU can develop through several mechanisms, including altered anabolic metabolism that limits the formation of its primary active metabolite, fluorodeoxyuridylate; increased expression or activity of its main enzymatic target, thymidylate synthase; and dysregulation of programmed cell death pathways ( 14 ). Each of these factors contributes significantly to 5-FU resistance. In addition, 5-FU therapy can be associated with predictable toxicity in patients carrying polymorphisms in the dihydropyrimidine dehydrogenase ( DPYD ) gene, which impair hepatic degradation of the drug ( 15 ). As a result, personalized treatment strategies are gaining importance—particularly at a dose for identifying genetic variations that may help overcome resistance and minimize treatment-related toxicity. Advances in biotechnology have enabled new approaches, such as the use of patient-derived xenograft models that incorporate individual genomic profiles to guide therapeutic decisions ( 16 ). Furthermore, prognosis can now be predicted by calculating the tumor necrosis ratio through artificial intelligence–driven digital pathology analysis of patient-derived tissue samples ( 17 ). Irinotecan, a topoisomerase inhibitor, is most frequently used in combination with other drugs to treat advanced or metastatic CRC. Common side effects of irinotecan include diarrhea, vomiting, hair loss, shortness of breath, fever, and marrow suppression ( 18 ). In the body, irinotecan is converted into an active metabolite known as SN-38, which is then detoxified by a uridine diphosphate-glucosyltransferase (UGT) enzyme encoded by the UGT1A1 gene. Consequently, the risk of irinotecan toxicity increases in the presence of genetic variants that reduce UGT enzyme activity, such as UGT1A1 *28 ( 19 ). Several studies have demonstrated that the UGT1A1 *28 allele is related to irinotecan-induced adverse events ( 20 , 21 ). Patients who possess two copies of the UGT1A1 *28 allele (homozygous, UGT1A1 *28/*28) are more likely to develop neutropenia following irinotecan treatment ( 22 ). Because current third- or later-line treatment options have demonstrated limited therapeutic efficacy, several recent studies have compared chemotherapy rechallenge using agents such as regorafenib, TAS-102, or fruquintinib ( 9 , 23 , 24 ). Irinotecan rechallenge with or without cetuximab has also been reported in several studies ( 9 , 25 , 26 ). However, most studies on rechallenge treatments have been retrospective. Therefore, in this prospective study, we investigated the efficacy and safety of high-dose irinotecan rechallenge guided by UGT1A1 genotype in patients with refractory mCRC as a later-line treatment option. The use of high-dose irinotecan carries a potential risk of bone marrow suppression. To reduce treatment-related adverse events, particularly neutropenia, UGT1A1 genotyping was planned prior to irinotecan treatment initiation. Methods Trial design and patients The study was designed as a single-arm, prospective phase II trial. The protocol was approved by the Institutional Review Board of the National Cancer Center (IRB No. NCC2020-0100). The trial was registered as the UHD trial and approved on September 22, 2022. Between October 2020 and March 2023, a total of 32 patients with metastatic colorectal cancer were enrolled at the National Cancer Center. Eligible patients were aged ≥ 19 years and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were required to have received at least two prior lines of systemic chemotherapy regimens, including irinotecan-based therapy. Additional inclusion criteria included having achieved a complete response (CR), partial response (PR), or stable disease (SD) lasting ≥ 24 weeks during prior irinotecan-containing chemotherapy. UGT1A1 testing was performed prior to treatment; patients with two copies of the defective alleles ( UGT1A1 *28/*28, *6/*6, *6/*28) were excluded. Patients without a defective allele ( UGT1A1 *1/*1) and those with one defective allele ( UGT1A1 *1/*6, *1/*28) received intravenous irinotecan at a dose of 300 mg/m 2 and 250 mg/m 2 , respectively, every 2 weeks until disease progression or unacceptable toxicity (Fig. 1 ). The detailed trial protocol is available in the Supplementary Material. UGT1A1 genotyping Genomic DNA was extracted from peripheral blood leukocytes using the Chemagic 360-D system following the manufacturer's instructions (PerkinElmer Chemagen Technologie GmbH, Germany). Conditions for PCR were as follows: denaturation for 5 min at 94°C, 30 sec at 94°C, 40 sec at 60°C, and 1 min at 72°C for 35 cycles, followed by a final extension for 5 min at 72°C with SimpliAmp (Applied Biosystems, USA). Direct sequencing was performed using the BigDye® Terminator v3.1 Cycle Sequencing Kit and 3730 DNA analyzer (Applied Biosystems, USA). The obtained sequences were compared with the UGT1A1 reference sequence (accession number: NM_000463.2) and the haplotype was annotated according to UGT1A1 allele nomenclature guidelines ( 27 ). Outcomes and statistical analysis Tumor responses were evaluated by computed tomography (CT) every 6 weeks from the initiation of chemotherapy, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Adverse events (AEs) were assessed prior to treatment, at each study visit, and for at least 100 days following treatment discontinuation. AEs were categorized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. The primary endpoint was the 12-week disease control rate (12-week DCR). The secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The DCR was defined as the proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD). The ORR was defined as the proportion of patients achieving CR or PR. PFS was measured from the initiation date of study drug to the first observation of disease progression or death from any cause. OS was calculated from the date of chemotherapy initiation to death from any cause. The sample size was calculated to reject 20% DCR in favor of a target DCR of 40%, with a significance level of 0.05 and a power of 80%, using Simon’s two-stage design. In the first stage, 18 patients were enrolled. If 5 or more of these patients demonstrated disease control at 12 weeks, the study proceeded to the second stage. In the second stage, at least 14 additional patients were enrolled. Categorical variables are presented as counts and percentages, and continuous variables are summarized using medians and ranges. The response rates and patients’ clinical characteristics were evaluated using the χ² test or Fisher’s exact test for categorical variables. Kaplan-Meier analysis was used to estimate PFS and OS. Logistic regression analyses were performed to identify factors associated with a higher likelihood of clinical benefit. All statistical analyses were performed using SPSS version 27.0.1 (SPSS Inc., Chicago, IL, USA). Results Patient characteristics Patient demographics are summarized in Table 1 . The median age was 61 years, and 63% of the patients were male. Eighteen patients had no defective UGT1A1 alleles ( UGT1Ain *1/*1), while 14 patients carried one defective allele ( UGT1A1 *1/*6, *1/*28). All patients had metastatic colorectal cancer and had received at least two prior systemic chemotherapy regimens, including seven who had undergone four or more lines of therapy. Most tumors were left-sided, with only one right-sided case. The most common metastatic sites were the lung (75.0%), liver (59.4%), and peritoneum (21.9%). The best response to prior irinotecan-based chemotherapy was partial response (PR) in 16 patients (50%) and stable disease (SD) in 16 patients (50%). The median irinotecan-free interval was 11.3 months (range 3.1–65.4). The UGT1A1 gene variants and allele type of all patients are presented in Supplementary Table S1 . Efficacy The data cutoff date was March 31, 2025, with a median follow-up of 10.0 months (range, 0.4–39.6). The primary endpoint, 12-week disease control rate (12-week DCR), was 40.6% (13 of 32), including 3 partial responses (PR) and 10 cases of stable disease (SD). Based on the best overall response, the disease control rate was 65.6% (21 of 32 patients) (Table 2 ). The objective response rate (ORR) was 15.6% (5 of 32). The median progression-free survival (PFS) was 2.9 months (95% CI, 2.5–3.3), and the median overall survival (OS) was 9.3 months (95% CI, 5.3–13.3) (Fig. 2 A and 2 B). In subgroup analysis, the median PFS was 4.0 months (95% CI, 1.7–6.3) for the UGT1A1 0-defective allele group and 1.6 months (95% CI, 0-3.3) for the UGT1A1 1-defective allele group (p = 0.20). The median OS was 9.3 months (95% CI, 4.3–14.3) for the UGT1A1 0-defective group and 8.4 months (95% CI, 0-18.6) for the UGT1A1 1-defective group (Fig. 2 C, 2 D). Among the 14 patients with one defective UGT1A1 allele, 8 had the *1/*6 genotype and 6 had the *1/*28 genotype. In subgroup analysis of the UGT1A1 *1 allele-deficient group, the OS for the *1/*6 UGT1A1 group was 4.6 months (95% CI, 0-11.9) and the PFS was 1.3 months (95% CI, 1.0-1.6). For the *1/*28 UGT1A1 group, the OS was 10.2 months (95% CI, 0.5–19.9), and the PFS was 2.3 months (95% CI, 0.7–3.3) (Figure S2). There was no statistically significant difference in OS or PFS among the *1/*1, *1/*6, and *1/*28 genotype groups. Analyses of predictive factors for PFS, OS, and response rate are provided in Supplementary Materials (Table S2-S4). An ECOG performance status of 1 was associated with a numerically worse OS compared to ECOG 0, although the difference was not statistically significant (HR 2.699, 95% CI 0.910–8.002, p = 0.073). No statistically significant factors affecting treatment outcomes were identified. Safety The treatment-related adverse events (AEs) are summarized in Table 3 . Treatment-related AEs of any grade were observed in 30 patients (30 of 32, 93.8%). The most frequently reported treatment-related AEs of any grade were nausea (68.8%), alopecia (62.5%), and mucositis (37.5%) (Table 3 ). Grade ≥ 3 adverse events occurred in 19 patients (59.4%). There was one case of treatment-related death due to sepsis. Grade 3 or 4 AEs included neutropenia (n = 9), nausea (n = 5), anemia (n = 2), vomiting (n = 2), anorexia (n = 2), and diarrhea (n = 1). Dose reduction was required in 9 of 18 patients (50.0%) in the UGT1A1 wild-type group and in 4 of 14 patients (28.6%) with a single defective allele. Discussion Patients with metastatic CRC who fail second-line chemotherapy generally tend to have poor survival outcomes. Regorafenib and TAS-102 have been approved as treatment options in the later-line setting for patients whose disease progressed after fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, combined with anti-VEGF therapy and, if RAS wild type, anti-EGFR therapy. In a phase 3 trial, regorafenib, an oral multi-kinase inhibitor, extended median overall survival (OS) by 1.4 months compared to placebo (6.4 versus 5.0 months; p = 0.0052). Grade 3 or 4 treatment-related AEs occurred in 54% of patients, and serious adverse events were reported in 44% ( 4 ). TAS-102 demonstrated a median OS benefit of 1.9 months over placebo (7.1 versus 5.3 months; p < 0.001). Grade 3 or higher AEs occurred in 69% of the TAS-102 group and 52% of the placebo group ( 7 ). Both regorafenib and TAS-102 are viable treatment options for refractory, metastatic CRC; however, their efficacies are modest, and the treatment-related adverse events can be significant. A study comparing TAS-102 plus bevacizumab to TAS-102 alone found that the combination improved median PFS (5.6 vs. 2.4 months) and 12-month OS (43% vs. 30%) ( 10 ). The FRESCO-2 study showed that fruquintinib extended overall survival by 2.6 months compared with placebo in metastatic CRC ( 11 ). Although these recent treatments have demonstrated improved outcomes, their use may be challenging in low-resource settings. In this phase II study, high-dose irinotecan rechallenge resulted in a 12-week disease control rate (12-week DCR) of 40.6% and an objective response rate (ORR) of 15.6% in patients with metastatic colorectal cancer (mCRC). The median progression-free survival (PFS) was 4.0 months in the UGT1A1 0-defective group and 1.6 months in the UGT1A1 1-defecitive group. The UGT1A1 0-defective group, which received a higher irinotecan dose of 300 mg/m², showed a numerically longer PFS than the UGT1A1 1-defecitive group, which received 250 mg/m²; however, this difference was not statistically significant (Fig. 2 ). This may be attributable to the small sample size and therefore warrants confirmation in larger studies. In addition, detailed subgroup analyses could not be performed due to the limited number of patients. Regarding adverse events (AEs), grade ≥ 3 AEs occurred in 59.4% of patients. In the SUN-LIGHT trial, the incidence of grade ≥ 3 AEs was 72.4% in the TAS-102 plus bevacizumab group and 69.5% in the TAS-102 monotherapy group ( 10 ), while in the CORRECT trial, regorafenib was associated with grade ≥ 3 AEs in 54% of patients ( 4 ). Thus, the incidence of severe AEs in our study was somewhat lower than that reported with TAS-102 but higher than with regorafenib. No new safety signals were identified; the observed toxicities were consistent with the known adverse profile of irinotecan, including nausea, vomiting, diarrhea, and bone marrow suppression. The administration of high-dose irinotecan may require more proactive use of antiemetics and antidiarrheal agents, and granulocyte-colony stimulating factor (G-CSF) for neutropenia management. Furthermore, UGT1A1 genotyping before treatment initiation remains important to identify patients at increased risk for hematologic toxicity and to guide appropriate dose adjustments. Despite genotype-guided dosing, treatment-related toxicities remained notable, and one treatment-related death from sepsis was observed. However, excluding patients with two defective alleles ( UGT1A1 *28/*28, *6/*6, or *6/*28) may have reduced the overall incidence of severe AEs. Given that all patients had heavily pretreated disease, including seven who had previously received TAS-102, these findings suggest that UGT1A1 genotype–guided irinotecan rechallenge could be explored as a potential option in selected mCRC patients, although its benefit and safety require further validation. Among the 18 patients in UGT1A1 0-defecitive group who received 300 mg/m 2 of irinotecan, 9 patients (50.0%) underwent dose reductions. Six patients had one dose reduction from 300 mg/m 2 to 250 mg/m 2 , and the remaining three patients had a further dose reduction from 250 mg/m 2 to 200 mg/m 2 due to treatment-related adverse events. In the UGT1A1 1-defecitive group, which received an initial dose of 250 mg/m², four patients (28.6%) required dose reductions—three reduced from 250 mg/m² to 200 mg/m² and one from 200 mg/m² to 150 mg/m². The primary reasons for dose reductions were neutropenia and nausea and vomiting. In the UGT1A1 0-defecitive group, the causes of dose reduction were nausea and vomiting (4 of 9), neutropenia (4 of 9) and diarrhea (1 of 9). In the UGT1A1 1-defecitive group, all causes of dose reduction were due to neutropenia, (4 of 4). The incidence of neutropenia was not higher in the 0-defecitive group despite the higher dose, possibly reflecting effective genotype-based dose adjustment. Four cases of grade 3 nausea and vomiting occurred in the group administered 300 mg/m 2 , suggesting that sufficient antiemetic and premedication strategies are important when rechallenging with higher irinotecan doses. To date, over 135 genetic variants of UGT1A1 have been identified, with the most common variant allele being UGT1A1*28 ( 28 , 29 ). The pyrosequencing method is a rapid and reliable approach for detecting UGT1A1 polymorphisms ( 30 ). After genotyping for UGT1A1 *28, patients homozygous for UGT1A1 *28/*28 should be carefully considered before initiating irinotecan therapy, as they have an increased risk of developing severe neutropenia following treatment initiation ( 31 ). Patients with two defective UGT1A1 alleles are generally recommended to receive a reduced dose of irinotecan ( 32 ). However, there is insufficient evidence to suggest that patients with no defective alleles are more tolerant of high-dose irinotecan than those with a single defective allele. Our study was designed with reference to a phase I trial in which the UGT1A1 genotype–guided maximum tolerated dose was confirmed. In that study, the recommended irinotecan dose was 300 mg/m² for patients with no defective alleles and 270 mg/m² for those with one defective allele ( 21 ) Further studies are warranted to determine whether a genuine difference in irinotecan tolerance exists between patients with one versus no defective alleles Irinotecan is a widely used anticancer agent, and high-dose irinotecan therapy remains a treatment option that can be considered for patients with refractory disease and relatively preserved performance status, including those who have experienced disease progression after TAS-102 plus bevacizumab or fruquintinib. When guided by genotype-based patient selection, irinotecan rechallenge may offer a potential therapeutic approach, although its clinical benefit requires further validation in larger studies. In resource-limited settings, this strategy could be a practical alternative when other treatment options are not available. Furthermore, unlike oxaliplatin, irinotecan is not typically associated with cumulative or irreversible peripheral neuropathy, which may allow its reuse in selected patients; however, this potential advantage should be interpreted with caution given the limited evidence. This study has several limitations. First, it was conducted as a single-arm trial with a relatively small sample size, which limits the generalizability of the findings. The absence of a control group makes it difficult to determine whether the observed outcomes can be directly attributed to the intervention rather than to patient selection or other confounding factors. Although direct comparisons with other third- or later-line chemotherapies are not appropriate, real-world data from Asian patients report median OS of 7.5 months with TAS-102 and 6.5 months with regorafenib ( 33 ). In addition, another real-world study showed a median PFS of 2.1 months for TAS-102 in Asian populations. In another real-world Asian study, the PFS of TAS-102 was 2.1 months( 34 ). Additionally, our study included patients with relatively good general condition (ECOG performance status of 0 or 1) who could tolerate high doses of irinotecan. Therefore, high-dose irinotecan may not be suitable for patients with poor performance status in real-world clinical practice. To the best of our knowledge, this is the first prospective clinical trial to evaluate irinotecan retreatment guided by UGT1A1 genotype. While UGT1A1 genotyping prior to high-dose irinotecan rechallenge could help identify patients who might benefit from dose-intensified therapy, the clinical benefit of this approach remains to be confirmed in larger, controlled studies. Conclusion Our study suggests that high-dose irinotecan rechallenge guided by UGT1A1 testing may provide disease control in selected patients with refractory metastatic colorectal cancer and preserved performance status. However, given the single-arm design, small sample size, and lack of a comparator, these results should be interpreted with caution. Further prospective, randomized studies are needed to validate the efficacy and safety of this approach and to define its role within the broader treatment landscape of metastatic colorectal cancer. Abbreviations 12-week DCR 12-week disease control rate ORR objective response rate PFS progression-free survival OS overall survival CRC colorectal cancer mCRC metastatic colorectal cancer anti-VEGF anti-vascular endothelial anti-EGFR anti-epidermal growth factor receptor TAS-102 trifluridine/tipiracil hydrochloride 5-FU 5-fluorouracil (5-FU) DPYD dihydropyrimidine dehydrogenase UDP uridine diphosphate UGT glucosyltransferase ECOG Eastern Cooperative Oncology Group CR complete response PR partial response SD stable disease RECIST Response Evaluation Criteria in Solid Tumors AEs Adverse events NCI-CTCAE National Cancer Institute Common Terminology Criteria for G-CSF granulocyte-colony stimulating factor Declarations Acknowledgements The authors thank the patients and their families, Boryung corporation for their support of this study. Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and the Korea Good Clinical Practice guidelines. The study protocol was approved (#IRB No. NCC2020-0100, KCT0005303) by the Institutional Review Board of National Cancer Center on March 31, 2020. We obtained consent from the patients involved. Consent for publication Not applicable Availability of data and materials Data are available on reasonable request. Competing interests The authors declare no competing interests. Funding This work was funded by National Cancer Center, Republic of Korea [grant number 1941231 and 2210960]. Irinotecan was provided by Boryung corporation. Authors' contributions Conceptualization, Hana Kim, Moon Ki Choi; methodology, acquisition, validation, formal analysis and investigation, Hana Kim, Joohyun Hong, Sun-Young Kong, Moon Ki Choi; data curation, Hana Kim, Joohyun Hong, Sun-Young Kong, Moon Ki Choi; writing-original draft preparation, Hana Kim, Moon Ki Choi; writing-review and editing, Hana Kim, Joohyun Hong, Sun-Young Kong, Moon Ki Choi; project administration, Moon Ki Choi; funding acquisition, Moon Ki Choi. All authors have read and agreed to the published version of the manuscript. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–93. 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Retreatment of Irinotecan in Later Lines of Therapy for Metastatic Colorectal Cancer: A Retrospective Study. Oncology. 2021;99(10):665–72. [Available from: https://www.pharmacogenomics.pha.ulaval.ca/wp-content/uploads/2015/04/UGT1A1-allele-nomenclature.html Strassburg CP. Pharmacogenetics of Gilbert's syndrome. Pharmacogenomics. 2008;9(6):703–15. Hall D, Ybazeta G, Destro-Bisol G, Petzl-Erler ML, Di Rienzo A. Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. Pharmacogenetics. 1999;9(5):591–9. Sukasem C, Atasilp C, Chansriwong P, Chamnanphon M, Puangpetch A, Sirachainan E. Development of Pyrosequencing Method for Detection of UGT1A1 Polymorphisms in Thai Colorectal Cancers. J Clin Lab Anal. 2016;30(1):84–9. FDA. 2017 Statement from the US Food and Drug Administration (FDA). 2017. Hulshof EC, Deenen MJ, Guchelaar HJ, Gelderblom H. 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Tables Table 1 Patient characteristics Characteristics N = 32 (%) Age (years) Median (range) 61 (47–73) Sex Male 20 (62.5) Female 12 (37.5) ECOG performance status 0 6 (18.8) 1 26 (56.3) Location of primary tumor Right-sided colon 1 (3.1) Left-sided colon 14 (43.8) Rectum 17 (53.1) UGT1A1 genotype 0 defective allele 18 (56.3) 1 defective allele 14 (43.8) Timing of metastases Synchronous 24 (75.0) Metachronous 8 (25.0) No. of metastatic sites 1 9 (28.1) 2 11 (34.4) ≥ 3 12 (37.5) Metastatic sites Lung 24 (75.0) Liver 19 (59.4) Peritoneum 7 (21.9) BRAF , KRAS , and NRAS mutation status All wild type 15 (46.9) BRAF mutant 0 (0) KRAS or NRAS mutant 17 (53.1) No. of prior regimens 2 12 (37.5) 3 13 (40.6) ≥ 4 7 (21.9) Prior systemic anticancer agents Fluoropyrimidine 32 (100.0) Oxaliplatin 32 (100.0) Bevacizumab 31 (96.9) Cetuximab 13 (40.6) TAS-102 7 (21.9) Prior irinotecan-based treatment Treatment line First 14 (43.8) Second 16 (50.0) Third 2 (6.3) Best response Partial response 16 (50.0) Stable disease 16 (50.0) Progression-free survival Median (95% CI) 13.3 (11.8–14.8) Irinotecan-free interval (months) Median (range) 11.3 (3.1–65.4) ECOG, Eastern Cooperative Oncology Group; UGT1A1, UDP-glucosyltransferase 1 family peptide A1; KRAS, Kirsten rat sarcoma; NRAS, neuroblastoma rat sarcoma. Table 2 Treatment outcome Tumor response N = 32 (%) Best overall response Complete response 0 (0) Partial response 5 (15.6) Stable disease 16 (50.0) Progressive disease 8 (25.0) Unable to determine* 3 (9.4) Total disease control No. (%) 21 (65.6) 12-week DCR No. (%) 13 (40.6) Median PFS months (95% CI) 2.9 (2.5–3.3) Median OS, months (95% CI) 9.3 (5.3–13.3) DCR, disease control rate; PFS, progression-free survival; OS, overall survival, * No disease evaluation results; 1 death, 2 EOTs (end of trial) Table 3 Treatment-related adverse events N = 32 Any grade (%) ≥Grade 3 (%) Hematologic Neutropenia 11 (34.4) 9 (28.2) Anemia 2 (6.3) 2 (6.3) Thrombocytopenia 1 (3.1) 1 (3.1) Non-hematologic Nausea 22 (68.8) 5 (15.6) Vomiting 10 (31.3) 2 (6.3) Anorexia 8 (25.0) 2 (6.3) Diarrhea 8 (25.0) 1 (3.1) Sepsis 1 (3.1) 1 (3.1) Fatigue 11 (34.4) 0 (0) Alopecia 20 (62.5) 0 (0) Mucositis 12 (37.5) 0 (0) Abdominal pain 6 (18.8) 0 (0) Weight loss 1 (3.1) 0 (0) Allergic rhinitis 2 (6.3) 0 (0) Skin rash 1 (3.1) 0 (0) Pruritus 1 (3.1) 0 (0) Additional Declarations No competing interests reported. Supplementary Files Supplement.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 20 Nov, 2025 Reviewers agreed at journal 20 Nov, 2025 Reviewers invited by journal 11 Nov, 2025 Editor assigned by journal 22 Oct, 2025 Editor invited by journal 18 Oct, 2025 Submission checks completed at journal 16 Oct, 2025 First submitted to journal 16 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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01:14:34","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":120151,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7811670/v1/7efe80a5974d99892323a811.html"},{"id":96423171,"identity":"3f781eba-1c1f-44d5-b500-98b29971e2ec","added_by":"auto","created_at":"2025-11-21 01:14:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":88706,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrial profile.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7811670/v1/483c8f415a2c4883ae7fe761.png"},{"id":96455229,"identity":"0aa2a6a6-edaf-461f-bbb2-753df767cd78","added_by":"auto","created_at":"2025-11-21 10:03:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":90225,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival (OS), Progression-free survival (PFS)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003eA) OS, all patients group (n=32), (B) PFS, all patients group (n=32), (C) OS analysis by \u003cem\u003eUGT1A1\u003c/em\u003e-defective allele group, (D) PFS by \u003cem\u003eUGT1A1\u003c/em\u003e-deffective allele group.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7811670/v1/0ac96a636ca7dd72cd7196f7.png"},{"id":96603513,"identity":"4e424d35-0728-4ac8-b23f-2a869e1d7265","added_by":"auto","created_at":"2025-11-24 09:09:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":911943,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7811670/v1/feab8b27-029d-4ba7-bb46-9fd9d135e93d.pdf"},{"id":96423175,"identity":"cb5826ba-4711-43aa-9cc5-2b17e0c0d69c","added_by":"auto","created_at":"2025-11-21 01:14:33","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":529755,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-7811670/v1/d76cfd4facaae161a1704dc9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A single-arm phase II trial of UGT1A1 genotype–guided high-dose irinotecan rechallenge in refractory metastatic colorectal cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is the second leading cause of cancer-related death worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), and the 5-year survival rate for metastatic colorectal cancer (mCRC) remains approximately 14% (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). First- and second-line treatment options for mCRC typically include fluoropyrimidine-based regimens combined with irinotecan or oxaliplatin, along with targeted agents such as anti-vascular endothelial growth factor (anti-VEGF) agent (bevacizumab) or anti-epidermal growth factor receptor (anti-EGFR) agent (cetuximab), particularly in patients with RAS wild-type tumors. These regimens have been shown to improve survival outcomes (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Regorafenib or trifluridine/tipiracil hydrochloride (TAS-102) has been approved as third- or later-line treatment options, but their efficacy remains modest, and concerns persist regarding treatment-related adverse events (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In a study comparing TAS-102 plus bevacizumab with TAS-102 monotherapy, the combination group demonstrated a median progression-free survival (PFS) of 5.6 months and a 12-month overall survival (OS) rate of 43%, while the TAS-102 alone group showed a median PFS of 2.4 months and a 12-month OS rate of 30% (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Another study comparing fruquintinib with placebo in metastatic CRC reported an extension of overall survival by 2.6 months (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Although both studies showed improved PFS and survival outcomes compared to their respective control groups, the observed benefits were clinically modest. The optimal treatment for patients with refractory mCRC remains uncertain. Consequently, there is an unmet need for more effective and safer third- or later-line therapies for patients with refractory mCRC.\u003c/p\u003e\u003cp\u003eThe most widely used chemotherapeutic agent for mCRC is 5-fluorouracil (5-FU), a synthetic fluorinated pyrimidine analogue of uracil. It is commonly administered as part of combination regimens such as FOLFOX and FOLFIRI, which include oxaliplatin or irinotecan, respectively, and are often used in conjunction with bevacizumab as frontline treatments for mCRC (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, resistance to 5-FU can develop through several mechanisms, including altered anabolic metabolism that limits the formation of its primary active metabolite, fluorodeoxyuridylate; increased expression or activity of its main enzymatic target, thymidylate synthase; and dysregulation of programmed cell death pathways (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Each of these factors contributes significantly to 5-FU resistance.\u003c/p\u003e\u003cp\u003eIn addition, 5-FU therapy can be associated with predictable toxicity in patients carrying polymorphisms in the dihydropyrimidine dehydrogenase (\u003cem\u003eDPYD\u003c/em\u003e) gene, which impair hepatic degradation of the drug (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). As a result, personalized treatment strategies are gaining importance\u0026mdash;particularly at a dose for identifying genetic variations that may help overcome resistance and minimize treatment-related toxicity. Advances in biotechnology have enabled new approaches, such as the use of patient-derived xenograft models that incorporate individual genomic profiles to guide therapeutic decisions (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Furthermore, prognosis can now be predicted by calculating the tumor necrosis ratio through artificial intelligence\u0026ndash;driven digital pathology analysis of patient-derived tissue samples (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIrinotecan, a topoisomerase inhibitor, is most frequently used in combination with other drugs to treat advanced or metastatic CRC. Common side effects of irinotecan include diarrhea, vomiting, hair loss, shortness of breath, fever, and marrow suppression (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In the body, irinotecan is converted into an active metabolite known as SN-38, which is then detoxified by a uridine diphosphate-glucosyltransferase (UGT) enzyme encoded by the \u003cem\u003eUGT1A1\u003c/em\u003e gene. Consequently, the risk of irinotecan toxicity increases in the presence of genetic variants that reduce UGT enzyme activity, such as \u003cem\u003eUGT1A1\u003c/em\u003e*28 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Several studies have demonstrated that the \u003cem\u003eUGT1A1\u003c/em\u003e*28 allele is related to irinotecan-induced adverse events (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Patients who possess two copies of the \u003cem\u003eUGT1A1\u003c/em\u003e*28 allele (homozygous, \u003cem\u003eUGT1A1\u003c/em\u003e *28/*28) are more likely to develop neutropenia following irinotecan treatment (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBecause current third- or later-line treatment options have demonstrated limited therapeutic efficacy, several recent studies have compared chemotherapy rechallenge using agents such as regorafenib, TAS-102, or fruquintinib (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Irinotecan rechallenge with or without cetuximab has also been reported in several studies (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). However, most studies on rechallenge treatments have been retrospective. Therefore, in this prospective study, we investigated the efficacy and safety of high-dose irinotecan rechallenge guided by \u003cem\u003eUGT1A1\u003c/em\u003e genotype in patients with refractory mCRC as a later-line treatment option. The use of high-dose irinotecan carries a potential risk of bone marrow suppression. To reduce treatment-related adverse events, particularly neutropenia, \u003cem\u003eUGT1A1\u003c/em\u003e genotyping was planned prior to irinotecan treatment initiation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eTrial design and patients\u003c/h2\u003e\u003cp\u003eThe study was designed as a single-arm, prospective phase II trial. The protocol was approved by the Institutional Review Board of the National Cancer Center (IRB No. NCC2020-0100). The trial was registered as the \u003cem\u003eUHD trial\u003c/em\u003e and approved on September 22, 2022. Between October 2020 and March 2023, a total of 32 patients with metastatic colorectal cancer were enrolled at the National Cancer Center. Eligible patients were aged\u0026thinsp;\u0026ge;\u0026thinsp;19 years and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were required to have received at least two prior lines of systemic chemotherapy regimens, including irinotecan-based therapy. Additional inclusion criteria included having achieved a complete response (CR), partial response (PR), or stable disease (SD) lasting\u0026thinsp;\u0026ge;\u0026thinsp;24 weeks during prior irinotecan-containing chemotherapy. \u003cem\u003eUGT1A1\u003c/em\u003e testing was performed prior to treatment; patients with two copies of the defective alleles (\u003cem\u003eUGT1A1\u003c/em\u003e*28/*28, *6/*6, *6/*28) were excluded. Patients without a defective allele (\u003cem\u003eUGT1A1\u003c/em\u003e*1/*1) and those with one defective allele (\u003cem\u003eUGT1A1\u003c/em\u003e*1/*6, *1/*28) received intravenous irinotecan at a dose of 300 mg/m\u003csup\u003e2\u003c/sup\u003e and 250 mg/m\u003csup\u003e2\u003c/sup\u003e, respectively, every 2 weeks until disease progression or unacceptable toxicity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The detailed trial protocol is available in the Supplementary Material.\u003c/p\u003e\u003cp\u003e\u003cb\u003eUGT1A1\u003c/b\u003e \u003cb\u003egenotyping\u003c/b\u003e\u003c/p\u003e\u003cp\u003eGenomic DNA was extracted from peripheral blood leukocytes using the Chemagic 360-D system following the manufacturer's instructions (PerkinElmer Chemagen Technologie GmbH, Germany). Conditions for PCR were as follows: denaturation for 5 min at 94\u0026deg;C, 30 sec at 94\u0026deg;C, 40 sec at 60\u0026deg;C, and 1 min at 72\u0026deg;C for 35 cycles, followed by a final extension for 5 min at 72\u0026deg;C with SimpliAmp (Applied Biosystems, USA). Direct sequencing was performed using the BigDye\u0026reg; Terminator v3.1 Cycle Sequencing Kit and 3730 DNA analyzer (Applied Biosystems, USA). The obtained sequences were compared with the \u003cem\u003eUGT1A1\u003c/em\u003e reference sequence (accession number: NM_000463.2) and the haplotype was annotated according to \u003cem\u003eUGT1A1\u003c/em\u003e allele nomenclature guidelines (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOutcomes and statistical analysis\u003c/h3\u003e\n\u003cp\u003eTumor responses were evaluated by computed tomography (CT) every 6 weeks from the initiation of chemotherapy, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Adverse events (AEs) were assessed prior to treatment, at each study visit, and for at least 100 days following treatment discontinuation. AEs were categorized and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0.\u003c/p\u003e\u003cp\u003eThe primary endpoint was the 12-week disease control rate (12-week DCR). The secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The DCR was defined as the proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD). The ORR was defined as the proportion of patients achieving CR or PR. PFS was measured from the initiation date of study drug to the first observation of disease progression or death from any cause. OS was calculated from the date of chemotherapy initiation to death from any cause.\u003c/p\u003e\u003cp\u003eThe sample size was calculated to reject 20% DCR in favor of a target DCR of 40%, with a significance level of 0.05 and a power of 80%, using Simon\u0026rsquo;s two-stage design. In the first stage, 18 patients were enrolled. If 5 or more of these patients demonstrated disease control at 12 weeks, the study proceeded to the second stage. In the second stage, at least 14 additional patients were enrolled. Categorical variables are presented as counts and percentages, and continuous variables are summarized using medians and ranges. The response rates and patients\u0026rsquo; clinical characteristics were evaluated using the χ\u0026sup2; test or Fisher\u0026rsquo;s exact test for categorical variables. Kaplan-Meier analysis was used to estimate PFS and OS. Logistic regression analyses were performed to identify factors associated with a higher likelihood of clinical benefit. All statistical analyses were performed using SPSS version 27.0.1 (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003ePatient characteristics\u003c/h2\u003e\u003cp\u003ePatient demographics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 61 years, and 63% of the patients were male. Eighteen patients had no defective \u003cem\u003eUGT1A1\u003c/em\u003e alleles (\u003cem\u003eUGT1Ain\u003c/em\u003e *1/*1), while 14 patients carried one defective allele (\u003cem\u003eUGT1A1\u003c/em\u003e*1/*6, *1/*28). All patients had metastatic colorectal cancer and had received at least two prior systemic chemotherapy regimens, including seven who had undergone four or more lines of therapy. Most tumors were left-sided, with only one right-sided case. The most common metastatic sites were the lung (75.0%), liver (59.4%), and peritoneum (21.9%). The best response to prior irinotecan-based chemotherapy was partial response (PR) in 16 patients (50%) and stable disease (SD) in 16 patients (50%). The median irinotecan-free interval was 11.3 months (range 3.1\u0026ndash;65.4). The \u003cem\u003eUGT1A1\u003c/em\u003e gene variants and allele type of all patients are presented in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003eThe data cutoff date was March 31, 2025, with a median follow-up of 10.0 months (range, 0.4\u0026ndash;39.6). The primary endpoint, 12-week disease control rate (12-week DCR), was 40.6% (13 of 32), including 3 partial responses (PR) and 10 cases of stable disease (SD). Based on the best overall response, the disease control rate was 65.6% (21 of 32 patients) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The objective response rate (ORR) was 15.6% (5 of 32). The median progression-free survival (PFS) was 2.9 months (95% CI, 2.5\u0026ndash;3.3), and the median overall survival (OS) was 9.3 months (95% CI, 5.3\u0026ndash;13.3) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003eIn subgroup analysis, the median PFS was 4.0 months (95% CI, 1.7\u0026ndash;6.3) for the \u003cem\u003eUGT1A1\u003c/em\u003e 0-defective allele group and 1.6 months (95% CI, 0-3.3) for the \u003cem\u003eUGT1A1\u003c/em\u003e 1-defective allele group (p\u0026thinsp;=\u0026thinsp;0.20). The median OS was 9.3 months (95% CI, 4.3\u0026ndash;14.3) for the \u003cem\u003eUGT1A1\u003c/em\u003e 0-defective group and 8.4 months (95% CI, 0-18.6) for the \u003cem\u003eUGT1A1\u003c/em\u003e 1-defective group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Among the 14 patients with one defective \u003cem\u003eUGT1A1\u003c/em\u003e allele, 8 had the *1/*6 genotype and 6 had the *1/*28 genotype. In subgroup analysis of the \u003cem\u003eUGT1A1\u003c/em\u003e *1 allele-deficient group, the OS for the *1/*6 \u003cem\u003eUGT1A1\u003c/em\u003e group was 4.6 months (95% CI, 0-11.9) and the PFS was 1.3 months (95% CI, 1.0-1.6). For the *1/*28 \u003cem\u003eUGT1A1\u003c/em\u003e group, the OS was 10.2 months (95% CI, 0.5\u0026ndash;19.9), and the PFS was 2.3 months (95% CI, 0.7\u0026ndash;3.3) (Figure S2). There was no statistically significant difference in OS or PFS among the *1/*1, *1/*6, and *1/*28 genotype groups. Analyses of predictive factors for PFS, OS, and response rate are provided in Supplementary Materials (Table S2-S4). An ECOG performance status of 1 was associated with a numerically worse OS compared to ECOG 0, although the difference was not statistically significant (HR 2.699, 95% CI 0.910\u0026ndash;8.002, p\u0026thinsp;=\u0026thinsp;0.073). No statistically significant factors affecting treatment outcomes were identified.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eSafety\u003c/h2\u003e\u003cp\u003eThe treatment-related adverse events (AEs) are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Treatment-related AEs of any grade were observed in 30 patients (30 of 32, 93.8%). The most frequently reported treatment-related AEs of any grade were nausea (68.8%), alopecia (62.5%), and mucositis (37.5%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events occurred in 19 patients (59.4%). There was one case of treatment-related death due to sepsis. Grade 3 or 4 AEs included neutropenia (n\u0026thinsp;=\u0026thinsp;9), nausea (n\u0026thinsp;=\u0026thinsp;5), anemia (n\u0026thinsp;=\u0026thinsp;2), vomiting (n\u0026thinsp;=\u0026thinsp;2), anorexia (n\u0026thinsp;=\u0026thinsp;2), and diarrhea (n\u0026thinsp;=\u0026thinsp;1). Dose reduction was required in 9 of 18 patients (50.0%) in the \u003cem\u003eUGT1A1\u003c/em\u003e wild-type group and in 4 of 14 patients (28.6%) with a single defective allele.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with metastatic CRC who fail second-line chemotherapy generally tend to have poor survival outcomes. Regorafenib and TAS-102 have been approved as treatment options in the later-line setting for patients whose disease progressed after fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, combined with anti-VEGF therapy and, if RAS wild type, anti-EGFR therapy. In a phase 3 trial, regorafenib, an oral multi-kinase inhibitor, extended median overall survival (OS) by 1.4 months compared to placebo (6.4 versus 5.0 months; p\u0026thinsp;=\u0026thinsp;0.0052). Grade 3 or 4 treatment-related AEs occurred in 54% of patients, and serious adverse events were reported in 44% (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). TAS-102 demonstrated a median OS benefit of 1.9 months over placebo (7.1 versus 5.3 months; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Grade 3 or higher AEs occurred in 69% of the TAS-102 group and 52% of the placebo group (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Both regorafenib and TAS-102 are viable treatment options for refractory, metastatic CRC; however, their efficacies are modest, and the treatment-related adverse events can be significant. A study comparing TAS-102 plus bevacizumab to TAS-102 alone found that the combination improved median PFS (5.6 vs. 2.4 months) and 12-month OS (43% vs. 30%) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The FRESCO-2 study showed that fruquintinib extended overall survival by 2.6 months compared with placebo in metastatic CRC (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Although these recent treatments have demonstrated improved outcomes, their use may be challenging in low-resource settings.\u003c/p\u003e\u003cp\u003eIn this phase II study, high-dose irinotecan rechallenge resulted in a 12-week disease control rate (12-week DCR) of 40.6% and an objective response rate (ORR) of 15.6% in patients with metastatic colorectal cancer (mCRC). The median progression-free survival (PFS) was 4.0 months in the \u003cem\u003eUGT1A1\u003c/em\u003e 0-defective group and 1.6 months in the \u003cem\u003eUGT1A1\u003c/em\u003e 1-defecitive group. The \u003cem\u003eUGT1A1\u003c/em\u003e 0-defective group, which received a higher irinotecan dose of 300 mg/m\u0026sup2;, showed a numerically longer PFS than the \u003cem\u003eUGT1A1\u003c/em\u003e 1-defecitive group, which received 250 mg/m\u0026sup2;; however, this difference was not statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This may be attributable to the small sample size and therefore warrants confirmation in larger studies. In addition, detailed subgroup analyses could not be performed due to the limited number of patients.\u003c/p\u003e\u003cp\u003eRegarding adverse events (AEs), grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs occurred in 59.4% of patients. In the SUN-LIGHT trial, the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs was 72.4% in the TAS-102 plus bevacizumab group and 69.5% in the TAS-102 monotherapy group (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), while in the CORRECT trial, regorafenib was associated with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs in 54% of patients (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Thus, the incidence of severe AEs in our study was somewhat lower than that reported with TAS-102 but higher than with regorafenib. No new safety signals were identified; the observed toxicities were consistent with the known adverse profile of irinotecan, including nausea, vomiting, diarrhea, and bone marrow suppression. The administration of high-dose irinotecan may require more proactive use of antiemetics and antidiarrheal agents, and granulocyte-colony stimulating factor (G-CSF) for neutropenia management. Furthermore, \u003cem\u003eUGT1A1\u003c/em\u003e genotyping before treatment initiation remains important to identify patients at increased risk for hematologic toxicity and to guide appropriate dose adjustments. Despite genotype-guided dosing, treatment-related toxicities remained notable, and one treatment-related death from sepsis was observed. However, excluding patients with two defective alleles (\u003cem\u003eUGT1A1\u003c/em\u003e*28/*28, *6/*6, or *6/*28) may have reduced the overall incidence of severe AEs. Given that all patients had heavily pretreated disease, including seven who had previously received TAS-102, these findings suggest that \u003cem\u003eUGT1A1\u003c/em\u003e genotype\u0026ndash;guided irinotecan rechallenge could be explored as a potential option in selected mCRC patients, although its benefit and safety require further validation.\u003c/p\u003e\u003cp\u003eAmong the 18 patients in \u003cem\u003eUGT1A1\u003c/em\u003e 0-defecitive group who received 300 mg/m\u003csup\u003e2\u003c/sup\u003e of irinotecan, 9 patients (50.0%) underwent dose reductions. Six patients had one dose reduction from 300 mg/m\u003csup\u003e2\u003c/sup\u003e to 250 mg/m\u003csup\u003e2\u003c/sup\u003e, and the remaining three patients had a further dose reduction from 250 mg/m\u003csup\u003e2\u003c/sup\u003e to 200 mg/m\u003csup\u003e2\u003c/sup\u003e due to treatment-related adverse events. In the \u003cem\u003eUGT1A1\u003c/em\u003e 1-defecitive group, which received an initial dose of 250 mg/m\u0026sup2;, four patients (28.6%) required dose reductions\u0026mdash;three reduced from 250 mg/m\u0026sup2; to 200 mg/m\u0026sup2; and one from 200 mg/m\u0026sup2; to 150 mg/m\u0026sup2;. The primary reasons for dose reductions were neutropenia and nausea and vomiting. In the \u003cem\u003eUGT1A1\u003c/em\u003e 0-defecitive group, the causes of dose reduction were nausea and vomiting (4 of 9), neutropenia (4 of 9) and diarrhea (1 of 9). In the \u003cem\u003eUGT1A1\u003c/em\u003e 1-defecitive group, all causes of dose reduction were due to neutropenia, (4 of 4). The incidence of neutropenia was not higher in the 0-defecitive group despite the higher dose, possibly reflecting effective genotype-based dose adjustment. Four cases of grade 3 nausea and vomiting occurred in the group administered 300 mg/m\u003csup\u003e2\u003c/sup\u003e, suggesting that sufficient antiemetic and premedication strategies are important when rechallenging with higher irinotecan doses.\u003c/p\u003e\u003cp\u003eTo date, over 135 genetic variants of \u003cem\u003eUGT1A1\u003c/em\u003e have been identified, with the most common variant allele being \u003cem\u003eUGT1A1*28\u003c/em\u003e (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). The pyrosequencing method is a rapid and reliable approach for detecting UGT1A1 polymorphisms (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). After genotyping for \u003cem\u003eUGT1A1\u003c/em\u003e*28, patients homozygous for \u003cem\u003eUGT1A1\u003c/em\u003e*28/*28 should be carefully considered before initiating irinotecan therapy, as they have an increased risk of developing severe neutropenia following treatment initiation (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Patients with two defective \u003cem\u003eUGT1A1\u003c/em\u003e alleles are generally recommended to receive a reduced dose of irinotecan (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). However, there is insufficient evidence to suggest that patients with no defective alleles are more tolerant of high-dose irinotecan than those with a single defective allele. Our study was designed with reference to a phase I trial in which the \u003cem\u003eUGT1A1\u003c/em\u003e genotype\u0026ndash;guided maximum tolerated dose was confirmed. In that study, the recommended irinotecan dose was 300 mg/m\u0026sup2; for patients with no defective alleles and 270 mg/m\u0026sup2; for those with one defective allele (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Further studies are warranted to determine whether a genuine difference in irinotecan tolerance exists between patients with one versus no defective alleles\u003c/p\u003e\u003cp\u003eIrinotecan is a widely used anticancer agent, and high-dose irinotecan therapy remains a treatment option that can be considered for patients with refractory disease and relatively preserved performance status, including those who have experienced disease progression after TAS-102 plus bevacizumab or fruquintinib. When guided by genotype-based patient selection, irinotecan rechallenge may offer a potential therapeutic approach, although its clinical benefit requires further validation in larger studies. In resource-limited settings, this strategy could be a practical alternative when other treatment options are not available. Furthermore, unlike oxaliplatin, irinotecan is not typically associated with cumulative or irreversible peripheral neuropathy, which may allow its reuse in selected patients; however, this potential advantage should be interpreted with caution given the limited evidence.\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, it was conducted as a single-arm trial with a relatively small sample size, which limits the generalizability of the findings. The absence of a control group makes it difficult to determine whether the observed outcomes can be directly attributed to the intervention rather than to patient selection or other confounding factors. Although direct comparisons with other third- or later-line chemotherapies are not appropriate, real-world data from Asian patients report median OS of 7.5 months with TAS-102 and 6.5 months with regorafenib (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). In addition, another real-world study showed a median PFS of 2.1 months for TAS-102 in Asian populations. In another real-world Asian study, the PFS of TAS-102 was 2.1 months(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Additionally, our study included patients with relatively good general condition (ECOG performance status of 0 or 1) who could tolerate high doses of irinotecan. Therefore, high-dose irinotecan may not be suitable for patients with poor performance status in real-world clinical practice.\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, this is the first prospective clinical trial to evaluate irinotecan retreatment guided by \u003cem\u003eUGT1A1\u003c/em\u003e genotype. While \u003cem\u003eUGT1A1\u003c/em\u003e genotyping prior to high-dose irinotecan rechallenge could help identify patients who might benefit from dose-intensified therapy, the clinical benefit of this approach remains to be confirmed in larger, controlled studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study suggests that high-dose irinotecan rechallenge guided by \u003cem\u003eUGT1A1\u003c/em\u003e testing may provide disease control in selected patients with refractory metastatic colorectal cancer and preserved performance status. However, given the single-arm design, small sample size, and lack of a comparator, these results should be interpreted with caution. Further prospective, randomized studies are needed to validate the efficacy and safety of this approach and to define its role within the broader treatment landscape of metastatic colorectal cancer.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e12-week DCR \u0026nbsp; 12-week disease control rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eORR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; objective response rate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePFS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;progression-free survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; overall survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCRC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; colorectal cancer\u0026nbsp;\u003c/p\u003e\n\u003cp\u003emCRC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; metastatic colorectal cancer\u003c/p\u003e\n\u003cp\u003eanti-VEGF \u0026nbsp; \u0026nbsp; anti-vascular endothelial\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eanti-EGFR \u0026nbsp; \u0026nbsp; anti-epidermal growth factor receptor\u003c/p\u003e\n\u003cp\u003eTAS-102 \u0026nbsp; \u0026nbsp; \u0026nbsp; trifluridine/tipiracil hydrochloride\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5-FU \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;5-fluorouracil (5-FU)\u003c/p\u003e\n\u003cp\u003eDPYD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; dihydropyrimidine dehydrogenase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUDP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;uridine diphosphate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUGT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;glucosyltransferase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eECOG \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Eastern Cooperative Oncology Group\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; complete response\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; partial response\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; stable disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRECIST \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Response Evaluation Criteria in Solid Tumors \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAEs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Adverse events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNCI-CTCAE \u0026nbsp; \u0026nbsp;National Cancer Institute Common Terminology Criteria for\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eG-CSF \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; granulocyte-colony stimulating factor\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the patients and their families, Boryung corporation for their support of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and the Korea Good Clinical Practice guidelines. The study protocol was approved (#IRB No. NCC2020-0100, KCT0005303) by the Institutional Review Board of National Cancer Center on March 31, 2020. We obtained consent from the patients involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by National Cancer Center, Republic of Korea [grant number 1941231 and 2210960]. Irinotecan was provided by Boryung corporation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, Hana Kim,\u0026nbsp;Moon Ki Choi; methodology, acquisition, validation, formal analysis and investigation, Hana Kim, Joohyun Hong, Sun-Young Kong, Moon Ki Choi; data curation, Hana Kim, Joohyun Hong, Sun-Young Kong, Moon Ki Choi; writing-original draft preparation,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eHana Kim, Moon Ki Choi; writing-review and editing, Hana Kim, Joohyun Hong, Sun-Young Kong, Moon Ki Choi; project administration, Moon Ki Choi; funding acquisition, Moon Ki Choi. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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Med Adv. 2023;1(1):30\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePharmaceuticals I. IRINOTECAN HYDROCHLORIDE-irinotecan hydrochloride injection2017.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFujita K, Sparreboom A. Pharmacogenetics of irinotecan disposition and toxicity: a review. Curr Clin Pharmacol. 2010;5(3):209\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarcuello E, Altes A, Menoyo A, Del Rio E, Gomez-Pardo M, Baiget M. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer. 2004;91(4):678\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim KP, Hong YS, Lee JL, Bae KS, Kim HS, Shin JG, et al. A phase I study of UGT1A1 *28/*6 genotype-directed dosing of irinotecan (CPT-11) in Korean patients with metastatic colorectal cancer receiving FOLFIRI. 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Biomedicines. 2025;13(4).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eCharacteristics N\u0026thinsp;=\u0026thinsp;32 (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMedian (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(47\u0026ndash;73)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(62.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(37.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECOG performance status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(18.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(56.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLocation of primary tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRight-sided colon\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLeft-sided colon\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(43.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRectum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(53.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eUGT1A1\u003c/em\u003e genotype\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 defective allele\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(56.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 defective allele\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(43.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTiming of metastases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSynchronous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(75.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMetachronous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(25.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of metastatic sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(28.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(34.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(37.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetastatic sites\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(75.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLiver\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(59.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePeritoneum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(21.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e, \u003cem\u003eKRAS\u003c/em\u003e, and \u003cem\u003eNRAS\u003c/em\u003e mutation status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll wild type\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(46.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e mutant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eKRAS\u003c/em\u003e or \u003cem\u003eNRAS\u003c/em\u003e mutant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(53.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo. of prior regimens\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(37.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(40.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(21.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrior systemic anticancer agents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFluoropyrimidine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(100.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOxaliplatin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(100.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBevacizumab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(96.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCetuximab\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(40.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTAS-102\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(21.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003ePrior irinotecan-based treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment line\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFirst\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(43.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSecond\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThird\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(6.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBest response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePartial response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStable disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgression-free survival\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMedian (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(11.8\u0026ndash;14.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIrinotecan-free interval (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMedian (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e(3.1\u0026ndash;65.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eECOG, Eastern Cooperative Oncology Group; UGT1A1, UDP-glucosyltransferase 1 family peptide A1; KRAS, Kirsten rat sarcoma; NRAS, neuroblastoma rat sarcoma.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTreatment outcome\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eTumor response \u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32 (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eBest overall response\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComplete response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePartial response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(15.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStable disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(50.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgressive disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(25.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnable to determine*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(9.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal disease control No. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(65.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12-week DCR No. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(40.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian PFS months (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(2.5\u0026ndash;3.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian OS, months (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(5.3\u0026ndash;13.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eDCR, disease control rate; PFS, progression-free survival; OS, overall survival, * No disease evaluation results; 1 death, 2 EOTs (end of trial)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTreatment-related adverse events\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAny grade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ge;Grade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eHematologic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutropenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(34.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(28.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(6.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(6.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eNon-hematologic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(68.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(15.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(31.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(6.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnorexia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(6.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSepsis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFatigue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(34.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlopecia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(62.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMucositis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(37.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal pain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(18.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight loss\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAllergic rhinitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(6.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin rash\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePruritus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e(0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"metastatic colorectal cancer, UGT1A1 genotype, irinotecan rechallenge","lastPublishedDoi":"10.21203/rs.3.rs-7811670/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7811670/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThere is an unmet need for optimal third- or later-line treatment options for patients with refractory or metastatic colorectal cancer (mCRC). This phase II study evaluated whether high-dose irinotecan rechallenge guided by \u003cem\u003eUGT1A1\u003c/em\u003e genotype could improve the 12-week disease control rate (12-week DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety among patients with refractory mCRC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003ePatients who had previously received at least two lines of chemotherapy, including 5-fluorouracil, oxaliplatin, and irinotecan, and who had shown a partial or durable response to irinotecan lasting more than 24 weeks were included. Patients without a defective allele of \u003cem\u003eUGT1A1\u003c/em\u003e (\u003cem\u003eUGT1A1\u003c/em\u003e *1/*1) and one defective allele (\u003cem\u003eUGT1A1\u003c/em\u003e*1/*6, *1/*28) were treated with intravenous irinotecan at doses of 300 mg/m\u003csup\u003e2\u003c/sup\u003e and 250 mg/m\u003csup\u003e2\u003c/sup\u003e, respectively, every 2 weeks until disease progression or unacceptable toxicity.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 32 patients were enrolled between October 2020 and March 2023. The primary endpoint, 12-week DCR, was 40.6% (13 of 32 patients). The ORR was 15.6% (5 of 32). The median OS was 9.3 months (95% CI, 5.3 to 13.3) and the median PFS was 2.9 months (95% CI, 2.5 to 3.3). Grade 3 or higher adverse events were observed in 19 patients (59.4%). Dose reduction occurred in 9 (50.0%) of the \u003cem\u003eUGT1A1\u003c/em\u003e wild-type group and 4 (28.6%) of the heterozygous group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eHigh-dose irinotecan rechallenge guided by \u003cem\u003eUGT1A1\u003c/em\u003e genotype appeared feasible and achieved disease control as a third- or later-line therapy in patients with mCRC who had previously responded to irinotecan.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eKCT0005303 (UHD clinical trial, approval date: September 22, 2022)\u003c/p\u003e","manuscriptTitle":"A single-arm phase II trial of UGT1A1 genotype–guided high-dose irinotecan rechallenge in refractory metastatic colorectal cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-21 01:14:29","doi":"10.21203/rs.3.rs-7811670/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-11-20T06:12:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79990895189571784525958133313247868841","date":"2025-11-20T05:24:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-11T11:22:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-22T12:54:50+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-18T17:48:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-17T00:04:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-10-17T00:01:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4b7d36a0-1a17-4c8a-9caa-e07c6a7f6a28","owner":[],"postedDate":"November 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-21T01:14:29+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-21 01:14:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7811670","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7811670","identity":"rs-7811670","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}