Prognostic advantage of irinotecan dose escalation according to uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping in patients with metastatic colorectal cancer treated with bevacizumab combined with 5-fluorouracil/leucovorin with irinotecan in a first-line setting

2014 ◽  
Vol 164 (2) ◽  
pp. 169-176 ◽  
Author(s):  
Chien-Yu Lu ◽  
Ching-Wen Huang ◽  
Huang-Ming Hu ◽  
Hsiang-Lin Tsai ◽  
Chun-Ming Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Uridine Diphosphate ◽  
First Line ◽  
Uridine Diphosphate Glucuronosyltransferase ◽  
Line Setting ◽  
Irinotecan Dose

Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab combined with FOLFIRI as the first-line setting.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 491-491
Author(s):  
Yung-Sung Yeh ◽  
Meng-Lin Huang ◽  
Chien-Yu Lu ◽  
Jaw-Yuan Wang
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Promoter Polymorphism ◽  
Line Treatment ◽  
First Line ◽  
Line Setting ◽  
Irinotecan Dose ◽  
First Line Treatment

491 Background: Infusional fluorouracil/leucovorin plus irinotecan-based regimen (FOLFIRI) with bevacizumab has been widely used as first-line treatment for patients with metastatic colorectal cancer (mCRC). We prospectively analyzed the influence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotyping for irinotecan dose escalation in mCRC patients treated with combination of FOLFIRI and bevacizumab as the first-line setting. Methods: A total of 65 mCRC patients undergoing first-line treatment with FOLFIRI combined with bevacizumab were analyzed. Genotypes were performed by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Genotype and clinical parameters were compared by univariate analysis. The irinotecan dose is escalating form 180 mg/m2 to 260 mg/m2 in UGT1A1 6/6 or 6/7, and from 120 mg/m2 to 210 mg/m2 in UGT1A17/7. Results: The response rate was observed in 44 of 60 UGT1A1 6/6 or 6/7 (73.3%) in comparison to 1 of 5 UGT1A1 7/7 (20%) patients (p=0.013). The grade III-IV adverse events (AE) was observed in 4 of 60 UGT1A1 6/6 or 6/7 (6.7%) in comparison to 3 of 5 UGT1A1 7/7 (60%) patients (p<0.001), but it was not different between age of ≥ 70 and < 70 (p=0.559). Fifteen of 60 (20%) patients with UGT1A1 6/6 or 6/7 could be performed with liver or lung metastaectomy in comparison to none of 5 patients with UGT1A1 7/7. In addition, the disease control rate was significantly higher in irinotecan dose of ≥ 210 mg/m2 than irinotecan dose of < 210 mg/m2(p=0.015). Conclusions: UGT1A1 promoter polymorphism was found to be predictive of toxicity and efficacy in mCRC patients with first-line treatment of FOLFIRI combined with bevacizumab. The higher dose of irinotecan (≥ 210 mg/m2) may achieve a better disease control rate but do not increase the incidence of GR III-IV AE in mCRC patients of age ≥ 70 years.

A prospective, multicenter, randomized clinical trial of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting (PURE FIST).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 625-625
Author(s):  
Jaw-Yuan Wang
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Control Group ◽  
Study Group ◽  
First Line ◽  
Line Setting ◽  
And Control ◽  
Irinotecan Dose

625 Background: The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of patients to chemotherapy. This study is a prospective, multicenter, randomized clinical trial to compare the clinical outcomes and adverse events in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with or without UGT1A1genotyping and irinotecan dose escalation as the first-line setting (NCT02256800). Methods: The enrolled patients were randomly assigned to one of two groups on the basis of receiving UGT1A1 genotyping or not. The study group receives a biweekly FOLFIRI plus bevacizumab, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receives the conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping. The primary endpoint was the overall response rate (ORR), and the second endpoint was progression-free survival (PFS), overall survival (OS) and toxicities between the two groups. Results: BetweenAugust 2013 and May 2016, eighty-eight mCRC patients were enrolled, including 45 patients in the study group and 43 patients in the control group. With a median follow up time of 12.5 months (range, 5-30), the ORR was 71.4% vs. 44.2% ( P = 0.011). The PFS was 14.04 ± 1.44 vs. 9.08 ± 0.58 months in study group and control group ( P = 0.195), OS was 19.12 ± 1.24 vs. 14.16 ± 1.04 months ( P = 0.098), and ≥ Gr. III anemia was 2.2% vs. 23.3% ( P= 0.002) in study group and control group, respectively. However, there were no significant differences in ≥ Gr. III leukopenia or diarrhea even though the 1.36 fold relative dose intensity (RDI) in the study group. Conclusions: In the current study, patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to acceptable toxicities. Such a personalized medicine based on genotyping may be feasible for potentially clinical practice. Clinical trial information: NCT02256800.

scholarly journals Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1 genotyping in previous treated metastatic colorectal cancer patients: study protocol for a randomized controlled trial

2019 ◽  
Author(s):  
Cheng-Jen Ma ◽  
Tsung-Kun Chang ◽  
Hsiang-Lin Tsai ◽  
Wei-Chih Su ◽  
Ching-Wen Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Dose Adjustment ◽  
Uridine Diphosphate ◽  
Efficacy And Safety ◽  
Uridine Diphosphate Glucuronosyltransferase ◽  
Previously Treated ◽  
Irinotecan Dose

Abstract Background Regorafenib is an oral multi-kinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor (VEGF), and monoclonal antibodies targeting epidermal growth factor receptor (EGFR). A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in FOLFIRI regimen on basis of individual uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. This study is trying to address the efficacy and safety of dose adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival (PFS) and the secondary endpoints are overall survival (OS), disease control rate (DCR), time to progression (TTP), and duration of treatment (DoT). Safety assessments are recorded as well. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidences regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC.

scholarly journals UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yi-Chien Hsieh ◽  
Tsung-Kun Chang ◽  
Wei-Chih Su ◽  
Ching-Wen Huang ◽  
Hsiang-Lin Tsai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Braf V600e ◽  
First Line ◽  
Oncological Outcomes ◽  
Ugt1a1 Polymorphism ◽  
Line Therapy ◽  
Irinotecan Dose

Background. Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results. Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions. The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.

scholarly journals Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1 genotyping in previous treated metastatic colorectal cancer patients: study protocol for a randomized controlled trial

2019 ◽  
Author(s):  
Cheng-Jen Ma ◽  
Tsung-Kun Chang ◽  
Hsiang-Lin Tsai ◽  
Wei-Chih Su ◽  
Ching-Wen Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Dose Adjustment ◽  
Uridine Diphosphate ◽  
Efficacy And Safety ◽  
Uridine Diphosphate Glucuronosyltransferase ◽  
Previously Treated ◽  
Irinotecan Dose

Abstract Background Regorafenib is an oral multi-kinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor (VEGF), and monoclonal antibodies targeting epidermal growth factor receptor (EGFR). A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in FOLFIRI regimen on basis of individual uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. This study is trying to address the efficacy and safety of dose adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival (PFS) and the secondary endpoints are overall survival (OS), disease control rate (DCR), time to progression (TTP), and duration of treatment (DoT). Safety assessments are recorded as well. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidences regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC.

scholarly journals Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1 genotyping in previous treated metastatic colorectal cancer patients: study protocol for a randomized controlled trial

2019 ◽  
Author(s):  
Cheng-Jen Ma ◽  
Tsung-Kun Chang ◽  
Hsiang-Lin Tsai ◽  
Wei-Chih Su ◽  
Ching-Wen Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Dose Adjustment ◽  
Uridine Diphosphate ◽  
Efficacy And Safety ◽  
Uridine Diphosphate Glucuronosyltransferase ◽  
Previously Treated ◽  
Irinotecan Dose

Abstract Background Regorafenib is an oral multi-kinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor (VEGF), and monoclonal antibodies targeting epidermal growth factor receptor (EGFR). A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in FOLFIRI regimen on basis of individual uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. This study is trying to address the efficacy and safety of dose adjusted combination of regorafenib and FOLFIRI for patients with mCRC. Methods A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival (PFS) and the secondary endpoints are overall survival (OS), disease control rate (DCR), time to progression (TTP), and duration of treatment (DoT). Safety assessments are recorded as well. Discussion Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidences regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC.

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