Hsiang-Lin Tsai1, Ching-Wen Huang2, Yi-Wen Lin3, Jui-Ho Wang4, Chang-Chieh Wu5, Yung-Chuan Sung6, Tzu-Liang Chen7, Hwei-Ming Wang8, Hsiu-Chin Tang9, Joe-Bin Chen10, Tao-Wei Ke11, Chang-Sung Tsai12, Hsuan-Yuan Huang13, Jaw-Yuan Wang14. 1. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: chunpin870132@yahoo.com.tw. 2. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: baseball5824@yahoo.com.tw. 3. Division of Colorectal Surgery, Department of Surgery, Tainan Municipal Hospital, Tainan, Taiwan. Electronic address: linyiewen@yahoo.com.tw. 4. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. Electronic address: rayhowang@gmail.com. 5. Division of Colorectal Surgery, Department of Surgery, Keelung Branch, Tri-Service General Hospital, Keelung, Taiwan. Electronic address: doc20276@gmail.com. 6. Division of Medical Oncology, Department of Internal Medicine, Taipei Cathay General Hospital, Taipei, Taiwan. Electronic address: yungchuans@cgh.org.tw. 7. Division of Colorectal Surgery, Department of Surgery, Taichung China Medical University Hospital, Taichung, Taiwan. Electronic address: golfma22@gmail.com. 8. Division of Colorectal Surgery, Department of Surgery, Taichung China Medical University Hospital, Taichung, Taiwan. Electronic address: phillipwhm@gmail.com. 9. Division of Colorectal Surgery, Department of Surgery, Tainan Sin-Lan Hospital, Tainan, Taiwan. Electronic address: schoetz.tang@gmail.com. 10. Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan. Electronic address: jbchen@vghtc.gov.tw. 11. Division of Colorectal Surgery, Department of Surgery, Taichung China Medical University Hospital, Taichung, Taiwan. Electronic address: ketaowei@gmail.com. 12. Division of Medical Oncology, Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan. Electronic address: chonsonechai@gmail.com. 13. Division of Colorectal Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan. Electronic address: 107431@cch.org.tw. 14. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: cy614112@ms14.hinet.net.
Abstract
AIM: Uridine diphosphate glucuronosyltransferase1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility of patients to irinotecan and its toxicity. This study is a multicenter, randomised clinical trial comparing the clinical outcomes and adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated withbevacizumab plus FOLFIRI with or without UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. METHODS: The control group received conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping, whereas the study group received the same regimen with irinotecan dose escalation based on UGT1A1 genotyping. The primary end-point was progression-free survival (PFS), and secondary end-points were overall response rate (ORR), disease control rate (DCR), overall survival (OS), AEs and metastasectomy rate. RESULTS: Over a median follow-up of 26.0 months (IQR, 17.0-35.0 months), study group (n = 107) was superior to the control group (n = 106) in PFS, OS, ORR, DCR, and metastasectomy rate (all P < 0.05). Furthermore, there were no significant differences in AEs ≥ grade III between the two groups, even with the 1.36-fold increase in the relative dose intensity of irinotecan in the study group. Dose escalation of irinotecan, an independent factor of ORR (P < 0.001) and DCR (P = 0.006), improved PFS in mCRC patients with wild-type and mutant KRAS (P = 0.007 and P = 0.019, respectively). CONCLUSION: The current study revealed that mCRC patients, regardless of KRAS gene status, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favourable clinical outcome without significantly increased toxicities. CLINICAL TRIAL REGISTRATION: NCT02256800.
RCT Entities:
AIM: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility of patients to irinotecan and its toxicity. This study is a multicenter, randomised clinical trial comparing the clinical outcomes and adverse events (AEs) in metastatic colorectal cancer (mCRC) patients treated with bevacizumab plus FOLFIRI with or without UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. METHODS: The control group received conventional biweekly FOLFIRI plus bevacizumab without UGT1A1 genotyping, whereas the study group received the same regimen with irinotecan dose escalation based on UGT1A1 genotyping. The primary end-point was progression-free survival (PFS), and secondary end-points were overall response rate (ORR), disease control rate (DCR), overall survival (OS), AEs and metastasectomy rate. RESULTS: Over a median follow-up of 26.0 months (IQR, 17.0-35.0 months), study group (n = 107) was superior to the control group (n = 106) in PFS, OS, ORR, DCR, and metastasectomy rate (all P < 0.05). Furthermore, there were no significant differences in AEs ≥ grade III between the two groups, even with the 1.36-fold increase in the relative dose intensity of irinotecan in the study group. Dose escalation of irinotecan, an independent factor of ORR (P < 0.001) and DCR (P = 0.006), improved PFS in mCRC patients with wild-type and mutant KRAS (P = 0.007 and P = 0.019, respectively). CONCLUSION: The current study revealed that mCRC patients, regardless of KRAS gene status, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favourable clinical outcome without significantly increased toxicities. CLINICAL TRIAL REGISTRATION: NCT02256800.
Authors: Natalie Reizine; Everett E Vokes; Ping Liu; Tien M Truong; Rita Nanda; Gini F Fleming; Daniel V T Catenacci; Alexander T Pearson; Sandeep Parsad; Keith Danahey; Xander M R van Wijk; Kiang-Teck J Yeo; Mark J Ratain; Peter H O'Donnell Journal: Ther Adv Med Oncol Date: 2020-12-17 Impact factor: 8.168