Value of plasma SN-38 levels and DPD activity in irinotecan-based individualized chemotherapy for advanced colorectal cancer with heterozygous type UGT1A1*6 or UGT1A1*28
Received 12 June 2018
Accepted for publication 11 September 2018
Published 22 November 2018 Volume 2018:10 Pages 6217—6226
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Dr Naduparambil K. Jacob
Chuan Tian,1,2,* Haifeng Ying,3,* Rongyuan Zhuang,4 Xiaowei Zhang,5 Hongmin Lu,6 Hui Wang,7 Shuowen Wang,8 Qi Li,1 Chungang Wang,9 Xun Cai1
1Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 2Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, People’s Republic of China; 3Department of Traditional Chinese Medicine, Ruijin Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200025, People’s Republic of China; 4Department of Oncology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 5Department of Medical Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 6Department of Oncology, Renji Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200127, People’s Republic of China; 7Department of Oncology, Shanghai Tenth People’s Hospital, Shanghai Tongji University, Shanghai 200072, People’s Republic of China; 8Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China; 9Department of Radiotherapy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People’s Republic of China
*These authors contributed equally to this work
Purpose: The relationship between the pharmacokinetics of irinotecan and outcomes of advanced colorectal cancer is unclear, and few studies have examined individualized irinotecan-based chemotherapy depending on plasma 7-ethyl-10-hydroxy camptothecin (SN-38) levels and dihydropyrimidine dehydrogenase (DPD) activity, particularly for the UGT1A1*6 or UGT1A1*28 heterozygous type.
Methods: This study retrospectively explored the relationship among plasma SN-38 level 1.5 hours after critical enzyme for irinotecan (CPT-11) administration (CSN-38 1.5h), plasma SN-38 level 49 hours after CPT-11 administration (CSN-38 49h), DPD activity, and clinical outcomes for the UGT1A1*6 and UGT1A1*28 heterozygous types.
Results: CSN-38 1.5h and CSN-38 49h of the UGT1A1*6 or UGT1A1*28 heterozygous type were close to those of UGT1A1*6 and UGT1A1*28 wild-types; some of those with relatively high CSN-38 1.5h levels obtained better median progression-free survival (mPFS), whereas others with higher CSN-38 49h concentrations showed a relatively high incidence of adverse reactions possibly because of the decreased activity of DPD.
Conclusion: Increasing the dosage of CPT-11 according to CSN-38 1.5h may improve the efficacy in patients with lower CSN-38 1.5h levels. For cases with comparably low DPD activity, advisable primary and subsequent dose adjustment of 5-fluorouracil based on plasma 5-fluorouracil levels may be a practical strategy for reducing the occurrence of adverse reactions for personalized treatment of the UGT1A1*6 or UGT1A1*28 heterozygous type.
Keywords: irinotecan, pharmacokinetics, enzyme activity, uridine diphosphate glucuronosyltransferase 1A1, colorectal cancer
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