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

Chuan Tian; Haifeng Ying; Rongyuan Zhuang; Xiaowei Zhang; Hongmin Lu; Hui Wang; Shuowen Wang; Qi Li; Chungang Wang; Xun Cai

doi:10.2147/CMAR.S176918

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

Cancer Manag Res. 2018 Nov 22:10:6217-6226. doi: 10.2147/CMAR.S176918. eCollection 2018.

Authors

Chuan Tian^{1

2}, Haifeng Ying³, Rongyuan Zhuang⁴, Xiaowei Zhang⁵, Hongmin Lu⁶, Hui Wang⁷, Shuowen Wang⁸, Qi Li¹, Chungang Wang⁹, Xun Cai¹

Affiliations

¹ Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People's Republic of China, caixuncn@163.com.
² Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210002, People's Republic of China.
³ Department of Traditional Chinese Medicine, Ruijin Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200025, People's Republic of China.
⁴ Department of Oncology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
⁵ Department of Medical Oncology, Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
⁶ Department of Oncology, Renji Hospital, Medical College, Shanghai Jiaotong University, Shanghai 200127, People's Republic of China.
⁷ Department of Oncology, Shanghai Tenth People's Hospital, Shanghai Tongji University, Shanghai 200072, People's Republic of China.
⁸ Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People's Republic of China.
⁹ Department of Radiotherapy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, People's Republic of China.

Abstract

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 (C_{SN-38 1.5h}), plasma SN-38 level 49 hours after CPT-11 administration (C_{SN-38 49h}), DPD activity, and clinical outcomes for the UGT1A1^*6 and UGT1A1^*28 heterozygous types.

Results: C_{SN-38 1.5h} and C_{SN-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 C_{SN-38 1.5h} levels obtained better median progression-free survival (mPFS), whereas others with higher C_{SN-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 C_{SN-38 1.5h} may improve the efficacy in patients with lower C_{SN-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: colorectal cancer; enzyme activity; irinotecan; pharmacokinetics; uridine diphosphate glucuronosyl-transferase 1A1.