How can we best monitor 5-FU administration to maximize benefit to risk ratio?

Abstract

Introduction: 5-FU is currently used as a chemotherapy in several cancers such as head-andneck (H&N) and colorectal cancers (CRC). 5-FU dosing is traditionally based on bodysurface-area, but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM). Areas covered: 5-FU Pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed. Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under-or over-exposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers.

Demethylzeylasteral inhibits proliferation, migration, and invasion through FBXW7/c‐Myc axis in gastric cancer

“…Hence, it is crucial to enhance the sensitivity of chemotherapy drugs. 5‐Fu and DOX are commonly used clinical anti‐tumor chemotherapy drugs, which have inhibitory effects on a variety of human tumors, mainly by inducing tumor cell apoptosis 40–46 . The present study showed that Dem can enhance the chemotherapy sensitivity of pancreatic cancer cells to gemcitabine and colorectal cancer cells to 5‐Fu 10,11 .…”

Intraperitoneal Chemotherapy Using Fluorouracil Implants Combined With Radical Resection and Postoperative Adjuvant Chemotherapy for Stage III Gastric Cancer: A Multi-Center, Randomized, Open-Label, Controlled Clinical Study

“…It is indispensable for many chemotherapy regimens in gastric cancer and intestinal cancer ( 24 ). However, the half-life of fluorouracil is short, and continuous intravenous injection or oral administration may be required for systemic chemotherapy based on fluorouracil ( 25 , 26 ). In the present study, intraperitoneal fluorouracil implants, where fluorouracil was encapsulated within the microcapsules, were used.…”

Overexpression of sortilin is associated with 5‐FU resistance and poor prognosis in colorectal cancer

“…Even if 5‐FU remains the reference molecule used in combination with other chemotherapeutic drugs, it is highly toxic and can lead to patients' death 42 . This observation recently suggested a fine monitoring 43 implying assays of dihydropyrimidine dehydrogenase (DPD) activity, 44,45 the enzyme responsible for the catabolism of 5‐FU. Moreover, resistance to 5‐FU is a major clinical problem and its mechanism is highly complex 7 .…”