BACKGROUND: This retrospective study aimed to determine the optimal metronomic chemotherapy duration (MTCD) as adjuvant therapy for patients with locally advanced nasopharyngeal carcinoma (LANPC).
METHODS: This study involved LANPC patients treated with metronomic chemotherapy (MTC) using a 5-FU prodrug (S1, capecitabine, or tegafur) from May 2013 to September 2020. The optimal MTCD threshold was established using X-tile Bioinformatics software. The overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) were compared between short-term and long-term groups using propensity score matching (PSM).
RESULTS: A total of 546 patients were analyzed. MTCD was an independent prognostic factor for OS, PFS, and DMFS (all P < 0.05). Patients were categorized into long-term (>3 months) and short-term (≤3 months) MTCD groups. After a median follow-up of 48 months, significant differences were observed in 4-year OS (97.0 % vs. 87.1 %; P < 0.01), PFS (84.6 % vs. 70.9 %; P < 0.01), DMFS (87.3 % vs. 78.8 %; P < 0.01), and LRRFS (95.3 % vs. 87.4 %; P < 0.01) between the long-term and short-term groups. In the PSM-matched cohort of 196 patients per group, the long-term group demonstrated superior 4-year OS and LRRFS (97.3 % vs. 87.1 %, P < 0.01; 95.2 % vs. 90.0 %, P < 0.05). No significant differences in acute toxicities were observed between the groups (P > 0.05).
CONCLUSIONS: Extended MTC with a 5-FU prodrug (>3 months) may benefit NPC patients. Further prospective studies are needed to validate these findings.

Recently, therapeutic drug monitoring of 5-fluorouracil (5-FU), the key chemotherapeutic drug for colorectal cancer, has been applied in daily clinical practice and has contributed towards improving clinical outcomes. However, current dose modifications are based only on values of the area under the plasma concentration-time profile, which are simply calculated from plasma 5-FU concentrations and infusion periods. When dose-limiting toxicities occur, the dosing is empirically reduced or discontinued, leading to treatment failure. To prevent this predictable failure and obtain better clinical outcomes, rational dosage-based strategies are required for 5-FU. Combining therapeutic drug monitoring with a mathematical approach using a pharmacokinetic- pharmacodynamic/toxicodynamic model is expected to help simulate time-course profiles of the efficacy of drugs and the degree of toxicity, thereby contributing towards dose setting for individual patients. Therefore, to facilitate pharmacometric modelling and simulation techniques for optimising current oncology therapies, this review focuses on pharmacometrics approaches for personalizing 5-FU-based chemotherapy.

Thymidine phosphorylase (TP) is structurally similar to platelet-derived endothelial cell growth factor, and it activates 5-fluorouracil (5-FU) prodrugs and also promotes angiogenesis. In the present study, the possibility of using TP expression as a biomarker for 5-FU prodrugs, and the significance of TP as an angiogenic factor, were investigated in patients with gynecological tumors. The subjects enrolled in the study were 188 patients with gynecological tumors who provided informed consent and underwent tumor resection at the Department of Obstetrics and Gynecology of Tokai University Hospital between February 2002 and January 2010. Measurement of the enzymatic activity of TP and dihydropyrimidine dehydrogenase (DPD) was performed by enzyme-linked immunosorbent assay. In addition, immunohistochemistry (IHC) analysis of microvessels by monochrome imaging, western blotting and reverse transcription-polymerase chain reaction were performed. The mean TP activity and the TP/DPD ratio were increased in squamous cell carcinoma of the cervix (306.9 and 2.2 U/mg protein, respectively) and adenosquamous carcinoma (317.6 and 1.4 U/mg protein, respectively) compared with benign tumors and other malignancies, including endometrial (uterine) carcinoma, ovarian serous adenocarcinoma and ovarian mucinous adenocarcinoma. However, these parameters were also elevated in other histological types of cancer such as clear cell adenocarcinoma of the ovary (115.2 and 2.1 U/mg protein, respectively), in which the microvessel area was the largest of all the histological types analyzed. Since high TP expression and a high TP/DPD ratio were identified in other tumors besides cervical cancer, it is possible that patients for whom 5-FU prodrugs are indicated could be selected appropriately if their TP activity is determined and their TP expression is analyzed by IHC prior to initiation of the treatment.