title: S-1-Induced Lacrimal Drainage Obstruction and Its Association with Ingredients/Metabolites of S-1 in Tears and Plasma: A Prospective Multi-institutional Study.
abstract: OBJECTIVE
  This prospective study was conducted to determine the incidence of lacrimal drainage obstruction (LDO) during S-1 chemotherapy and evaluate the association between the development of LDO and the concentrations of ingredients/metabolites of S-1 in tears and plasma.
  
  
  METHODS
  A total of 145 patients with gastric cancer who received adjuvant S-1 therapy were enrolled. Ophthalmologic examinations were performed regularly during S-1 chemotherapy. Concentrations of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and 5-fluorouracil at steady-state trough level were measured in both tears and plasma.
  
  
  RESULTS
  Fifty-three patients (37%) developed LDO. The median time to the onset of LDO was 10.9 weeks, and LDO developed most frequently in the nasolacrimal duct. Univariable analyses revealed that an older age (≥ 70 years), creatinine clearance rate (Ccr) < 80 mL/min, 5-fluorouracil concentration in plasma ≥ 22.3 ng/mL (median), CDHP concentration in plasma ≥ 42.0 ng/mL (median), and tegafur concentration in tears ≥ 479.2 ng/mL (median) were related to increased development of LDO. Multivariable analysis indicated that a high plasma 5-fluorouracil concentration was predictive of increased development of LDO (hazard ratio, 2.02; p=0.040), along with older age and decreased Ccr. Patients with LDO also developed S-1-related non-hematologic toxicity more frequently than those without LDO (p=0.016).
  
  
  CONCLUSIONS
  LDO is a frequent adverse event during S-1 chemotherapy. An older age, decreased Ccr, and high plasma 5-fluorouracil concentration were found to be independent risk factors for LDO. The high incidence of LDO warrants regular ophthalmologic examination and early intervention in patients receiving S-1 therapy.
authors.affiliation: Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Namju
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Center of Biomedical Mass Spectrometry, Diatech Korea Co., Ltd., Seoul, Korea.
authors.forename: Je-Hyun
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.
authors.forename: Jin-Soo
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Seoul National University Boramae Medical Center, Seoul, Korea.
authors.forename: Ho-Kyung
authors.initials: HK
authors.lastname: Choung
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Sang In
authors.initials: SI
authors.lastname: Khwarg
authors.affiliation: Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.affiliation: Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Do Joong
authors.initials: DJ
authors.lastname: Park
authors.affiliation: Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Hyung-Ho
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Chung
authors.affiliation: Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Keun-Wook
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009301:Nasolacrimal Duct / Q000473:pathology*; D010094:Oxonic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D010949:Plasma / Q000378:metabolism*; D011446:Prospective Studies; D013666:Tears / Q000378:metabolism*; D005641:Tegafur / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid
keywords: Fluorouracil; Lacrimal drainage obstruction; S-1; Stomach neoplasms; Tears