Cancer Res Treat.  2018 Jan;50(1):30-39. 10.4143/crt.2016.569.

S-1–Induced Lacrimal Drainage Obstruction and Its Association with Ingredients/Metabolites of S-1 in Tears and Plasma: A Prospective Multi-institutional Study

• Kim N
• Kim JW
• Baek JH
• Kim JS
• Choung HK
• Kim TY
• Lee KH
• Bang YJ
• Khwarg SI
• Ahn SH
• Park DJ
• Kim HH
• Chung JY
• Ahn S
• Lee KW

• KMID: 2403472
• DOI: http://doi.org/10.4143/crt.2016.569

Abstract

PURPOSE
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.
MATERIALS AND 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).
CONCLUSION
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.

Keyword

Lacrimal drainage obstruction; S-1; Fluorouracil; Tears; Stomach neoplasms

MeSH Terms

Creatinine
Drainage*
Drug Therapy
Early Intervention (Education)
Fluorouracil
Humans
Incidence
Nasolacrimal Duct
Plasma*
Prospective Studies*
Risk Factors
Stomach Neoplasms
Tears*
Tegafur
Creatinine
Fluorouracil
Tegafur

Figure

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  Fig. 1. CONSORT diagram of the patients in this study.

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  Fig. 2. A Kaplan-Meier curve of the cumulative incidence of lacrimal drainage obstruction (LDO) in patients with gastric cancer receiving adjuvant S-1 chemotherapy (n=145). Fifty-three patients (37%) developed LDO, and the cumulative incidences of LDO were 22%, 31%, 36%, and 37% at 3, 6, 9, and 12 months after the initiation of S-1 therapy, respectively.

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  Fig. 3. (A-F) Correlations among the concentrations of tear tegafur, plasma tegafur, plasma 5-fluorouracil (5-FU), plasma 5-chloro-2,4-dihydroxypyridine (CDHP), and the creatinine clearance rate.

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  Fig. 4. Univariable analysis of risk factors for the development of lacrimal drainage obstruction (LDO). (A) Patients aged ≥ 70 years developed LDO more commonly than those aged < 70 years (long-rank test, p < 0.001). (B) Three groups of patients with different levels of creatinine clearance (Ccr ≥ 80 mL/min, 60 mL/min ≤ Ccr < 80 mL/min, and Ccr < 60 mL/min) showed different incidences of LDO, exhibiting an increased incidence of LDO development with decreased Ccr (log-rank test, p < 0.001). (C) Patients with high 5-fluorouracil (5-FU) concentrations in plasma (≥ 22.3 ng/mL [median]) developed LDO more frequently than those with low plasma 5-FU concentrations (p < 0.001). (D) Patients with high 5-chloro-2,4-dihydroxypyridine (CDHP) concentrations in plasma (≥ 42.0 ng/mL [median]) developed LDO more frequently than those with low plasma CDHP concentrations (p=0.032). (E) There was no difference in the development of LDO between patients with high and low plasma tegafur concentrations (median, 1,835.0 ng/mL; p=0.528). (F) Patients with high tegafur concentrations in tears (≥ 479.2 ng/mL [median]) developed LDO more frequently than those with low tear tegafur concentrations (p=0.006).

Reference

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