Safety and Efficacy of S-1, a Novel Oral Fluorouracil Antitumor Drug, for a Chronic Renal Failure Patient Maintained on Hemodialysis

Abstract

Objective: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. Methods: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m²/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and C_max, T_max, AUC_0–24, and T_1/2 were calculated. The dose of consecutive or maintained administrations was determined. Results: Both an increase in C_max and an elongation of T_1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC_0–24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). Conclusion: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.

Successful treatment of pulmonary metastases associated with advanced hepatocellular carcinoma by systemic 5‐fluorouracil combined with interferon‐α in a hemodialysis patient

“…As we reported previously, the overall response rate (complete response + partial response) to S‐1–IFN is 17%, and the response rate among patients with lung metastases is 21% 9 . With regard to drug metabolism, 53.7% of CDHP, an inhibitor of dihydropyrimidine dehydrogenase, is excreted into the urine, 11 and thus S‐1 promotes high plasma concentrations of 5‐FU in hemodialysis patients 14,15 . In this regard, the safety of S‐1 is yet to be ascertained in hemodialysis patients.…”

“…9 With regard to drug metabolism, 53.7% of CDHP, an inhibitor of dihydropyrimidine dehydrogenase, is excreted into the urine, 11 and thus S-1 promotes high plasma concentrations of 5-FU in hemodialysis patients. 14,15 In this regard, the safety of S-1 is yet to be ascertained in hemodialysis patients.…”

Gastric Cancer Patients Receiving Maintenance Hemodialysis After Surgery With and Without Postoperative Chemotherapy: A Case Series of 6

“…20 However, several studies have reported that adjusting S-1 doses based on the results of pharmacokinetics studies improves the safety and efficacy of treatment for advanced gastric cancer, even in maintenance for HD patients with chronic renal failure. 15,21,22 As for UFT, a previous report indicated that although the plasma 5-fluorouracil concentrations of HD patients treated with UFT were approximately double those seen in patients with normal renal function, no severe adverse reactions occurred in any of these patients. 23 The optimal doses of chemotherapy drugs for HD patients are uncertain, because there are few previous case reports about the use of chemotherapy to treat HD patients.…”

Weekly paclitaxel therapy for gastric cancer in patients with renal dysfunction: A case report

“…The first-line regimen in Japan for advanced and unresectable gastric cancer is S-1/cisplatin combined chemotherapy, for which safety and efficacy have been characterized in the SPIRITS trial [2] . Nevertheless, both drugs are known to be nephrotoxic and should not be administered to renal failure patients [6] . Recently, oxaliplatin has been used to treat gastric cancer in Japan based on the results of the CLASSIC trial [7] .…”