A case of advanced gastric cancer complicated by severe toxicity induced by a combination of tegafur, uracil and mitomycin C, and associated with abnormal pharmacokinetics.
A 60-year-old female patient with gastric cancer and lymph node and liver metastases was treated with a combination of tegafur and uracil (UFT) (375 mg/m2/day) and mitomycin C (MMC) (5 mg/m2 once weekly). On day 15, when diarrhea appeared, chemotherapy was stopped immediately. On day 21, the WBC decreased to 900/microl and high fever developed. Despite treatment with granulocyte colony-stimulating factor and antibiotics, leukopenia persisted and the patient went into septic shock on day 26. On day 34, WBC increased to 5,400/microl and she recovered, with reduction in the size of the lymph node and liver metastases. Pharmacokinetic examination after intravenous injection of low-dose MMC (0.5 mg/m2) showed a markedly high peak plasma concentration (PPC), a large area under the time-versus-concentration curve (AUC) and reduced clearance. Similarly, oral administration of UFT (tegafur 300 mg/body) produced a relatively higher PPC and a larger AUC of 5-fluorouracil (FU). The activity of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in the metabolism of FU, in peripheral mononuclear cells was within the normal range (0.265 nmol/min/mg). MMC is believed to have played a large part in inducing the severe toxicity observed in this patient. Physicians should be aware of the possibility of severe toxicity during treatment with UFT and MMC, although details of its incidence and mechanism are unclear.
Department of Internal Medicine, National Cancer Center Hospital East, Kashiwa, Chiba.
N
N
Boku
A
A
Ohtsu
K
K
Muro
K
K
Kaneko
M
M
Muto
M
M
Ohkuwa
H
H
Ishii
Y
Y
Sasaki
H
H
Tajiri
S
S
Yoshida
O
O
Kusada
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001855:Bone Marrow Diseases / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D042943:Dihydrouracil Dehydrogenase (NADP); D004338:Drug Combinations; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008207:Lymphatic Metastasis; D008875:Middle Aged; D016685:Mitomycin / Q000009:adverse effects* / Q000493:pharmacokinetics; D010088:Oxidoreductases / Q000097:blood; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005641:Tegafur / Q000009:adverse effects / Q000493:pharmacokinetics; D014498:Uracil / Q000009:adverse effects / Q000493:pharmacokinetics
D004338:Drug Combinations; C096910:UFT(R) drug; D005641:Tegafur; D016685:Mitomycin; D014498:Uracil; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)