Altered pharmacokinetics and clinical consequences of low dose methotrexate plus cisplatin in the treatment of advanced head and neck cancer.
Thirty-two patients with head and neck carcinoma received a multidrug chemotherapy protocol including low dose methotrexate (LDMTX) (30 mg/m2) and cisplatin as their initial treatment. A sensitive immunoenzymatic technique was used for systematic MTX blood monitoring (0-56 hr) in all patients. The MTX-related side effects observed in 15 patients (47%) were significantly associated with an increase in systemic drug exposure occurring early during drug infusion. The average end-of-infusion concentration varied from 8 X 10(-7) M for nontoxic patients to 1.45 and 3.12 10(-6) M for moderately and severely toxic patients respectively. The area under the curve (AUC) (0-56 hr) was also directly related to the increase in side-effects. Total body clearance was reduced in an inverse manner. Volumes of distribution and terminal elimination half-lives were not related to the presence or intensity of MTX side-effects. Based on these data, the institution of folinic acid rescue adapted to the MTX blood concentration, a measure previously not suggested for LDMTX, completely prevented severe toxicity in a subsequent series of 26 patients without modification of the response rate.
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D002945:Cisplatin / Q000008:administration & dosage; D003404:Creatinine / Q000097:blood; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008875:Middle Aged
D003404:Creatinine; D002945:Cisplatin; D008727:Methotrexate