Phase II trial of cisplatin, fluorouracil, and pure folinic acid for locally advanced head and neck cancer: a pharmacokinetic and clinical survey.
OBJECTIVE
To analyze clinical and pharmacokinetic data of cisplatin (CP)/fluorouracil (FU)/l folinic acid (l FA) chemotherapy administered as first-line treatment to locally advanced head and neck cancer patients.


METHODS
Thirty-nine patients (35 men and four women; median age, 60 years; six stage III and 33 stage IV) received CP on day 1 (100 mg/m2) followed by l FA (200 mg/m2/d x 5) plus FU (500 mg/m2/d x 5) administered by continuous venous infusion (three cycles planned). Mean plasma concentrations of FU, l FA, and 5-methyltetrahydrofolate (5MTHF) over the cycle were computed.


RESULTS
Clinical response was assessable for 33 patients. Response rates on the primary tumor site (n = 33) were 63.7% complete responses (CRs), 24.2% partial responses (PRs), and 12.1% treatment failures. Response rates on lymph nodes (n = 27) were 40.7% CRs, 37.1% PRs, and 22.2% treatment failures. The most frequent toxicity was mucositis (36.2% of cycles grade 3 to 4). Grade 3 to 4 nausea-vomiting, diarrhea, neutropenia, and thrombocytopenia occurred in 6.7%, 1.9%, 13.3%, and 1% of cycles, respectively. Pharmacokinetic analysis showed a wide interpatient variability for both FU (mean, 1.01 mumol/L; range, 0.16 to 2.09), l FA (mean, 1.89, mumol/L; range, 0.52 to 7.88) and 5MTHF plasma concentrations (mean, 3.85 mumol/L; range, 1.30 to 8.11). A significant correlation was demonstrated between FU concentration and hematologic toxicity grade, mucositis grade, and nausea-vomiting/diarrhea grade. Regarding tumor response, patients who failed to respond significantly exhibited lower FU and total folate concentrations than patients with a CR or PR.


CONCLUSIONS
This study highlights the efficacy of CP/FU/l FA in head and neck carcinoma and establishes the clinical importance of coupled FU/FA pharmacokinetics to predict pharmacodynamic variability.
Schneider
M
M
Centre Antoine Lacassagne, Nice, France.
Etienne
M C
MC
Milano
G
G
Thyss
A
A
Otto
J
J
Dassonville
O
O
Mobayen
H
H
Saudes
L
L
Guillot
T
T
Demard
F
F
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007822:Laryngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009669:Nose Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013763:Tetrahydrofolates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D013763:Tetrahydrofolates; D002945:Cisplatin; D002955:Leucovorin; C005984:5-methyltetrahydrofolate; D005472:Fluorouracil