Pharmacokinetic and toxicity evaluation of five-day continuous infusion versus intermittent bolus cis-diamminedichloroplatinum(II) in head and neck cancer patients.

We administered cis-diamminedichloroplatinum(II), 30 mg/m2/day for 5 days by continuous infusion to six patients with head and neck cancer, and compared the total and filterable plasma concentrations of platinum, and toxic effects, with those observed in five additional patients who received the same dose and schedule of cis-diamminedichloroplatinum(II) by intermittent bolus. In the continuous infusion group, the total 5-day exposure to filterable platinum, determined from the area under the concentration-time curve, was 1.5 to 2-fold higher (P less than 0.01) than that observed in the intermittent bolus group although the maximum filterable platinum concentration achieved was 8-fold lower (P less than 0.01). These differences were not reflected by total platinum levels. Subclinical nephrotoxicity, as judged by monitoring the urinary excretion of the renal enzymes N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase, as well as ototoxicity, and the incidence and severity of nausea and vomiting were similar in both groups. In contrast, myelosuppression, and hypomagnesemia were more frequent in the continuous-infusion patients, suggesting that the total exposure to free platinum contributes more to these toxicities than peak levels achieved. Considering the clinically acceptable toxicity observed after administration by continuous infusion, we recommend larger therapeutic trials to define the efficacy of increased tumor exposure to filterable platinum.

A phase I-II trial of carboplatin and 5-fluorouracil combination chemotherapy in advanced carcinoma of the head and neck.

Twenty-nine patients with recurrent or advanced, incurable head and neck cancer were entered into a phase I-II trial of carboplatin in combination with 5-fluorouracil (5-FU), 1,000 mg/m2/d continuous intravenous (IV) infusion for five days every 28 days. The initial dose of carboplatin was 300 mg/m2 for patients with Karnofsky performance scores greater than or equal to 70%, and 240 mg/m2 for patients with scores of 50% to 60%. Subsequent doses were modified to achieve grade 2 myelo-suppression: WBC, 2,000 to 2,999 cells/microL; granulocytes, 1,000 to 1,499 cells/microL; and platelets, 50,000 to 75,000 cells/microL. Dose levels were 180, 240, 300, 360, and 420 mg/m2. Twenty-eight patients had squamous-cell cancers and one had an adenoid cystic carcinoma of the parotid. There were 26 patients with recurrent disease; 22 had received prior RT; only two had received other chemotherapy immediately before study entry. Three patients had newly diagnosed incurable stage IV disease. The median performance status was 80% (range, 60% to 90%). All patients had objectively measurable disease, and 28 were evaluable for response. There were three complete responses (CRs) and ten partial responses (PRs) (48% CR and PR); the median duration of response was 4.7 months (range, 1.5 to 15+ months). Dose-limiting toxicities were granulocytopenia, thrombocytopenia, and stomatitis. Prolonged myelosuppression delayed retreatment in eight patients and delayed 19 of 107 (18%) courses. Stomatitis occurred in 61% and diarrhea in 29%. 5-FU dosage was decreased in ten patients (36%) for grade 2 or greater stomatitis or diarrhea. Mild to moderate nausea and vomiting occurred in 66% of patient trials in which no pretreatment antiemetics were administered. Other toxicities included phlebitis from 5-FU in 71%, skin toxicity in 11%, mild alopecia in 25%, and fatigue in 54% of patients. Nephrotoxicity (creatinine greater than 2.0 mg/dL) occurred in one patient. The dose of carboplatin resulting in grade 2 toxicity was 180 mg/m2 in one patient, 240 mg/m2 in one, 300 mg/m2 in seven, 360 mg/m2 in ten, and 420 mg/m2 in one. Based on these results, we recommend a starting dose of carboplatin, 300 mg/m2, in combination with five days of continuous infusion 5-FU. In this dose and schedule, this combination was well tolerated and demonstrated antitumor activity in head and neck cancer. To confirm these promising results, a Southwest Oncology Group prospective randomized trial is in progress comparing carboplatin and 5-FU, cisplatin and 5-FU, and standard-dose weekly methotrexate in recurrent-disease patients.

Post-heparin serum lecithinase in man and its positional specificity.

Lecithinase activity in post-heparin serum has been demonstrated. Phosphatidyl choline (PC) can be degraded to lysophosphatidyl choline and fatty acids at a rate of more than 1 micromole/hr per ml of serum in an incubation system containing PC, 0.1 M glycine-NaOH buffer (pH 9.6), and deoxycholate. This activity cannot be found in serum obtained prior to the injection of heparin. Post-heparin serum lecithinase can be distinguished from the heat-stable pancreatic lecithinase by the markedly different effects of heat, paraoxon, and EDTA, and from serum lecithin:cholesterol acyltransferase by the differential effect of p-hydroxymercuribenzoate. In contrast to the acyltransferase and to pancreatic lecithinase, which are active at the beta (C-2) position of lecithin, post-heparin serum lecithinase is active at alpha' (C-1) position.

Phase II trial of N-methylformamide in advanced head and neck cancer.

Eighteen patients with advanced epidermoid carcinoma of the head and neck were entered into a phase II trial of N-Methylformamide (NMF), 800 mg/M2 IV daily for 5 days every 4 weeks. Seventeen patients had received prior radiation therapy and 11 were previously treated with chemotherapy. No complete or partial responses were observed. The major toxicity was gastrointestinal. Fifty percent of patients experienced nausea and vomiting or reversible hepatotoxicity with greater than a 3-fold elevation of liver enzymes. Mild reversible myelosuppression occurred in 2 patients. NMF in this dose and schedule was not a useful agent to treat recurrent epidermoid carcinoma of the head and neck.