ABSTRACT
PURPOSE: To explore the use of SD/01 (a polyethylene glycol-conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Thirteen patients with non-small-cell lung cancer were randomized to receive daily filgrastim (5 microg/kg/d) or a single injection of SD/01 (30, 100, or 300 microg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 microg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 microg/kg. Dose-limiting toxicities were not noted. CD34(+) cells were mobilized in all cohorts. CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34(+) cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.
Subject(s)
Antineoplastic Agents/adverse effects , Granulocyte Colony-Stimulating Factor/administration & dosage , Neutropenia/drug therapy , Polyethylene Glycols/administration & dosage , Aged , Antigens, CD34/analysis , Carcinoma, Non-Small-Cell Lung/drug therapy , Dose-Response Relationship, Drug , Female , Filgrastim , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/pharmacokinetics , Hematopoietic Stem Cell Mobilization , Hemoglobins/analysis , Humans , Leukocyte Count/drug effects , Lung Neoplasms/drug therapy , Male , Middle Aged , Neutropenia/blood , Neutropenia/chemically induced , Neutrophils , Pilot Projects , Platelet Count/drug effects , Polyethylene Glycols/adverse effects , Polyethylene Glycols/pharmacokinetics , Recombinant ProteinsABSTRACT
The effect of a typical 5-day chemotherapy treatment with cisplatin (20-40 mg/m2 per day) and 5-fluorouracil (5-FU, 1 gm/m2 per day) on the pharmacokinetics of ondansetron was investigated. Twenty cancer patients received 8 mg of ondansetron in three periods, including an oral tablet on day 1, an intravenous infusion on day 4, and an oral tablet on day 5. Absolute bioavailability after the oral dosing on day 1 was 87.5 +/- 31.3%, and on day 5 was 85.2 +/- 22.1% (P > .05). Mean values of AUC, Cmax, Tmax, and half life on days 1 and 5 were 399 +/- 275 and 381 +/- 222 ng.hour/mL, 53.3 +/- 26.8 and 43.6 +/- 21.7 ng/mL, 1.9 +/- 1.4 and 2 +/- 1.4 hours, and 5.21 +/- 1.78 and 6.19 +/- 1.99 hours, respectively. These values were not significantly different (P > .05). In summary, this study showed that cisplatin and 5-FU did not significantly alter the pharmacokinetics of oral ondansetron in cancer patients during the 5 days of chemotherapy. Oral bioavailability of ondansetron appeared to be greater in cancer patients than in healthy subjects.
Subject(s)
Cisplatin/pharmacology , Fluorouracil/pharmacology , Neoplasms/metabolism , Ondansetron/pharmacokinetics , Administration, Oral , Adolescent , Adult , Biological Availability , Cisplatin/therapeutic use , Female , Fluorouracil/therapeutic use , Half-Life , Humans , Infusions, Intravenous , Male , Neoplasms/drug therapy , Ondansetron/administration & dosage , TabletsABSTRACT
PURPOSE: This study was designed to test the toxicity and efficacy of a regimen of twice daily irradiation and concurrent multiagent chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: This was a prospective Phase I/II trial. Patients received 125 cGy b.i.d. to 7000 cGy with a 6 hr interfraction interval. Chemotherapy was given during weeks 1 and 6 of irradiation and consisted of a 5 day infusion of 5-fluorouracil at 600 mg/M2/day and 5 daily injections of cisplatin at 12 mg/M2/day. Two additional cycles of chemotherapy were given after the completion of radiotherapy. RESULTS: Forty-six patients were evaluable: 28 had technically unresectable disease and 18 had resectable tumors. All had Stage III or IV disease: 84% had T3 or T4 primaries while 53% had > or = N2 neck disease. The primary acute toxicity, confluent mucositis, was seen in 74% of patients. Late side effects occurred in four patients. Median follow-up is 36 months (range 25-44 months). Kaplan-Meier estimates of 2-year disease-free survival and overall survival are 65% and 73%, respectively, while 2-year local regional control and distant disease-free survival are 72% and 88%, respectively. Multivariate analysis revealed that resectability and receiving > 2 cycles of chemotherapy significantly influenced local regional control while age < 60 significantly influenced disease-free survival. CONCLUSION: This form of treatment can be delivered safely. The encouraging results have led to the initiation of a Phase III trial comparing this regimen with b.i.d. radiation alone.
