Author(s): Steinberg L, Hassan M, Olmsted L, Sharan V, Stepnick D,
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Abstract Preclinical studies have demonstrated that tumor cells exposed to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) for protracted periods (ie, 24 hours) and then irradiated undergo enhanced radiation-induced cell kill. Importantly, paclitaxel-induced tumor cell mitotic arrest at the time of radiation was associated with the enhanced cell kill. At the Case Western Reserve Cancer Center, we have conducted a phase I trial in 24 patients with either locally advanced or recurrent/metastatic head and neck squamous cell carcinoma to evaluate the clinical and pharmacologic effects of a 24-hour paclitaxel infusion combined with radiotherapy. The maximum tolerated dose was < or =75 mg/m2. Dose-limiting toxicity was febrile granulocytopenia. Mucositis was significant and necessitated the use of enteral feeding tubes in the majority of patients. All patients with locally advanced disease demonstrated either a complete response or major partial response. At a median follow-up of 13.4 months, disease has relapsed in only two of 22 patients with locally advanced disease. Pharmacokinetic studies revealed that a dose of > or =75 mg/m2 achieved near steady-state mean paclitaxel plasma concentrations greatly exceeding the threshold concentrations shown to alter microtubule function and induce tumor cell mitotic arrest in vitro. Pharmacodynamic studies performed at 21 to 26 hours after initiation of infusion demonstrated that a dose of > or =75 mg/m2 uniformly induced tumor cell mitotic arrest and oral epithelial mitotic arrest. The pharmacologic data and outcome results provide a strong rationale for the continued use of a 24-hour paclitaxel infusion and concurrent radiation for the treatment of newly diagnosed, locally advanced head and neck squamous cell carcinoma in an experimental setting.
This article was published in Semin Oncol
and referenced in Journal of Cancer Science & Therapy