Paclitaxel Administered over 3 h Followed by Cisplatin in Patients with Advanced Head and Neck Squamous Cell Carcinoma: A Clinical Phase I Study

Abstract

We have performed a clinical phase I trial of a combination treatment with paclitaxel given as 3-hour infusion and cisplatin to determine the maximum tolerated dose and the dose-limiting toxicity in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Treatment was repeated every 21 days. Doses administered ranged from 135 mg/m² paclitax-el/75 mg/m² cisplatin to 250 mg/m² paclitaxel/l00 mg/m² cisplatin. Twenty-four patients have been entered into this study. The maximum tolerated dose was determined to be 225-250 mg/m² paclitaxel/l00 mg/m² cisplatin. The dose-limiting toxicity of this regimen was myelosuppression (granulocytopenia). Neurosensory and neuromotor toxicity was moderate. However, analyses of threshold electrotonus studies indicated subclinical neurotoxicity in most patients. One patient receiving 200 mg/m² paclitaxel/l00 mg/m² cisplatin developed grade 3 motor-neurotoxicity. Orthostatic hypotension was observed in 8 patients receiving doses of 200 mg/m² paclitaxel/l00 mg/m² cisplatin or higher. Objective responses were observed at paclitaxel 175 mg/m²/ cisplatin 100 mg/m² (n = 5; complete response in 1 patient), paclitaxel 200 mg/ m²/cisplatin 100 mg/m² (n = 3; partial response in 3 patients) and at paclitaxel 225 mg/m²/cisplatin 100 mg/m² (n = 8; partial response in 1 patient). Eleven additional patients had stable disease. We conclude that paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer and that orthostatic hypotension may be a potentially significant clinical toxicity.

Effect of maturation on nerve excitability in an experimental model of threshold electrotonus

“…Abnormal TE has also been reported in ALS, 8,13 a toxic neuropathy, 20 multifocal motor neuropathy, 14 and in monomelic amyotrophy with spinal hemiatrophy. 17 Although TE is able to reveal otherwise undetectable abnormalities in nerve membranes, its clinical utility has been limited partly by the uncertainties regarding its interpretation.…”

Phase II Trial of a Paclitaxel-Carboplatin Combination in Recurrent Squamous Cell Carcinoma of the Head and Neck

“…Consequently, further studies were performed to analyze the activity of paclitaxel-containing regimens. Phase I trials reported by Hanauske et al [9]and Schilling et al [10]showed the feasibility of the administration of paclitaxel and cisplatin at recommended doses of 200 and 100 mg/m 2 every 21 days, respectively. The association of paclitaxel 200 mg/m 2 and cisplatin 100 mg/m 2 obtained a 44% objective response rate, but produced a median overall survival of 7 months [11].…”

Threshold tracking techniques in the study of human peripheral nerve

“…These disturbances in membrane excitability were detected by threshold electrotonus after only one or two doses of chemotherapy, before any clinical or neurological signs of neuropathy. 70 Taxol also depolarized human sural nerves in vitro. 64 …”

“…26 Threshold electrotonus has been used to investigate this neuropathy in 15 patients. 36,70 There was a marked symmetrical ''fanning in'' or flattening of the threshold electrotonus responses, indicating that the axons were depolarized or the conductance of the internodal axon membrane was increased. As already mentioned, the axons also became more sensitive to ischemia.…”