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The pharmacokinetics of midazolam and its metabolites were studied in 17 patients on mechanical ventilation in a general intensive care unit who were receiving a continuous intravenous infusion of midazolam, adjusted according to the level of induced sedation. Three patients were studied twice. Serum midazolam and alpha-hydroxymidazolamglucuronide levels were determined during and after infusion. The sedation level was scored on a four-point scale. Half of the observed patients were still drowsy or asleep 10 hours after termination of midazolam infusion. In only one patient was midazolam serum elimination half-life less than 2 hours and in six patients the half-life was greater than 10 hours. A wide range of midazolam serum levels was associated with adequate sedation, and similarly the midazolam levels at the moment of awakening were highly variable. The serum concentration ratio of midazolam/alpha-hydroxymidazolamglucuronide at the end of the infusion varied from 0.03 to 15.6. Renal function could account for only a part of this variation.

PurposeLongitudinal studies in laryngeal cancer can provide clinicians information about short-term and long-term functional outcomes, like quality of life (QoL) and voice outcome. This information is important when counseling patients or choosing a primary treatment modality. The present study assessed long-term (2 years) QoL and voice outcome in patients with extended T1 and limited T2 glottic carcinoma treated with transoral CO2 laser microsurgery (TLM) (unilateral type III or bilateral type II resections).MethodsThree questionnaires were administered: the Voice Handicap Index (VHI), the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaire (QLQ)-C30, the EORTC QLQ-HN35. A perceptual voice evaluation at six different time points was conducted: preoperatively, and postoperatively at 6 weeks, 3 months, 6 months, 1 year, and 2 years. Fluctuations over time were investigated.ResultsSixty-one patients were included in the analysis. Patients reported high-level functioning and low symptom scores 2 years postoperatively. Gender significantly affected the VHI scores at 2 years (mean VHI scores: female 8.7 vs. male, 23.9; p = 0.023). The major improvement in VHI scores was observed within the first 6 months. The tumor stage (T1a, T1b, and T2) significantly impacted the grade (mean scores at 2 years: 1.0, 1.9, and 1.7; p = 0.001). These scores stabilized at 6 months.ConclusionsPatients show good long-term QoL with low symptom scores, a low voice handicap, and mild to moderate dysphonia, 2 years postoperatively. Scores stabilize at 6 months and provide a clear indication of status at 1 and 2 years.

Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx. Patients (N=272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome. A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p=0.02) and disease-specific survival (92% versus 77% p=0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p=0.009). In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON.

6057 Background: Standard treatment for patients (pts) with LAHNC is concomitant CRT containing cisplatin. In general 70% of the pts receive all planned cisplatin cycles. TPF IC is associated with survival benefit, but has never been studied in combination with standard CRT. We aimed to determine if TPF followed by cisplatin-containing CRT, in 2 different schedules, was feasible. Methods: In this multicenter randomized phase II trial LAHNC pts, PS 0-1, were treated with maximal 4 TPF courses (T 75 mg/m2, P 75mg/m2 and F 750 mg/m2 day 1-5) and thereafter randomized between P 100 mg/m2 on days 1, 22, 43 combined with conventional RT (arm A) or P 40 mg/m2weekly, maximally 6, combined with accelerated RT (arm B). Primary endpoint was feasibility, defined as receiving ≥ 90% of the planned total radiation dose. Based on power analysis 70 pts were needed. Results: Following an interim-analysis, the study was early terminated after inclusion of 65 pts because only 32% of pts could be treated with the full cisplatin dose during CRT after TPF. 81,5% of pts was male, median age was 56 yrs and PS was 0 in 79% and 1 in 21%, primary site: oral cavity (23%), oropharynx (57%), hypopharynx (12%), larynx (8%). 3 pts did not start TPF; 6/62 pts were not randomized after TPF, due to death (1), toxicity (3) or severe PD (2). RR after TPF was CR 4%, PR 64% and SD 28% in the randomized pts. 27 pts were randomized in arm A and 29 in arm B. 97% of the pts received at least 90% of the planned total radiation dose. However, in arm A only 6 of the 27 pts (22%) and in arm B 12 of the 29 pts (41%) received the total planned chemotherapy part of the CRT. Most common grade 3-4 toxicity during TPF was febrile neutropenia (18%),and during CRT arm A vs arm B dehydration (26% vs 14% ), dysphagia (26% vs 24%), mucositis (22% vs 57%) and creatinin increase (19% vs 3%). After a median follow-up of 21 (7-42) months 66% of the pts was still alive. Conclusions: After TPF IC cisplatin-containing concomitant CRT is not feasible in LAHNC, because the total planned dose of cisplatin could only be administered in 32% of the pts due to severe toxicity. Clinical trial information: NCT00774319.