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Validation of a 15-gene hypoxia classifier in head and neck cancer for prospective use in clinical trials., Toustrup, Kasper, Sørensen Brita Singers, Metwally Mohamed Hassan A., Tramm Trine, Mortensen Lise Saksø, Overgaard Jens, and Alsner Jan , Acta oncologica (Stockholm, Sweden), 2016 Sep - Oct, Volume 55, Issue 9-10, p.1091-1098, (2016) Abstract

BACKGROUND: In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15-gene hypoxia classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here.

MATERIAL AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts [DAHANCA 18 (n = 96), 24 (n = 40), and IAEA Hypo (n = 55)] was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenograft tumors (FaDuDD, UTSCC33), where gene expression in complementary sections was compared after fixation and embedding locally and at international institutions, respectively. Intra-tumor heterogeneity was addressed by classifying biopsy samples from HNSCC tumors, where 2-4 biopsies from each tumor was accessible.

RESULTS: Procedures were successfully established for individual classification of HNSCC patients in retrospective and prospective cohorts. Measurements of gene expression levels were reproducible between different international institutions.

CONCLUSION: Technical validation of the 15-gene hypoxia classifier demonstrated that it is suitable for implementation in prospective clinical trials.

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Compliance and toxicity of the hypoxic radiosensitizer nimorazole in the treatment of patients with head and neck squamous cell carcinoma (HNSCC)., Metwally, Mohamed Hassan A., Frederiksen Katrine Diemer, and Overgaard Jens , Acta oncologica (Stockholm, Sweden), 2014 May, Volume 53, Issue 5, p.654-61, (2014) Abstract

PURPOSE: To evaluate the compliance and toxicity of the hypoxic radiosensitizer nimorazole in head and neck cancer patients.

METHODS: A retrospective study of patients with head and neck squamous cell carcinoma (HNSCC), treated in Denmark between 1990 and 2013. All patients treated with radical radiotherapy (± chemotherapy) [66-70 Gy; 33-35 fractions; 2 Gy/fraction; 5-6 fractions/week] concomitant with the hypoxic radiosensitizer nimorazole. Nimorazole was administered as oral tablets in doses of approximately 1.2 g/m(2) body surface area in connection with the first of each daily radiation treatment. A second daily dose of 1 g was given in connection with the second radiotherapy fraction in the accelerated fractionation regimen. The compliance was estimated as the percentage of the initially prescribed dose, which was received by each patient. The main side effects were recorded.

RESULTS: A total of 1049 patients were investigated. The tolerance to nimorazole was fair: 58% of patients received the full prescribed total dose. Nausea and vomiting were the major complaints: among the 260 patients with dose reductions due to known side effects, (87%) were due to nausea/vomiting. All side effects ceased when treatment was interrupted, and neither severe nor long lasting side effects were observed. Female patients were significantly more likely to have dose reduction (OR 2.02; 95% CI 1.50-2.70), and nausea/vomiting. Patients aged more than 70 years were significantly more likely to have dose reduction. Patients who received less than 1100 mg/m(2) were significantly less likely to have dose reduction (OR 0.58; CI 0.44-0.78), and nausea/vomiting, compared to those who received 1100-1300 mg/m(2). The tolerance was also less in the group of patients received accelerated chemoradiotherapy (OR 1.70; CI 1.20-2.50) with more association with nausea/vomiting (OR 2.09; CI 1.40-3.10).

CONCLUSION: The compliance to nimorazole is fair, with tolerable acute, but neither persistent nor late, toxicity. It can be administered with chemotherapy and different radiotherapy fractionation schedules.

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Study of the population pharmacokinetic characteristics of nimorazole in head and neck cancer patients treated in the DAHANCA-5 trial., Hassan Metwally, M. A., Jansen J. A., and Overgaard J. , Clinical oncology (Royal College of Radiologists (Great Britain)), Volume 27, Issue 3, p.168-75, (2015) Abstract

AIMS: To study the pharmacokinetic characteristics of the hypoxic radiosensitiser nimorazole in patients with head and neck squamous cell carcinoma.

MATERIALS AND METHODS: The pharmacokinetics of the hypoxic radiosensitiser nimorazole were studied in 63 patients treated in the DAHANCA-5 trial. After the first day of treatment, serial venous blood samples were taken and plasma concentrations of nimorazole measured by high pressure liquid chromatography (HPLC). Plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using validated PC-based software. The different pharmacokinetic parameters were calculated and correlated with the different patient- and treatment-related variables.

RESULTS: HPLC measurements showed a linear relationship between peak plasma concentration and administered dose. The mean peak concentration adjusted for dose (in g/m(2)) was 32.2 ± 0.9 μg/ml. The time of peak concentration ranged between 30 and 180 min (median 60 min). Plasma elimination occurred with a mean half-life of 3.35 ± 0.09 h and was not significantly altered as a function of dose. There was a well-established linear-linear relationship between area under the concentration-time curve (AUC; mean 191 ± 6 μg·h/ml) and administered dose, especially when expressed as g/m(2). The mean apparent volume of distribution was 0.77 ± 0.02 l/kg. A statistically significant longer elimination half-life in men relative to women (mean difference 0.40 h; 95% confidence interval 0.77-0.03; P 0.03) was detected. Nimorazole was well tolerated; with 67% of patients reporting no toxicity; nausea/vomiting was the most reported toxicity in the remaining patients.

CONCLUSION: The study supports the current nimorazole dose scheduling in patients.

Radiotherapy quality assurance of the IAEA-HypoX trial of the accelerated radiotherapy in the treatment of head and neck squamous cell carcinoma with or without the hypoxic radiosensitizer nimorazole., Hassan Metwally, Mohamed A., Ali Rubina, Kuddu Maire, Shouman Tarek, Strojan Primoz, Overgaard Jens, and Grau Cai , Acta oncologica (Stockholm, Sweden), 2015, Volume 54, Issue 9, p.1673-7, (2015)
IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma., Hassan Metwally, Mohamed A., Ali Rubina, Kuddu Maire, Shouman Tarek, Strojan Primoz, Iqbal Kashif, Prasad Rajiv, Grau Cai, and Overgaard Jens , Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, Volume 116, Issue 1, p.15-20, (2015) Abstract

PURPOSE: To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation.

MATERIALS AND METHODS: The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66-70Gy, 33-35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2gperm(2), 90min before the first daily RT fraction. The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines.

RESULTS: The trial was dimensioned to include 600 patients in 3years, but only 104 patients were randomized between March 2012 and May 2014 due to the inability to involve three major centers and the insufficient recruitment rate from the other participating centers. Twenty patients from two centers had to be excluded from the analysis due to the unavailability of the follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT+NIM and the RT-alone arms, respectively). The treatment compliance was good with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco-regional tumor control with an 18month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI -3% to 39%; P=0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI -3% to 42%; P=0.10). Sixteen patients, out of 55 patients analyzed for hypoxic gene expression, were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco-regional tumor failure rate as compared to the rest of the patients with known hypoxic status (P=0.05).

CONCLUSION: Although the trial was incomplete and suffered from a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational study combining drug and RT in developing countries may suffer from uncontrolled and unsolvable problems.