Electrophysiological assessment and pharmacological treatment of blast-induced tinnitus.

Tinnitus, the phantom perception of sound, often occurs as a clinical sequela of auditory traumas. In an effort to develop an objective test and therapeutic approach for tinnitus, the present study was performed in blast-exposed rats and focused on measurements of auditory brainstem responses (ABRs), prepulse inhibition of the acoustic startle response, and presynaptic ribbon densities on cochlear inner hair cells (IHCs). Although the exact mechanism is unknown, the "central gain theory" posits that tinnitus is a perceptual indicator of abnormal increases in the gain (or neural amplification) of the central auditory system to compensate for peripheral loss of sensory input from the cochlea. Our data from vehicle-treated rats supports this rationale; namely, blast-induced cochlear synaptopathy correlated with imbalanced elevations in the ratio of centrally-derived ABR wave V amplitudes to peripherally-derived wave I amplitudes, resulting in behavioral evidence of tinnitus. Logistic regression modeling demonstrated that the ABR wave V/I amplitude ratio served as a reliable metric for objectively identifying tinnitus. Furthermore, histopathological examinations in blast-exposed rats revealed tinnitus-related changes in the expression patterns of key plasticity factors in the central auditory pathway, including chronic loss of Arc/Arg3.1 mobilization. Using a formulation of N-acetylcysteine (NAC) and disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07) as a therapeutic for addressing blast-induced neurodegeneration, we measured a significant treatment effect on preservation or restoration of IHC ribbon synapses, normalization of ABR wave V/I amplitude ratios, and reduced behavioral evidence of tinnitus in blast-exposed rats, all of which accorded with mitigated histopathological evidence of tinnitus-related neuropathy and maladaptive neuroplasticity.

MRI assessment of early tumor response in metastatic renal cell carcinoma patients treated with sorafenib.

OBJECTIVE: The purpose of this study was to examine early MRI changes in renal cell carcinoma (RCC) treated with the antiangiogenic agent sorafenib and to identify MRI biomarkers of RCC response to sorafenib. MATERIALS AND METHODS: Sixteen patients with RCC were evaluated by MRI before and 3-12 weeks after commencing treatment with sorafenib. Two experienced MR radiologists, blinded to treatment status, independently graded tumor appearance on T1-weighted, T2-weighted, and gadolinium-enhanced images. The proportional odds mixed model was used to compare qualitative appearance of tumors before and after therapy. Time-to-progression was correlated with Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and MR-modified Choi criteria, incorporating changes in both tumor enhancement and size. RESULTS: After sorafenib therapy, there was a significant increase in T1 signal intensity of tumors (p < 0.0001) and a significant decrease in degree of tumor enhancement (p < 0.0001). The sum of unidimensional tumor diameters decreased significantly after therapy (p = 0.005). However, the average decrease in size at early follow-up was 13%, and all patients except one had stable disease by RECIST 1.0. Early responders defined by MR-modified Choi criteria had increased time-to-progression compared with nonresponders, whereas early RECIST evaluation did not predict clinical outcome. CONCLUSION: Decreased enhancement and T1 shortening of tumors on MRI may be useful biomarkers of RCC response to angiogenesis inhibitors. Response criteria combining early changes in size and enhancement lead to better correlation with clinical outcome compared with size decrease alone.

Impact of restricting access to high-cost medications for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally, and its incidence is increasing in the West, including the UK, with the increasing burden of chronic liver disease. Until recently, systemic treatment options for advanced disease were limited. However, randomized clinical trials have demonstrated that the multikinase inhibitor sorafenib prolongs survival in appropriately selected patients, and this drug has become the standard of care for patients with advanced HCC. However, a single-technology appraisal by the NICE recommended that the UK National Health Service should not fund sorafenib on the grounds of cost-effectiveness. A number of other novel agents and combinations are currently in clinical trials, the results of which may further expand the treatment options and indications for systemic therapy in HCC. This review discusses the impact of restricting access to high-cost medications for patients with HCC in the UK, and describes potential strategies and future directions that may improve the cost-effectiveness of such drugs. It also describes the potential impact, pending national guidance, of variations in local funding decision-making on patient outcomes.

Erlotinib and sorafenib in an orthotopic rat model of hepatocellular carcinoma.

BACKGROUND & AIMS: The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model. METHODS: The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 µM) and erlotinib (1-5 µM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay. In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10mg/kg, erlotinib 10mg/kg, and respective combinations. RESULTS: In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 µM). No additional effect was observed upon combination with erlotinib. Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib. CONCLUSIONS: Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.

Early assessment by FDG-PET/CT of patients with advanced renal cell carcinoma treated with tyrosine kinase inhibitors is predictive of disease course.

BACKGROUND: We reported previously that (18)F-2-fluoro-2-deoxyglucose positron emission tomography/ computed tomography (FDG PET/CT) had potential for evaluating early response to treatment by tyrosine kinase inhibitors (TKIs) in advanced renal cell carcinoma (RCC). This time we investigated the relation of the early assessment by FDG PET/CT to long-term prognosis with an expanded number of patients and period of observation. METHODS: Patients for whom TKI treatment for advanced RCC was planned were enrolled. FDG PET/CT was performed before TKI treatment and after one month of TKI treatment. The relations of the FDGPET/CT assessment to progression free survival (PFS) and overall survival (OS) were investigated. RESULTS: Thirty-five patients were enrolled (sunitinib 19 cases, sorafenib 16 cases). The patients with RCC showing high SUVmax in pretreatment FDG PET/CT demonstrated short PFS (P =0.024, hazard ratio 1.137, 95% CI 1.017-1.271) and short OS (P =0.004, hazard ratio 1.210 95% CI 1.062-1.379). Thirty patients (sunitinib 16 cases, sorafenib 14 cases) were evaluated again after 1 month. The PFS of the patients whose SUVmax decreased<20% was shorter than that of the patients whose SUVmax decreased<20% (P = 0.027, hazard ratio 3.043, 95% CI 1.134-8.167). The PFS of patients whose tumor diameter sum increased was shorter than that of the patient with tumors whose diameter sum did not (P =0.006, hazard ratio 4.555, 95% CI 1.543-13.448). The patients were classified into three response groups: good responder (diameter sum did not increase, and SUVmax decreased ≥ 20%), intermediate responder (diameter sum did not increase, and SUVmax decreased<20%), and poor responder (diameter sum increased, or one or more new lesions appeared). The median PFS of good, intermediate, and poor responders were 458 ± 146 days, 131 ± 9 days, and 88 ± 26 days (good vs. intermediate P = 0.0366, intermediate vs. poor P = 0.0097, log-rank test). Additionally the mean OSs were 999 ± 70 days, 469 ± 34 days, and 374 ± 125 days, respectively (good vs. intermediate P = 0.0385, intermediate vs. poor P = 0.0305, log-rank test). CONCLUSIONS: The evaluation of RCC response to TKI by tumor size and FDG uptake using FDG PET/CT after 1 month can predict PFS and OS.

Cost-effectiveness evaluation of sunitinib as first-line targeted therapy for metastatic renal cell carcinoma in Spain.

INTRODUCTION Sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, delays disease progression, with a median overall survival (OS) of more than 2 years, improves quality of life and is becoming the first-line standard of care for metastatic renal carcinoma (mRCC). PURPOSE To assess the economic value of sunitinib as fi rst-line therapy in mRCC within the Spanish healthcare system. METHODS An adapted Markov model with a 10-year time horizon was used to analyse the cost effectiveness of sunitinib vs. sorafenib (SFN) and bevacizumab/interferon-α (BEV/IFN) as first-line mRCC therapy from the Spanish third-party payer perspective. Progression-free survival (PFS) and OS data from sunitinib, SFN and BEV/IFN pivotal trials were extrapolated to project survival and costs in 6-week cycles. Results, in progression-free life-years (PFLY), life years (LY) and quality-adjusted life-years (QALY) gained, expressed as incremental cost-effectiveness ratios (ICER) with costs and benefits discounted annually at 3%, were obtained using deterministic and probabilistic analyses. RESULTS Sunitinib was more effective and less costly than both SFN (gains of 0.52 PFLY, 0.16 LY, 0.17 QALY) and BEV/IFN (gains of 0.19 PFLY, 0.23 LY, 0.16 QALY) with average cost savings/patients of €1,124 and €23,218, respectively. Using a willingness-to-pay (WTP) threshold of €50,000/QALY, sunitinib achieved an incremental net benefit (INB) of €9,717 and €31,211 compared with SFN and BEV/IFN, respectively. At this WTP, the probability of sunitinib providing the highest INB was 75%. CONCLUSION Our analysis suggests that sunitinib is a costeffective alternative to other targeted therapies as first-line mRCC therapy in the Spanish healthcare setting.

Tyrosine kinase inhibitors for metastatic renal cell carcinoma.

Renal cell carcinoma accounts for 2-3% of all adult malignancies worldwide, and around 30% of patients with the condition present with advanced or metastatic disease.1,2 Until recently, cytokine therapy (e.g. interleukin-2 or interferon-alfa) was the standard treatment for metastatic renal cell carcinoma but provided only a small survival advantage (e.g. extending life by a median of 2.5 months).3 A key development has been the introduction of drugs known as receptor tyrosine kinase inhibitors, which include ▾sunitinib (Sutent-Pfizer), ▾sorafenib (Nexavar-Bayer) and ▾pazopanib (Votrient-GlaxoSmithKline). Here we review the evidence on the efficacy, tolerability and cost-effectiveness of these treatments in renal cell carcinoma.

Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

BACKGROUND: A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. METHODS: A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. CONCLUSIONS: As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC.

Cautions regarding the fitting and interpretation of survival curves: examples from NICE single technology appraisals of drugs for cancer.

The UK National Institute for Health and Clinical Excellence (NICE) has used its Single Technology Appraisal (STA) programme to assess several drugs for cancer. Typically, the evidence submitted by the manufacturer comes from one short-term randomized controlled trial (RCT) demonstrating improvement in overall survival and/or in delay of disease progression, and these are the pre-eminent drivers of cost effectiveness. We draw attention to key issues encountered in assessing the quality and rigour of the manufacturers' modelling of overall survival and disease progression. Our examples are two recent STAs: sorafenib (Nexavar®) for advanced hepatocellular carcinoma, and azacitidine (Vidaza®) for higher-risk myelodysplastic syndromes (MDS). The choice of parametric model had a large effect on the predicted treatment-dependent survival gain. Logarithmic models (log-Normal and log-logistic) delivered double the survival advantage that was derived from Weibull models. Both submissions selected the logarithmic fits for their base-case economic analyses and justified selection solely on Akaike Information Criterion (AIC) scores. AIC scores in the azacitidine submission failed to match the choice of the log-logistic over Weibull or exponential models, and the modelled survival in the intervention arm lacked face validity. AIC scores for sorafenib models favoured log-Normal fits; however, since there is no statistical method for comparing AIC scores, and differences may be trivial, it is generally advised that the plausibility of competing models should be tested against external data and explored in diagnostic plots. Function fitting to observed data should not be a mechanical process validated by a single crude indicator (AIC). Projective models should show clear plausibility for the patients concerned and should be consistent with other published information. Multiple rather than single parametric functions should be explored and tested with diagnostic plots. When trials have survival curves with long tails exhibiting few events then the robustness of extrapolations using information in such tails should be tested.

Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and anti-angiogenic drug effects.

Early imaging or blood biomarkers of tumor response is needed to customize anti-tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U-87 MG) and randomized into three groups: one group received an anti-angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment-dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti-tumor drugs and the optimization of combined therapies.

Assessment of objective responses using volumetric evaluation in advanced thymic malignancies and metastatic non-small cell lung cancer.

INTRODUCTION: Measurement of tumor response by standard response criteria is challenging in thymic malignancies, especially when the pleura is involved, as it often is in stage IV disease. In this study, we aimed to determine the effectiveness of volumetric response evaluation criteria in solid tumors (volumetrics) for evaluating response in patients with thymic malignancies treated on a phase II study of belinostat. METHODS: We evaluated the tumor responses of 25 patients with thymic cancer using computed tomography-based RECIST, World Health Organization (WHO), modified RECIST, and volumetrics. As a control, we assessed 37 patients with non-small cell lung cancer (NSCLC) with RECIST and volumetrics. RESULTS: Agreement analyses in 23 patients with thymic cancer at the time of RECIST-determined progressive disease (PD) compared volumetrics with RECIST, modified RECIST, and WHO criteria. Use of volumetrics was associated with 22% discordance compared with RECIST, 15% versus modified RECIST, and 22% versus WHO criteria. Volumetrics revealed PD 72 days earlier than RECIST (p = 0.016). In another cohort of 35 patients with NSCLC, there was 9% discordance between volumetrics and RECIST at the time of PD. Volumetrics demonstrated PD 32 days earlier than RECIST in NSCLC (p = 0.0078). CONCLUSIONS: Our study suggests that volumetrics might improve detection of PD. Prospective evaluation of this technique in a larger series of patients with thymic malignancies will be required.

Assessment of the treatment response of HCC.

Surgical hepatectomy or liver transplantation are considered as curative treatment modalities for hepatocellular carcinoma (HCC). However, many patients are not surgical candidates at the time of diagnosis. Great improvements in locoregional therapies including local ablative therapy [radiofrequency (RF) ablation or ethanol ablation] and transarterial techniques (transarterial embolization or transarterial radioembolization) have made possible local control of HCC. For unresectable HCC, a targeted therapy with sorafenib may improve survival. Unlike treatment of other oncologic tumor, the locoregional therapies are mainstay in the treatment of HCC. Therefore, the application of classical criteria such as the World Health Organization (WHO) guideline may not be suitable for accurate treatment response assessment of locoregional therapies or targeted therapy of HCC. An understanding of the imaging features of post-treatment imaging after various treatment modalities for HCC is crucial for treatment response assessment and for determining further therapy. In this article, we review the role of various imaging modalities in assessing treatment response of locoregional therapies and the targeted molecular therapy.

Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma.

OBJECTIVE: • To assess the economic value of targeted therapies as first-line metastatic renal cell carcinoma (mRCC) treatment in the US and Sweden by indirect comparison of survival data. METHODS: • A Markov model simulated disease progression, adverse events and survival with sunitinib vs sorafenib in the US and bevacizumab plus interferon-α (IFN-α) in both countries. • Results, in life-years (LYs), progression-free LYs (PFLYs), quality-adjusted LYs (QALYs) gained and treatment costs (2008 USD) were obtained through deterministic and probabilistic analyses over the patient's lifetime. RESULTS: • Sunitinib was more effective and less costly than sorafenib (gains of 0.52 PFLYs, 0.16 LYs and 0.17 QALYs and savings/patient of $13,576 in the US) and bevacizumab plus IFN-α (gains of 0.19 PFLYs, 0.23 LYs and 0.16 QALYs in both countries and savings/patient of $67,798 and $47,264 in the US and Sweden, respectively). • Results were most influenced by hazard ratios for progression-free and overall survival and treatment costs, making results generalizable across other countries if relative costs were to fall within the ranges of those in the US and Sweden. CONCLUSION: • The present analyses suggest that first-line mRCC treatment with sunitinib is a cost-effective alternative to sorafenib and bevacizumab plus IFN-α.

Economic evaluation of sorafenib in unresectable hepatocellular carcinoma.

BACKGROUND AND AIM: A double-blind, randomized phase III trial of sorafenib in advanced hepatocellular carcinoma demonstrated that sorafenib significantly prolonged overall survival compared to placebo (median overall survival = 10.7 months vs 7.9 months, P < 0.001). Sorafenib is the first and only systemic agent demonstrating survival benefit in these patients. The aim of this study was to assess the cost-effectiveness of sorafenib versus best supportive care in the treatment of advanced hepatocellular carcinoma in the USA. METHODS: A Markov model was developed following time-to-progression and survival using phase III trial data. Health effects are expressed as life-years gained. Resource utilization included drugs, physician visits, laboratory tests, scans, and hospitalizations. Unit costs, expressed in 2007 $US, came from diagnosis-related groupings, fee schedules, and the Red Book. Costs and effects were evaluated over a patient's lifetime and discounted at 3%. RESULTS: Results are presented as incremental cost/life-year gained. Deterministic and probabilistic sensitivity analyses were conducted. Life-years gained were increased for sorafenib compared to best supportive care (mean ± standard deviation: 1.58 ± 0.17 vs 1.05 ± 0.10 life-years gained/sorafenib patient and best supportive care, respectively). Lifetime total costs were $US40,639 ± $US3052 for sorafenib and $US7, 804 ± $US1349 for best supportive care. The incremental cost-effectiveness ratio was $US62,473/life-year gained. CONCLUSIONS: The economic evaluation indicates that sorafenib is cost-effective compared to best supportive care, with a cost-effectiveness ratio within the established threshold that US society is willing to pay (i.e. $US50,000-$US100,000) and significantly lower than alternative thresholds suggested in recent years ($US183,000-$US264,000/life-year gained, or $US300,000/quality-adjusted life-year) in oncology.

Sunitinib, sorafenib, temsirolimus or bevacizumab in the treatment of metastatic renal cell carcinoma: a review of health economic evaluations.

Renal cell carcinoma (RCC) is the most prevalent kidney cancer and the 5-year overall survival figure in metastatic disease (mRCC) is about 10%. New targeted drugs (sunitinib, sorafenib, bevacizumab, temsirolimus) have shown activity in the treatment of mRCC, but they are all associated with a significant burden of cost. To support decision makers in their allocation of resources, costeffectiveness models are constructed to compare the costs and outcomes of anticancer therapy. This survey focuses on studies since 2003 exploring health economics in the treatment of metastatic and/or advanced RCC employing these new drugs. This paper summarizes the results, focuses on the level of evidence of these studies, compares the calculated cost-effectiveness ratios and makes suggestions for future studies. This review reveals costs per life years gained (LYG) or quality-adjusted life years (QALY) in the range of euro 22,648 to euro203,692, depending on whether the setting is first-line or second-line and drug used. When compared to the other agents, sunitinib has the best cost-effectiveness figure. Second-line therapy does not offer valid incremental cost-effectiveness ratios.

Sorafenib for the treatment of advanced hepatocellular carcinoma.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of sorafenib according to its licensed indication for advanced hepatocellular carcinoma (HCC). The ERG report was based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The licensed indication for sorafenib specifies advanced HCC patients for whom locoregional intervention and surgery are unsuitable or had been unsuccessful. The clinical evidence came from a multicentre randomised controlled trial (Sorafenib HCC Assessment Randomized Protocol; SHARP) of sorafenib plus best supportive care versus placebo plus best supportive care, with 602 participants of a predominantly European ethnicity broadly comparable to the UK population. The submitted evidence indicated that for advanced HCC patients with Child-Pugh grade A liver function and relatively good Eastern Cooperative Oncology Group performance status, sorafenib on average improves overall survival by 83 days relative to placebo, and also increases time-to-radiological disease progression. Sorafenib therapy had little or no effect on time-to-symptom progression or on quality of life as measured using a disease-specific questionnaire. Sorafenib treatment was associated with increased incidence of hypertension and of gastrointestinal and dermatological problems. However, the therapy was reasonably well tolerated and, in SHARP, withdrawals from treatment due to adverse events were similar in the sorafenib and placebo arms, although more temporary reductions in dose were required in the sorafenib than in the placebo group. In the base case, the manufacturer's submitted economic analysis generated a deterministic incremental cost-effectiveness ratio (ICER) of 64,754 pounds per quality-adjusted life-year (QALY). The ERG extracted individual patient data for overall survival and disease progression, reran the economic model to check the submitted cost-effectiveness results, and performed new analyses which the ERG considered relevant to the decision problem; these analyses delivered ICERs between 76,000 pounds/QALY and 86,000 pounds/QALY. The guidance issued by NICE (7 May 2009) stated that sorafenib, within its licensed indication, is not recommended for the treatment of advanced (Barcelona-Clínic Liver Cancer stage C) HCC patients for whom surgical or locoregional therapies have failed or are not suitable, and people currently receiving sorafenib for the treatment of HCC should have the option to continue treatment until they and their clinician consider it appropriate to stop. Subsequently the manufacturer submitted a patient access scheme to the Department of Health. The base-case ICER submitted by the manufacturer for this scheme was 51,899 pounds/QALY. When the ERG reran the model with inputs considered relevant to the decision problem the ICER estimates ranged between 53,000 pounds to 58,000 pounds/QALY and substantially higher values depending on the nature of the sensitivity analyses. NICE considered the impact of the patient access scheme and determined that it was not sufficient to alter the guidance.

Multiparametric assessment of the anti-glioma properties of OKN007 by magnetic resonance imaging.

PURPOSE: To demonstrate that OKN007, a disulfonyl derivative of phenyl-tert-butyl nitrone (PBN), has anti-glioma activity in the clinically relevant C6 rat glioma model using multi-parametric magnetic resonance imaging. MATERIALS AND METHODS: Twenty-one rats were intracerebrally implanted with C6 cells and administered OKN007 or kept as controls. Animals were monitored with MRI at 7 Tesla (T), using morphologic, diffusion-weighted and perfusion imaging, followed by histology and Western blots of angiogenesis and inflammatory markers. RESULTS: OKN007 was found to decrease tumor volumes and increase survival. The glioma tissues of OKN007-treated rats were found to have longitudinal apparent diffusion coefficients (ADC(z)) of 0.76 +/- 0.06 x 10(-3) mm(2)/s, similar to the contralateral tissue and significantly smaller than untreated gliomas (0.97 +/- 0.13 x 10(-3) mm(2)/s). They had higher perfusion rates (66 +/- 4 mL/100 g.min) than untreated gliomas (26 +/- 7 mL/100 g.min). All examined molecular markers were decreased in OKN007-treated rat gliomas, compared with elevated levels in untreated rats. CONCLUSION: MRI assessment was successfully used to monitor a decrease in tumor growth, and corresponding alterations in ADC and perfusion rates in rat C6 gliomas treated with the anti-glioma agent, OKN007.