Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial

BACKGROUND: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach. METHODS: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n  38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat. RESULTS: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm. CONCLUSIONS: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases

REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

Purpose: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. Methods: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. Results: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician-(47,025 forms) and patient-(54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade >= 2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). Conclusion: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. Patient summary: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short-and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity

Crioterapia para la prevenci?n de la neuropat?a perif?rica secundaria a quimioterapia. Dispositivo para el enfriamiento de manos y pies

Esta ficha de evaluaci?n de tecnolog?as emergentes eval?a el grado de desarrollo de la crioterapia para la prevenci?n de la neuropat?a perif?rica secundaria a quimioterapia (CIPN, siglas en ingl?s). La ficha analiza aspectos relativos a la efectividad (en variables como dolor o calidad de vida), la seguridad o los costes. La evidencia es amplia, mostrando que el uso de crioterapia podr?a prevenir o disminuir la gravedad de los s?ntomas de la CIPN. Sin embargo, hay que destacar la limitaci?n en el uso del dispositivo que supone la baja tolerancia por parte de los pacientes a la crioterapia mediante guantes y calcetines congelados. Nuevos dispositivos con mayor control de la temperatura (refrigeraci?n l?quida y criocompresi?n) est?n en desarrollo lo que podr? ayudar a mejorar el papel de la crioterapia en la prevenci?n de la CIPN.Esta ficha de avaliaci?n de tecnolox?as emerxentes aval?a o grao de desenvolvemento da crioterapia para a prevenci?n da neuropat?a perif?rica secundaria a quimioterapia (CIPN, siglas en ingl?s). A ficha analiza aspectos relativos ? efectividade (en variables como dor ou calidade de vida), a seguridade ou os custos. A evidencia ? ampla, mostrando que o uso de crioterapia poder?a previr ou diminu?r a gravidade dos s?ntomas da CIPN. Con todo, hai que destacar a limitaci?n no uso do dispositivo que sup?n a baixa tolerancia por parte dos pacientes ? crioterapia mediante luvas e calcet?ns conxelados. Novos dispositivos con maior control da temperatura (refrixeraci?n l?quida e criocompresi?n) est?n en desenvolvemento o que poder? axudar a mellorar o papel da crioterapia na prevenci?n da CIPN

The economics of diagnostic test: the cost-effectiveness of screening test for gestational diabetes mellitus in Scotland

Gestational diabetes mellitus (GDM) is the most common medical complication during pregnancy and is defined as carbohydrate intolerance with varying levels of severity, with the onset or first recognition occurring during pregnancy. A variety of different tests and guidelines have been used to screen for GDM over the past decade and due to this the prevalence’s for GDM that are reported in studies tend to vary considerably. However, in Scotland there has been controversy over the method for the screening and the diagnosis of GDM, reflecting the lack of consensus for the diagnosis of this condition. This thesis therefore undertakes a cost-effectiveness analysis that compares four screening test strategies that use various combinations of screening and diagnostic tests with a strategy that involves no screening. The first objective was to explore the economic approach to evaluating diagnostic testing in GDM. In consultation with experts and informed by comparable diagnostic testing models, the thesis adapted a conceptual model to the practice of GDM detection. The thesis found that the most appropriate model makes use of a combination of tests as either “negative dominant strategy” (NDS) or “positive dominant strategy” (PDS), allowing the clinician to consider test results in terms of the differences in false negative (FN) and false positive (FP) test results, as combining the tests in terms of NDS and PDS involves a tread-off between sensitivity and specificity. A key input parameter of the model was identified to be the disease prevalence. However, due to limited known evidence in Scotland, the second objective was to assess the evidence on this key parameter. A systematic review was conducted to evaluate the prevalence of GDM, considering not just screening test characteristics, but also population characteristics. The review explores the possibility that variations in over half of the studies can be explained by ethnicity and diagnostic screening strategies and whether 75g or 100g oral glucose tolerance test (OGTT) methods of testing for GDM can cause variations in the results. Mothers with risk factors are prone to testing positive which in turn leads to higher prevalence rates compared to other populations and screening ethnic groups that have a high risk of developing GDM can indeed result in high prevalence estimates, ranging from 8.5% to 12.8%. Decision making in healthcare over the past decade has increasingly been based on considerations of cost effectiveness, including national guidelines for GDM screening. The third objective was to summarize and appraise the present economic evaluation literature. Thus, a systematic review of economic evaluations, as outlined in the various cost and cost-effectiveness studies that have been published in recent years, was performed to critically appraise the current analytical methods used to measure the cost-effectiveness of screening tests in order to develop a standardised economic model. Costs associated with the screening and management of GDM vary widely by country, ranging approximately from £2.42 to £50.9 per case detection, and are dependent on the tests used, the screening approach, how the costs are calculated and the prevalence of GDM in the population. The review of the CEA studies has significant implications for future research and policy making and as such long term consequences are appropriate outcomes for the CEA of screening tests for GDM in order to capture all long term adverse health outcomes for GDM. Therefore, the economic evaluation for GDM should account for the effectiveness of postpartum screening for type 2 DM. The aforementioned conceptual model and the results of the systematic reviews of diabetes prevalence and GDM screening cost-effectiveness have been synthesised into a model to estimate the cost-effectiveness of screening for GDM based on four screening guidelines that include 1) SIGN 2001 (random plasma glucose followed by 75g OGTT) , 2) NICE 2008 (risk factors screening followed by fasting plasma glucose and 75g OGTT) , 3) Consensus 2010 (75g OGTT) and 4) SIGN 2010 (risk factors screening followed by 75g OGTT) versus 5) no screening. This probabilistic model was used to estimate and compare the costs and quality adjusted life years (QALYs) of screening tests for GDM. Three independent decision trees, for case detections, short term complications in the first year and long term complications over the lifetime, explored and considered the combinations of screening and diagnostic tests in terms of NDS and PDS. Independent decision trees would allow policy makers to focus on each part of the model separately. The primary outcomes of the analysis were the incremental cost per case identification, one year QALYs for short term complications and lifetime QALYs for type 2 diabetes mellitus for long term complications. Case identification was insufficient for policy makers because it fails to take account of the consequence of false positive and false negative results of tests. For short term complications, the incremental cost-effectiveness ratio was £46,760 per QALY for the two-step approach with SIGN 2001 (NDS) using 75g OGTT to confirm any positive random plasma glucose (RPG) before treatment compared with no screening. At willingness to pay £30,000/QALY, this strategy has 64% probability of being cost-effective for short term complications. The cost effectiveness of screening tests for GDM, to prevent short term complications, is dependent on the probability of GDM being undiagnosed. Additionally, treatments during gestation are important as they reduce additional costs that may be required to treat serious adverse complications. PDS screening where all pregnant women with one or more high risk factors are requested to undertake 75g OGTT diagnostic test, proposed by SIGN 2010, is the most cost-effective strategy in long term complications. SIGN 2010 (PDS) has higher QALY (80.9736) and is less expensive (£4,088) than the other strategies and dominates the other screening test strategies for long term complications. At a threshold of £30,000/QALY, the CEA illustrates that the probability that SIGN 2010 (PDS) will be cost-effective is approximately 55.8%. The cost effectiveness of screening tests for GDM, to prevent long term complications, is dependent on the probability of GDM being over diagnosed. If mothers have received previous diagnoses of GDM, this should trigger regular screening for type 2 DM so that it is discovered early on, before the onset of symptoms or the development of complications associated with type 2 DM. Postpartum screening and the subsequent treatment of GDM presents an important opportunity to reduce type 2 DM. This thesis provides the first economic model of a screening test using independent decision trees, split by NDS and PDS. By using NDS and PDS, decision makers can interpret the combination of test results. This better presents the consequences of false positive and false negatives and a trade-off between sensitive and specificity. The thesis finds novel value of applying this methodology to GDM screening. By using independent decision trees for NDS and PDS, the model was able to identify long term complications as the most important factors affecting the results of screening test strategies. Currently, all guidelines for GDM screening tests which also included two Scottish guidelines SIGN 2001 and SIGN 2010 are performed as NDS with regard to both screening tests and postpartum screening. Thus, in Scotland, policy makers or clinicians should consider SIGN 2010 with PDS for screening tests for GDM in order to prevent long term complications. Lastly, this work is also the first to apply the expected value of information (EVPI) to the area of GDM screening. The population EVPPI of £784,042 for long term complications shows that there is greater uncertainty with respect to long term complications and that collecting information on long term complications is likely to be worthwhile. Thus, it captures the long time horizons in screening programmes required for decisions about the value of further research and the expected payoff of conducting further research to resolve the model uncertainties