First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy : a subgroup analysis of data from the FLEX phase 3 study

Background: The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit. Methods: We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: 518 patients in the chemotherapy plus cetuximab group-290 of whom had first-cycle rash-and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months [95% CI 12·8-16·4] vs 8·8 months [7·6-11·1]; hazard ratio [HR] 0·631 [0·515-0·774]; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months [5·2-5·7] vs 4·3 months [4·1-5·3]; HR 0·741 [0·607-0·905]; p=0·0031) and response (rate 44·8% [39·0-50·8] vs 32·0% [26·0-38·5]; odds ratio 1·703 [1·186-2·448]; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months [7·6-11·1] vs 10·3 months [9·6-11·3]; HR 1·085 [0·910-1·293]; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, [14·1-20·6] vs 9·3 months [7·7-13·2]; HR 0·614 [0·453-0·832]; p=0·0015), squamous-cell carcinoma (median 13·2 months [10·6-16·0] vs 8·1 months [6·7-12·6]; HR 0·659 [0·472-0·921]; p=0·014), and carcinomas of other histology (median 12·6 months [9·2-16·4] vs 6·9 months [5·2-11·0]; HR 0·616 [0·392-0·966]; p=0·033). Interpretation: First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit. Funding: Merck KGaA. © 2011 Elsevier Ltd.

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer : analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.

The increasing cost of healthy food

OBJECTIVE: To assess changes in the cost and availability of a standard basket of healthy food items (the Healthy Food Access Basket [HFAB]) in Queensland. METHODS: Analysis of five cross-sectional surveys (1998, 2000, 2001, 2004 and 2006) describes changes over time. Eighty-nine stores in five remoteness categories were surveyed during May 2006. For the first time a sampling framework based on randomisation of towns throughout the state was applied and the survey was conducted by Queensland Treasury. RESULTS: Compared with the costs in major cities, in 2006 the mean cost of the HFAB was $107.81 (24.2%) higher in very remote stores in Queensland, but $145.57 (32.6%) higher in stores more than 2,000 kilometres from Brisbane. Over six years the cost of the HFAB has increased by around 50% ($148.87) across Queensland and, where data was available, by more than the cost of less healthy alternatives. The Consumer Price Index for food in Brisbane increased by 32.5% over the same period. CONCLUSIONS AND IMPLICATIONS: Australians, no matter where they live, need access to affordable, healthy food. Issues of food security in the face of rising food costs are of concern particularly in the current global economic downturn. There is an urgent need to nationally monitor, but also sustainably address the factors affecting the price of healthy foods, particularly for vulnerable groups who suffer a disproportionate burden of poor health.

Public Economics and the Assessment of Tourism Developments and Policies

Public economics covers both topics in welfare economic of social (as opposed to private) interest and aspects of public finance. This chapter considers the application of two methods of social economic evaluation of tourist developments, namely, social cost-benefit analysis and economic impact analysis. The role of social cost-benefit analysis in the assessment of tourism is illustrated by its application to the evaluation of inbound tourism. This is followed by a discussion of taxes on tourism and subsidies to promote it. The principle focus is on hotel room taxes. The analysis of taxes on tourism involves both public finance and welfare economics issues. The scope for and desirability of applying the user-pays principle to tourism is then examined.

Prevention and treatment of acute radiation-induced skin reactions : a systematic review and meta-analysis of randomized controlled trials

Background Radiation-induced skin reaction (RISR) is a common side effect that affects the majority of cancer patients receiving radiation treatment. RISR is often characterised by swelling,redness, pigmentation, fibrosis, and ulceration, pain, warmth, burning, and itching of the skin. The aim of this systematic review was to assess the effects of interventions which aim to prevent or manage RISR in people with cancer. Methods We searched the following databases up to November 2012: Cochrane Skin Group Specialised Register, CENTRAL (2012, Issue 11), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), CINAHL (from 1981) and LILACS (from 1982). Randomized controlled trials evaluating interventions for preventing or managing RISR in cancer patients were included. The primary outcomes were development of RISR, and levels of RISR and symptom severity. Secondary outcomes were time taken to develop erythema or dry desquamation; quality of life; time taken to heal, a number of skin reaction and symptom severity measures; cost, participant satisfaction; ease of use and adverse effects. Where appropriate, we pooled results of randomized controlled trials using mean differences (MD) or odd ratios (OR) with 95% confidence intervals (CI). Results Forty-seven studies were included in this review. These evaluated six types of interventions (oral systemic medications; skin care practices; steroidal topical therapies; non-steroidal topical therapies; dressings and other). Findings from two meta-analyses demonstrated significant benefits of oral Wobe-Mugos E for preventing RISR (OR 0.13 (95% CI 0.05 to 0.38)) and limiting the maximal level of RISR (MD −0.92 (95% CI −1.36 to −0.48)). Another meta-analysis reported that wearing deodorant does not influence the development of RISR (OR 0.80 (95% CI 0.47 to 1.37)). Conclusions Despite the high number of trials in this area, there is limited good, comparative research that provides definitive results suggesting the effectiveness of any single intervention for reducing RISR. More research is required to demonstrate the usefulness of a wide range of products that are being used for reducing RISR. Future efforts for reducing RISR severity should focus on promising interventions, such as Wobe-Mugos E and oral zinc.

Efficacy of a children's procedural preparation and distraction device on healing in acute burn wound care procedures : study protocol for a randomized controlled trial

BACKGROUND: The intense pain and anxiety triggered by burns and their associated wound care procedures are well established in the literature. Non-pharmacological intervention is a critical component of total pain management protocols and is used as an adjunct to pharmacological analgesia. An example is virtual reality, which has been used effectively to dampen pain intensity and unpleasantness. Possible links or causal relationships between pain/anxiety/stress and burn wound healing have previously not been investigated. The purpose of this study is to investigate these relationships, specifically by determining if a newly developed multi-modal procedural preparation and distraction device (Ditto) used during acute burn wound care procedures will reduce the pain and anxiety of a child and increase the rate of re-epithelialization. METHODS/DESIGN: Children (4 to 12 years) with acute burn injuries presenting for their first dressing change will be randomly assigned to either the (1) Control group (standard distraction) or (2) Ditto intervention group (receiving Ditto, procedural preparation and Ditto distraction). It is intended that a minimum of 29 participants will be recruited for each treatment group. Repeated measures of pain intensity, anxiety, stress and healing will be taken at every dressing change until complete wound re-epithelialization. Further data collection will aid in determining patient satisfaction and cost effectiveness of the Ditto intervention, as well as its effect on speed of wound re-epithelialization. DISCUSSION: Results of this study will provide data on whether the disease process can be altered by reducing stress, pain and anxiety in the context of acute burn wounds. TRIAL REGISTRATION: ACTRN12611000913976.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

Contemporary comments: The limited benefit of prison in controlling crime

A number of recent developments in the United State (US), United Kingdom (UK) and Australia suggest that conditions may be ripe for a political shift in the reliance on escalating rates of imprisonment as a default criminal justice strategy for responding to crime. The default position is illustrated by the Yabsleyite response of former New South Wales (NSW) Premier Nathan Rees’s to questioning over the cost of prison building and NSW’s high recidivism rate: ‘[t]he advice to me is we have still got 500 cells empty, I don't mind if we fill them up, and if we fill them up and have to build another jail, we'll build another jail’ (Knox and Tadros 2008)...

The Limited Benefit of Prison in Controlling Crime : On the Threshold of a Political Shift

In 2012 the New Zealand government spent $3.4 billion, or nearly $800 per person, on responses to crime via the justice system. Research shows that much of this spending does little to reduce the changes of re-offending. Relatively little money is spent on victims, the rehabilitation of offenders or to support the families of offenders. This book is based on papers presented at the Costs of Crime forum held by the Institute of Policy Studies in February 2011. It presents lessons from what is happening in Australia, Britain and the United States and focuses on how best to manage crime, respond to victims, and reduce offending in a cost-effective manner in a New Zealand context. It is clear that strategies are needed that are based on better research and a more informed approach to policy development. Such strategies must assist victims constructively while also reducing offending. Using public resources to lock as many people in our prisons as possible cannot be justified by the evidence and is fiscally unsustainable; nor does such an approach make society safer. To reduce the costs of crime we need to reinvest resources in effective strategies to build positive futures for those at risk and the communities needed to sustain them.

Analysis of construction dispute review boards

The construction industry has long been burdened with inherent adversarial relationships among the parties and the resulting disputes. Dispute review boards (DRBs) have emerged as alternatives to settle construction-related disputes outside courts. Although DRBs have found support in some quarters of the construction industry, the quantitative assessment of the impact of DRBs has not been adequately addressed. This paper presents the results of a research project undertaken to assess the impact of DRBs on the construction program of a large-scale highway agency. Three dimensions of DRB impact were assessed: (1) influence on project cost and schedule performance, (2) effectiveness of DRBs in preventing and resolving construction disputes, and (3) costs of DRB implementation. The analyses encompass data from approximately 3,000 projects extending over a 10-year period (2000–2009). Quantitative measures of performance were developed and analyzed for each category. Projects that used DRBs faced reduced costs and schedule growth (6.88 and 12.92%, respectively) when compared to non-DRB projects (11.53 and 28.96%). DRBs were also found to be effective in avoiding and settling disputes; the number of arbitration cases reduced consistently after DRB implementation, and DRBs have a success rate of 97% in settling disputes for which DRBs were used. Moreover, costs of DRBs were found to comprise a relatively small fraction (i.e., approximately 0.3%) of total project budgets. It was concluded that DRBs were effective dispute prevention and resolution alternatives with no significant adverse effects on project performance.

Quantitative fit analysis of orthopedic bone plates : methods, criteria and approach

Studies on quantitative fit analysis of precontoured fracture fixation plates emerged within the last few years and therefore, there is a wide research gap in this area. Quantitative fit assessment facilitates the measure of the gap between a fracture fixation plate and the underlying bone, and specifies the required plate fit criteria. For clinically meaningful fit assessment outcome, it is necessary to establish the appropriate criteria and parameter. The present paper studies this subject and recommends using multiple fit criteria and the maximum distance between the plate and underlying bone as fit parameter for clinically relevant outcome. We also propose the development of a software tool for automatic plate positioning and fit assessment for the purpose of implant design validation and optimization in an effort to provide better fitting implant that can assist proper fracture healing. The fundamental specifications of the software are discussed.

Critical analysis of spam prevention techniques

E-mail spam has remained a scourge and menacing nuisance for users, internet and network service operators and providers, in spite of the anti-spam techniques available; and spammers are relentlessly circumventing these anti-spam techniques embedded or installed in form of software products on both client and server sides of both fixed and mobile devices to their advantage. This continuous evasion degrades the capabilities of these anti-spam techniques as none of them provides a comprehensive reliable solution to the problem posed by spam and spammers. Major problem for instance arises when these anti-spam techniques misjudge or misclassify legitimate emails as spam (false positive); or fail to deliver or block spam on the SMTP server (false negative); and the spam passes-on to the receiver, and yet this server from where it originates does not notice or even have an auto alert service to indicate that the spam it was designed to prevent has slipped and moved on to the receiver’s SMTP server; and the receiver’s SMTP server still fail to stop the spam from reaching user’s device and with no auto alert mechanism to inform itself of this inability; thus causing a staggering cost in loss of time, effort and finance. This paper takes a comparative literature overview of some of these anti-spam techniques, especially the filtering technological endorsements designed to prevent spam, their merits and demerits to entrench their capability enhancements, as well as evaluative analytical recommendations that will be subject to further research.

A game theoretical approach to construction safety in the Repair, Maintenance, Alteration and Addition (RMAA) sector

Safety has long been a problem in the construction industry. Repair, maintenance, alteration and addition (RMAA) sector has emerged to play an important role in the construction industry. It accounted for 53% of the total construction market in Hong Kong in 2007. Safety performance of the RMAA words has been alarming. Statistics indicate that the percentage of fatal industrial accidents arising from RMAA work in Hong Kong was over 56% in 2006 while the remaining 44% was from new works. Effective safety measures to address the safety problems and improve safety performance of the RMAA sector are urgently needed. Unsafe behaviour has been attributed to one of the major causes of accidents. Traditional cost-benefit analysis of workers' safety behaviour seems to be inadequate. This paper proposes to adopt a game theoretical approach to analyse safety behaviour of RMAA workers. Game theory is concerned with the decision-making process in situations where outcomes depend upon choices made by one or more players. A game theoretical model between contractor and worker has been proffered. Mathematical analysis of this game model has been done and implications of the analysis have been discussed.

Lumbar epidural steroids are not cost effective in sciatica

Background Lumbar Epidural Steroids Injections (ESI’s) have previously been shown to provide some degree of pain relief in sciatica. Number Needed To Treat (NNT) to achieve 50% pain relief has been estimated at 7 from the results of randomised controlled trials. Pain relief is temporary. They remain one of the most commonly provided procedures in the UK. It is unknown whether this pain relief represents good value for money. Methods 228 patients were randomised into a multi-centre Double Blind Randomised Controlled Trial. Subjects received up to 3 ESI’s or intra-spinous saline depending on response and fall off with the first injection. All other treatments were permitted. All received a review of analgesia, education and physical therapy. Quality of life was assessed using the SF36 at 6 points and compared using independent sample t-tests. Follow up was up to 1 yr. Missing data was imputed using last observation carried forward (LOCF). QALY’s (Quality of Life Years) were derived from preference based heath values (summary health utility score). SF-6D health state classification was derived from SF-36 raw score data. Standard gambles (SG) were calculated using Model 10. SG scores were calculated on trial results. LOCF was not used for this. Instead average SG were derived for a subset of patients with observations for all visits up to week 12. Incremental QALY’s were derived as the difference in the area between the SG curve for the active group and placebo group. Results SF36 domains showed a significant improvement in pain at week 3 but this was not sustained (mean 54 Active vs 61 Placebo P<0.05). Other domains did not show any significant gains compared with placebo. For derivation of SG the number in the sample in each period differed. In week 12, average SG scores for active and placebo converged. In other words, the health gain for the active group as measured by SG was achieved by the placebo group by week 12. The incremental QALY gained for a patient under the trial protocol compared with the standard care package was 0.0059350. This is equivalent to an additional 2.2 days of full health. The cost per QALY gained to the provider from a patient management strategy administering one epidural as suggested by results was £25 745.68. This result was derived assuming that the gain in QALY data calculated for patients under the trial protocol would approximate that under a patient management strategy based on the trial results (one ESI). This is above the threshold suggested by some as a cost effective treatment. Conclusions The transient benefit in pain relief afforded by ESI’s does not appear to be cost-effective. Further work is needed to develop more cost-effective conservative treatments for sciatica.

Impact and energy absorption of portable water-filled road safety barrier system fitted with foam

Portable water-filled barriers (PWFBs) are roadside appurtenances that are used to prevent errant vehicles from penetrating into temporary construction zones on roadways. A numerical model of the composite PWFB, consisting of a plastic shell, steel frame, water and foam was developed and validated against results from full scale experimental tests. This model can be extended to larger scale impact cases, specifically ones that include actual vehicle models. The cost-benefit of having a validated numerical model is significant and this allows the road barrier designer to conduct extensive tests via numerical simulations prior to standard impact tests Effects of foam cladding as additional energy absorption material in the PWFB was investigated. Different types of foam were treated and it was found that XPS foam was the most suitable foam type. Results from this study will aid PWFB designers in developing new generation of roadside structures which will provide enhanced road safety.