The cost-effectiveness of follow-up strategies after cancer treatment: a systematic literature review.

Introduction: The cost of treatment and follow-up of cancer patients in the UK is substantial. In a budget-constrained system such as the NHS, it is necessary to consider the cost-effectiveness of the range of management strategies at different points on cancer patients' care pathways to ensure that they provide adequate value for money. Sources of data: We conducted a systematic literature review to explore the cost-effectiveness of follow-up strategies of patients previously treated for cancer with the aim of informing UK policy. All papers that were considered to be economic evaluations in the subject areas described above were extracted. Areas of agreement: The existing literature suggests that intensive follow-up of patients with colorectal disease is likely to be cost-effective, but the opposite holds for breast cancer. Areas of controversy: Interventions and strategies for follow-up in cancer patients were variable across type of cancer and setting. Drawing general conclusions about the cost-effectiveness of these interventions/strategies is difficult. Growing points: The search identified 2036 references but applying inclusion/exclusion criteria a total of 44 articles were included in the analysis. Breast cancer was the most common (n = 11) cancer type followed by colorectal (n = 10) cancer. In general, there were relatively few studies of cost-effectiveness of follow-up that could influence UK guidance. Where there was evidence, in the most part, NICE guidance broadly reflected this evidence. Areas timely to develop research: In terms of future research around the timing, frequency and composition of follow-ups, this is dependent on the type of cancer being considered. Nevertheless, across most cancers, the possibility of remote follow-up (or testing) by health professionals other than hospital consultants in other settings appears to warrant further work.

Are preferences over health states informed?

BACKGROUND: The use of preference-elicitation tasks for valuing health states is well established, but little is known about whether these preferences are informed. Preferences may not be informed because individuals with little experience of ill health are asked to value health states. The use of uninformed preferences in cost-effectiveness can result in sub-optimal resource allocation. The aim of this study was to pilot a novel method to assess whether members of the public are informed about health states they value in preference-elicitation tasks. METHODS: The general public was said to be informed if the expectations of the public about the effect of ill health on people's lives were in agreement with the experience of patients. Sixty-two members of the public provided their expectations of the consequences of ill health on five life domains (activities, enjoyment, independence, relationships, and avoiding being a burden). A secondary dataset was used to measure patient experience on those five consequences. RESULTS: There were differences between the expectations of the public and the experience of patients. For example, for all five life consequences the public underestimated the effects of problems in usual activities compared to problems in mobility. They also underestimated the effect of 'anxiety or depression' compared to physical problems on enjoyment of life and on the quality of personal relationships. CONCLUSIONS: This proof-of-concept study showed that it is possible to test whether preferences are informed. This study should be replicated using a larger sample. The findings suggest that preferences over health states in this sample are not fully informed because the participants do not have accurate expectations about the consequences of ill health. These uninformed preferences may not be adequate for allocation of public resources, and research is needed into methods to make them better informed.

How do individuals value health states? A qualitative investigation.

Despite the importance of health state values in informing resource allocation in health care, there is arguably little known about how individuals value health. Previous studies have shown that a variety of non-health factors and beliefs are important in valuing health, but there is less evidence in the literature about how individuals' beliefs affect their preferences or what role non-health factors play in the process of forming preferences. This study investigated the thought processes of 21 U.K. based participants in March 2013 who valued health states using semi-structured interviews and a think-aloud protocol, with the aim to better understand the relationship between health states, the individual's underlying beliefs, and the individual's preferences. Participants followed several stages in valuing health. First, participants interpreted the health states more concretely, relying on their imagination and their experience of ill health. Participants judged how the concrete health problems combined with their personal interests, circumstances, and environment would affect them personally. Ultimately, participants valued health by estimating and weighing the non-health consequences of the health states. Six consequences were most frequently mentioned: activities, enjoyment, independence, relationships, dignity, and avoiding being a burden. At each stage participants encountered difficulties and expressed concerns. The findings have implications for methods of describing health, for example, whether the focus should be on health or a broader notion of well-being and capability. This is because the consequences are similar to the domains of broader measures such as the ICECAP measures for adults and older people, and the Warwick-Edinburgh Mental Wellbeing Scale. The findings suggest the need for testing whether individuals are informed about the health states they are valuing. Participants valued health by estimating the non-health consequences of health states and these estimates relied on individuals' beliefs about the interaction of the health state and their personal and social circumstances.

Small intestinal growth measures are correlated with feed efficiency in market weight cattle, despite minimal effects of maternal nutrition during early to midgestation.

We hypothesized that gestational nutrition would affect calf feed efficiency and small intestinal biology, which would be correlated with feed efficiency. Multiparous beef cows (n = 36) were individually fed 1 of 3 diets from d 45 to 185 of gestation: native grass hay and supplement to meet NRC recommendations (control [CON]), 70% of CON NEm (nutrient restricted [NR]), or a NR diet with a RUP supplement (NR+RUP) to provide similar essential AA as CON. After d 185 of gestation, cows were managed as a single group, and calf individual feed intake was measured with the GrowSafe System during finishing. At slaughter, the small intestine was dissected and sampled. Data were analyzed with calf sex as a block. There was no effect (P ≥ 0.33) of maternal treatment on residual feed intake, G:F, DMI, ADG, or final BW. Small intestinal mass did not differ (P ≥ 0.38) among treatments, although calf small intestinal length tended (P = 0.07) to be greater for NR than NR+RUP. There were no differences (P ≥ 0.20) in calf small intestinal density or jejunal cellularity, proliferation, or vascularity among treatments. Jejunal soluble guanylate cyclase mRNA was greater (P < 0.03) for NR+RUP than CON and NR. Residual feed intake was positively correlated (P ≤ 0.09) with small intestinal mass and relative mass and jejunal RNA content but was negatively correlated (P ≤ 0.09) with jejunal mucosal density and DNA concentration. Gain:feed was positively correlated (P ≤ 0.09) with jejunal mucosal density, DNA, protein, and total cells and was negatively correlated (P ≤ 0.05) with small intestinal relative mass, jejunal RNA, and RNA:DNA. Dry matter intake was positively correlated (P ≤ 0.09) with small intestinal mass, relative mass, length, and density as well as jejunal DNA and protein content, total cells, total vascularity, and kinase insert domain receptor and endothelial nitric oxide synthase 3 mRNA and was negatively correlated (P = 0.02) with relative small intestinal length. In this study, calf performance and efficiency during finishing as well as most measures of small intestinal growth were not affected by maternal nutrient restriction during early and midgestation. Results indicate that offspring small intestinal gene expression may be affected by gestational nutrition even when apparent tissue growth is unchanged. Furthermore, small intestinal size and growth may explain some variation in efficiency of nutrient utilization in feedlot cattle.

Effects of early- to mid-gestational undernutrition with or without protein supplementation on offspring growth, carcass characteristics, and adipocyte size in beef cattle.

Angus × Gelbvieh cows with 2 to 3 previous pregnancies were used to evaluate effects of maternal nutrient restriction on offspring adipose tissue morphology at standard production endpoints. At 45 d after AI to a single sire, pregnancy was confirmed and cows randomly allotted into groups and fed a control (Con, 100% of NRC recommendations), nutrient-restricted (NR, 70% of Con diet), or nutrient-restricted + protein-supplemented (NRP, 70% of Con + essential AA supply to the small intestine equal to Con) diet. At d 185 of gestation, cows were commingled and received the Con diet thereafter. Bull calves were castrated at 2 mo of age. Calves were weaned at 210 d, backgrounded for 28 d, and then placed in the feedlot for 195 d. Steers and heifers were slaughtered at an average 12th-rib fat thickness of 7.6 mm. Adipose tissue from selected depots was collected for adipocyte size analysis. There was no significant difference in BW or BCS between Con, NRP, and NR cows at d 45 of gestation, which averaged 489.7 ± 17.7 kg and 5.35 ± 0.13, respectively. At d 185 of gestation, Con and NRP groups had similar BW (566.1 ± 14.8 and 550.2 ± 14.8 kg) and BCS (6.34 ± 0.27 and 5.59 ± 0.27), but NR cows exhibited reduced (P < 0.05) BW (517.9 ± 14.8 kg) and BCS (4.81 ± 0.27). Among offspring (steers and heifers) at slaughter, there were no significant differences in BW or organ weights among treatment groups. Yield grade was reduced (P < 0.05) and semitendinosus weight/HCW tended (P = 0.09) to be reduced in NR offspring compared with Con and NRP offspring. Average adipocyte diameter was increased (P < 0.05) in subcutaneous, mesenteric, and omental adipose tissue and tended (P = 0.09) to increase in perirenal adipose tissue in NR compared with Con offspring with NRP offspring adipocyte diameter being either intermediate or similar to Con calves. The adipocyte size alterations observed in NR offspring were confirmed by DNA concentration of the adipose tissue depots. There also was an increased mRNA expression (P < 0.05) of fatty acid transporter 1 in subcutaneous adipose tissue from NR offspring compared with Con and NRP offspring. Nutritional restriction during early and mid gestation increased or tended to increase (P < 0.09) adipocyte diameter in all adipose tissue depots in finished steer and heifer calves.

Avoiding and identifying errors in health technology assessment models: qualitative study and methodological review.

BACKGROUND: Health policy decisions must be relevant, evidence-based and transparent. Decision-analytic modelling supports this process but its role is reliant on its credibility. Errors in mathematical decision models or simulation exercises are unavoidable but little attention has been paid to processes in model development. Numerous error avoidance/identification strategies could be adopted but it is difficult to evaluate the merits of strategies for improving the credibility of models without first developing an understanding of error types and causes. OBJECTIVES: The study aims to describe the current comprehension of errors in the HTA modelling community and generate a taxonomy of model errors. Four primary objectives are to: (1) describe the current understanding of errors in HTA modelling; (2) understand current processes applied by the technology assessment community for avoiding errors in development, debugging and critically appraising models for errors; (3) use HTA modellers' perceptions of model errors with the wider non-HTA literature to develop a taxonomy of model errors; and (4) explore potential methods and procedures to reduce the occurrence of errors in models. It also describes the model development process as perceived by practitioners working within the HTA community. DATA SOURCES: A methodological review was undertaken using an iterative search methodology. Exploratory searches informed the scope of interviews; later searches focused on issues arising from the interviews. Searches were undertaken in February 2008 and January 2009. In-depth qualitative interviews were performed with 12 HTA modellers from academic and commercial modelling sectors. REVIEW METHODS: All qualitative data were analysed using the Framework approach. Descriptive and explanatory accounts were used to interrogate the data within and across themes and subthemes: organisation, roles and communication; the model development process; definition of error; types of model error; strategies for avoiding errors; strategies for identifying errors; and barriers and facilitators. RESULTS: There was no common language in the discussion of modelling errors and there was inconsistency in the perceived boundaries of what constitutes an error. Asked about the definition of model error, there was a tendency for interviewees to exclude matters of judgement from being errors and focus on 'slips' and 'lapses', but discussion of slips and lapses comprised less than 20% of the discussion on types of errors. Interviewees devoted 70% of the discussion to softer elements of the process of defining the decision question and conceptual modelling, mostly the realms of judgement, skills, experience and training. The original focus concerned model errors, but it may be more useful to refer to modelling risks. Several interviewees discussed concepts of validation and verification, with notable consistency in interpretation: verification meaning the process of ensuring that the computer model correctly implemented the intended model, whereas validation means the process of ensuring that a model is fit for purpose. Methodological literature on verification and validation of models makes reference to the Hermeneutic philosophical position, highlighting that the concept of model validation should not be externalized from the decision-makers and the decision-making process. Interviewees demonstrated examples of all major error types identified in the literature: errors in the description of the decision problem, in model structure, in use of evidence, in implementation of the model, in operation of the model, and in presentation and understanding of results. The HTA error classifications were compared against existing classifications of model errors in the literature. A range of techniques and processes are currently used to avoid errors in HTA models: engaging with clinical experts, clients and decision-makers to ensure mutual understanding, producing written documentation of the proposed model, explicit conceptual modelling, stepping through skeleton models with experts, ensuring transparency in reporting, adopting standard housekeeping techniques, and ensuring that those parties involved in the model development process have sufficient and relevant training. Clarity and mutual understanding were identified as key issues. However, their current implementation is not framed within an overall strategy for structuring complex problems. LIMITATIONS: Some of the questioning may have biased interviewees responses but as all interviewees were represented in the analysis no rebalancing of the report was deemed necessary. A potential weakness of the literature review was its focus on spreadsheet and program development rather than specifically on model development. It should also be noted that the identified literature concerning programming errors was very narrow despite broad searches being undertaken. CONCLUSIONS: Published definitions of overall model validity comprising conceptual model validation, verification of the computer model, and operational validity of the use of the model in addressing the real-world problem are consistent with the views expressed by the HTA community and are therefore recommended as the basis for further discussions of model credibility. Such discussions should focus on risks, including errors of implementation, errors in matters of judgement and violations. Discussions of modelling risks should reflect the potentially complex network of cognitive breakdowns that lead to errors in models and existing research on the cognitive basis of human error should be included in an examination of modelling errors. There is a need to develop a better understanding of the skills requirements for the development, operation and use of HTA models. Interaction between modeller and client in developing mutual understanding of a model establishes that model's significance and its warranty. This highlights that model credibility is the central concern of decision-makers using models so it is crucial that the concept of model validation should not be externalized from the decision-makers and the decision-making process. Recommendations for future research would be studies of verification and validation; the model development process; and identification of modifications to the modelling process with the aim of preventing the occurrence of errors and improving the identification of errors in models.

Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs, with a minimum treatment duration of 12 weeks, which compared ezetimibe monotherapy (10 mg per day) with placebo. RESULTS: In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid concentrations were used as indicators of clinical outcomes. A meta-analysis of eight randomized, double-blind, placebo-controlled trials (all 12 weeks) showed that ezetimibe monotherapy was associated with a statistically significant mean reduction in LDL cholesterol (from baseline to endpoint) of -18.58%, (95% CI: -19.67 to -17.48, P < 0.00001) compared with placebo. Significant (P < 0.00001) changes were also found in total cholesterol (-13.46%, 95% CI: -14.22 to -12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride levels (-8.06%, 95% CI: -10.92 to -5.20). Ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo. CONCLUSIONS: In a meta-analysis restricted to short-term trials in hypercholesterolaemia, significant potentially favourable changes in lipid and lipoprotein levels relative to baseline occurred with ezetimibe monotherapy. Further long-term studies with cardiovascular and other clinical outcome data are needed to assess the efficacy and safety of ezetimibe more fully.

Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

OBJECTIVES: To review the clinical and cost-effectiveness of ezetimibe as a combination therapy or monotherapy for the treatment of primary hypercholesterolaemia in the UK. DATA SOURCES: Twelve electronic databases were searched from inception to June 2006. Searches were supplemented by hand-searching relevant articles, sponsor and other submissions of evidence to the National Institute of Health and Clinical Excellence and conference proceedings. REVIEW METHODS: A systematic review and meta-analysis (where appropriate) of the clinical efficacy evidence was undertaken following recommended guidelines. A Markov model was developed to explore the costs and health outcomes associated with ezetimibe treatment. RESULTS: No published clinical outcome trials (> 12 weeks) were identified. In the absence of clinical end-point data from trials, 13 (of which five were multi-arm) phase III multi-centre randomised controlled trials (RCTs) (of varying methodological quality) of short-term duration (12-48 weeks) with surrogate end-point data were included. For patients not adequately controlled with a statin alone, a meta-analysis of six studies showed that a fixed-dose combination of ezetimibe and statin treatment was associated with a statistically significant reduction in low-density lipoprotein cholesterol (LDL-c) and total cholesterol (Total-c) compared with statin alone (p < 0.00001). Four studies (not eligible for meta-analysis) that titrated (either forced or stepwise) the statin doses to LDL-c targets generally showed that the co-administration of ezetimibe and statin was significantly more effective in reducing plasma LDL-c concentrations than statin monotherapy (p < 0.05 for all studies). For patients where a statin is not considered appropriate, a meta-analysis of seven studies demonstrated that ezetimibe monotherapy significantly reduced LDL-c levels compared with placebo (p < 0.00001). There were no statistically significant differences in LDL-c-lowering effects across different subgroups. Ezetimibe therapy (either in combination with a statin or monotherapy) appeared to be well tolerated compared to statin monotherapy or placebo, respectively. No ezetimibe studies reported data on health-related quality of life (HRQoL). There was a wide range in the economic results depending on the treatment strategies evaluated. When comparing ezetimibe monotherapy with no treatment in individuals with baseline LDL-c values of 3.0-4.0 mmol/l, the results range from 21,000 pounds to 50,000 pounds per quality-adjusted life-year (QALY). Results for individuals with baseline LDL-c values over 5.0 mmol/l are below 30,000 pounds per QALY. When comparing the costs and benefits of adding ezetimibe to ongoing statin treatment compared with maintaining statin treatment at the current dose, the majority of results are above values generally considered to be cost-effective (range 19,000 pounds to 48,000 pounds per QALY). Based on the evidence available, when comparing the costs and benefits associated with adding ezetimibe to ongoing statin treatment compared with a switch to a more potent statin, the results are governed by the difference in the cost of the treatment regimens compared and results range from 1500 pounds to 116,000 pounds per QALY. CONCLUSIONS: The short-term RCT clinical evidence demonstrated that ezetimibe was effective in reducing LDL-c when administered as monotherapy or in combination with a statin. However, when used as a monotherapy, ezetimibe is less effective than statins in lowering LDL-c. Given the limitations in the effectiveness data, there is great uncertainty in the economic results. These suggest that ezetimibe could be a cost-effective treatment for individuals with high baseline LDL-c values, for patients with diabetes and for individuals with heterozygous familial hypercholesterolaemia. Long-term clinical outcome studies are needed to allow more precise cost-effectiveness estimates to be calculated.

Use of evidence in economic decision models: practical issues and methodological challenges.

This paper outlines the current 'state of play' regarding the use of evidence in decision modelling and highlights both practical issues and methodological challenges related to identifying, combining and reporting evidence to inform decision model parameters and structure. Based on discussions at two MRC HSRC-funded workshops consisting of 37 experts from a range of disciplines (i.e. decision-makers, health economists, information specialists, operations researchers and statisticians), it aims to derive a multi-disciplinary standpoint on the appropriate use of evidence in economic decision models and, where applicable, offer some suggestions for good modelling practice. Gaps in the established methodology knowledge base are identified for future research.

The cost-effectiveness of bevacizumab in the first-line treatment of metastatic colorectal cancer in England and Wales.

BACKGROUND: Bevacizumab is a humanised monoclonal antibody, which has demonstrated significant activity in metastatic colorectal cancer. The aim of this study is to estimate the cost-effectiveness of adding bevacizumab to chemotherapy for patients with untreated metastatic colorectal cancer. METHODS: A decision-analytic model was developed to estimate the lifetime costs and benefits of adding bevacizumab to irinotecan plus FU/LV (IFL) or 5-FU/LV alone. Effectiveness outcomes, health utilities and resource use data were derived from recent bevacizumab RCTs and from the literature. RESULTS: Adding bevacizumab to IFL costs approximately pound62,857 per QALY gained. Adding bevacizumab to 5-FU/LV costs approximately pound88,436 per QALY gained. The acquisition cost of bevacizumab is a key determinant of its cost-effectiveness. The probability that bevacizumab has a cost-effectiveness ratio that is better than pound30,000 per QALY gained is close to zero. CONCLUSIONS: Given high acquisition costs in relation to clinical benefits, bevacizumab is unlikely to represent a cost-effective use of NHS resources.

Effects of restricted feeding of beef heifers during the postweaning period on growth, efficiency, and ultrasound carcass characteristics.

Traits used for identification of replacement beef heifers and feeding levels provided during postweaning development may have major financial implications due to effects on maintenance requirements and level of lifetime production. The current study evaluated the effects of 2 levels of feeding during the postweaning period on growth, G:F, and ultrasound carcass measurements of heifers, and the associations among these traits. Heifers (1/2 Red Angus, 1/4 Charolais, and 1/4 Tarentaise) born in 3 yr were randomly assigned to a control (fed to appetite; n = 205) or restricted (fed at 80% of that consumed by controls adjusted to a common BW basis; n = 192) feeding during a 140-d postweaning period. Heifers were individually fed a diet of 68% corn silage, 18% alfalfa, and protein-mineral supplement (DM basis) in pens equipped with Calan gates. Ultrasound measurements of LM area, intramuscular fat, and subcutaneous fat thickness over the LM were made on d 140 (382 +/- 0.8 d of age). Average daily DMI was 4.1 and 5.6 kg/d for restricted and control heifers, respectively (P < 0.001). Feed restriction decreased (P < 0.001) BW (292 vs. 314 kg), ADG (0.52 vs. 0.65 kg/d), LM area (55 vs. 59 cm2), intramuscular fat (3.2 vs. 3.5%), and subcutaneous fat thickness over the LM (3.2 vs. 3.9 mm), but increased G:F (0.12 vs. 0.11) when compared with control at the end of the 140-d study. The magnitude of the associations of DMI with ADG (r = 0.32 vs. 0.21), 140-d BW (r = 0.78 vs. 0.36), hip height (r = 0.57 vs. 0.17), LMA (r = 0.30 vs. 0.18), and BCS (r = 0.17 vs. 0.11) was greater in restricted- than control-fed heifers. Variance of residual feed intake, calculated within each treatment, was greater (P < 0.01) in control (0.088) than restricted (0.004) heifers, and magnitude of association between residual feed intake and average DMI was greater in control (r = 0.88) than restricted (r = 0.41) heifers. Pregnancy rate tended (P = 0.11) to be reduced in heifers that had been developed on restricted feeding (86.3 +/- 2.3 vs. 91.5 +/- 2.3%). However, ADG was greater (P < 0.001) in restricted than control heifers (0.51 vs. 0.46 kg/d) while grazing native range in the 7 mo after restriction. In summary, restricted heifers consumed 22% less feed on a per-pregnant-heifer basis during the development period and had a greater magnitude of association between DMI and several growth-related traits at the end of the 140-d postweaning feeding period, which is indicative of improved efficiency.

Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of bevacizumab and cetuximab in the treatment of individuals with metastatic colorectal cancer (CRC). DATA SOURCES: Searches of main electronic databases were conducted in April and May 2005. REVIEW METHODS: For the assessment of bevacizumab, trials were included if they recruited participants with untreated metastatic CRC for first-line treatment. Only trials comparing bevacizumab in combination with irinotecan and/or established fluorouracil (5-FU)-containing or releasing regimens given as first-line therapy were included. For the assessment of cetuximab, trials were included if they recruited participants with epidermal growth-factor receptor-expressing metastatic CRC who had previously failed irinotecan-including therapy. Independent cost-effectiveness models of bevacizumab and cetuximab were developed using survival modelling methods. RESULTS: Adding bevacizumab to irinotecan in combination with 5-FU/folic acid (FA) plus irinotecan resulted in a statistically significant increase in median overall survival (OS) of 4.7 months. Adding bevacizumab to 5-FU/FA resulted in a non-significant increase in median OS of 3.7 months within one study and 7.7 months in another. Adding bevacizumab to irinotecan, fluorouracil and leucovorin (IFL) resulted in a statistically significant increase in median progression-free survival (PFS) of 4.4 months. Adding bevacizumab to 5-FU/FA resulted in a statistically significant increase in median PFS of 3.7 months, and a statistically significant increase in time to disease progression of 3.8 months compared to FU/FA alone. An overall tumour response rate of 44.8% was reported for bevacizumab plus IFL compared to 34.8% for IFL plus placebo. This addition was statistically significant. The addition of bevacizumab to 5-FU/FA resulted in a significant difference in tumour response rate within one study, but not another. Bevacizumab in combination with IFL or 5-FU/FA was observed to result in an increase of grade 3/4 adverse events. The independent health economic assessment suggests that the cost-effectiveness of bevacizumab plus IFL is unlikely to be better than pound 46,853 per life-year gained (LYG); the cost-utility of bevacizumab plus IFL is unlikely to be better than pound 62,857 per quality-adjusted life-year (QALY) gained. The cost-effectiveness of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 84,607 per LYG; the cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. A Phase II trial reported a median OS duration of 8.6 months for patients receiving cetuximab plus irinotecan, plus a median time to progression of 4.1 months, a tumour response rate of 22.9% and suggested that treatment with cetuximab in combination with irinotecan is associated with significantly more adverse events (any grade 3 or grade 4 adverse event) than cetuximab monotherapy. The single arm study of cetuximab plus irinotecan reported a median OS duration of 8.4 months, a median time to progression of 2.9 months and a tumour response rate of 15.2%. The cost-effectiveness model suggested that the expected survival duration of patients receiving cetuximab plus irinotecan is 0.79 years (9.5 months) when the proposed continuation rule is applied. In order for cetuximab plus irinotecan to achieve a cost-utility ratio of pound 30,000 per QALY gained, treatment with cetuximab plus irinotecan must provide an additional 0.65 life years (7.8 months) over treatment with active/best supportive care, implying that survival in the active/best supportive care group must be 0.14 life years (1.7 months) or less. CONCLUSIONS: The trials indicate that bevacizumab in combination with 5-FU/FA, and bevacizumab in combination with IFL, is clinically effective in comparison to standard chemotherapy options for the first-line treatment of metastatic CRC. The health economic analysis suggests that the marginal cost-utility of bevacizumab plus IFL versus IFL is unlikely to be better than pound 62,857 per QALY gained, and the marginal cost-utility of bevacizumab plus 5-FU/FA versus 5-FU/FA is unlikely to be better than pound 88,658 per QALY gained. There is no direct evidence to demonstrate whether cetuximab in combination with irinotecan improves health-related quality of life or OS in comparison to active/best supportive care or oxaliplatin plus 5-FU/FA, although the evidence on tumour response rates suggests that cetuximab plus irinotecan has some clinical activity. While it is difficult to suggest whether cetuximab represents value for money, indirect comparisons suggest that the incremental cost-utility of cetuximab plus irinotecan is unlikely to be better than pound 30,000 per QALY gained. This review highlights a number of areas for further research, including clarifying the true impact of first-line bevacizumab in combination with irinotecan and/or infusional 5-FU/FA, without subsequent bevacizumab treatment following disease progression, on OS in patients with metastatic CRC who are representative of the typical population of CRC patients in England and Wales. Further research concerning the impact of therapies on health-related quality of life is essential.

Cost-effectiveness of oxaliplatin and capecitabine in the adjuvant treatment of stage III colon cancer.

For many years, the standard treatment for stage III colon cancer has been surgical resection followed by 5-fluorouracil in combination with folinic acid (5-FU/LV). Ongoing clinical trial evidence suggests that capecitabine and oxaliplatin (in combination with 5-FU/LV) may improve disease-free survival and overall survival when compared against 5-FU/LV alone in the adjuvant setting. This study evaluates the cost-effectiveness profiles of these two regimens in comparison to standard chemotherapy, using evidence from two international randomised controlled trials. Survival modelling techniques were employed to extrapolate survival curves from the two trials in order to estimate the long-term benefits of alternative treatment options over the remaining lifetime of patients. The health economic analysis suggests that capecitabine is expected to produce greater health gains at a lower cost than 5-FU/LV. Oxaliplatin in combination with 5-FU/LV is estimated to cost pounds 2970 per additional QALY gained when compared to 5-FU/LV alone. Future research should attempt to elucidate uncertainties concerning the optimal roles of capecitabine and/or oxaliplatin in the adjuvant setting in order to achieve the maximum level of clinical benefit.

The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of oxaliplatin in combination with 5-fluorouracil/leucovorin (5-FU/LV), and capecitabine monotherapy (within their licensed indications), as adjuvant therapies in the treatment of patients with Stage III (Dukes' C) colon cancer after complete surgical resection of the primary tumour, as compared with adjuvant chemotherapy with an established fluorouracil-containing regimen. DATA SOURCES: Ten electronic bibliographic databases were searched from inception to January 2005. Searches were supplemented by hand searching relevant articles, sponsor and other submissions of evidence to the National Institute of Health and Clinical Excellence and conference proceedings. REVIEW METHODS: A systematic review and meta-analysis (where appropriate) of clinical efficacy evidence and a cost-effectiveness review and economic modelling were carried out. Marginal costs, life years gained and cost-effectiveness acceptability curves were estimated. Probabilistic sensitivity analysis was used to generate information on the likelihood that each of the interventions was optimal. RESULTS: Three randomised active-controlled trials, of varying methodological quality, were included in the review. The MOSAIC trial and NSABP C-07 study considered the addition of oxaliplatin to adjuvant treatment (albeit administered in different 5-FU/LV regimens) and the X-ACT study compared oral capecitabine with bolus 5-FU/LV alone. A review of the available evidence indicated that in patients with Stage III colon cancer, oxaliplatin in combination with an infusional de Gramont schedule of 5-FU/LV (FOLFOX4) was more effective in preventing and delaying disease recurrence than infusional 5-FU/LV alone (de Gramont regimen). Serious adverse events and treatment discontinuations due to toxicity were more evident with oxaliplatin-based regimens (FOLFOX4 and FLOX regimen) than infusional or bolus 5-FU/LV alone (de Gramont and Roswell Park regimen). Oral capecitabine was at least equivalent in disease-free survival to the bolus Mayo Clinic 5-FU/LV regimen for patients with resected Stage III colon cancer. Although, the safety and tolerability profile of capecitabine was superior to that of the Mayo Clinic 5-FU/LV regimen, it has not been evaluated in comparison with other less toxic 5-FU/LV regimens currently in common use in the UK. Based on the assumptions and survival analysis methods used, the cost-effectiveness analysis using economic modelling estimated that capecitabine was a dominating strategy and resulted in a cost-saving of approximately pound 3320 per patient in comparison with the Mayo Clinic 5-FU/LV regimen, while also providing an additional 0.98 quality-adjusted life-years (QALYs) over a 50-year model time horizon. Oxaliplatin in combination with 5-FU/LV (FOLFOX4 regimen) is estimated to cost an additional pound 2970 per QALY gained when compared with the de Gramont 5-FU/LV regimen and demonstrated superior survival outcomes with marginal costs. The uncertainty analysis suggests that both interventions have a high probability of being cost-effective at a threshold of both pound 20,000 and pound 30,000. An indirect comparison of the FOLFOX4 and Mayo Clinic 5-FU/LV regimens suggests that the use of FOLFOX4 in place of the Mayo Clinic 5-FU/LV regimen would cost an additional pound 5777 per QALY gained. An incremental cost-effectiveness ratio (ICER) is estimated to be approximately pound 13,000 per QALY gained from treatment with FOLFOX4 compared with capecitabine. However, if the Mayo Clinic and the de Gramont 5-FU/LV regimens are assumed to be equivalent in terms of effectiveness, the ICER of FOLFOX4 in comparison with capecitabine may be greater than pound 30,000 per QALY. CONCLUSIONS: The evidence suggests that both capecitabine and FOLFOX4 are clinically effective and cost-effective in comparison with 5-FU/LV regimens (Mayo Clinic and de Gramont schedules). Further research is suggested into the effectiveness, tolerability, patient acceptability and costs of different oxaliplatin/fluoropyrimidine schedules in the adjuvant setting; the effects of treatment duration on efficacy; adverse events; resource data collection strategies and reporting of summary statistics; subgroups benefiting most from adjuvant chemotherapy; and methods for estimating mean survival.

Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

OBJECTIVES: To summarise the available evidence on the clinical effectiveness and cost-effectiveness of psychological therapies including dialectical behaviour therapy (DBT) for borderline personality disorder (BPD). DATA SOURCES: Electronic databases were searched up to March 2005. REVIEW METHODS: Relevant studies were assessed using standard checklists and data were abstracted by two reviewers using standardised forms. Separate economic evaluations were undertaken for six selected randomised controlled trials (RCTs). Cost-effectiveness was assessed in terms of cost per parasuicide event avoided in all six trials and cost per quality-adjusted life-year (QALY) in four of them. All results are at 2003-4 prices and for 12 months follow-up. RESULTS: Nine RCTs and one non-RCT of moderate to poor quality were identified in the clinical effectiveness review. They provided some evidence that DBT is more effective than treatment as usual (TAU) for the treatment of chronically parasuicidal and drug-dependent borderline women; that DBT-orientated therapy is more effective than client-centred therapy (CCT) for the treatment of BPD; and that DBT is as effective as comprehensive validation therapy plus 12-Step for the treatment of opioid-dependent borderline women. There was also some evidence that partial hospitalisation is more effective than TAU in the treatment of BPD, good evidence that manual-assisted cognitive behavioural therapy (MACT) is no more effective than TAU in the treatment of BPD and some evidence that interpersonal group therapy is no more effective than individual mentalisation-based partial hospitalisation (MBT) for the treatment of BPD. However, these results should be interpreted with caution as not all studies were primarily targeted to borderline symptoms and there were considerable differences between the studies. The assessment of cost-effectiveness found a mix of results in the four trials of DBT, along with the high levels of uncertainty and the limitations in the analyses. The findings do not support the cost-effectiveness of DBT though they suggest it has the potential to be cost-effective. The results for MBT are promising, though again surrounded by a high degree of uncertainty and for MACT, the analysis suggests that the intervention is unlikely to be cost-effective. CONCLUSIONS: The overall efficacy of psychological therapies is promising; however, at this stage the evidence is inconclusive. The cost-effectiveness of the intervention in six RCTs examined, however, does not support the cost-effectiveness of DBT although potential is suggested. There is a need for considerable research in this area. This research should involve appropriately powered head-to-head RCTs of psychological therapies; a survey of current practice and the use of the full range of services by people with BPD to inform future economic analyses; full resource-use data collected in the context of pragmatic clinical trials; psychometric assessment of the validity of the EQ-5D or other generic and condition-specific preference-based measures in BPD, and the development of a more formal cost-effectiveness model using the above data.

Immune response and serum immunoglobulin G concentrations in beef calves suckling cows of differing body condition score at parturition and supplemented with high-linoleate or high-oleate safflower seeds.

Two experiments were conducted to determine the effect of maternal lipid supplementation on the immune response to antigenic challenge in suckling calves. In Exp. 1, beginning 1 d postpartum, 18 primiparous crossbred beef cows were fed Foxtail millet hay and a low-fat (control) supplement or a supplement containing cracked, high-linoleate safflower seed in individual feeding stanchions until d 40 of lactation. The diets were formulated to provide similar quantities of N and TDN, and the linoleate diet was formulated to contain 5% of DMI as fat. Calves were injected s.c. with 15 mg of antigen (ovalbumin) at d 21 and again at d 35 of age. To measure the total serum antibody production in response to the antigen, blood samples were collected from the calves every 7 d via jugular venipuncture from d 14 to 42. Calves from linoleate-supplemented cows had a decrease (P = 0.04) in total antibody production in response to ovalbumin and appeared to have a delayed response to antigen challenge. Total antibody production increased (P < 0.001) after secondary exposure to ovalbumin. In Exp. 2, 36 Angus x Gelbvieh beef cows that were nutritionally managed to achieve a BCS of 4 or 6 at parturition were used to determine the effects of prepartum energy balance and postpartum lipid supplementation on the passive transfer of immunoglobulins and the immune response to antigenic challenge in their calves. Beginning at 3 d postpartum and continuing until d 60 of lactation, cows were fed hay and a low-fat control supplement or supplements consisting of either cracked, high-linoleate or high-oleate safflower seeds. Safflower seed supplements were formulated to provide 5% of DMI as fat. Calves were injected s.c. with 15 mg of ovalbumin at 21 d of age and again at 48 d of age. The antibody responses were determined in serum; cell-mediated immunity was assessed by intradermal antigen injection at 60 d of age. A trend was noted (P = 0.10) for calves suckling control-supplemented cows to have a greater response to antigen compared with calves from linoleate- and oleate-supplemented cows; however, no difference was observed among treatments (P = 0.86) in cell-mediated immune response. Postpartum oilseed supplementation in beef cows appears to decrease antibody production in response to antigenic challenge in suckling calves. However, BCS at parturition did not influence passive transfer of immunoglobulins in neonatal calves.

Body condition score at parturition and postpartum supplemental fat effects on cow and calf performance.

Three-year-old Angus x Gelbvieh beef cows nutritionally managed to achieve a BCS of 4 +/- 0.07 (479.3 +/- 36.3 kg of BW) or 6 +/- 0.07 (579.6 +/- 53.1 kg of BW) at parturition were used in a 2-yr experiment (n = 36/yr) to determine the effects of prepartum energy balance and postpartum lipid supplementation on cow and calf performance. Beginning 3 d postpartum, cows within each BCS were assigned randomly to be fed hay and a low-fat control supplement or supplements with either high-linoleate cracked safflower seeds or high-oleate cracked safflower seeds until d 60 of lactation. Diets were formulated to be isonitrogenous and isocaloric, and safflower seed supplements were provided to achieve 5% of DMI as fat. Ultrasonic 12th rib fat and LM area were lower (P < 0.001) for cows in BCS 4 compared with BCS 6 cows throughout the study. Cows in BCS 4 at parturition maintained (P = 0.02) condition over the course of the study, whereas cows in BCS 6 lost condition. No differences (P = 0.44 to 0.71) were detected for milk yield, milk energy, milk fat percentage, or milk lactose percentage because of BCS; however, milk protein percentage was less (P = 0.03) for BCS 4 cows. First-service conception rates did not differ (P = 0.22) because of BCS at parturition, but overall pregnancy rate was greater (P = 0.02) in BCS 6 cows. No differences (P = 0.48 to 0.83) were detected in calf birth weight or ADG because of BCS at parturition. Dietary lipid supplementation did not influence (P = 0.23 to 0.96) cow BW change, BCS change, 12th rib fat, LM area, milk yield, milk energy, milk fat percentage, milk lactose percentage, first service conception, overall pregnancy rates, or calf performance. Although cows in BCS of 4 at parturition seemed capable of maintaining BCS during lactation, the overall decrease in pregnancy rate indicates cows should be managed to achieve a BCS >4 before parturition to improve reproductive success.

Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with Haemophilia A and inhibitors.

BACKGROUND: In some people with haemophilia, therapeutic clotting agents are recognised as a foreign protein and anti-FVIII antibodies, known as 'inhibitors', are produced. This review investigates which treatment most effectively arrests acute bleeding in people with haemophilia A and inhibitors. OBJECTIVES: To determine the clinical effectiveness of recombinant FVIIa concentrate in comparison to plasma-derived concentrates for the treatment of acute bleeding episodes in people with haemophilia A and inhibitors. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group trials register which comprises of references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. Date of the most recent search of the Group's trials register: September 2003. SELECTION CRITERIA: Randomised (RCTs) and quasi-randomised controlled clinical trials comparing Recombinant FVIIa concentrate to human plasma-derived concentrates (high-dose human or recombinant FVIII concentrate; prothrombin complex concentrates (PCCs); activated prothrombin complex concentrate (aPCC)) in people with haemophilia A. Comparisons with animal derived products were excluded. DATA COLLECTION AND ANALYSIS: No studies were found that were eligible for inclusion in this review. MAIN RESULTS: A total of four studies were identified by the searches, however, none of these were eligible for inclusion in this review. REVIEWERS' CONCLUSIONS: No RCTs on the relative effectiveness of Recombinant FVIIa concentrate compared to human plasma-derived concentrates in people with haemophilia A and inhibitors were identified for inclusion in this review. The research evidence on which to base clinical decisions is therefore limited to case reports, and other less robust evidence. There is need for a well-designed, adequately-powered randomised controlled trial to assess the relative benefits and risks of using Recombinant FVIIa concentrate compared to human plasma-derived concentrates in people with haemophilia A and inhibitors.