European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full supplement publication.

Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010.  They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of Endoscopy. The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.

European guidelines for quality assurance in colorectal cancer screening and diagnosis. First Edition--Communication.

Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The chapter on communication includes 35 graded recommendations. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of screening programmes and services.

Factors influencing quality of life in caregivers of people with Parkinson's disease and implications for clinical guidelines.

The quality of life (QoL) of informal caregivers can be adversely affected by a number of factors. This issue, however, has not been well explored for carers of people with Parkinson's (PwP), with research largely restricted to the assessment of caregiver burden and caregiver strain. This study aims to determine the main influences on carer QoL in this population and consider results in the context of current clinical guidelines for the management of Parkinson's disease (PD). Carers completed the newly validated PDQ-Carer, and PwP completed the PDQ-39. The sample comprised 238 carers (mean age 68.20 years) and 238 PwP (mean age 71.64). Results suggest multiple influences on caregiver QoL. These include carer age, gender, health status, and duration of the caregiving role. PwP levels of mobility and cognitive impairment are also significant influences on carer QoL. Not only should practitioners and service providers be particularly aware of the heightened impact of PD on carers over time and as PwP symptoms deteriorate, but this should also be reflected in clinical guidelines for the management of PD.

Primary care endorsement letter and a patient leaflet to improve participation in colorectal cancer screening: results of a factorial randomised trial.

BACKGROUND: The trial aimed to investigate whether a general practitioner's (GP) letter encouraging participation and a more explicit leaflet explaining how to complete faecal occult blood test (FOBT) included with the England Bowel Cancer Screening Programme invitation materials would improve uptake. METHODS: A randomised controlled 2 × 2 factorial trial was conducted in the south of England. Overall, 1288 patients registered with 20 GPs invited for screening in October 2009 participated in the trial. Participants were randomised to either a GP's endorsement letter and/or an enhanced information leaflet with their FOBT kit. The primary outcome was verified with return of the test kit within 20 weeks. RESULTS: Both the GP's endorsement letter and the enhanced procedural leaflet, each increased participation by ∼6% - the GP's letter by 5.8% (95% CI: 4.1-7.8%) and the leaflet by 6.0% (95% CI: 4.3-8.1%). On the basis of the intention-to-treat analysis, the random effects logistic regression model confirmed that there was no important interaction between the two interventions, and estimated an adjusted rate ratio of 1.11 (P=0.038) for the GP's letter and 1.12 (P=0.029) for the leaflet. In the absence of an interaction, an additive effect for receiving both the GP's letter and leaflet (11.8%, 95% CI: 8.5-16%) was confirmed. The per-protocol analysis indicated that the insertion of an electronic GP's signature on the endorsement letter was associated with increased participation (P=0.039). CONCLUSION: Including both an endorsement letter from each patient's GP and a more explicit procedural leaflet could increase participation in the English Bowel Cancer Screening Programme by ∼10%, a relative improvement of 20% on current performance.

Rapid linear scale-up of a protein separation by centrifugal partition chromatography.

The scaling up of the separation of two proteins with an aqueous two-phase system (ATPS) from 176 mg with a 500 ml laboratory scale centrifugal partition chromatography (CPC) column to 2.2g with a 6.25 litre pilot-scale column is presented. A model sample system of a mixture of lysozyme and myoglobin was chosen for this study using an ATPS system comprising 12.5% (w/w) PEG-1000:12.5% (w/w) K2HPO4. It was found that the maximum sample concentration possible without precipitation was 2.2mg/ml for each constituent. The optimisation of rotor speed, mobile phase flow rate and sample loading was performed on a laboratory-scale device. It was found that a centrifuge speed of 2000 rpm (224 'g'), 10 ml/min mobile phase flow rate with a 43 ml (10% of active column volume) sample volume gave optimum operating conditions. This was linearly scaled up to pilot scale by increasing mobile phase flow rate, fraction size and sample loading in the ratio of the system capacities (i.e. 12.5:1). Flow rate was therefore increased from 10 ml/min to 125 ml/min, fraction size from 10 ml to 125 ml and sample loading from 43 ml to 500 ml. Rotor speed however was reduced from 2000 rpm on the laboratory device to 1293 rpm on the pilot-scale device to maintain the same 224 'g' field in each chamber, as the pilot-scale CPC unit has a larger rotor radius than the laboratory one. Resolution increased from Rs=1.28 on the 500 ml rotor to Rs=1.88 on the 6.25 litre rotor, giving potential throughputs in batch mode of over 40 g/day.

Screening for colorectal cancer using the faecal occult blood test, Hemoccult.

BACKGROUND: Colorectal cancer is a leading cause of morbidity and mortality, especially in the Western world. The human and financial costs of this disease have prompted considerable research efforts to evaluate the ability of screening tests to detect the cancer at an early curable stage. Tests that have been considered for population screening include variants of the faecal occult blood test, flexible sigmoidoscopy and colonoscopy. Reducing mortality from colorectal cancer (CRC) may be achieved by the introduction of population-based screening programmes. OBJECTIVES: To determine whether screening for colorectal cancer using the faecal occult blood test (guaiac or immunochemical) reduces colorectal cancer mortality and to consider the benefits, harms and potential consequences of screening. SEARCH STRATEGY: Published and unpublished data for this review were identified by: Reviewing studies included in the previous Cochrane review; Searching several electronic databases (Cochrane Library, Medline, Embase, CINAHL, PsychInfo, Amed, SIGLE, HMIC); and Writing to the principal investigators of potentially eligible trials. SELECTION CRITERIA: We included in this review all randomised trials of screening for colorectal cancer that compared faecal occult blood test (guaiac or immunochemical) on more than one occasion with no screening and reported colorectal cancer mortality. DATA COLLECTION AND ANALYSIS: Data from the eligible trials were independently extracted by two reviewers. The primary data analysis was performed using the group participants were originally randomised to ('intention to screen'), whether or not they attended screening; a secondary analysis adjusted for non-attendence. We calculated the relative risks and risk differences for each trial, and then overall, using fixed and random effects models (including testing for heterogeneity of effects). We identified nine articles concerning four randomised controlled trials and two controlled trials involving over 320,000 participants with follow-up ranging from 8 to 18 years. MAIN RESULTS: Combined results from the 4 eligible randomised controlled trials shows that participants allocated to screening had a 16% reduction in the relative risk of colorectal cancer mortality (RR 0.84, CI: 0.78-0.90). In the 3 studies that used biennial screening (Funen, Minnesota, Nottingham) there was a 15% relative risk reduction (RR 0.85, CI: 0.78-0.92) in colorectal cancer mortality. When adjusted for screening attendance in the individual studies, there was a 25% relative risk reduction (RR 0.75, CI: 0.66 - 0.84) for those attending at least one round of screening using the faecal occult blood test. AUTHORS' CONCLUSIONS: Benefits of screening include a modest reduction in colorectal cancer mortality, a possible reduction in cancer incidence through the detection and removal of colorectal adenomas, and potentially, the less invasive surgery that earlier treatment of colorectal cancers may involve. Harmful effects of screening include the psycho-social consequences of receiving a false-positive result, the potentially significant complications of colonoscopy or a false-negative result, the possibility of overdiagnosis (leading to unnecessary investigations or treatment) and the complications associated with treatment.

Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review.

BACKGROUND: Lung cancer remains a devastating disease with few effective treatment options. Recent developments in chemotherapy have led to cautious optimism. This paper reviews the evidence on the clinical and cost effectiveness of four of the new generation drugs for patients with lung cancer. METHODS: A systematic review of randomised controlled trials (RCTs) identified from 11 electronic databases (including Medline, Cochrane library and Embase), reference lists and contact with experts and industry was performed to assess clinical effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine. Clinical effectiveness was assessed using the outcomes of patient survival, quality of life, and adverse effects. Cost effectiveness was assessed by development of a costing model and presented as incremental cost per life year saved (LYS) compared with best supportive care (BSC). RESULTS: Of the 33 RCTs included, five were judged to be of good quality, 10 of adequate quality, and 18 of poor quality. Gemcitabine, paclitaxel, and vinorelbine as first line treatment and docetaxel as second line treatment appear to be more beneficial for non-small cell lung cancer than BSC and older chemotherapy agents, increasing patient survival by 2-4 months against BSC and some comparator regimes. These gains in survival do not appear to be at the expense of quality of life. Survival gains were delivered at reasonable levels of incremental cost effectiveness for vinorelbine, vinorelbine with cisplatin, gemcitabine, gemcitabine with cisplatin, and paclitaxel with cisplatin regimens compared with BSC. CONCLUSION: Although the clinical benefits of the new drugs appear relatively small, their benefit to patients with lung cancer appears to be worthwhile and cost effective.

Factors influencing the uptake of technologies to minimize perioperative allogeneic blood transfusion: an interview study of national and institutional stakeholders.

BACKGROUND: Alternatives to allogeneic blood transfusion exist and are being used to varying extents in Australian hospitals. Evidence on effectiveness and cost-effectiveness is generally inconclusive and provides a suboptimal basis for policy development. AIM: To describe the influences on uptake of transfusion technologies as perceived by national and institutional stakeholders. METHODS: Qualitative interview study. Interview transcripts were coded and analysed independently by at least two researchers. Participants had opportunity to comment on their transcript and the manuscript. RESULTS: A total of 71 interviews were conducted with representatives of the media, specialist medical societies, consumer special interest groups, the Australian Red Cross Blood Service (ARCBS), government, private health insurers, technology manufacturers, prominent clinicians in the area and a sample of clinicians drawn from hospitals with variable use of blood-saving technologies. Technical advances and acceptance of lower transfusion triggers were identified as the main influences on the decrease in use of allogeneic blood transfusion in the past decade. Participants indicated that patients were most aware and supportive of autologous predonation. Participants noted that 'enthusiasts' were involved in educating about the need for alternatives, negotiating resourcing and maintaining the use of a technology. Funding mechanisms were seen as main barriers to use of alternatives. A discrepancy was noted in the rigour of evaluation and regulation of pharmaceuticals and devices/procedures. CONCLUSIONS: Uptake of blood transfusion technologies by institutions was dependent mostly on funding arrangements and the presence of an 'enthusiast'. Critical review of the evidence for effectiveness or cost-effectiveness of these technologies was rarely mentioned. Opportunities exist for evidence-based medicine principles to play a greater role in policy decisions in this area.

A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

BACKGROUND: The incidence of lung cancer is declining following a drop in smoking rates, but it is still the leading cause of death from cancer in England and Wales, with about 30,000 deaths a year. Survival rates for lung cancer are poor everywhere, but they appear to be better in the rest of the European Community and the USA than in the UK. Only about 5 per cent of people with lung cancer survive for 5 years, and nearly all of these are cured by surgery after fortuitously early diagnosis. At present, only a small proportion of patients (probably about 5 per cent) with non-small-cell lung cancer are being given chemotherapy. Some centres treat a greater proportion. OBJECTIVES: This review examines the clinical effectiveness and cost-effectiveness of four of the newer drugs - vinorelbine, gemcitabine, paclitaxel and docetaxel - used for treating the most common type of lung cancer (non-small-cell lung cancer). The first three drugs are used for first-line treatment, but at present docetaxel is used only after first-line chemotherapy has failed. METHODS: This report was based on a systematic literature review and economic modelling, supplemented by cost data. RESULTS - NUMBER AND QUALITY OF STUDIES: A reasonable number of randomised trials were found - three for docetaxel, six for gemcitabine, five for paclitaxel and 13 for vinorelbine. The quality of the trials was variable but good overall. There was a wide range of comparators. Some trials compared chemotherapy with best supportive care (BSC), which involves care that aims to control symptoms, with palliative radiotherapy if needed, but not to prolong life. Others compared the newer drugs against previous drugs or combinations. RESULTS - SUMMARY OF BENEFITS: The gains in duration of survival with the new drugs are modest - a few months - but worthwhile in a condition for which the untreated survival is only about 5 months. There are also gains in quality of life compared with BSC, because on balance the side-effects of some forms of chemotherapy have less effect on quality of life than the effects of uncontrolled spread of cancer. RESULTS - COSTS: The total cost to the NHS of using these new drugs in England and Wales might be about GBP 10 million per annum, but is subject to a number of factors. There would be non-financial constraints on any increase in chemotherapy for the next few years, such as staffing; the number of patients choosing to have the newer forms of chemotherapy is not yet known; and the costs of the drugs may fall, for example, as generic forms appear. RESULTS - COST PER LIFE-YEAR GAINED: The available data did not provide an entirely satisfactory basis for cost-effectiveness calculations. The main problem was the lack of direct comparisons of the new drugs. In order to strengthen the analysis, three different modelling approaches were used: pairwise comparisons using trial data; cost-minimisation analysis, as if all the new regimens were of equal efficacy; and cost-effectiveness analysis pooling the results of several trials with different comparators, giving indirect comparisons of the new drugs by using BSC as the common comparator. A number of different scenarios were explored through extensive sensitivity analysis in each model. Outcomes were expressed in incremental cost per life-year saved or incremental cost, versus BSC. There was insufficient evidence from which to derive cost per quality-adjusted life-year. In first-line treatment, vinorelbine, gemcitabine, and the lower-dose paclitaxel plus cisplatin combinations generally performed well against BSC under a range of different scenarios and especially when given as a maximum of 3 cycles. Incremental cost per life-year gained (LYG) versus BSC varied depending on scenario, but baseline figures based on trial data and protocols were: single-agent vinorelbine, pound 2194 per LYG; vinorelbine plus cisplatin, pound 5206; single-agent gemcitabine, pound 5690; gemcitabine plus cisplatin, pound 10,041; and paclitaxel plus cisplatin, pound 8537. In second-line chemotherapy, docetaxel gave a cost per LYG of pound 17,546, again well within the range usually accepted as cost-effective. However, in routine care, the impact of therapy would be regularly reviewed, and continuation would depend on response, side-effects, patient choice and clinical judgement. Chemotherapy would be stopped in non-responders, making chemotherapy more cost-effective. A 'real-life' scenario in which 60 per cent of patients receive only 1 or 2 cycles of chemotherapy gives much lower costs per LYG, with single-agent gemcitabine, single-agent vinorelbine, and paclitaxel plus platinum appearing to be cost-saving compared with BSC; the incremental cost of gemcitabine plus cisplatin would be pound 2478 per LYG, and of vinorelbine plus cisplatin, pound 2808. At the very least, gains in duration of survival were achieved without diminution of quality of life (at best, they improved quality) and with relatively low incremental cost. Comparisons among the individual drugs should be viewed with caution because they have had to be based on indirect comparisons. RESULTS - LIMITATIONS OF THE ANALYSIS: Each of the three models had limitations. The cost-effectiveness estimates from the pairwise comparisons were based on single studies. The cost-minimisation analysis assumed that the regimens have equal efficacy in practice. The cost-effectiveness analysis had to be based on pooling data from individual trials. The costs of BSC, inpatient stay and outpatient visits were from Scottish data. Median rather than mean data on duration of survival have been used in the analysis, because most of the trials reported only median data. Median survival and number of drug cycles were calculated by averaging across a number of studies, rather than being reliant on one particular study. The costs of the less expensive antiemetics cited in the trials were omitted. The use of more modern and costly antiemetics would have a modest detrimental effect on cost-effectiveness. In the absence of published data, an estimate was made of the cost of side-effects of chemotherapy, in particular hospital admissions, and applied to all the new regimens. In practice, admissions related to side-effects and their respective costs are likely to vary by regimen. CONCLUSIONS: The new drugs for non-small-cell lung cancer extend life by only a few months compared with BSC, but appear to do so without net loss in quality of life and at a cost per LYG that is much lower than for many other NHS activities. Depending on assumptions used, these new drugs range from being cost-effective, as conventionally accepted, to being cost-saving. CONCLUSIONS - IMPLICATIONS OF THE NEWER DRUGS: One of the present constraints on chemotherapy is availability of inpatient beds. The advent of newer and gentler forms of chemotherapy given on an outpatient basis would not only overcome this, but it would allow more patients to be treated. This might apply particularly to older patients. The treatment of more patients would increase workload for oncologists, cancer nurses and pharmacists. The Government has already announced increased expenditure on staff for cancer care. The previously pessimistic attitudes to chemotherapy in non-small-cell lung cancer are changing in the wake of the newer agents, and this shift is likely to increase referral. CONCLUSIONS - NEED FOR FURTHER RESEARCH: Recent advances in chemotherapy are welcome, but their effects remain small for patients with non-small-cell lung cancer. Much more research is needed into better drugs, better combinations, new ways of assessing the likelihood of response and especially direct comparisons between the new regimens. This research would be aided by having a greater proportion of patients involved in trials, but there will be infrastructure implications of increased participation.

Leflunomide and rheumatoid arthritis: a systematic review of effectiveness, safety and cost implications.

OBJECTIVE: To assess the effectiveness, safety and cost implications of leflunomide treatment for rheumatoid arthritis. DESIGN: Systematic review. SETTING: Four trials retrieved from Medline, Embase, the Cochrane Library, Econlit, HMIC (Dhdata), HMIC (Helmis), HMIC (King's Fund Database) and Best Evidence3. MAIN OUTCOME MEASURES: Efficacy measures (including tender joint counts, swollen joint counts, assessment of functioning, Health Assessment Questionnaire, Modified Health Assessment Questionnaire, pain (visual analogue scale), Erythrocyte Sedimentation Rate, C-reactive Protein), radiological progression and treatment adverse events. RESULTS: Leflunomide therapy was demonstrated to be significantly superior to placebo in relation to the efficacy outcome measures and it slowed the radiological progression of patients' disease in three studies. Treatment success and duration of sustained response were also significantly superior than on placebo, as were quality of life measures. Leflunomide treatment was comparable to sulphasalazine and methotrexate with respect to efficacy, radiological progression and quality of life measures. The most common adverse effects leading to withdrawal from leflunomide treatment were gastrointestinal symptoms (diarrhoea and nausea), allergic reactions (rash and pruritus), alopecia, dyspepsia, hypertension and elevated transaminase levels. Weight loss and dizziness have also been reported for leflunomide therapy. Leflunomide is more expensive than most DMARDs, costing about pound400 a year more than sulphasalazine. CONCLUSION: Despite the small number of published articles relating to leflunomide treatment, the evidence suggests that leflunomide is similar in efficacy to both sulphasalazine and methotrexate, although with a differential pattern of side-effects. There is a need for further research to assess the long-term outcomes of leflunomide treatment.

Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

BACKGROUND: Hepatitis C is a viral disease of the liver, which frequently causes few or no symptoms at first infection but has a high probability of becoming an insidious chronic disease. Treatment has traditionally been with interferon alfa but only a small proportion of patients have been cured by this method. The recent introduction of ribavirin, given in combination, has led to a re-appraisal of the management of chronic hepatitis C. The current report considers the additional benefit of combination therapy (interferon alfa and ribavirin) compared with monotherapy (interferon alfa alone) for the treatment of patients with chronic hepatitis C. It supersedes two reports of combination therapy conducted by the Scottish Health Purchasing Information Centre and the Wessex Institute for Health Research and Development. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of combination therapy with interferon alfa and ribavirin in patients with chronic hepatitis C. METHODS - EFFECTIVENESS: Electronic databases were searched from 1993 to the end of 1999, to identify randomised controlled trials (RCTs) or systematic reviews of RCTs that evaluated interferon alfa in combination with ribavirin compared with interferon alfa alone (or placebo) in patients with chronic hepatitis C. Bibliographies from previous studies were also examined. METHODS - ECONOMIC ANALYSIS: The economic evaluation is based on the three largest RCTs of combination therapy, and a pooled analysis of two of these trials. Sustained virological response rates were entered into a spreadsheet model incorporating a hypothetical cohort of 1000 patients who were followed over a 30-year period. RESULTS - EFFECTIVENESS: Nineteen RCTs and two meta-analyses were identified. The methodological quality of the included studies was variable, though the larger RCTs and meta-analyses were considered to be of high quality. Results of these trials indicate that combination therapy produces larger sustained response rates than monotherapy. For patients naive to interferon treatment, sustained virological response rates were: 33% (95% confidence interval (CI), 29 to 37) for combination therapy compared with 6% (95% CI, 3 to 10) for monotherapy, based on 24 weeks of treatment; and 41% (95% CI, 36 to 45) compared with 16% (95% CI, 13 to 19), respectively, for 48 weeks of treatment. For patients who had relapsed following a previous course of interferon, sustained virological response rates were 49% (95% CI, 42 to 57) compared with 5% (95% CI, 2 to 9), respectively, based on 24 weeks of treatment. Two groups of chronic hepatitis C patients are expected to benefit from combination therapy: interferon-naive patients and relapse patients. RESULTS - ECONOMIC ANALYSIS: A 4-week cycle of interferon alfa at 3 mU three times a week costs pound 194; ribavirin costs pound 543. Thus, ribavirin substantially increases drug costs compared with interferon monotherapy. Six months of combination therapy will cost pound 4422 (excluding monitoring costs). For interferon alfa-naive patients, the additional discounted cost per quality-adjusted life-year (QALY) gained from treatment with combination therapy for 6 months compared with no active treatment is pound 7578. For patients who have relapsed after a previous course of interferon alfa, the additional discounted cost per QALY gained from treatment with combination therapy for 6 months compared with monotherapy for 6 months is pound 3503. A subgroup analysis was conducted to examine the sensitivity of the cost per QALY based on the response rates of different patient subgroups (chronic hepatitis C patients with between none and five favourable response factors). This shows it is worth treating all patients with combination therapy as first-line treatment for 6 months, but only worth treating those with one or two response factors for a further 6 months. Those with three or four factors do well by 6 months, but gain very little from furt

Decontamination and the law. A better understanding.

A manufacturer is usually liable in law for a defective product; however, processors are also viewed as manufacturers. Theatre staff who sterilise and label products are also liable; a liability which exists for ten years. Pat Hewitson discusses the implications.