Effectiveness of emergency surgery for five common acute conditions: an instrumental variable analysis of a national routine database.

The effectiveness of emergency surgery vs. non-emergency surgery strategies for emergency admissions with acute appendicitis, gallstone disease, diverticular disease, abdominal wall hernia or intestinal obstruction is unknown. Data on emergency admissions for adult patients from 2010 to 2019 at 175 acute National Health Service hospitals in England were extracted from the Hospital Episode Statistics database. Cohort sizes were: 268,144 (appendicitis); 240,977 (gallstone disease); 138,869 (diverticular disease); 106,432 (hernia); and 133,073 (intestinal obstruction). The primary outcome was number of days alive and out of hospital at 90 days. The effectiveness of emergency surgery vs. non-emergency surgery strategies was estimated using an instrumental variable design and is reported for the cohort and pre-specified sub-groups (age, sex, number of comorbidities and frailty level). Average days alive and out of hospital at 90 days for all five cohorts were similar, with the following mean differences (95%CI) for emergency surgery minus non-emergency surgery after adjusting for confounding: -0.73 days (-2.10-0.64) for appendicitis; 0.60 (-0.10-1.30) for gallstone disease; -2.66 (-15.7-10.4) for diverticular disease; -0.07 (-2.40-2.25) for hernia; and 3.32 (-3.13-9.76) for intestinal obstruction. For patients with 'severe frailty', mean differences (95%CI) in days alive and out of hospital for emergency surgery were lower than for non-emergency surgery strategies: -21.0 (-27.4 to -14.6) for appendicitis; -5.72 (-11.3 to -0.2) for gallstone disease, -38.9 (-63.3 to -14.6) for diverticular disease; -19.5 (-26.6 to -12.3) for hernia; and - 34.5 (-46.7 to -22.4) for intestinal obstruction. For patients without frailty, the mean differences (95%CI) in days alive and out of hospital were: -0.18 (-1.56-1.20) for appendicitis; 0.93 (0.48-1.39) for gallstone disease; 5.35 (-2.56-13.28) for diverticular disease; 2.26 (0.37-4.15) for hernia; and 18.2 (14.8-22.47) for intestinal obstruction. Emergency surgery and non-emergency surgery strategies led to similar average days alive and out of hospital at 90 days for five acute conditions. The comparative effectiveness of emergency surgery and non-emergency surgery strategies for these conditions may be modified by patient factors.

Antibiotics as first-line alternative to appendicectomy in adult appendicitis: 90-day follow-up from a prospective, multicentre cohort study.

BACKGROUND: Uncomplicated acute appendicitis can be managed with non-operative (antibiotic) treatment, but laparoscopic appendicectomy remains the first-line management in the UK. During the COVID-19 pandemic the practice altered, with more patients offered antibiotics as treatment. A large-scale observational study was designed comparing operative and non-operative management of appendicitis. The aim of this study was to evaluate 90-day follow-up. METHODS: A prospective, cohort study at 97 sites in the UK and Republic of Ireland included adult patients with a clinical or radiological diagnosis of appendicitis that either had surgery or non-operative management. Propensity score matching was conducted using age, sex, BMI, frailty, co-morbidity, Adult Appendicitis Score and C-reactive protein. Outcomes were 90-day treatment failure in the non-operative group, and in the matched groups 30-day complications, length of hospital stay (LOS) and total healthcare costs associated with each treatment. RESULTS: A total of 3420 patients were recorded: 1402 (41 per cent) had initial antibiotic management and 2018 (59 per cent) had appendicectomy. At 90-day follow-up, antibiotics were successful in 80 per cent (1116) of cases. After propensity score matching (2444 patients), fewer overall complications (OR 0.36 (95 per cent c.i. 0.26 to 0.50)) and a shorter median LOS (2.5 versus 3 days, P < 0.001) were noted in the antibiotic management group. Accounting for interval appendicectomy rates, the mean total cost was €1034 lower per patient managed without surgery. CONCLUSION: This study found that antibiotics is an alternative first-line treatment for adult acute appendicitis and can lead to cost reductions.

Cost-effectiveness of alternative changes to a national blood collection service.

OBJECTIVES: To evaluate the cost-effectiveness of changing opening times, introducing a donor health report and reducing the minimum inter-donation interval for donors attending static centres. BACKGROUND: Evidence is required about the effect of changes to the blood collection service on costs and the frequency of donation. METHODS/MATERIALS: This study estimated the effect of changes to the blood collection service in England on the annual number of whole-blood donations by current donors. We used donors' responses to a stated preference survey, donor registry data on donation frequency and deferral rates from the INTERVAL trial. Costs measured were those anticipated to differ between strategies. We reported the cost per additional unit of blood collected for each strategy versus current practice. Strategies with a cost per additional unit of whole blood less than £30 (an estimate of the current cost of collection) were judged likely to be cost-effective. RESULTS: In static donor centres, extending opening times to evenings and weekends provided an additional unit of whole blood at a cost of £23 and £29, respectively. Introducing a health report cost £130 per additional unit of blood collected. Although the strategy of reducing the minimum inter-donation interval had the lowest cost per additional unit of blood collected (£10), this increased the rate of deferrals due to low haemoglobin (Hb). CONCLUSION: The introduction of a donor health report is unlikely to provide a sufficient increase in donation frequency to justify the additional costs. A more cost-effective change is to extend opening hours for blood collection at static centres.

Facilitated self-reported anaesthetic medication errors before and after implementation of a safety bundle and barcode-based safety system.

BACKGROUND: Anaesthetic medication administration errors are a significant threat to patient safety. In 2002, we began collecting data about the rate and nature of anaesthetic medication errors and implemented a variety of measures to reduce errors. METHODS: Facilitated self-reporting of errors was carried out in 2002-2003. Subsequently, a medication safety bundle including 'smart' infusion pumps were implemented. During 2014 facilitated self-reporting commenced again. A barcode-based medication safety system was then implemented and the facilitated self-reporting was continued through 2015. RESULTS: During 2002-2003, a total of 11 709 paper forms were returned. There were 73 reports of errors (0.62% of anaesthetics) and 27 reports of intercepted errors (0.23%). During 2014, 14 572 computerised forms were completed. There were 57 reports of errors (0.39%) and 11 reports of intercepted errors (0.075%). Errors associated with medication infusions were reduced in comparison with those recorded in 2002-2003 (P<0.001). The rate of syringe swap error was also reduced (P=0.001). The reduction in error rate between 2002-2003 and 2014 was statistically significant (P=0.0076 and P=0.001 for errors and intercepted errors, respectively). From December 2014 through December 2015, 24 264 computerised forms were completed after implementation of a barcode-based medication safety system. There were 56 reports of errors (0.23%) and six reports of intercepted errors (0.025%). Vial swap errors in 2014-2015 were significantly reduced compared with those in 2014 (P=0.004). The reduction in error rate after implementation of the barcode-based medication safety system was statistically significant (P=0.0045 and P=0.021 for errors and intercepted errors, respectively). CONCLUSIONS: Reforms intended to reduce medication errors were associated with substantial improvement.

Multiple imputation methods for bivariate outcomes in cluster randomised trials.

Missing observations are common in cluster randomised trials. The problem is exacerbated when modelling bivariate outcomes jointly, as the proportion of complete cases is often considerably smaller than the proportion having either of the outcomes fully observed. Approaches taken to handling such missing data include the following: complete case analysis, single-level multiple imputation that ignores the clustering, multiple imputation with a fixed effect for each cluster and multilevel multiple imputation. We contrasted the alternative approaches to handling missing data in a cost-effectiveness analysis that uses data from a cluster randomised trial to evaluate an exercise intervention for care home residents. We then conducted a simulation study to assess the performance of these approaches on bivariate continuous outcomes, in terms of confidence interval coverage and empirical bias in the estimated treatment effects. Missing-at-random clustered data scenarios were simulated following a full-factorial design. Across all the missing data mechanisms considered, the multiple imputation methods provided estimators with negligible bias, while complete case analysis resulted in biased treatment effect estimates in scenarios where the randomised treatment arm was associated with missingness. Confidence interval coverage was generally in excess of nominal levels (up to 99.8%) following fixed-effects multiple imputation and too low following single-level multiple imputation. Multilevel multiple imputation led to coverage levels of approximately 95% throughout. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

An evaluation of the clinical and cost-effectiveness of alternative care locations for critically ill adult patients with acute traumatic brain injury.

BACKGROUND: For critically ill adult patients with acute traumatic brain injury (TBI), we assessed the clinical and cost-effectiveness of: (a) Management in dedicated neurocritical care units versus combined neuro/general critical care units within neuroscience centres. (b) 'Early' transfer to a neuroscience centre versus 'no or late' transfer for those who present at a non-neuroscience centre. METHODS: The Risk Adjustment In Neurocritical care (RAIN) Study included prospective admissions following acute TBI to 67 UK adult critical care units during 2009-11. Data were collected on baseline case-mix, mortality, resource use, and at six months, Glasgow Outcome Scale Extended (GOSE), and quality of life (QOL) (EuroQol 5D-3L). We report incremental effectiveness, costs and cost per Quality-Adjusted Life Year (QALY) of the alternative care locations, adjusting for baseline differences with validated risk prediction models. We tested the robustness of results in sensitivity analyses. FINDINGS: Dedicated neurocritical care unit patients (N = 1324) had similar six-month mortality, higher QOL (mean gain 0.048, 95% CI -0.002 to 0.099) and increased average costs compared with those managed in combined neuro/general units (N = 1341), with a lifetime cost per QALY gained of £14,000. 'Early' transfer to a neuroscience centre (N = 584) was associated with lower mortality (odds ratio 0.52, 0.34-0.80), higher QOL for survivors (mean gain 0.13, 0.032-0.225), but positive incremental costs (£15,001, £11,123 to £18,880) compared with 'late or no transfer' (N = 263). The lifetime cost per QALY gained for 'early' transfer was £11,000. CONCLUSIONS: For critically ill adult patients with acute TBI, within neuroscience centres management in dedicated neurocritical care units versus combined neuro/general units led to improved QoL and higher costs, on average, but these differences were not statistically significant. This study finds that 'early' transfer to a neuroscience centre is associated with reduced mortality, improvement in QOL and is cost-effective.

A randomised trial of secondary prophylaxis using granulocyte colony-stimulating factor ('SPROG' trial) for maintaining dose intensity of standard adjuvant chemotherapy for breast cancer by the Anglo-Celtic Cooperative Group and NCRN.

BACKGROUND: Guidelines on the use of haematopoietic colony-stimulating factors for patients having adjuvant chemotherapy for breast cancer are designed to minimise the risk of neutropaenic infection (Smith TJ, Khatcheressian J, Lyman GH et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 3: 187-205; Aapro MS, Bohlius J, Cameron DA et al. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 2011; 47: 8-32; Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009; 7: 122-192). Non-randomised data suggest that the achievement of planned dose intensity (DI) may have an important effect on survival. This trial compared the effects of granulocyte colony-stimulating factor, GCSF, against standard management following a first neutropaenic event (NE) in achieving planned DI. PATIENTS AND METHODS: Adult patients receiving adjuvant or neoadjuvant chemotherapy were randomised following a first NE, defined as hospitalisation due to neutropaenic fever, an absolute neutrophil count (ANC) ≤1.5 × 10(9)/l requiring treatment delay or dose reduction of 15% or more of planned dose. The study was initially planned to enrol 816 patients to detect a difference of 10%. This was difficult to achieve in the timeframe and the trial size was amended. Thus, 407 patients were randomly assigned to filgrastim for 7 days or pegfilgrastim versus standard care. The amended study was designed to have 80% power to detect an absolute difference of 14% of planned DI between the two groups. RESULTS: Most regimens were anthracycline-based many of which included a sequential taxane and/or were in clinical trials. Around 82.7% had an NE in the first three cycles. A total of 401 had calculable relative dose intensity (RDI) data. A target of 85% planned RDI was achieved in only 50% of patients in the control arm compared with 75% in the GCSF arm (P < 0.0001). A secondary end point revealed a reduction in post-randomisation NEs, 65.7% controls versus 18.2% with GCSF. CONCLUSIONS: Secondary intervention with GCSF showed a statistically significant improvement in the achievement of adequate RDI in non-intensive regimens. This may have important clinical implications for outcome.

Observations from the IMPROVE trial concerning the clinical care of patients with ruptured abdominal aortic aneurysm.

BACKGROUND: Single-centre series of the management of patients with ruptured abdominal aortic aneurysm (AAA) are usually too small to identify clinical factors that could improve patient outcomes. METHODS: IMPROVE is a pragmatic, multicentre randomized clinical trial in which eligible patients with a clinical diagnosis of ruptured aneurysm were allocated to a strategy of endovascular aneurysm repair (EVAR) or to open repair. The influences of time and manner of hospital presentation, fluid volume status, type of anaesthesia, type of endovascular repair and time to aneurysm repair on 30-day mortality were investigated according to a prespecified plan, for the subgroup of patients with a proven diagnosis of ruptured or symptomatic AAA. Adjustment was made for potential confounding factors. RESULTS: Some 558 of 613 randomized patients had a symptomatic or ruptured aneurysm: diagnostic accuracy was 91·0 per cent. Patients randomized outside routine working hours had higher operative mortality (adjusted odds ratio (OR) 1·47, 95 per cent confidence interval 1·00 to 2·17). Mortality rates after primary and secondary presentation were similar. Lowest systolic blood pressure was strongly and independently associated with 30-day mortality (51 per cent among those with pressure below 70 mmHg). Patients who received EVAR under local anaesthesia alone had greatly reduced 30-day mortality compared with those who had general anaesthesia (adjusted OR 0·27, 0·10 to 0·70). CONCLUSION: These findings suggest that the outcome of ruptured AAA might be improved by wider use of local anaesthesia for EVAR and that a minimum blood pressure of 70 mmHg is too low a threshold for permissive hypotension.

An integrated approach to evaluating alternative risk prediction strategies: a case study comparing alternative approaches for preventing invasive fungal disease.

OBJECTIVES: This article proposes an integrated approach to the development, validation, and evaluation of new risk prediction models illustrated with the Fungal Infection Risk Evaluation study, which developed risk models to identify non-neutropenic, critically ill adult patients at high risk of invasive fungal disease (IFD). METHODS: Our decision-analytical model compared alternative strategies for preventing IFD at up to three clinical decision time points (critical care admission, after 24 hours, and end of day 3), followed with antifungal prophylaxis for those judged "high" risk versus "no formal risk assessment." We developed prognostic models to predict the risk of IFD before critical care unit discharge, with data from 35,455 admissions to 70 UK adult, critical care units, and validated the models externally. The decision model was populated with positive predictive values and negative predictive values from the best-fitting risk models. We projected lifetime cost-effectiveness and expected value of partial perfect information for groups of parameters. RESULTS: The risk prediction models performed well in internal and external validation. Risk assessment and prophylaxis at the end of day 3 was the most cost-effective strategy at the 2% and 1% risk threshold. Risk assessment at each time point was the most cost-effective strategy at a 0.5% risk threshold. Expected values of partial perfect information were high for positive predictive values or negative predictive values (£11 million-£13 million) and quality-adjusted life-years (£11 million). CONCLUSIONS: It is cost-effective to formally assess the risk of IFD for non-neutropenic, critically ill adult patients. This integrated approach to developing and evaluating risk models is useful for informing clinical practice and future research investment.

Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials.

BACKGROUND: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. METHODS: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. RESULTS: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. CONCLUSION: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

The use of herbal medicines by people with cancer: a cross-sectional survey.

BACKGROUND: A large proportion of cancer patients are estimated to use herbal medicines, but data to substantiate this are lacking. This study aimed to investigate the prevalence of herbal medicine use among cancer patients in the West Midlands, and determine the characteristics predicting herbal medicine use. METHODS: A cross-sectional survey of oncology patients (n=1498) being followed up at a hospital in Coventry was undertaken. Recipients were asked about herbal medicine use since their cancer diagnosis, and the association between sociodemographic and cancer-related characteristics and herbal medicine use was evaluated. RESULTS: A total of 1134 responses were received (75.7%). The prevalence of herbal medicine use was 19.7% (95% CI: 17.4-22.1; n=223). Users were more likely to be affluent, female, and aged under 50 years. Usage increased with time since cancer diagnosis (X(2) for trend=4.63; P=0.031). A validation data set, derived from a survey of oncology patients in Birmingham (n=541) with differing socioeconomic characteristics showed no significant difference in estimated prevalence (16.6%; 95% CI: 11.9-22.2). CONCLUSION: A substantial number of people with cancer are likely to be taking herbal medicines. Understanding the self-medication behaviours of these individuals is essential if health-care professionals are to support treatment adherence and avoid unwanted pharmacological interactions.

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer.

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

The Immediate Management of the Patient with Rupture: Open Versus Endovascular repair (IMPROVE) aneurysm trial--ISRCTN 48334791 IMPROVE trialists.

BACKGROUND: Systematic reviews have suggested a survival advantage for patients with ruptured abdominal aortic aneurysm (AAA), who are managed by endovascular repair. These reviews are based on single centre experiences of selected patients. OBJECTIVE: To determine whether a policy of endovascular repair improves the survival of all patients with ruptured AAA. METHODS: A randomized controlled trial, IMPROVE (ISRCTN 48334791) will randomize patients with a clinical diagnosis of rAAA, made in hospital, either to immediate CT scan and endovascular repair whenever anatomically suitable (endovascular first), or to open repair, with CT scan being optional (normal care), The trial is set on a background of guidelines for emergency care, CT scanning and anaesthesia, which incorporate the protocol of permissive hypotension. Recruitment started in October 2009 and 600 patients are required to show a 14% survival benefit at 30 days (primary outcome) for the endovascular first policy. Recruitment will be from the UK and Europe. Secondary outcomes include 24h, in-hospital and 1 year survival, complications, major morbidities, costs and quality of life. DISCUSSION: This is a "real life" trial that will answer the fundamental relevant clinical dilemma, namely, do patients who present with ruptured AAA derive benefit from treatment in a system, which offers a preferential strategy of endovascular repair? The trial addresses whether the anticipated reduced mortality and morbidity associated with endovascular repair is offset by the relatively greater ease of access and speed to conventional surgery. This issue is pivotal to future patient care and provision of services.

NEAT: National Epirubicin Adjuvant Trial--toxicity, delivered dose intensity and quality of life.

The NEAT trial reported considerable benefit for ECMF (epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil) of 28% for relapse-free survival (RFS) and 30% for overall survival (OS), when compared with classical CMF in early breast cancer. To assess tolerability, toxicity, dose intensity and quality of life (QoL) analyses were undertaken. All 2021 eligible patients had common toxicity criteria (CTC), delivered chemotherapy and supportive treatments details and long-term morbidities recorded. The QoL substudy used multiple validated measures. ECMF produced low CTC scores, although higher than CMF for nausea, vomiting, alopecia, constipation, stomatitis (P<0.001), infection (P=0.001) and fatigue (P=0.03). Supportive treatments required, however, were similar across randomised treatments. On-treatment deaths were more common with CMF (13) than ECMF(5). Optimal course-delivered dose intensity (CDDI > or =85%) was received more often by ECMF patients (83 vs 76%: P=0.0002), and was associated with better RFS (P=0.0006). QoL over 2 years was equivalent across treatments, despite minimally worse side effects for ECMF during treatment. ECMF benefit spanned all levels of toxicity, CDDI and QoL. There are no reported acute myeloid leukaemias or cardiac dysfunctions. ECMF is tolerable, deliverable, and significantly more effective than CMF, with no serious long-term toxicity or QoL detriment.

Response rates to combination therapy for chronic HCV infection in a clinical setting and derivation of probability tables for individual patient management.

Evidence for efficacy of established treatment guidelines for chronic hepatitis C virus (HCV) disease is based on multinational randomized controlled trials (RCTs). Strategies for managing HCV, however, require an assessment of the effectiveness of intervention in routine clinical practice. We report the outcomes of combination therapy in a large cohort of HCV-infected individuals in the UK. A total of 347 (113 genotype 1, 234 genotype non-1) patients were treated with pegylated interferon and ribavirin according to current guidelines. Forty-two (37.2%) of those with genotype 1 infection and 164 (70.1%) with genotype non-1 infection achieved sustained viral response (SVR). Thirty-nine (11%) patients withdrew from treatment. In addition to viral genotype, factors predictive of a response to therapy were age at start of treatment and disease stage on pretreatment liver biopsy. Multivariate regression analysis demonstrated that the effects of age [odds ratio 0.5; 95% confidence interval (0.31-0.82) per 10-year increment (P = 0.006)] were confined to genotype 1 disease. In order to further inform the management of the individual patient, a multivariate logistic model was used to predict the probability of SVR for subgroups defined by disease stage, genotype and age at commencement of therapy. This model revealed striking differences in predicted response rates between subgroups and provided a strong rationale for early treatment, particularly for those with genotype 1 disease. Our study demonstrates that results comparable with those of RCTs can be achieved in clinical practice, and suggests that prediction of response rates based on probability modelling will provide a valuable adjunct to individual patient management.

Methods for estimating complier average causal effects for cost-effectiveness analysis.

In randomized controlled trials with treatment non-compliance, instrumental variable approaches are used to estimate complier average causal effects. We extend these approaches to cost-effectiveness analyses, where methods need to recognize the correlation between cost and health outcomes. We propose a Bayesian full likelihood approach, which jointly models the effects of random assignment on treatment received and the outcomes, and a three-stage least squares method, which acknowledges the correlation between the end points and the endogeneity of the treatment received. This investigation is motivated by the REFLUX study, which exemplifies the setting where compliance differs between the randomized controlled trial and routine practice. A simulation is used to compare the methods' performance. We find that failure to model the correlation between the outcomes and treatment received correctly can result in poor confidence interval coverage and biased estimates. By contrast, Bayesian full likelihood and three-stage least squares methods provide unbiased estimates with good coverage.

TEXAS (Taxotere EXperience with Anthracyclines Study) trial: mature results of activity/toxicity of docetaxel given with anthracyclines in a community setting, as first line therapy for MBC.

PURPOSE: The TEXAS (Taxotere EXperience with Anthracyclines Study) study examined docetaxel in combination with an anthracycline, as first line treatment of metastatic breast cancer (MBC), in everyday practice, and compared the findings with a randomised controlled trial. METHODS: Four hundred and seventy patients were registered on the TEXAS trial. Patients were assigned, according to treating clinician's discretion, to either doxorubicin 50 mg/m2 or epirubicin 75 mg/m2 both given day1 15 min intravenous bolus every 3 weeks, followed by docetaxel 75 mg/m2, day 1, 1 h intravenous infusion every 3 weeks. RESULTS: The overall response rate (ORR) was approximately 61%. The main toxicity reported was neutropenia, with 75 patients (55%) in the AT group and 203 (61%) in the ET arm. Febrile neutropenia or neutropenic sepsis was reported for 32 (24%) of the AT arm and 78 (23%) of the ET arm. CONCLUSIONS: This open access study demonstrates that AT or ET are highly active treatments for MBC, with similar response rates to those observed in a phase III clinical trial. This may be important for patients with rapidly progressive visceral disease. Side effects can be managed effectively with growth factors and/or prophylactic antibiotic.

Combined modality treatment of early rectal cancer: the UK experience.

With the introduction of colorectal screening in the UK, more patients will probably be diagnosed with early rectal cancer. The UK has an increasingly elderly population and not all patients diagnosed with early rectal cancer will be suitable for radical surgery. Therefore, a national plan is needed to develop the provision of alternative local treatment with equity of access across the country. Here we review the Clatterbridge Centre for Oncology multimodality treatment policy, which has been in clinical practice since 1993 and we discuss its rationale. Clatterbridge is the only centre in the UK offering Papillon-style contact radiotherapy. In total, 220 patients have been treated over 14 years, most of whom were referred from other centres. One hundred and twenty-four patients received Papillon (contact radiotherapy) as part of their multimodality management. The guidelines of the Association of Coloproctology of Great Britain and Ireland recommend local treatment for T1 tumours<3 cm in diameter, but this refers to treatment by surgery alone. There are no published national guidelines for radiotherapy. We plan each treatment in stages and achieve excellent local control (93% at 3 years) with low morbidity. We conclude that radical local treatment for cure can be offered safely to carefully selected elderly patients. Close follow-up is necessary so that effective salvage treatment can be offered. Because of a lack of randomised trial evidence, at present local radiotherapy is not yet accepted as an alternative option to the gold standard surgical treatment. Even with international collaboration, a randomised trial will be difficult to complete as the number of cases requiring local radiotherapy is small due to the highly selective nature of the treatment involved. However, an observational phase II trial is planned. In addition, the Transanal Endoscopic Microsurgery Users Group is also planning a phase II trial using preoperative radiotherapy. These studies will provide evidence to help establish the true role of radiotherapy in early rectal cancer.

Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

OBJECTIVES: To determine whether combined therapy with interferon-alpha and ribavirin was more effective and cost-effective than no treatment for patients with mild chronic hepatitis C. DESIGN: A multicentre, randomised, controlled, non-blinded trial assessed the efficacy of combination therapy. A Markov model used these efficacy data combined with data on transition probabilities, costs and health-related quality of life (HRQoL) to assess the lifetime cost-effectiveness of the intervention. SETTING: A multicentre NHS setting. PARTICIPANTS: Treatment-naive, adult patients with histologically mild chronic hepatitis C (Ishak necroinflammatory scores <4 and fibrosis scores <3 on liver biopsy). INTERVENTIONS: Patients were randomised to receive interferon-alpha and ribavirin for 48 weeks or no treatment (control). MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of patients having a sustained virological response (SVR), measured at 6 months after cessation of therapy. Secondary outcome measures were: the ability of early phase kinetics to predict the eventual outcome of treating mild disease; HRQoL measured using the Short Form 36 and EuroQol (5 Dimensions) questionnaires, and the cost per quality-adjusted life-year (QALY) of interferon-alpha and ribavirin for mild disease compared with no treatment. RESULTS: In the treatment group, 32 out of 98 patients (33%) achieved an SVR. Patients infected with genotype 1 had a lower SVR than those infected with genotype non-1 (18% versus 49%, p = 0.02). No patients who failed to achieve a 2-log drop in viral load at 12 weeks achieved an SVR. HRQoL fell during treatment and rose with treatment cessation. For patients having an SVR there were modest improvements in HRQoL at 6 months post-treatment. The mean cost per QALY gained was 4535 pounds sterling for 40-year-old patients with genotype non-1 and 25,188 pounds sterling for patients with genotype 1. For patients with genotype 1 aged 65, providing interferon-alpha and ribavirin for mild disease led to fewer QALYs gained, and a mean cost per QALY of 53,017 pounds sterling. The model using efficacy estimates from the literature, showed that the cost per QALY gained from providing pegylated interferon alpha-2b and ribavirin at a mild stage rather than a moderate stage was 7821 pounds sterling for patients with genotype non-1 and 28,409 pounds sterling for patients with genotype 1. CONCLUSIONS: Based on the evidence collected in this study, interferon-alpha and ribavirin treatment for mild chronic hepatitis C patients is in general cost-effective at the 30,000 pounds sterling per QALY threshold previously used by policy-makers in the NHS. For patients with chronic hepatitis C aged 65 or over with genotype 1, antiviral treatment at a mild stage does not appear cost-effective. Further research is required on the cost-effectiveness of pegylated interferon and ribavirin, in particular the intervention's long-term impact on HRQoL and health service costs requires further evaluation. Further research is also needed to develop predictive tests, based on pharmacogenomics, that can identify those cases most likely to respond to antiviral therapy. Liver biopsy before treatment no longer appears justified apart from for older patients (aged 65 or over) with genotype 1. However, further research should monitor the impact this strategy would have on costs and outcomes.

ChlVPP/PABlOE and radiotherapy in advanced Hodgkin's disease. The Central Lymphoma Group.

PURPOSE: The United Kingdom Central Lymphoma Group (CLG) has modified mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) by substituting mechlorethamine with chlorambucil and dacarbazine with etoposide in the treatment of patients with advanced Hodgkin's disease (HD). Prednisolone is included in the bleomycin-containing combination, and the vinca alkaloids have been switched to balance the myelotoxicity of the two component regimens. PATIENTS AND METHODS: The resulting ChlVPP/PABlOE regimen is as follows: on days 1 to 14, chlorambucil 6 mg/m2 orally, procarbazine 100 mg/m2 orally, and prednisolone 30 mg/m2 orally; on days 1 and 8, vinblastine 6 mg/m2 intravenously (i.v.); on day 29, doxorubicin 40 mg/m2 i.v.; on days 29 and 36, vincristine 1.4 mg/m2 (maximum, 2 mg) i.v., and bleomycin 10 mg/m2 i.v.; on days 30, 31, and 32, etoposide 200 mg/m2/d orally; on days 29 to 43, inclusive, prednisolone, 30 mg/m2 orally. The second full cycle restarts on day 50. Treatment continues to maximum response plus two full cycles, but with a minimum of three full cycles. Radiotherapy is administered, after chemotherapy, to sites of previously bulky disease. Since 1983, 216 patients with previously untreated, advanced Hodgkin's disease (HD) have entered this study. RESULTS: The complete remission (CR) rate after chemotherapy was 73% (95% confidence interval [CI], 67% to 79%), and after additional radiotherapy was 85% (95% CI, 80% to 90%). The failure-free survival (FFS) rate at 5 years was 68% (95% CI, 61% to 74%), and the overall actuarial survival at 5 years was 78% (95% CI, 72% to 84%). The CR rate in patients in the poorer prognostic categories was high: 81% in patients with albumin levels less than 37 g/L, 79% in patients older than 40 years of age, 84% in stages IIIB plus i.v. disease, and 79% in patients presenting with B symptoms. As expected, nausea and vomiting were not major problems, although infection, often in the context of myelosuppression, complicated almost half the cases, and 29% of patients required admission at some stage for treatment of infection. CONCLUSION: In this multicenter study, ChlVPP/PABlOE produced results comparable to those reported for MOPP/ABVD, but with less nausea and vomiting. Treatment duration was shorter than in the original MOPP/ABVD regimen, and than that used in the Cancer and Leukemia Group B (CALGB) trial. It will now be compared with PABlOE alone.