Sue Ward

Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis

PURPOSE Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) are used to assess axillary nodal status in breast cancer, but are invasive procedures associated with morbidity, including lymphoedema. This systematic review evaluates the diagnostic accuracy of positron emission tomography (PET), with or without computed tomography (CT), for assessment of axillary nodes in early breast cancer. METHODS Eleven databases including MEDLINE, EMBASE and the Cochrane Library, plus research registers and conference proceedings, were searched in April 2009. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Sensitivity and specificity were meta-analysed using a bivariate random effects approach. RESULTS Across 26 studies evaluating PET or PET/CT (n = 2591 patients), mean sensitivity was 63% (95% CI: 52-74%; range 20-100%) and mean specificity 94% (95% CI: 91-96%; range 75-100%). Across 7 studies of PET/CT (n = 862), mean sensitivity was 56% (95% CI: 44-67%) and mean specificity 96% (90-99%). Across 19 studies of PET-only (n = 1729), mean sensitivity was 66% (50-79%) and mean specificity 93% (89-96%). Mean sensitivity was 11% (5-22%) for micrometastases (≤2 mm; five studies; n = 63), and 57% (47-66%) for macrometastases (>2 mm; four studies; n = 111). CONCLUSIONS PET had lower sensitivity and specificity than SLNB. Therefore, replacing SLNB with PET would avoid the adverse effects of SLNB, but lead to more false negative patients at risk of recurrence and more false positive patients undergoing unnecessary ALND. The present evidence does not support the routine use of PET or PET-CT for the assessment of the clinically negative axilla.

Health-state utility values in breast cancer

Health-related quality of life is an important issue in the treatment of breast cancer and health-state utility values are essential for cost–utility analysis. A literature review was conducted to identify published values for common health states for breast cancer. In total, 13 databases were searched and 49 articles were identified providing 476 unique utility values. Where possible mean utility estimates were pooled using ordinary least squares with utilities clustered within study group and weighted by both number of respondents and inverse of the variance of each utility. Regressions included controls for disease state, utility assessment method and other features of study design. Utility values found in the review were summarized for six categories: screening-related states; preventative states; adverse events in breast cancer and its treatment; nonspecific breast cancer; metastatic breast cancer states; and early breast cancer states. The large number of values identified for metastatic breast cancer and early breast cancer states enabled data to be synthesized by meta-regression. Utilities were found to vary significantly between valuation methods and depending on who conducted the valuation. For metastatic breast cancer, values significantly varied by severity of condition, treatment and side-effects. Despite the numerous studies it is not feasible to generate a definitive list of health-state utility values that can be used in future economic evaluations owing to the complexity of the health states involved and the variety of methods used to obtain values. Future research into quality of life in breast cancer should make greater use of validated generic preference-based measures for which public preferences exist.

Magnetic Resonance for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis

INTRODUCTION Current methods of identifying axillary node metastases in breast cancer patients are highly accurate, but are associated with several adverse events. This review evaluates the diagnostic accuracy of magnetic resonance imaging (MRI) techniques for identification of axillary metastases in early stage newly diagnosed breast cancer patients. METHODS Comprehensive searches were conducted in April 2009. Study quality was assessed. Sensitivity and specificity were meta-analysed using a bivariate random effects approach, utilising pathological diagnosis via node biopsy as the comparative gold standard. RESULTS Based on the highest sensitivity and specificity reported in each of the nine studies evaluating MRI (n = 307 patients), mean sensitivity was 90% (95% CI: 78-96%; range 65-100%) and mean specificity 90% (95% CI: 75-96%; range 54-100%). Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), mean sensitivity was 98% (95% CI: 61-100%) and mean specificity 96% (95% CI: 72-100%). Across three studies of gadolinium-enhanced MRI (n = 187), mean sensitivity was 88% (95% CI: 78-94%) and mean specificity 73% (95% CI: 63-81%). In the single study of in-vivo proton MR spectroscopy (n = 27), sensitivity was 65% (95% CI: 38-86%) and specificity 100% (95% CI: 69-100%). CONCLUSIONS USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity and may make a useful addition to the current diagnostic pathway. Additional larger studies with standardised methods and standardised criteria for classifying a node as positive are needed. Current estimates of sensitivity and specificity do not support replacement of SLNB with any current MRI technology in this patient group.

Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) for the Assessment of Axillary Lymph Node Metastases in Early Breast Cancer: Systematic Review and Economic Evaluation

BACKGROUND Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning. OBJECTIVES To evaluate the diagnostic accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer. DATA SOURCES A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK. REVIEW METHODS One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second. RESULTS Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% [95% confidence interval (CI) 44% to 67%] and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (≤ 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients. LIMITATIONS No included studies directly compared PET and MRI. CONCLUSIONS Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques. FUNDING This study was funded by the Health Technology Assessment programme of the National Institute of Health Research.

Cholesterol and coronary heart disease: screening and treatment.

Coronary heart disease (CHD) is a major cause of morbidity and mortality in the United Kingdom, accounting for just under one quarter of all deaths in 1995: 27% among men and 21% among women.1 Although many CHD deaths occur among elderly people, CHD accounts for 31% of male and 13% of female deaths within the 45–64 age group.

Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: a systematic review and cost-effectiveness analysis

BACKGROUND Gene expression profiling (GEP) and expanded immunohistochemistry (IHC) tests aim to improve decision-making relating to adjuvant chemotherapy for women with early breast cancer. OBJECTIVE The aim of this report is to assess the clinical effectiveness and cost-effectiveness of nine GEP and expanded IHC tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer in England and Wales. The nine tests are BluePrint, Breast Cancer Index (BCI), IHC4, MammaPrint, Mammostrat, NPI plus (NPI+), OncotypeDX, PAM50 and Randox Breast Cancer Array. DATA SOURCES Databases searched included MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. Databases were searched from January 2009 to May 2011 for the OncotypeDX and MammaPrint tests and from January 2002 to May 2011 for the other tests. REVIEW METHODS A systematic review of the evidence on clinical effectiveness (analytical validity, clinical validity and clinical utility) and cost-effectiveness was conducted. An economic model was developed to evaluate the cost-effectiveness of adjuvant chemotherapy treatment guided by four of the nine test (OncotypeDX, IHC4, MammaPrint and Mammostrat) compared with current clinical practice in England and Wales, using clinicopathological parameters, in women with oestrogen receptor-positive (ER+), lymph node-negative (LN-), human epidermal growth factor receptor type 2-negative (HER2-) early breast cancer. RESULTS The literature searches for clinical effectiveness identified 5993 citations, of which 32 full-text papers or abstracts (30 studies) satisfied the criteria for the effectiveness review. A narrative synthesis was performed. Evidence for OncotypeDX supported the prognostic capability of the test. There was some evidence on the impact of the test on decision-making and to support the case that OncotypeDX predicts chemotherapy benefit; however, few studies were UK based and limitations in relation to study design were identified. Evidence for MammaPrint demonstrated that the test score was a strong independent prognostic factor, but the evidence is non-UK based and is based on small sample sizes. Evidence on the Mammostrat test showed that the test was an independent prognostic tool for women with ER+, tamoxifen-treated breast cancer. The three studies appeared to be of reasonable quality and provided data from a UK setting (one study). One large study reported on clinical validity of the IHC4 test, with IHC4 score a highly significant predictor of distant recurrence. This study included data from a UK setting and appeared to be of reasonable quality. Evidence for the remaining five tests (PAM50, NPI+, BCI, BluePrint and Randox) was limited. The economic analysis suggests that treatment guided using IHC4 has the greatest potential to be cost-effective at a £20,000 threshold, given the low cost of the test; however, further research is needed on the analytical validity and clinical utility of IHC4, and the exact cost of the test needs to be confirmed. Current limitations in the evidence base produce significant uncertainty in the results. OncotypeDX has a more robust evidence base, but further evidence on its impact on decision-making in the UK and the predictive ability of the test in an ER+, LN-, HER- population receiving current drug regimens is needed. For MammaPrint and Mammostrat there were significant gaps in the available evidence and the estimates of cost-effectiveness produced were not considered to be robust by the External Assessment Group. LIMITATIONS Methodological weaknesses in the clinical evidence base relate to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence. Further evidence is required on the clinical utility of all of the tests and on UK-based populations. A key area of uncertainty relates to whether the tests provide prognostic or predictive ability. CONCLUSIONS The clinical evidence base for OncotypeDX is considered to be the most robust. The economic analysis suggested that treatment guided using IHC4 has the most potential to be cost-effective at a threshold of £20,000; however, the evidence base to support IHC4 needs significant further research. STUDY REGISTRATION PROSPERO 2011:CRD42011001361, available from www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001361.

The clinical and economic benefits of capecitabine and tegafur with uracil in metastatic colorectal cancer

Two oral fluoropyrimidine therapies have been introduced for metastatic colorectal cancer. One is a 5-fluorouracil pro-drug, capecitabine; the other is a combination of tegafur and uracil administered together with leucovorin. The purpose of this study was to compare the clinical effectiveness and cost-effectiveness of these oral therapies against standard intravenous 5-fluorouracil regimens. A systematic literature review was conducted to assess the clinical effectiveness of the therapies and costs were calculated from the UK National Health Service perspective for drug acquisition, drug administration, and the treatment of adverse events. A cost-minimisation analysis was used; this assumes that the treatments are of equal efficacy, although direct randomised controlled trial (RCT) comparisons of the oral therapies with infusional 5-fluorouracil schedules were not available. The cost-minimisation analysis showed that treatment costs for a 12-week course of capecitabine (£2132) and tegafur with uracil (£3385) were lower than costs for the intravenous Mayo regimen (£3593) and infusional regimens on the de Gramont (£6255) and Modified de Gramont (£3485) schedules over the same treatment period. Oral therapies result in lower costs to the health service than intravenous therapies. Further research is needed to determine the relative clinical effectiveness of oral therapies vs infusional regimens.

The clinical efficacy of cytotoxic agents in locally advanced or metastatic breast cancer patients pretreated with an anthracycline and a taxane: a systematic review

INTRODUCTION Currently available evidence does not provide definitive guidance regarding the optimal chemotherapy agents and combinations in anthracycline- and taxane-pretreated advanced breast cancer. We performed a systematic review of controlled clinical trials of the cytotoxic agents currently used for this population in Europe: capecitabine, gemcitabine, vinorelbine, docetaxel, paclitaxel and paclitaxel protein-bound particles. METHOD A systematic review of randomised (RCT) and non-randomised controlled clinical trials (non-RCTs). The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS); secondary outcomes were duration of response (DR), overall response rate (ORR), adverse events and quality of life (QoL). Six electronic databases and grey literature sources were searched; reference tracking was performed on included publications. A narrative synthesis was conducted: heterogeneity of study design and interventions prevented meta-analysis. RESULTS No randomised controlled trial (RCT) found any significant differences between any of the regimens in terms of OS. In terms of PFS, only gemcitabine plus vinorelbine performed significantly better than its comparator, vinorelbine alone. For secondary outcomes, only capecitabine plus bevacizumab had a significantly better outcome than its comparator, capecitabine alone, in terms of ORR. A low quality non-RCT found that both capecitabine monotherapy and a combination of capecitabine plus vinorelbine were significantly more effective than vinorelbine alone in terms of OS and ORR. Across all trials, median OS for these patients typically remained less than 16 months. CONCLUSION The quantity and quality of the available evidence regarding the efficacy of the particular chemotherapy regimens in patients with advanced breast cancer pretreated with an anthracycline and a taxane is extremely limited. New effective therapies are sorely needed in this population.

Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

This paper presents a summary of the evidence review group (ERG) report into the the clinical and cost-effectiveness of trastuzumab for the treatment of primary breast cancer in human epidermal growth factor 2 (HER2)-positive women based upon a review of the manufacturers submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturers scope restricts the intervention to intravenous trastuzumab given for 1 year after surgery and after the completion of standard adjuvant chemotherapy, and the comparator to standard therapy without trastuzumab. The clinical rationale for the duration of treatment in the scope is open to question and leads to the exclsuion of one potentially relevant trial. The submitted evidence reports that the 3-weekly regimen of trastuzumab produced a relative reduction in all-cause mortality of 24-33%. Meta-analysis of all available studies based on 12 months of trastuzumab showed that there was a statistically significant 30% relative improvement in overall survival using the 3-weekly regimen. A study looking at weekly cycles of trastuzumab, excluded in the manufacturers submission, produced a relative reduction in all-cause mortality of 59%, which was not statistically significant. All included studies showed a statistically significant difference in the risk of recurrence or death from any cause (disease-free survival), favouring trastuzumab. There was a statistically significant increase in the relative risk of a serious adverse event in women treated with 3-weekly cycles of trastuzumab, with no excess toxicity in the study evaluating weekly cycles. Estimates of cost-effectiveness provided by the manufacturer were based on data from the HERA trial using the 3-weekly regimen of trastuzumab. The economic model was a state-transition model that compared the lifetime impact of adding 1 year of trastuzumab therapy to standard care with standard care alone. The initial cost-effectiveness estimate was 5687 pounds per additional quality-adjusted life-year (QALY) gained, rising to a maximum of 8689 pounds upon one-way sensitivity analysis. The base-case estimate of cost-effectiveness was subsequently revised by the manufacturer, resulting in an estimated incremental cost per additional QALY gained of 2387 pounds. A number of assumptions behind the manufacturers model may be optimistic and could mean that the incremental costs per QALY gained were underestimated. Additional analysis carried out by the evidence review group concluded that the incremental cost-effectiveness ratio (ICER) is expected to be around 20,000 pounds to 30,000 pounds. The addition of potential long-term cardiac events could push the ICER above 30,000 pounds, although there is no long-term evidence to date surrounding this issue. In addition, the small study excluded from the manufacturers submission raises the possibility of an equally effective but shorter regimen, incurring lower cost and toxicity and with greater patient convenience. The guidance issued by NICE in June 2006 as a result of the STA states that trastuzumab, given at 3-week intervals for 1 year or until disease recurrence, is recommended as a treatment option for women with early-stage HER2-positive breast cancer following surgery, chemotherapy and radiotherapy.

Statin therapy in rheumatoid arthritis: a cost-effectiveness and value-of-information analysis.

AbstractBackground: HMG-CoA reductase inhibitors (statins) are potentially excellent candidate agents for patients with rheumatoid arthritis (RA). They reduce both cardiovascular risks and RA disease activity. Objective: To evaluate the potential long-term effects of statin therapy among patients with RA, and to determine their associated cost effectiveness by incorporating both the cardiovascular and the anti-rheumatic benefits. Methods: A Markov decision-analytic model was developed to simulate cardiovascular and RA disease profiles over time. The impact of statin therapy was estimated by adjusting the risk of coronary heart disease (CHD) events and changes in the RA Disease Activity Score (DAS28), based on the results of a randomized trial. The benefits (QALYs) and costs (in year 2005 values) were evaluated from a US payer perspective. A full uncertainty analysis, including a value-of-information (VOI) analysis, was undertaken to evaluate the importance of individual parameters. Results: Using a 10-year time horizon, the additional cost and QALYs of statin therapy were estimated to be