Exhaled nitric oxide in the diagnosis of asthma in adults: a systematic review.

OBJECTIVES: To identify and synthesize evidence on the diagnostic accuracy of FE NO for asthma in adults. MATERIALS AND METHODS: Systematic searches (nine key biomedical databases and trial registers) were carried out on November 2014. Records were included if they recruited patients with the symptoms of asthma; used a single set of inclusion criteria; measured FE NO50 in accordance with American Thoracic Society guidelines, 2005 (off-line excluded); reported/allowed calculation of true-positive, true-negative, false-positive and false-negative patients as classified against any reference standard. Study quality was assessed using QUADAS II. Meta-analysis was planned where clinical study heterogeneity allowed. Rule-in and rule-out uses of FE NO were considered. RESULTS: A total of 4861 records were identified originally and 1312 in an update. Twenty-seven studies were included. Heterogeneity precluded meta-analysis. Results varied even within subgroups of studies. Cut-off values for the best sum of sensitivity and specificity varied from 12 to 55 p.p.b., but did not produce high accuracy. 100% sensitivity or 100% specificity was reported by some studies indicating potential use as a rule-in or rule-out strategy. CONCLUSIONS AND CLINICAL RELEVANCE: FE NO50 had variable diagnostic accuracy even within subgroups of studies with similar characteristics. Diagnostic accuracy, optimal cut-off values and best position for FE NO50 within a pathway remain poorly evidenced.

Colistimethate sodium powder and tobramycin powder for inhalation for the treatment of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis: systematic review and economic model.

BACKGROUND: Cystic fibrosis (CF) is an inherited condition characterised by the abnormal transport of chloride ions across transporting epithelia. This leads to the production of thick sticky mucus in the lungs, pancreas, liver, intestine and reproductive tract, and an increase in the salt content in sweat. Among other problems, people with CF experience recurrent respiratory infections and have difficulties digesting food. CF affects over 9000 individuals in the UK. CF shortens life expectancy and adversely affects quality of life. In 2010, CF was recorded as the cause of 103 deaths in England and Wales. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of colistimethate sodium dry powder for inhalation (DPI) (Colobreathe(®), Forest Laboratories) and tobramycin DPI (TOBI Podhaler(®), Novartis Pharmaceuticals) for the treatment of Pseudomonas aeruginosa lung infection in CF. DATA SOURCES: Electronic databases were searched in February and March 2011 [MEDLINE, MEDLINE In-Process & Other Non-Indexed citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Conference Proceedings Citation Index (CPCI) and Bioscience Information Service (BIOSIS) Previews]. Relevant databases were searched for ongoing and unpublished studies, and bibliographies of relevant systematic reviews and the manufacturers' submissions were also hand-searched. REVIEW METHODS: A systematic review of the clinical effectiveness and cost-effectiveness of colistimethate sodium DPI and tobramycin DPI for the treatment of chronic P. aeruginosa lung infection in CF was conducted. Existing economic evidence within the literature was reviewed and a de novo health economic model was also developed. RESULTS: Three randomised controlled trials (RCTs) were included in the clinical effectiveness review. Both colistimethate sodium DPI and tobramycin DPI were reported to be non-inferior to nebulised tobramycin for the outcome forced expiratory volume in first second percentage predicted (FEV1%). It was not possible to draw any firm conclusions as to the relative efficacy of colistimethate sodium DPI compared with tobramycin DPI. The economic analysis suggests that colistimethate sodium DPI produces fewer quality-adjusted life-years (QALYs) than nebulised tobramycin. Given the incremental discounted lifetime cost of tobramycin DPI compared with nebulised tobramycin, it highly unlikely that tobramycin DPI has an incremental cost-effectiveness ratio that is better than £30,000 per QALY gained. LIMITATION: The uncertainty surrounding the short-term evidence base inevitably results in uncertainty surrounding the long-term clinical effectiveness and cost-effectiveness of colistimethate sodium DPI. CONCLUSIONS: Both DPI formulations have been shown to be non-inferior to nebulised tobramycin as measured by FEV1%. The results of these trials should be interpreted with caution owing to the means by which the results were analysed, the length of follow-up, and concerns about the ability of FEV1% to accurately represent changes in lung health. Although the increase in QALYs is expected to be lower with colistimethate sodium DPI than with nebulised tobramycin, a price for this intervention had not been agreed at the time of the assessment. Depending on the price of colistimethate sodium DPI, this results either in a situation whereby colistimethate sodium DPI is dominated by nebulised tobramycin or in one whereby the incremental cost-effectiveness of nebulised tobramycin compared with colistimethate sodium DPI is in the range of £24,000-277,000 per QALY gained. The economic analysis also suggests that, given its price, it is unlikely that tobramycin DPI has a cost-effectiveness ratio of < £30,000 per QALY gained when compared with nebulised tobramycin. A RCT to assess the longer-term (≥ 12 months) efficacy of colistimethate sodium DPI and tobramycin DPI in comparison with nebulised treatments would be beneficial. Such a study should include the direct assessment of HRQoL using a relevant preference-based instrument. Future studies should ensure that the European Medicines Agency guidelines are adhered to. In addition, high-quality research concerning the relationship between forced expiratory volume in first second % (FEV1%) predicted or other measures of lung function and survival/health-related quality of life (HRQoL) would be useful. STUDY REGISTRATION: PROSPERO CRD42011001350. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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.

Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication.

BACKGROUND: A systematic review and network meta-analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD). METHODS: MEDLINE, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings, BIOSIS, National Research Register and MetaRegister databases were searched. Eligible studies were randomized controlled trials (RCTs) and published systematic reviews of patients with intermittent claudication due to PAD and whose symptoms persisted despite a period of conservative management. Study selection was conducted by one reviewer with involvement from a clinician. Data were extracted by one reviewer with no blinding to authors or journal, and checked by a second reviewer. Outcome measures were maximum walking distance (MWD) and pain-free walking distance (PFWD). RESULTS: The review identified 1876 citations; 26 RCTs met the inclusion criteria for the systematic review. Eleven trials provided data relevant for the meta-analysis. Naftidrofuryl oxalate was ranked first for both MWD and PFWD (probability of 0·947 and 0·987, respectively, of being the best treatment) followed by cilostazol and pentoxifylline. For naftidrofuryl oxalate, cilostazol and pentoxifylline, MWD increased by 60 (95 per cent credible interval 20 to 114) per cent, 25 (11 to 40) per cent and 11 (-1 to 24) per cent respectively relative to placebo, and PFWD increased by 49, 13 and 9 per cent. CONCLUSION: Naftidrofuryl oxalate and cilostazol are both effective treatments for claudication; naftidrofuryl oxalate is likely to be the most effective, with minimal serious adverse events.

A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. OBJECTIVE: To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. DATA SOURCE: Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). REVIEW METHODS: Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. RESULTS: Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs). CONCLUSIONS: Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

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.

Diagnostic management strategies for adults and children with minor head injury: a systematic review and an economic evaluation.

BACKGROUND: Patients with minor head injury [Glasgow Coma Scale (GCS) score 13-15] have a small but important risk of intracranial injury (ICI) that requires early identification and neurosurgical treatment. Diagnostic assessment can use either a clinical decision rule or unstructured assessment of individual clinical features to identify those who are at risk of ICI and in need of computerised tomography (CT) scanning and/or hospital admission. Selective use of CT investigations helps minimise unnecessary radiation exposure and resource use, but can lead to missed opportunities to provide early treatment for ICI. OBJECTIVES: To determine the diagnostic accuracy of decision rules, individual clinical characteristics, skull radiography and biomarkers, and the clinical effectiveness and cost-effectiveness of diagnostic management strategies for minor head injury (MHI). DATA SOURCES: Several electronic databases [including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE and The Cochrane Library] were searched from inception to April 2009 (updated searches to March 2010 were conducted on the MEDLINE databases only). Searches were supplemented by hand-searching relevant articles (including citation searching) and contacting experts in the field. For each of the systematic reviews the following studies were included (1) cohort studies of patients with MHI in which a clinical decision rule or individual clinical characteristics (including biomarkers and skull radiography) were compared with a reference standard test for ICI or need for neurosurgical intervention and (2) controlled trials comparing alternative management strategies for MHI. REVIEW METHODS: Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool (for the assessment of diagnostic accuracy) or criteria recommended by the Effective Practice and Organisation of Care Review Group (for the assessment of management practices). Where sufficient data existed, a meta-analysis was undertaken to generate pooled estimates of diagnostic parameters. A decision-analysis model was developed using Simul8 2008 Professional software (Simul8 Corporation, Boston, MA, USA) to estimate the costs and quality-adjusted life-years (QALYs) accrued by management strategies for MHI. The model took a lifetime horizon and NHS perspective. Estimates of the benefits of early treatment, harm of radiation exposure and long-term costs were obtained through literature reviews. Initial analysis was deterministic, but probabilistic sensitivity analysis was also performed. Secondary analyses were undertaken to explore the trade-off between sensitivity and specificity in diagnostic strategies and to determine the cost-effectiveness of scenarios involving hospital admission. RESULTS: The literature searches identified 8003 citations. Of these, 93 full-text papers were included for the assessment of diagnostic accuracy and one for the assessment of management practices. The quality of studies and reporting was generally poor. The Canadian CT Head Rule (CCHR) was the most widely validated adult rule, with sensitivity of 99-100% and 80-100% for neurosurgical and any ICI, respectively (high- or medium-risk criteria), and specificity of 39-51%. Rules for children had high sensitivity and acceptable specificity in derivation cohorts, but limited validation. Depressed, basal or radiological skull fracture and post-traumatic seizure (PTS) [positive likelihood ratio (PLR) > 10]; focal neurological deficit, persistent vomiting, decrease in GCS and previous neurosurgery (PLR 5-10); and fall from a height, coagulopathy, chronic alcohol use, age > 60 years, pedestrian motor vehicle accident (MVA), any seizure, undefined vomiting, amnesia, GCS < 14 and GCS < 15 (PLR 2-5) increased the likelihood of ICI in adults. Depressed or basal skull fracture and focal neurological deficit (PLR > 10), coagulopathy, PTS and previous neurosurgery (PLR 5-10), visual symptoms, bicycle and pedestrian MVA, any seizure, loss of consciousness, vomiting, severe or persistent headache, amnesia, GCS < 14, GCS < 15, intoxication and radiological skull fracture (PLR 2-5) increased the likelihood of ICI in children. S100 calcium-binding protein B had pooled sensitivity of 96.8% [95% highest-density region (HDR) 93.8% to 98.6%] and specificity of 42.5% (95% HDR 31.0% to 54.2%). The only controlled trial showed that early CT and discharge is cheaper and at least as effective as hospital admission. Economic analysis showed that selective CT use dominated 'CT all' and 'discharge all' strategies. The optimal strategies were the CCHR (adults) and the CHALICE (Children's Head injury Algorithm for the prediction of Important Clinical Events) or NEXUS II (National Emergency X-Radiography Utilization Study II) rule (children). The sensitivity and specificity of the CCHR (99% and 47%, respectively) represented an appropriate trade-off of these parameters. Hospital admission dominated discharge home for patients with non-neurosurgical injury, but cost £39 M per QALY for clinically normal patients with a normal CT. CONCLUSIONS: The CCHR is widely validated and cost-effective for adults. Decision rules for children appear cost-effective, but need further validation. Hospital admission is cost-effective for patients with abnormal, but not normal, CT. The main research priorities are to (1) validate decision rules for children; (2) determine the prognosis and treatment benefit for non-neurosurgical injuries; (3) evaluate the use of S100B alongside a validated decision rule; (4) evaluate the diagnosis and outcomes of anticoagulated patients with MHI; and (5) evaluate the implementation of guidelines, clinical decision rules and diagnostic strategies. Formal expected value of sample information analysis would be recommended to appraise the cost-effectiveness of future studies. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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.

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.

Cost-effectiveness of MRI and PET imaging for the evaluation of axillary lymph node metastases in early stage breast cancer.

BACKGROUND: UK guidelines for breast cancer recommend axillary nodal assessment via surgical methods such as sentinel lymph node biopsy (SLNB). However, these procedures are associated with adverse effects such as lymphoedema. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are non-invasive imaging techniques. The aim of this study is to evaluate the cost-effectiveness of MRI and PET compared with SLNB for assessment of axillary lymph node metastases in newly-diagnosed early stage breast cancer patients in the UK. METHODS: An individual patient discrete-event simulation model was developed in SIMUL8(®) to estimate the lifetime costs and benefits of replacing SLNB with MRI or PET, or adding MRI or PET before SLNB. Effectiveness outcomes were derived from a recent systematic review; patient utilities and resource use data were sourced from the literature. RESULTS: Based on our analysis the baseline SLNB strategy is dominated by the strategies of replacing SLNB with either MRI or PET. The strategy of replacing SLNB with MRI has the highest total quality-adjusted life years (QALYs) and lowest total costs. However, clinical evidence for MRI is based on a limited number of small studies and replacing SLNB with MRI or PET leads to more false-positive and false-negative cases. The strategy of adding MRI before SLNB is cost-effective, but subject to greater uncertainty. CONCLUSIONS: Based on this analysis the most cost-effective strategy is to replace SLNB with MRI. However, further large studies using up-to-date techniques are required to obtain more accurate data on the sensitivity and specificity of MRI.