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+{"file": "ukhta1902_NBK269043/s2.nxml", "text": "The question addressed by this health technology assessment is as set out in the final scope published by NICE and reproduced here for reader convenience.\nA protocol was developed a priori by the authors to address the decision problem. The aspects of this involving systematic review were registered on the PROSPERO website (registration number CRD42012002889).\nThe methods used to address specific aspects of the decision problem are detailed at the beginning of each of the relevant chapters that follow.\nDecision question\nAre the RD-100i OSNA system and any alternative technologies identified during scoping clinically effective and cost-effective if used in the NHS in England?\nPopulation\nIndividuals with invasive breast cancer who undergo a SLNB.\nIntervention\nThe RD-100i OSNA system using a whole-node sample.\nThe RD-100i OSNA system using a half-node sample with postoperative histopathology confirmation.\nAlternative diagnostic technologies\nThe Metasin test using a whole-node sample (intraoperative in-house molecular test developed at Princess Alexandra Hospital, Harlow, Essex).\nThe Metasin test using a half-node sample with postoperative histopathology confirmation.\nComparators\nPostoperative standard histopathology alone.\nHealth-care setting\nSecondary and tertiary care settings.\nHealth outcomes\nClinical considerations\nThe intermediate measures for consideration include:\ndiagnostic test accuracy (DTA)\ntest failure rate\ndiscordant test results\ntime to test result\nduration of anaesthesia.\nThe clinical outcomes for consideration include:\npatient anxiety associated with waiting time for results and not knowing the extent of surgery before the operation\nthe number of repeat operations (except for re-excision of positive margins)\ntime in operating theatre\ntime to start of and nature of adjuvant therapy\nmorbidity and mortality from biopsies, axillary dissections, first and second operations and treatment of cancer\nadverse events from false test results including patient distress and sequelae.\nData on these outcomes are likely to be used along with clinical utility scores to estimate quality-adjusted life-years (QALYs).\nCost considerations\nThe cost analysis will be based on the UK NHS setting and will comprise both NHS and Personal Social Services costs.\nThe costs for consideration include:\nthe costs of equipment, any additional tests (pre-screening), reagents and consumables\nstaff and staff training costs\nequipment maintenance costs\ncosts associated with surgeon time and the management of operating theatre time\nmedical costs arising from ongoing care following test results, including those associated with surgery, time spent in hospital and treatment of cancer\nmedical costs arising from adverse events, including those associated with biopsies, surgery, cancer treatment and false test results.\nThe cost of the hardware for the RD-100i OSNA system is approximately \u00a370,000 [excluding value-added tax (VAT)] The cost of consumables is approximately \u00a3150\u2013250 per patient (excluding VAT). This consumable cost is dependent on the number of tests performed per theatre day and the number of patient samples tested. The maintenance cost is \u00a36180 per annum (excluding VAT) following the expiry of the 1-year warranty.", "pairs": [], "interleaved": []}
+{"file": "ukhta1902_NBK269043/g2.nxml", "text": "axillary lymph node\naxillary lymph node dissection\nBreast Complete Lymphadenectomy OSNA Study for Enhanced Review-I\nConformit\u00e9e Europ\u00e9enne\nconfidence interval\ncytokeratin-19\ncrossing point\nductal carcinoma in situ\ndiscrete event simulation\ndeoxyribonucleic acid\ndiagnostic test accuracy\nEuropean Quality of Life-5 Dimensions\nEvidence Review Group\nfine-needle aspiration cytology\nHealth Economic Evaluations Database\nhazard ratio\nHealthcare Research Group\nhierarchical summary receiver operating characteristic\nincremental cost-effectiveness ratio\nInternational Clinical Trials Registry Platform\nisolated tumour cell\nlymph node\nmultidisciplinary team\nmessenger ribonucleic acid\nNational Institute for Health and Care Excellence\nnegative predictive value\none-step nucleic acid amplification\npositive predictive value\nquality-adjusted life-year\nquantitative reverse transcriptase-polymerase chain reaction\nQuality Assessment of Diagnostic Accuracy Studies\nribonucleic acid\nSchool of Health and Related Research\nstandard deviation\nstandard error\nsentinel lymph node\nsentinel lymph node biopsy\nsummary receiver operating characteristic\nStandards for the Reporting of Diagnostic Accuracy Studies\ntissue allocation bias\ntumour, node, metastasis\nvalue added tax\nWorld Health Organization\nYork Health Economics Consortium\nNote\nThis monograph is based on the Technology Assessment Report produced for the National Institute for Health and Care Excellence (NICE). The full report contained a considerable number of data that were deemed academic-in-confidence. The full report was used by the Appraisal Committee at NICE in their deliberations. The full report with each piece of academic-in-confidence information (or data) removed and replaced by the statement \u2018academic-in-confidence information has been removed\u2019 is available on the NICE website: www.nice.org.uk.\nThe present monograph presents as full a version of the report as possible while retaining readability, but some sections, sentences, tables and figures have been removed. Readers should bear in mind that the discussion, conclusions and implications for practice and research are all based on the data considered in the original full NICE report.", "pairs": [], "interleaved": []}
+{"file": "ukhta1902_NBK269043/ack1.nxml", "text": "We would like to thank Katie Cooper, Research Fellow in Health Economics, ScHARR.\nWe would also like to acknowledge Sue Whiffin and Jenny Lowe for their administrative support throughout the project.\nContributions of authors\nNicola Huxley developed the short-term model and adapted the long-term model, executed the economic model and wrote the sections on the design and results of the economic model.\nTracey Jones-Hughes assessed abstracts and titles for inclusion, led the systematic review of clinical effectiveness and contributed to the writing and editing of the report.\nHelen Coelho assessed abstracts and titles for inclusion and contributed to the writing and editing of the report.\nTristan Snowsill performed the statistical analysis and contributed to the writing of the report.\nChris Cooper designed and carried out the literature searches for the systematic reviews and identification of model parameters and contributed to the writing and editing of the report.\nYang Meng co-authored the original long-term economic model, advised on its adaptation to the analysis and contributed to writing the report.\nChris Hyde developed the protocol and contributed to the systematic review, design of the model and the writing and editing of the report. He is the director of the Technology Assessment Review Group at the Peninsula Technology Assessment Group (PenTAG).\nRub\u00e9n M\u00fajica-Mota contributed to the development of the protocol, led the systematic review of economic evaluations, contributed to the design of the analysis and writing and editing of the report and was the overall lead for the project and final report and guarantor of the report.\nDisclaimers\nThis report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health.", "pairs": [], "interleaved": []}
+{"file": "ukhta1902_NBK269043/s6.nxml", "text": "Implications for service provision\nThe OSNA and Metasin tests may provide some advantages over histopathology. They are automated and standardised, with the capacity to be used intraoperatively. However, information gained by histology, such as the location of metastatic foci and morphological evaluation, is not provided by these intraoperative tests. OSNA displays a higher rate of false positives, possibly because of contamination from epithelial cells. In contrast, false negatives may occur when the breast cancer does not express CK19 protein.\n(Academic-in-confidence information has been removed.)\nIt is not clear that the adoption of OSNA or Metasin will bring significant benefits to patients and cost-savings to the NHS. There remain important questions regarding whether, ultimately, the reduction in NHS costs with intraoperative testing is worth the reduction in diagnostic accuracy and potentially inferior long-term health outcomes for patients. Although the long-term uncertainty of breast cancer patient management and outcomes may determine long-term patient benefits, thus limiting the effects of the reduced diagnostic accuracy of the intraoperative tests on survival and quality of life, it is likely that a decision-maker would err on the side of caution and wait for more evidence before abandoning the current standard, postoperative histopathology. Some centres may not feel at ease performing ALND without the information that is currently available at MDT meetings through postoperative histopathology. Ultimately, in view of the current uncertainty in the evidence base on the benefits of performing ALND and the impact of this uncertainty on clinicians\u2019 views, there is a possibility that intraoperative testing for SLNs will not be routine practice in the future.\nSuggested research priorities\nThe uncertainty in decision-making because of a lack of data on, and variation in, available estimates of diagnostic accuracy and a lack of data on short-term implications of diagnostic approaches and long-term patient management may be reduced by undertaking further research. Priority should be placed on documenting the performance of intraoperative tests under different protocols. There is limited information about the performance of such tests under routine established practice and many of the existing studies are likely to apply to an early experience with these technologies. Peer-reviewed and formally published research on Metasin is also essential as the presumed low cost of this test makes it a potentially attractive option for the NHS.\nGreater clarity on the true costs of the alternative tests, and the variation in resource utilisation at the level of the patient, would help to identify the significance and the distribution of costs and benefits of intraoperative diagnosis. Observational studies should be conducted to verify and quantify the hypothesised effects of introducing intraoperative SLNB, namely a reduction in the number of operations and costs to hospitals and the amelioration of anxiety and its impact on patients\u2019 and their families\u2019 quality of life by discarding postoperative diagnosis and second operations. Although much uncertainty is likely to remain over the magnitude of the long-term benefits of increased diagnostic accuracy, a natural target for great returns on investment in research may be found in documenting what the impact on patient-reported outcomes is of uncertainty associated with a delayed diagnosis and a second possible operation. Indeed, we may expect greater prominence of this aspect of the decision-making problem in populations with a greater prevalence of node-positive SLNs.\nHowever, improving on the accuracy of estimates for OSNA in particular and overcoming concerns about TAB and the validity of currently available reference standards may be challenging. A test\u2013treat randomised trial may be the only way to truly resolve whether the introduction of intraoperative testing in SLNB would be effective and thus cost-effective. The outcome would need to be the locoregional recurrence rate or even survival to capture the trade-off between the potential short-term gains associated with a single operation for achieving ALND and the longer-term disbenefits arising from the occurrence of false-negative and false-positive cases with intraoperative testing.\nAlso, a strong assumption in this report is that ALND is the usual best treatment if micro- and macrometastases, or their equivalents, are identified in a SLNB. Evidence on this is evolving and needs to be followed closely as it could impact on decision-making around intraoperative testing in SLNB in the future.", "pairs": [], "interleaved": []}
+{"file": "ukhta1902_NBK269043/abs2.nxml", "text": "Background\nOne of the key steps in the management of breast cancer is determining if there is spread to the axillary lymph nodes (ALNs) from the main (primary) tumour.\nSentinel lymph node biopsy (SLNB) is first carried out at the same time as removal of the main tumour to determine if there are regional metastases in the sentinel lymph nodes (SLNs), the first ALNs into which the breast drains lymph. If there are any more than isolated tumour cells in the SLNs, complete axillary lymph node dissection (ALND) is required because of the possibility that tumour cells have spread beyond the SLNs into the other ALNs.\nWhether the SLNB is positive or not is usually determined by histopathology \u2013 examining slides under a microscope \u2013 after the operation to remove the primary tumour, and so there is a delay before an ALND is performed, if required. If positivity of the SLNB could be established during the operation, intraoperatively, ALND could be performed without delay, with potential benefits for the patient and the health service.\nOne-step nucleic acid amplification (OSNA) (Sysmex, Norderstedt, Germany) and Metasin (Cellular Pathology, Princess Alexandra Hospital NHS Trust, Harlow, Essex, UK) are two types of test that claim to be able to accurately diagnose regional metastases in the SLNs sufficiently quickly to be used intraoperatively. OSNA is an automated molecular test in which genetic material (messenger ribonucleic acid, mRNA) is amplified and the presence of the cytokeratin-19 (CK19) gene is detected. OSNA does not require the mRNA to be extracted from the tissue and purified before being analysed. Minimal details are available for the Metasin test, which detects the presence of CK19 and mammaglobin. However, for the Metasin test it appears that ribonucleic acid (RNA) must be extracted from tissue, purified and quantified before nucleic acid amplification and analysis.\nThe OSNA and Metasin tests could be used as a replacement for postoperative histopathology or as an adjunct to it. If used as a replacement all of each SLN would be used in either the OSNA test or the Metasin test intraoperatively; if used as an adjunct, half of each node would be used in either the OSNA test or the Metasin test and half would be used for histopathology if the OSNA or Metasin test result was negative.\nTissue allocation bias (TAB) is a major challenge when evaluating OSNA and Metasin, particularly their accuracy. The SLNs are divided between the test of interest (OSNA or Metasin) and the test with which OSNA or Metasin is being compared (usually histopathology) and therefore tumour cells may be present in only one of the sections. Apparent errors in identifying metastases may therefore not be the fault of the test but rather a problem with sampling.\nObjective\nTo evaluate the clinical effectiveness and cost-effectiveness of OSNA and Metasin, if used in the NHS in England, for the intraoperative analysis of metastases in SLNs of breast cancer patients.\nMethods\nThe assessment comprises a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of data supplied by the manufacturer and a de novo economic analysis.\nClinical effectiveness systematic review\nA systematic review was conducted to summarise the evidence on the clinical effectiveness of RD-100i (OSNA) and Metasin for the intraoperative analysis of breast cancer metastases in SLNs. The search strategy focused on the interventions specifically applied to lymph node diagnosis.\nThe following bibliographic databases were searched in this review: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE (all via Ovid), Web of Science (including conference proceedings, via ISI), The Cochrane Library (all) and the NHS Economic Evaluations Database (EED) (via The Cochrane Collaboration). The searches did not use any form of limit (e.g. date).\nThe following trials registries were also searched: ClinicalTrials.gov, Current Controlled Trials, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the European Union Clinical Trials Register. The Google search engine (Google Inc., Menlo Park, CA, USA) was also used to identify grey literature and conference publications. Items included after full-text screening were forward citation chased using Web of Science (Thompson Reuters).\nCritical appraisal was performed using the Cochrane risk of bias tool and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Results were summarised in tables and text, stratified by level of data (patient or node), node analysed (sentinel or axillary) and correction for TAB.\nCost-effectiveness systematic review\nIn addition to the electronic sources searched for the clinical effectiveness review, EconLit and the bibliographies of relevant studies were searched for cost, cost-effectiveness and cost\u2013utility studies of intraoperative testing options for metastatic disease in early breast cancer.\nPeninsula Technology Assessment Group cost-effectiveness analysis\nThe Peninsula Technology Assessment Group (PenTAG) model was split into two sections: the diagnostic pathway and the management pathway.\nThe diagnostic pathway was a decision tree built to represent the diagnosis of regional metastases in the SLNs. Three pathways were examined: current practice histopathology (the \u2018gold standard\u2019), replacement testing of the full node by intraoperative testing and half-node intraoperative testing followed by histopathology on the other half node.\nIn the diagnostic pathway, patients who were diagnosed with SLN metastases received ALND. For those diagnosed intraoperatively this occurred during the same surgery as their SLNB; for those diagnosed by histopathology this occurred during follow-up surgery.\nDiagnostic accuracy was taken from the clinical effectiveness systematic review. For OSNA, studies were split into those that included adjustment for TAB and those that did not include adjustment for TAB.\nPatients incurred costs depending on their diagnostic strategy, their surgery, any additional hospital stay and the occurrence of adverse events. The intraoperative test costs (OSNA and Metasin) were derived from information provided by the technology sponsors. Costs for histopathology were taken from a previous study based on data from the Queen Alexandra Hospital in Portsmouth. The costs of surgery were obtained from NHS reference costs and from a previous microcosting study (York Health Economics Consortium costs).\nShort-term disutility for patients waiting for results or undergoing a second operation was investigated.\nThe management pathway was concerned with lifetime results and used an updated version of a previously published discrete event simulation model that followed individual patients through a series of health states, calculating their accrued costs and quality-adjusted life-years (QALYs) according to their different outcomes in the diagnostic pathway and, consequently, management pathway. The sum of the short- and long-term costs and QALYs gave the overall lifetime costs and QALYs.\nMost parameters for the management model were taken from the original report of the model published in 2011, with costs updated when new reports were found, and reflating all costs to 2010 prices.\nSensitivity analysis adopted the range of sensitivity and specificity values identified by the clinical effectiveness systematic review. In addition, the prevalence of SLN metastases was varied from 20% (from the clinical effectiveness systematic review) to 10% and 40%. Costs of tests and surgeries and management costs were varied by plus or minus 10%.\nResults\nClinical effectiveness systematic review\nSeventeen studies were included that investigated the performance, particularly test accuracy, of either OSNA or Metasin for detecting metastases in the SLNs or ALNs of breast cancer patients. Two of the studies reported on Metasin; however, both were unpublished and reported in draft form. The remaining 15 studies reported on OSNA, with one study reported in two papers.\nThe majority of studies were considered to be at low risk of bias, although many were considered to have an unclear risk of bias with regard to their method of patient recruitment and patient characteristics.\nNo data were found for clinical outcomes such as patient anxiety and number of repeat operations. Only one study provided evidence on time spent in the operating theatre.\nIn accuracy studies the reference standard (i.e. histopathology), although plausible, may be performed with varying levels of analysis and, as such, it may not be a true indicator of the target condition.\nThe main issue within the included studies has been TAB. Some studies have dealt with this by reanalysing both the histopathology and the molecular samples or by choosing to reanalyse just one technology.\nIt should also be noted that more than one SLN may be removed from a patient, which means that results for a study may be presented by patient or by individual node or by both. There is also a potential conflict of interest as one of the two unpublished Metasin studies was performed at the institution in which the technology was developed and the majority of the OSNA studies were financially supported by Sysmex, the company that manufactures OSNA.\nAll accuracy studies implicitly assumed that the reference standard, histopathology, is a true measure of the target disorder.\nThe pooled OSNA patient node status sensitivity was 84.5% [95% confidence interval (CI) 74.7% to 91.0%] and its specificity was 91.8% (95% CI 87.8% to 94.6%), based on five available studies including a total of 991 subjects. As only two studies reported on Metasin, a meta-analysis was not performed. As these data were taken from draft papers, before peer review, the results, which indicate an increased sensitivity and specificity relative to OSNA results, must be used with caution.\nSome studies adjusted for TAB, generally taking a conservative approach by excluding affected samples. This does improve the test accuracy, increasing sensitivity from 84.5% to 91.3% (95% CI 83.6% to 95.6%, with the SLN as the unit of analysis) and increasing specificity from 91.8% to 94.2% (95% CI 91.2% to 96.2%), based on three reports and 453 subjects.\nWith regard to the time taken to perform OSNA, there was a lack of detail in the studies explaining which aspects of the procedure were monitored. However, the time reported ranged from <\u200930 minutes to 39.6 minutes for one node. This increases by approximately 5\u201310 minutes per additional node analysed.\nCost-effectiveness systematic review\nTwo studies of the diagnostic phase were identified by the searches. One was a study of OSNA conducted in one centre in Spain, which did not measure benefits to patients. The other study evaluated a diagnostic testing option in the UK that has been withdrawn from the market (GeneSearch BLN assay; Veridex, Warren, NJ, USA) and is therefore no longer relevant for the present evaluation. Therefore, a de novo analysis was justified.\nIndependent Evidence Review Group assessment\nIn the base case, short-term results show that, in general, half-node OSNA was not cost-effective in terms of cost per patient correctly diagnosed, cost per node-positive case detected or cost per node-negative case detected. In all cases in which half-node OSNA was dominated or extendedly dominated, the cost per additional diagnostic yield of histopathology compared with full-node OSNA was <\u2009\u00a317,000. These results were insensitive to setting the sensitivity and specificity of OSNA equal to TAB-adjusted values.\nLong-term results revealed that histopathology resulted in more QALYs at a lower cost per QALY than half-node OSNA when both were compared with full-node OSNA. The incremental cost-effectiveness ratio (ICER) of histopathology relative to full-node OSNA was <\u2009\u00a35000 per QALY gained, for both costing strategies. When diagnostic test accuracy parameter values in the model were adjusted for TAB, half-node OSNA remained extendedly dominated, except for TAB-adjusted diagnostic test accuracy values reported by Snook et al. using NHS reference costs, which resulted in an incremental cost of \u00a38063 per QALY gained for half-node OSNA relative to full-node OSNA (Snook KL, Layer GT, Jackson PA, de Vries CS, Shousha S, Sinnett HD, et al. Multicentre evaluation of intraoperative molecular analysis of sentinel lymph nodes in breast carcinoma. Br J Surg 2011;98:527\u201335). Using TAB-adjusted values reported by Snook et al., histopathology compared with full-node OSNA had ICERs of <\u2009\u00a310,000 per QALY gained using NHS reference costs or York Health Economics Consortium costs (Snook et al. 2011). However, when values from the study by Khaddage et al. were used, full-node OSNA dominated both half-node OSNA and histopathology under both costing scenarios (Khaddage A, Berremila SA, Forest F, Clemenson A, Bouteille C, Seffert P, et al. Implementation of molecular intra-operative assessment of sentinel lymph node in breast cancer. Anticancer Res 2011;31:585\u201390).\nThe long-term ICERs for histopathology compared with full-node OSNA remained at <\u2009\u00a320,000 per QALY gained for all values of sensitivity up to 95% and the ICER was \u00a38430 per QALY gained when OSNA had 100% specificity.\nSensitivity analysis was also conducted on the effect of the prevalence of SLN metastases in the patient population. This showed that the lower the prevalence the more attractive histopathology is.\nProbabilistic analysis showed that, when comparing full-node OSNA with histopathology, the former has less than a one in three probability of being cost-effective. This result was obtained by combining all of the available accuracy estimates from the three studies that adjusted for TAB. This finding was driven by the studies of Le Fr\u00e8re-Belda et al. and Snook et al., which contributed 88% of all patients with available data (Le Fr\u00e8re-Belda MA, Bats AS, Gillaizeau F, Poulet B, Clough KB, Nos C, et al. Diagnostic performance of one-step nucleic acid amplification for intraoperative sentinel node metastasis detection in breast cancer patients. Int J Cancer 2012;130:2377\u201386; Snook et al. 2011).\nAltering individual costs and utility parameter values in both sections of the model had very little impact on overall cost-effectiveness results.\nResults for Metasin were provided on a purely illustrative basis as the only values available for the sensitivity and specificity of Metasin are unpublished and have not been peer reviewed.\nConclusions\nThe evidence base for OSNA and Metasin is restricted to studies on their test accuracy (sensitivity and specificity) relative to a reference standard of histopathology. All other conclusions are based on the predictions of a health economic model in a linked-evidence approach.\nOne-step nucleic acid amplification and Metasin appear to be effective in reducing the number of separate second ALND operations, which leads to cost-savings and benefits to patients. However, this is at the expense of diagnostic errors, both false negatives and false positives.\nOverall, the cost-effectiveness evidence on OSNA is inconclusive. The evidence on Metasin is incipient and may only be suggestive. In general, the potential long-term benefits of increased accuracy with histopathology more than compensate for its disadvantage in terms of expediency of test results, but such balance is sensitive to how different studies address the issue of TAB.\nThe available evidence suggests that full-node OSNA is not cost-effective relative to histopathology. The only study that contradicts this assertion (that by Khaddage et al. 2011) represents only 11% of the total study subjects for whom robust evidence exists.\nExploratory analyses clearly suggest that the cost-effectiveness of intraoperative testing is inversely related to the node-positive prevalence rate. Therefore, improvements in the detection of node-positive cases before the first operation for newly diagnosed breast cancer will make the cost-effectiveness of intraoperative testing less likely.\nSuggested research priorities\nDevoting resources to generating peer-reviewed published research evidence on the test accuracy of Metasin, the costs of alternative tests and the variation in resource utilisation across individual patients is warranted by current limitations in our knowledge on the value of diagnostic approaches in early breast cancer. Observational studies may seek to test and quantify empirically the claimed reductions in the numbers of operations, the anxiety experienced by patients who await test results, the quality of life lost as a result of a second operation and the costs to hospitals that are associated with the introduction of intraoperative testing in SLNB.\nA key assumption in the report is that ALND is the usual best treatment if micro- and macrometastases are identified in a SLNB. Evidence on this is evolving and needs to be followed closely as it could impact on decisions about intraoperative testing in SLNB in the future.\nStudy registration\nThis study is registered as PROSPERO CRD42012002889.\nFunding\nThe National Institute for Health Research Health Technology Assessment programme.", "pairs": [], "interleaved": []}