What is the impact of OSNA or Metasin on patient outcome?

What is the impact of OSNA or Metasin on the process of care?

What is the test accuracy of OSNA or Metasin?

The following databases will be searched for relevant studies from inception to the present:

• MEDLINE (OvidSP)

• MEDLINE In-Process Citations and Daily Update (OvidSP)

• EMBASE (OvidSP)

• Cochrane Database of Systematic Reviews (CDSR ) (Internet)

• Cochrane Central Register of Controlled Trials (CENTRAL) (Internet)

• Database of Abstracts of Reviews of Effects (DARE) (Internet)

• Health Technology Assessment Database (HTA) (Internet)

• Science Citation Index (SCI) (Web of Science)

• NIHR Health Technology Assessment Programme (Internet)

Completed and ongoing trials will be identified by searches of the following resources (up to 2011):

• NIH ClinicalTrials.gov (http://www.clinicaltrials.gov/)

• Current Controlled Trials (http://www.controlled-trials.com/)

• WHO International Clinical Trials Registry Platform (ICTRP)

(http://www.who.int/ictrp/en/)

• EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/)

The following study/publication types will be not be considered:

• Pre-clinical and animal

• Reviews, editorials, and opinion pieces

• Case reports

• Studies reporting only technical aspects of the tests

• Studies with fewer than 10 participants

Beyond this no study design will be excluded unless evidence on the intervention and outcome of interest is already available from study designs less open to bias as judged with reference to standard hierarchies of evidence

The RD-100i OSNA System ("OSNA") and Metasin are new tests to help identify whether a breast cancer has spread to the lymph nodes in the armpit (axilla). Except where there are occasional isolated cells, if there are breast cancer cells in any of these lymph nodes, all the lymph nodes in the armpit need to be removed in an operation called axillary lymph node clearance. This can be associated with later side-effects such as swelling, pain, numbness and difficulty moving the arm, and so should not be undertaken unless necessary.

Normally, in the NHS, the test to check if the breast cancer has spread to the lymph nodes in the armpit takes several days and involves cutting very thin slices of one to three key or "sentinel" lymph nodes and carefully examining them under a microscope (histopathology). This means that if breast cancer cells are found in these lymph nodes, there is a delay until this is discovered and that the axillary lymph node clearance has to be done separately from the first operation to remove the breast cancer itself.

There are claims that OSNA and Metasin can be performed sufficiently quickly, that spread to the lymph nodes can be detected during the first operation to remove the breast cancer, and that, if required, the axillary lymph node clearance can be done at the same time without delay. It is further claimed that these new tests are as accurate as examination under a microscope as well as being quicker.

Individuals with, or at risk of, invasive breast cancer who undergo a sentinel lymph node biopsy during the primary operation to excise a suspected breast cancer.

OSNA: The RD100i OSNA system is an automated molecular test that uses one-step nucleic acid amplification technology to indicate if cancer has spread to the axillary lymph nodes in people diagnosed with breast cancer. The test analyses and amplifies genetic material (mRNA) from solubilised biopsy samples of sentinel lymph node tissue and detects the presence of the Cytokeratin 19 (CK19) gene, a biological marker associated with metastatic spread breast cancer and not normally present in lymph node tissue. It is claimed that the RD 100i OSNA test will provide a result within a short time and therefore, can be used during breast surgery to determine if other lymph nodes should be removed at the same time as the initial tumour. This could avoid a second operation for the patient and enable subsequent treatments such as chemotherapy to begin earlier.

Metasin: The Metasin test is an intraoperative molecular test developed within the NHS at the Princess Alexandra Hospital in Harlow, Essex. The test has similarities to a discontinued commercial test (Veridex Genesearch BLNA assay) and uses the technique of quantitative reverse transcriptase PCR (qRT-PCR) to detect two predictive markers of metastases, CK19 and mammaglobin. Mammaglobin is expressed mainly by breast epithelial cells and high levels of mammaglobin are associated with breast cancer. A reference gene, PBGD, is used to confirm the validity of the mRNA used in the test and two other controls, positive and negative, are also included. The test uses reagents that can be purchased from Roche and Qiagen and can be used on any platform (PCR machine). This in-house test differs from the discontinued commercial test by using distinctly different and unique primer-probe combinations to detect the CK19 and mammaglobin genes. The test is reported to take 26 minutes to results after 6-10 minutes for extracting and purifying mRNA from the tissue.

Where appropriate to the study design the comparator will be standard histopathology. Again where appropriate the reference standard will be the results of standard histopathology, with careful attention to the number of sections taken and the experience of the histopathologist undertaking the examination.

Secondary and tertiary care settings

Primary outcomes

The intermediate measures for consideration include:

• Test failure rate

• Diagnostic test accuracy

• Discordant test results

• Time to test result

• Duration of anaesthesia/time in operating theatre

• Number of repeat operations (except for re-excision of positive margins)

• Time to start and nature of adjuvant therapy

The clinical outcomes for consideration include:

• Patient anxiety associated with waiting time for result and not knowing the extent of surgery prior to operation

• Adverse events from false test results including patient distress and sequelae

• Morbidity and mortality from biopsies, axillary dissections, first and second operations and treatment of cancer

No further information

Secondary outcomes

There is no differentiation between primary and secondary outcomes. See primary outcomes for all outcomes considered likely to be important

No further information

Two reviewers will independently screen titles and abstracts of all reports identified by searches and discrepancies will be discussed. Full copies of all studies deemed potentially relevant, after discussion, will be obtained and two reviewers will independently assess these for inclusion; any disagreements will be resolved by consensus or discussion with a third reviewer.

Data relating to study details, participants, intervention and comparator tests, reference standard, and outcome measures will be extracted by one reviewer, using a piloted, standard data extraction form. A second reviewer will check data extraction and any disagreements will be resolved by consensus or discussion with a third reviewer.

The methodological quality of included studies will be assessed using standard tools appropriate to the study designs being included. Thus for experimental studies, particularly RCTs, the Cochrane Collaboration quality assessment checklist will be used.

QUADAS-2 will be used for test accuracy studies, noting that amendments need to be made should comparative accuracy studies be included.

All quality assessment will be carried out independently by two reviewers. Any disagreements will be resolved by consensus. The results of the quality assessment will be used for descriptive purposes to provide an evaluation of the overall quality of the included studies and to provide a transparent method of recommendation for design of any future studies. In addition, if enough data are available from the included studies, each of the quality components will be included as explanatory variables in a meta-regression analysis to investigate the association of each of these components with study results as a way of explaining possible heterogeneity. Based on the findings of the quality assessment, recommendations will be made for the conduct of future studies.

The main method of analysis will be narrative synthesis, with conclusions based on patterns of results across all included studies clearly presented in tables. Careful account will be taken of issues of generalisability and study quality.

Where sufficient data are available, meta-analysis will be undertaken using techniques appropriate to the different types of study design. Test accuracy requires a different approach and the methods suggested by the Cochrane Collaboration will be employed

None planned

Via NICE guidance

Christopher HYDE

PenTAG

University of Exeter

Veysey Building

Salmon Pool Lane

EXETER

EX4 6BZ

christopher.hyde@pcmd.ac.uk

PenTAG, University of Exeter Medical School (UEMS)

http://sites.pcmd.ac.uk/pentag

Professor Christopher HYDE, PenTAG, UEMS
Dr Ruben MUJICA-MOTA , PenTAG, UEMS
Mr Christopher COOPER, PenTAG, UEMS
Dr Tracey JONES-HUGHES, PenTAG, UEMS
Dr Nicola HUXLEY, PenTAG, UEMS
Dr Helen COELHO, PenTAG, UEMS
Dr Martin HOYLE, PenTAG, UEMS
Dr Tristan SNOWSHILL, PenTAG, UEMS
Ms Louisa CRATHORNE, PenTAG, UEMS

01 September 2012

30 April 2013

UK Department of Health

None known

NICE

English

England

Subject indexing assigned by CRD

Breast Neoplasms; Humans; Lymphatic Metastasis; Sentinel Lymph Node Biopsy

04 September 2012

04 September 2012