National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Clinical Practice: Quality requirements




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НазваниеNational Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for Use of Tumor Markers in Clinical Practice: Quality requirements
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Conclusions: Implementation of these recommendations, adapted to local practice, should encourage more optimal use of tumor markers in the clinic.


NACB QUALITY REQUIREMENTS FOR THE USE OF TUMOR MARKERS1 2

Here, further developing previous recommendations of the NACB and EGTM (1), we present quality requirements relevant to all tumor marker measurements under the following broad headings

  • Pre-analytical requirements - choice of tumor marker, specimen type, specimen timing, sample handling.

  • Analytical requirements – assay standardisation, internal and external quality control, interferences.

  • Post-analytical requirements – reference intervals, interpretation and reporting of tumor marker results.

Finally, some of the clinical issues relevant to enhance the clinical utility of tumor marker testing, both now and in the future, are briefly considered.


Pre-analytical quality requirements

Reporting of erroneous tumor marker results is more likely to cause undue alarm to patients than is the case for many other laboratory tests. As well as adhering to general pre-analytical recommendations applicable to all diagnostic tests (2) and encouraging appropriate test requesting (1, 3, 4), the laboratory must exercise extra vigilance in ensuring that correct results are reported (5). Errors reportedly occur more often in the pre-analytical than analytical phase [30-75% and 13-31% respectively as quoted in one review (6) and ten times as often in a transfusion medicine study (7)]. As for other analytes, the majority of pre-analytical errors for tumor markers will be simple specimen handling errors – e.g. inappropriate sampling handling, hemolyzed specimens, insufficient specimens, incorrect specimens and errors at data entry – and their occurrence should be minimized by adherence to good laboratory practice and assessment in an effective audit cycle. As outlined in Tables 1 and 2, there are a number of additional circumstances in which misleading results may be obtained, particularly for PSA and CA125. Implementing the NACB recommendations that are presented in the following papers and are currently available on the web (8) – in particular by discouraging inappropriate test requesting (9, 10), ensuring appropriate specimen timing and requesting confirmatory specimens when required – should reduce the risk of causing patients unwarranted distress and the likelihood of unnecessary clinical investigations.

With the advent of Electronic Health Records (EHRs), every effort should be made to link the tumor marker ordering process with pre-analytical precautions available through Clinical Decision Support (CDS) databases of (11) such as that recently made available through the American Association of Clinical Chemistry (12). These databases are in the process of standardization to produce common conventions for the reference knowledge and means of accessing and using it (13)

Analytical quality requirements


The almost universal use of automated immunoassay analysers for many commonly requested tests means that responsibility for analytical quality now rests largely with the diagnostic industry, which must meet quality requirements defined by national or international regulatory authorities [e.g. US Food and Drug Administration (FDA) regulations, European Commission In Vitro Diagnostics Directive (IVDD)]. It is nevertheless crucial for satisfactory measurement of any analyte that laboratories independently monitor their own performance carefully, both to ensure that analyzers are being used appropriately and to confirm that individual methods are performing according to specification. This is best achieved by implementation of rigorous Internal Quality Control (IQC) and participation in well-designed Proficiency Testing (PT) [External Quality Assessment (EQA)] programs (1). It is of course crucial that laboratories not only participate in such programs but also take appropriate action to investigate the cause of unsatisfactory results immediately.

NACB recommendations for both IQC and PT are presented in Table 2. Most of these are common to all analytes, but several have particular relevance to tumor markers. Specimens for both IQC and PT should always resemble clinical sera as closely as feasible. Where clinical decision points are commonly employed, it is important to ensure stable and consistent performance, and inclusion of IQC specimens at concentrations close to such decision points is highly desirable. This is especially critical when screening asymptomatic individuals, e.g. for prostate cancer using PSA (14), or where chemotherapy may be instituted on the basis of a rising tumor marker level in the absence of other scan evidence, e.g. when monitoring testicular cancer patients with α-fetoprotein (AFP) or human chorionic gonadotropin (hCG) (15). The functional sensitivity [i.e. lowest result that can be reliably reported, best defined as the concentration at which the day-to-day coefficient of variation is <20%] is also very important for certain tumor marker applications, e.g. when using prostate specific antigen (PSA) to monitor prostate cancer patients after radical prostatectomy or thyroglobulin or calcitonin to monitor patients with thyroid cancer or medullary carcinoma of the thyroid following total thyroidectomy. Similarly, by issuing specimens of the same low concentration pool repeatedly, PT schemes can provide valuable complementary information about the stability of results over time (16). Since cancer patients are often monitored using tumor markers over months or years, similar assessment of long-term assay stability is also desirable at other analyte concentrations.

Long-term monitoring presents major challenges as patients may change hospital and laboratories may change the tumor marker methods during the relevant time period. While ideally results obtained in different methods would be fully interchangeable, data from PT schemes confirm that this is not the case, with between-method coefficients of variation in excess of 20% still observed for some tumor markers (17). Major causes of observed between-method variation for these complex analytes include poor calibration, differences in the specificity of antibodies used, and differences in method design (18).

It should be possible to achieve reasonably standardized and accurate calibration, but only for those analytes for which a recognized International Standard (IS) or Reference Reagent (IRR) is both available (Table 5) and universally adopted by diagnostic manufacturers for primary calibration of their methods. Unfortunately, as yet there are no IS for any of the important CA series of tumor markers, a major gap that should be addressed urgently. Where relevant IS or IRR are available, recovery experiments undertaken by PT schemes (Table 2) provide (together with linearity and stability studies) the independent validation of consensus target values that is essential in a well-designed PT scheme. Conveniently, since PT schemes should be working towards improving between-method agreement, the same experiments also permit assessment of the correctness of calibration of individual methods and identification of those methods requiring improvement (e.g. methods over- or under-recovering the relevant IS by more than 10%). Long-term PT scheme data can also confirm the effect of successful introduction of a new IS. Data from the UK National External Quality Assessment Service (UK NEQAS) for PSA, for example, confirm that mean geometric coefficients of variation (which reflect scatter) decreased from 21.9% in 1995, before the 1st IRR was introduced, to 9.5% in 2004 (19).

The recently established IRR for isoforms of hCG (20) [developed under the auspices of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)] and PSA (21) provide additional tools for elucidating method-related differences associated with the second major cause of method-related differences, namely antibody specificity. Carefully designed experiments with the IRR for PSA and free PSA have allowed assessment of the calibration and equimolarity of assays for PSA, which are particularly critical in the context of prostate cancer screening. Similarly, experiments currently in progress with six recently established IRR for hCG isoforms should provide valuable information about what currently available methods for hCG really “measure” (20, 22), an issue of major importance for oncology applications where recognition of a broad spectrum of hCG-related molecules is recommended (23). Complementary epitope-mapping projects such as those carried out under the auspices of the International Society for Oncodevelopmental Biology and Medicine (ISOBM) may enable broad recommendations to be made regarding the most clinically appropriate antibody specificities for some tumor markers, with some progress towards this objective already having been made for hCG (23).

The results of such studies may lead to better understanding of optimal method design for the complex tumor markers, thereby addressing the third major cause of method-related differences. Differences in method design are likely to contribute both to the numerical differences in results observed, and to differences in method robustness to clinically relevant interferences, the most important of which are described in Table 3. Maintaining vigilant awareness of the potential for such interferences is very important. Ultimately, the most effective way of minimizing the risk of such interference leading to serious clinical errors is to promote regular dialogue between laboratory and clinical staff, thereby encouraging early discussion and investigation of any results that are not in accord with the clinical picture (15).

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