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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Post-analytical quality requirements


Provision of helpful reports following the NACB recommendations in Table 4 encourages good communication between laboratory and clinic, which is highly desirable to achieve best use of tumor marker tests. Clinical biochemistry laboratories should be prepared to engage more actively in the interpretation of tumor marker results, ensuring that appropriately validated reference intervals are provided (taking account of age and/or sex where relevant), and incorporating estimates of analytical and biological variation, as well as taking account of other factors specific to particular tumor markers and malignancies such as tumor marker half-lives (24) and kinetics (25). In this context it should be recognized evaluating and assessing the contribution of tumor markers to the evolving health status of the patient requires specific identification of correlated observations from defined data elements in the patient care record. Tumor marker results, together with all other observations made during patient care, can be contained in Electronic Health Records (11, 26). These data should be used to determine the “baseline” tumor marker level for individual cancer patients during periods of remission, thereby facilitating earlier diagnosis of progression. Clinical laboratory studies of each marker should explicitly identify the Electronic Health Record data elements that contain observations used in evaluating the changes in patient health status, together with contributions of laboratory measurements to either diagnosis or treatment of the individual patient. The Electronic Health Record definition has matured both nationally and internationally to a sufficient degree that these attributes can now be documented in a common fashion (26) so that patient data can be effectively related to the knowledge structures used in CDS components in health enterprise information architectures to help guide tumor marker data interpretation for the requesting practitioner (13).

Clinical issues that enhance the reliability and utility of tumor markers

As with all diagnostic tests, tumor markers are surrogate indicators that can be used clinically to increase or decrease the clinician’s suspicion that a future clinically important event, such as a new cancer, recurrence, progression, or death will or will not happen, and/or that a specific treatment will reduce that risk. Markers can be used to determine risk, screen for early cancers, establish diagnosis, estimate prognosis, predict that a specific therapy will work, or monitor for disease recurrence or progression (27). The value of tumor markers is that they permit more efficient application of therapies, which should result in applying the therapy to those patients most likely to benefit while reducing exposure to toxicities for those patients who would not benefit (28).

Tumor markers are only useful if three circumstances pertain:

  • The marker results are appropriate precisely for the required application, i.e. risk assessment, screening, diagnosis, prognosis, prediction, or post-treatment monitoring.

  • The marker results separate patients into two or more populations whose outcomes differ so strikingly that they and their caregiver would treat one group differently than another. [This consideration depends on several factors, including the endpoint in question (patients might be more willing to accept therapy for very small mortality reductions but not for similar reductions in occurrence of a new cancer), the toxicity of the therapy (patients are more likely to accept a therapy with small benefits if the toxicities are few), and the cost of the therapy.]

  • The estimate of the separation in outcomes for marker positive and negative is reliable.

These issues are inter-related. For example, studies of the prognostic value of a marker that do not consider the manner in which the study populations were treated are not helpful to the clinician trying to decide whether to apply treatment. Indeed, in breast cancer, one might conclude that HER2 over-expression is associated with a poor prognosis, a favorable prognosis, or not associated with either if one studied a patient population that had been variably treated in either the adjuvant or metastatic setting with different types of chemotherapies, different types of hormone therapies, and trastuzumab (29). These variable conclusions might be reached since HER2 is a weak or moderately unfavorable prognostic factor in patients who receive no therapy, it appears to predict weakly or moderately for resistance to chemotherapy regimens that do not contain anthracyclines or taxanes but it may predict for sensitivity to chemotherapy regimens that do have these, it appears to predict for resistance to selective estrogen receptor modulators like tamoxifen but for sensitivity to estrogen ablation strategies like aromatase inhibitors, and it is a very strong predictor of response and benefit from the anti-HER2 humanized monoclonal antibody, trastuzumab.

Furthermore, while statistical analysis is, of course, important to estimate the reliability of how likely two marker-identified groups might be different, the p-value alone does not indicate clinical utility. If a study is sufficiently powered, a small difference in outcomes of two groups separated by marker results (“positive vs. negative”) might be statistically significant. Too often an investigator will conclude that a marker is clinically useful because a derived p-value is <0.05. Rather, it is more important, for clinical utility, that one population (marker positive or negative) does extremely well while the other does very poorly, so that one group might accept the therapy of interest while the other would elect not to. In this case, it is imperative that the p-value does suggest statistical significance, but it is not the determining factor for clinical utility. Finally, a single study does not establish a scientific fact. Rather, secondary validation of the results of an interesting study in a subsequent data set is imperative, and the validation study should use the same assay, the same cut point(s), and, importantly, patient populations that are very similar.

In summary, acceptance of a tumor marker for clinical utility requires careful and thoughtful study design so that the results are meaningful in the clinical setting. Unfortunately, most tumor marker investigations have been studies of convenience, using archived samples that happen to be available (27). Such studies [Level of Evidence (LOE) III] are useful to generate hypotheses, but as in all science, without careful investigational planning and design the results cannot be accepted as fact. Indeed, LOE II studies, in which the marker is considered prospectively as a secondary objective in a clinical trial, or better yet, LOE I studies in which the marker question is the primary objective, are much more likely to yield acceptable results. In other words, it is better to ask the question and get an answer, rather than to get an answer and then ponder the question. Such evidence-based considerations are particularly important when patient lives are at stake and should be remembered whenever a tumor marker test is requested.


Table 1. NACB recommendations: Quality requirements in the pre-analytical phase


Requirements

Recommendations

Comments / specific examples

References

Analyte-related








Type of specimen

Requirements should be checked in the product information supplied with the kit. It is the laboratory’s responsibility to provide clear advice about the appropriate tube type for each test, thereby ensuring that manufacturers’ instructions are always followed.


Serum or plasma are usually (but not always) equally appropriate. Gel tubes may not be suitable for some assays.

Where feasible using primary tubes for analysis minimizes the risk of identification errors that occur when serum aliquots are prepared.

Anti-coagulating agents such as ethylene- diamine tetraacetic acid (EDTA) may interfere in some detection methods.


(15)




Standardised conditions of specimen collection and fixation are crucial for immunohistochemical analyses.

Immunohistochemical studies with tumor markers that do not define the type of specimen and fixative used definitely prejudice the value of the results.


(30)

Specimen stability

Tumor markers are generally stable, but serum or plasma should be separated from the clot and stored at 4C (short-term) or -30C (long-term) as soon as possible. For longer term storage specimens should be stored at -70C.


The stability of total and free PSA under different storage conditions is especially critical in the context of a screening programme. [See (1, 31), and Section on Prostate Cancer]


(1, 31),






Heat treatment (e.g. to deplete serum complement components or to inactivate human immunodeficiency virus (HIV) should be avoided, particularly for hCG and PSA. At high ambient temperature the potential influence of transit time on analyte results should be considered.


HCG may dissociate at elevated temperature to form its free - and -subunits.


(15)

Patient-related










Test selection

Ordering of tumor marker tests should be according to locally agreed protocols, based on established national and international guidelines.


Previous NACB recommendations for use of tumor markers in routine clinical practice and those of other international groups have previously been reviewed elsewhere (32). Updates to the NACB recommendations, are now available on the AACC website (8), and are being published in the present series of papers. Abbreviated versions of such recommendations, tailored for local practice, e.g. as by the Association of Clinical Biochemists in Ireland (33) or in user-friendly laboratory handbooks, are likely to be most effective.


(32, 33)




Although in certain circumstances tumor markers may aid in diagnosis, speculative measurement of panels of tumor markers (“fishing”) should be discouraged, with the possible exception of patients with known malignancy of unknown origin (34).

PSA should never be measured routinely in females.

CA125 should never be measured routinely in males.

CA15-3 should only be measured routinely in males with an established diagnosis of breast cancer.





Specimen schedule

The following baseline concentrations are of particular importance:

A pre-operative concentration and a nadir concentration.

A pre-treatment concentration and a nadir concentration.

A pre-follow-up concentration.


Interpretation of subsequent results is aided by knowledge of the pre-treatment “baseline” level.

(15)

Specimen timing

No strong evidence of diurnal variation for most markers, so specimens can be taken at any time of day.





(15)




Blood for PSA should be taken before any clinical manipulation of the prostate. Any measurements taken too soon should be repeated.

Prostatic biopsy, transurethral resection of the prostate, or traumatic catheterization may markedly elevate serum PSA and/or free PSA . [See (31) and Prostate Cancer Section for details of recommended delay in sampling after such intervention.]


(15, 31)




Blood for CA125 should not be taken during menstruation, which may increase the serum concentration two to three-fold. A confirmatory specimen avoiding sampling during menses should be requested.





(35)

Clinical conditions

Generally liver and renal disease as well as inflammation and infection may cause elevated tumor marker concentrations. Benign diseases of tumor marker producing tissues also frequently cause elevated concentrations.


Awareness of these caveats is essential for proper interpretation.

(1),




Renal failure is most likely to cause inappropriately elevated results for CEA and cytokeratins. For patients in this category this should be noted on the clinical report. Impaired renal clearance has also been reported to cause such results for hCG (36).


Awareness of these caveats is essential for proper interpretation.

(15)




HCG may be persistently raised in menopausal women and/or women with a high normal level.


Awareness of these caveats is essential for proper interpretation. Elevated serum and urinary hCG levels in healthy women should be investigated systematically to exclude an underlying malignant process and to avoid inappropriate surgical and medical intervention. Long-term follow-up is required as tumours may not become apparent for many months or years (37).


(37, 38)




CA125 may be mildly elevated in endometriosis and the first two trimesters of pregnancy, and markedly raised in any patient with benign (non-tumoral) ascites. Lavels >1000 kU/L have been reported in a patient with hypothyroidism and ascites (39). Careful interpretation of results for patients with these conditions is essential, and their implications should be noted on the clinical report.


Awareness of these caveats is essential for proper interpretation.

(1, 39-41)




CA125 may be markedly elevated in patients with heart failure.


Awareness of this caveat is essential for proper interpretation.

(42, 43)




CA125 may be elevated in patients with liver cirrhosis and chronic active hepatitis [35% and 10% of patients respectively in one study (44)].


Awareness of this caveat is essential for proper interpretation.

(44)




MUC-1 antigens (e.g. CA-15.3 and BR27.29) may be increased in some non-breast pathologies – both malignant (e.g. ovary, lung, myeloma) and non-malignant (e.g. dermatological conditions, colitis, benign hepatitis).


Awareness of this caveat is essential for proper interpretation.

(45)




Markedly elevated levels of CA125 may be associated with recurrent ischemic strokes in patients with metastatic cancer.


Awareness of this caveat is essential for proper interpretation.

(46)




Urinary tract infections and prostatitis may increase PSA markedly, and confirmatory specimens should be taken following successful antibiotic treatment.

Serum PSA usually falls relatively rapidly but results may take more than a month (up to 9 months in one study) to return to within normal limits.


(31, 47)




CA19.9 may be increased in common benign gynecologic diseases including endometriosis and leiomyoma.

Awareness of this caveat is essential for proper interpretation.

(48)




Cholestasis may markedly increase CA19.9 concentrations. For patients in this category this should be noted on the clinical report.


Awareness of this caveat is essential for proper interpretation.

(15)

Medication / other treatment / lifestyle

5-reductase inhibitors [Finasteride (Proscar; Propecia), Dutasteride (Avodart)] cause a median decrease in PSA concentration of ~50%. For patients in this category this should be noted on the clinical report.


Awareness of this caveat is essential for proper interpretation.

(15, 31)




Transient increases in tumor marker concentrations may occur following chemotherapy.


Awareness of this caveat is essential for proper interpretation.

(15)




Cannabis may transiently increase hCG.


Awareness of this caveat is essential for proper interpretation.

(49)




Smoking may slightly increase apparent CEA levels in some immunoassays.


Awareness of this caveat is essential for proper interpretation.

(15)

Specimen contamination

Salivary contamination can markedly increase apparent concentrations of CEA, CA19.9 and tissue polypeptide specific antigen (TPS). If contamination is suspected a repeat specimen should be requested. [Where procedures are fully automated this is unlikely to be a problem.]


Awareness of this caveat is essential for proper interpretation.

(15)
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