Tumor markers evaluation

Pilo, A., Zucchelli, G. C., Cohen, R., Bizollon, C. A. Performance of immunoassays for CA 19-9, CA 15-3 and CA 125 tumor markers evaluated from an international quality assessment survey. Ear. J. Clin. Chem. Clin. Biochem. 34,143-150 (1996). 

Serum cancer antigen 125 (CA-125) is the most extensively evaluated tumor marker for ovarian cancer. Unfortunately, the CA-125 determination is non-specific, and elevated levels can be associated with a number of other gynecologic and gastrointestinal diseases. CA-125 levels in a woman without ovarian cancer, though, are static or tend to decrease over time, whereas levels associated with malignancy will continue to rise.10 Since CA-125 is a non-specific marker, there is no standard recommendation for routine screening for prevention of ovarian cancer. 

The premarket notification application, 510(k), is reviewed by the FDA scientific staff. This evaluation takes into consideration tumor-associated analytes, test requirements, medical usefulness of the test system for a particular clinical claim, and its application (i.e., monitoring or treatment follow-up). The FDA determines the appropriate performance requirements for each tumor analyte category. The agency s staff considers factors, such as consequences of a false positive or false negative, and the importance or impact of an absolute versus a significant change in the results or values of the tumor marker tests. The performance criteria (parameters) of a particular tumor marker test are compared with those of previously... 

The FDA evaluates each tumor marker test against its own labeling claims as to how well it performs and compares it with other cleared and marketed devices identified in the 510(k) submission. The intended use claim for monitoring must be supported by valid scientific and clinical data. Labeling a tumor marker test for a particular claim can mean that the testing system may have to show supporting data for that claim. For example, a tumor marker proposed for a monitoring claim will require laboratory and clinical data to support that claim (4,5). 

The Role of Receiver Operating Characteristic (ROC) Curves in the Evaluation of Tumor Markers... 

A new tumor marker is evaluated using the same criteria used for many diagnostic tests (i.e., sensitivity, specificity, and accuracy). The diagnostic sensitivity and specificity are best represented by a receiver operating characteristic (ROC) curve. The ROC curve is constructed with the true-positive rate versus false-positive rate at various decision levels. As a test improves in its diagnostic performance, it shifts upward and to the left as the true-positive rate increases and the false-positive rate decreases. 

Hayes, D. F., Bast, R Desch, C. E., et al. A tumor marker utility grading system (TMUGS) A framework to evaluate clinical utility of tumor markers. J. Natl. Cancer Inst. 818, 1456-1466... 

For definitive, curative therapy, objective parameters to monitor include primary tumor size, involved lymph nodes, and tumor markers such as PSA. PSA level is checked every 6 months for the first 5 years, and then annually. With metastatic disease, clinical benefit can be documented by evaluating performance status, weight, quality of life, analgesic requirements, and PSA or DRE at 3-month intervals. 

The availability of new molecular approaches to the selection of drug therapy is an emerging need, because the traditional approach based on the evaluation of patient and tumor characteristics is clearly far from optimal. Many treated patients do not experience significant benefits from the treatment, while they often experience moderate to severe toxicities. In addition, the development and clinical use of novel molecularly targeted agents (alone or in combination with classical cytotoxic therapy) requires the understanding of the molecular features of the tumors and the identification of tumor markers of response. 

An ideal tumor marker would be a molecule specific to one type of tumor (100% specificity, i.e. no false positives) and detectable right from the initial stage of the disease (100% sensitivity, i.e. no false negatives). It would be undetectable in healthy subjects, and enable the screening and diagnosis of cancer. The tumor marker level should correlate closely with tumor size, contribute to the initial extension of the profile and evaluation of therapeutic efficacy, as well as the early detection of recurrent diseases. 

Aziz KJ. Tumor markers Reclassification and new approaches to evaluation. Adv Clin Chem 1999 33 169-99. 

To evaluate the clinical usefulness of a tumor marker, it is necessary to establish reference values, calculate predictive values, evaluate the distribution of marker values, and determine the role of the values in disease management. 

Correale M, Abbate I, Gargano G, et al. Analytical and clinical evaluation of a new tumor marker in breast cancer CA 27.29. Int J Biol Markers 1992 7 43-46. 

Eldrup E, Clausen N, Scherling B, Schmiegelow R. Evaluation of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma 3,4-dihydroxyphenyialanine (DOPA) as tumor markers in children with neuroblastoma. Scand J Clin Lab Invest 2001 61 479-90. 

---