Tumor Marker Monitoring

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 establishment of performance criteria for a given tumor marker test is not a simple process because accuracy and precision are unique for each type of analyte and its application. Establishing methodological limits for accuracy, precision, sensitivity, and specificity often requires standard reference materials, quality control materials, comparative studies, and actual clinical specimens. Accuracy and precision must be measured over the analyte reportable range for which the device is intended to be used. Sensitivity and specificity must be considered with respect to the intended clinical use of the device. Also, the indications for use should be carefully considered in the design of the study protocol. The indications for class II should be to monitor residual tumor after surgery (or radiation), the recurrence of tumor, or response to therapy. A 510(k) must provide clear evidence that the device is accurate, safe, effective, and substantially equivalent to a device legally marketed in the United States. 

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). 

Aziz, K. J. Perspectives on tumor marker tests for cancer diagnosis and monitoring. J. Biomed Lab. Sci. 6, 1-9 (1994). 

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 other well-known member of this superfamily is CEA or carcinoem-bryonic antigen. CEA is a widely used tumor marker, especially for monitoring patients with diagnosed colorectal cancer (M5). It is a high-molecular-weight (Afr 200,000, approximately) glycoprotein containing about 60% carbohydrate. In normal colonic cells and in well-differentiated colon carcinomas, the distribution of CEA is apical. However, in undifferentiated colonic tumors, CEA is present on all of the cell membrane (J3). Whether this altered subcellular localization of CEA mediates cancer spread is presently unclear. 

Sometimes it is not possible to measure the direct effect of the drug. Endpoints or surrogate biomarkers are used to monitor the pharmacodynamics and pharmacokinetics of the drug. These markers may be changes in blood pressure, cholesterol level, concentrations of certain enzymes, proteins, blood glucose levels, and similar factors (see Table 6.2 for serum tumor markers and Appendix 7 for general biomarkers). 

Bidart J-M, Thuillier F, Augereau C, Chalas J, Daver A, Jacob N, Labrousse F, Voitot H. Kinetics of serum tumor marker concentrations and usefulness in clinical monitoring. Clin Chem 1999 45 1695-707. 

The potential uses of tumor markers are summarized in Table 23-3. In general, tumor markers may be used for diagnosis, prognosis, and monitoring the effects of therapy and as targets for localization and therapy. Ideally a tumor marker should be produced by the tumor cells and be... 

Most tumor marker values correlate with the effectiveness of treatment and responses to therapy. In breast cancer, the concentration of markers, such as CA 15-3 or CA 27.29, changes with the treatment and the clinical outcome of the patient. Marker values usually increase with progressive disease, decrease with remission, and do not change significantly with stable disease. The tumor marker kinetics in the monitoring of cancer may be more complicated. The marker values in response to treatment may show an initial delay before demonstrating the expected pattern of change. ... 

Most tumor markers are used to monitor treatment and progression of cancer. The selection of patient groups is important to illustrate the usefulness of the marker in various clinical settings. Markers may be used to determine the success of the initial treatment (e.g., surgery or radiation), detect the recurrence of cancer, and monitor the effectiveness of the treatment modality. 

PSA is an extremely useful tumor marker for prostate cancer. It is used to detect and stage the cancer and to monitor treatment of prostate cancer. It is also thought to be involved in tumor progression. 

Hormones have been recognized as tumor markers for more than 50 years. The introduction of specific RIA methods for a particular hormone that has very little cross-reactivity with similar hormones made it possible to monitor the treatment of cancer patients. ... 

Elevated human chorionic gonadotropin (hCG) levels are seen in pregnancy, trophoblastic diseases, and germ cell tumors. It is a useful tumor marker for tumors of the placenta (trophoblastic tumors) and some tumors of the testes. It is also useful for diagnosing and monitoring pregnancy (see Chapter 54 for a discussion of hCG and pregnancy). 

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