Clinical Use of Tumor Markers Based on Outcome Analysis

Transcription

1 CE UPDATE TUMOR MARKERS I Douglas C. Aziz, MD, PhD Does the test result change the way the clinician ABSTRACT Tumor markers are substances found in the thinks about the patient? serum or urine that can be used in cancer for case-finding or Does that change in thinking alter the way the screening, confirming diagnosis, estimating prognosis, moni-clinician manages the patient (ie, through surgery, medicine, consultation, or no treattoring response to therapy, or detecting recurrences. No tumor marker is 100% sensitive and 100% specific, but optimal ment)? Does that change in treatment affect outcome, clinical use can be ensured by applying appropriate cutoff as measured by death, sickness, or reduced cost of points. Positive and negative predictive values are calculated care? to assess the efficiency of each tumor marker in a particular clinical situation. The goal is to affect patient outcome, whichif the answer to any of these questions is no, then is the key criterion in the assessment of any laboratory test. the test probably should not have been ordered. Tumor markers are substances detectable in Most tumor markers are not sensitive enough or specific the serum or urine that can be used in case-findenough to be used as a screening test, except for prostate- ing or screening, confirming diagnoses, estimatspecific antigen (PSA), which is used to screen for prostate ing prognoses, monitoring response to therapy, cancer. Specificity can be improved by calculating the PSA and detecting recurrences of cancer. Not all density, the PSA velocity, or the ratio of free-to-total PSA. Notumor markers are equally useful in each clinical role. Knowing how and when to use individual tumor marker with sufficient sensitivity or specificity exists totumor markers in the management of a specific be used as a screening test for breast cancer. CA 15-3, patient is key to assessing their overall effectiveness as clinical laboratory assays. however, is used to monitor patients after mastectomy. This is the first article in a two-part series on tumor markers. The final article discusses the roles of CA 125, carcinoembryonic antigen (CEA), CA 19-9, p-human chorionic gonadotropin (p-hcg), and a-fetoprotein (AFP) in various cancers. On completion of the series, participants will be able to determine how changing a tumor marker's cutoff point affects its sensitivity and specificity, list ways that the specificity of prostate-specific antigen for the detection of prostate cancer can be improved, and describe the appropriate uses and limitations of the following: CA 15-3 in the management of breast cancer, CEA in colon cancer, CA 19-9 in pancreatic cancer, and AFP and p-hcg in patient management. From Specialty Laboratories, Santa Monica, Calif. Reprint requests to Dr Aziz, Specialty Laboratories, 2211 Michigan Ave, Santa Monica, CA 90404, or special ix.netcom.com. In today's cost-conscious health care environment, it is essential to analyze the appropriateness of laboratory tests. Clinical outcome is an integral "yardstick" in the analysis of any laboratory test. The provider of laboratory services must answer the following questions: LABORATORY MEDICINE VOLUME 27, N U MBER 1 1 Tumor markers must be considered in light of the goal of cancer testing to reduce sickness and death due to cancer. For solid tumors, such as those of the breast, colon, prostate, and ovary, early detection and surgical removal is the most effective way to reduce sickness and death; therapy for late-stage disease rarely is effective. Thus, case-finding protocols for screening the general population require relatively high specificity and sensitivity, especially if the disease prevalence is low. Most tumor markers are not specific enough clinically to be used in case-finding except in defined groups of patients at high risk. Screening has a limited role except in well-defined clinical populations. The use of tumor markers in case-finding is complicated further by their poor clinical sensitivity in early-stage disease when case-finding is most useful. Choosing an appropriate cutoff point affects the specificity, sensitivity, and predictive value, on 01 October 2018 Clinical Use of Tumor Markers Based on Outcome Analysis

2 Prostate-Specific Antigen Overview of Prostate Cancer It is expected that 317,000 new cases of prostate cancer will be diagnosed in 1996, an increase from 244,000 in 1995; 200,000 in 1994, and 165,000 in 1993.' This dramatic increase in the incidence of prostate cancer can be attributed to widespread use of prostate-specific antigen (PSA) as a screening test.2 The death rate from prostate cancer increased from 35,000 to 41,400 during the same period,1 but because prostate cancer has a slow rate of growth, outcome data in terms of improved survival may not become available for 10 to 20 years. Death rates due to prostate cancer can be reduced if the cancer is detected early. Although the 5-year survival rate is 91% for tumors confined to the prostate, only 58% of tumors are detected at this stage. Radical prostatectomy in patients with cancers clinically confined to the gland offers a cure rate of 86% to 93%, 3-5 and complete excision by radical prostatectomy is recommended for men with a life expectancy of 10 years or more and a tumor confined to the gland. In contrast, less than 15% of patients with prostate cancer who have lymph node metastasis are cured with any treatment; pelvic lymph adenectomy should be performed before proceeding with a radical prostatectomy.3'6 Predictive Value (Cutoff = 4.0 ng/ml) With Cancer Analyte Concentration Role of Prostate-Specific Antigen Testing Prostate-specific antigen is useful in the management of patients with prostate cancer. It affects outcome by improving the detection rate for early prostate cancer; increasing the accuracy of staging patients prior to surgery; and monitoring patient response to therapy. Using a cutoff point of 4.0 ng/ml, 8% of healthy men older than 50 years test positive for prostate cancer. Men with benign prostatic hyperplasia (BPH) account for most (28%) of the false-positive cases at this cutoff point. 7 The detection rate (sensitivity) is 58% in patients with cancer confined to the prostate gland and 80% in those with extracapsular tumor growth (extensive disease) In screening for prostate cancer, using a serum PSA with a cutoff value of greater than 4.0 ng/ml and digital rectal examination with referral for transrectal ultrasound in positive cases, 2.2% of the population will be found to have cancer The positive predictive value is 55%.3'15 Most of the false-positive cases occur in patients with BPH and can be reduced7'16'17 by calculating the following: Fig 1. This hypothetical example uses a cutoff point of 4.0 units to screen for cancer. True-positive (TP) cases are those patients with cancer w h o have a t u m o r marker result greater than 4.0. True-negative (TN) cases are those patients without cancer w h o have a value less than 4.0. In this example, there are some false-positive (FP) cases (patients w i t h out cancer and a tumor marker value greater than the cutoff point) and some false-negative (FN) cases (patients with cancer and a t u m o r marker value less than the cutoff point). The serum PSA concentration per unit volume of prostate gland (PSA density) The change in serum PSA concentration over time (PSA velocity or PSA rate) The ratio of free-to-total PSA VOLUME 27, NUMBER 11 LABORATORY MEDICINE 761 on 01 October 2018 and ultimately determines the usefulness of the tumor marker in a given clinical situation. A low cutoff point will improve the sensitivity of the test, but at the expense of specificity. Different cutoff points may be chosen to predict an outcome in specific clinical situations, depending on the sensitivity or the specificity that is needed (Figs 1 and 2). Bayes' theorem is an algebraic expression for calculating the posttest probability of disease (the probability of disease after the test result is known) if the pretest probability (prevalence) of disease and the sensitivity and specificity of the test are well known. Even if the test has relatively high sensitivity and specificity, if the prevalence or pretest probability is low (as with case-finding in the general population), then the posttest probability cannot be very high. This translates into low positive predictive value.

3 Predictive Value (Cutoff = 3.0 ng/ml) With Cancer GO Prostate-Specific Antigen Ratio cu V) CO u Prostate-Specific Antigen Density Transrectal ultrasound can estimate the dimensions of the prostate. The prostate volume can be calculated from these dimensions. For any given concentration of PSA, prostate glands with BPH typically are much larger than those glands with prostate cancer, because cancerous prostate releases much more PSA into the serum than prostate glands with BPH for any given volume of tissue. By calculating the PSA density (the PSA concentration divided by the prostate gland volume), elevated PSA concentrations are corrected for large gland volumes due to BPH. In patients with a PSA concentration from 4.1 to 10.0 ng/ml, the probability that a prostate biopsy contains cancer is 15% if the PSA density is 0.15 ng/ml/cc of prostate volume, compared with 90% if the PSA density is 0.50 ng/ml/cc of prostate volume.18'19 A cutoff point of 0.15 TABLE 1. SERUM PROSTATE-SPECIFIC ng/ml/cc often is ANTIGEN AND PATIENT AGE* cited, but in practice, the coefficient of variage Range Reference Range (Years) ation among ultrasonographers is too <2.5 high to determine <3.5 meaningful cutoff points. < <6.5 Adapted from Oesterling JE, Jacobsen SJ, Chute CG, et al. 2 3 Prostate-Specific Antigen Velocity A rapid increase in the concentration of serum PSA over time more likely is due to prostate cancer than to BPH. If the PSA concentration increases more than LABORATORY MEDICINE VOLUME 27, NUMBER 1 1 A third way to reduce the false-positive rate of PSA determination caused by BPH is to measure the major forms of PSA. Prostate-specific antigen is present in the serum in a free or unbound form and as PSA bound to aj-antichymotrypsin. 21 Bound PSA is found in higher concentrations in patients with prostate cancer; free PSA concentrations are higher in patients with BPH. For men with PSA concentrations between 4.1 and 10.0 ng/ml, BPH and prostate cancer are common, 80% to 85% and 15% to 20%, respectively. Within this range, if the percentage of free PSA is less than 10% of the total PSA, prostate cancer is eight times more common. Using 23% as the free-to-total PSA ratio cutoff point, 31% of negative biopsies can be avoided while maintaining a sensitivity of 90%.22 Recommendations Men older than 50 years should be screened annually with a digital rectal exam and serum PSA assay. Men at high risk for prostate cancer, such as those with a family history or African heritage, should begin annual testing at age 40. If tests are normal (ie, serum PSA <4.0 ng/ml), patients can be followed with annual evaluations and monitored to determine the rate of change. A rapid rise in the PSA concentration (PSA rate >0.75 ng/ml/year) or a very high PSA concentration (>10.0 ng/ml) warrants transrectal ultrasound and biopsy. Intermediate concentrations of PSA ( ng/ml) require further studies. A PSA ratio of greater than 23% indicates that prostate cancer is unlikely, and the patient can be followed for 6 months, when a repeat PSA is performed; a PSA ratio of less than 23% indicates that cancer is a possibility and a biopsy is recommended. Because PSA concentrations normally increase with age, age-specific reference ranges should be used to determine cutoff points. Agespecific reference ranges improve the sensitivity in younger men (at the expense of specificity) and improve the specificity in older men (at the expense of sensitivity)23 (Table 1). on 01 October 2018 Analyte Concentration Fig 2. Changing the cutoff point to 3.0 units to predict cancer recurrence reduces the number of false-negative (FN) cases but increases the number of false-positive (FP) cases. The definition of a positive case will change as the cutoff point moves to maximize the sensitivity or specificity of the assay in relation to the clinical need. TN indicates true negative; TP, true positive. ng/ml per year, the specificity improves to 90% without loss of sensitivity (70%) compared with using a serum PSA cutoff point of 4.0 ng/ml alone.16,20 At least three measurements at 1-year intervals should be used in the calculation to minimize the variability.

4 CA 15-3 Overview of Breast Cancer In 1996, 185,000 new cases of breast cancer and 44,500 associated deaths are expected.1 The best way to reduce sickness and death due to breast cancer is to detect the tumor early and to remove it surgically. The increase in the rate of detection of breast tumors less than 1 cm in diameter during the past 10 years primarily can be attributed to improvements in the sensitivity and use of mammography.26 The probability of recurrence for patients with a 1- to 2-cm lesion is 31%, compared with 14% for patients with a lesion less than 1 cm in diameter.27 None of the tumor markers available are specific enough or sensitive enough to screen all women for breast cancer. The main use of CA 15-3 (a large mucin glycoprotein antigen [>400 kd] expressed in most breast cancers) in breast cancer is to monitor patients after mastectomy. Role of CA 15-3 Testing The detection rate for stage I breast cancer using a CA 15-3 cutoff point of 25 U/mL is only 5%, precluding its use as a screening test. In higher-stage disease, the sensitivity is much better, making CA 15-3 a good measure of total body tumor mass 28 ' 29 (Table 2). CA 15-3 is positive in other conditions (benign and malignant), including patients with liver disease (eg, chronic hepatitis, cirrhosis, and cancer), some inflammatory conditions (sarcoidosis, tuberculosis, and systemic lupus erythematosus) and other cancers TABLE 2. CA15-3* (lung and ovary). 30 The clinician must be Breast Cancer aware that a positive CA 15-3 test result Stage I does not necessarily Stage II indicate cancer. Increases in CA15-3 % of Cases >25 U/mL 5% 29% Stage III 32% Stage IV 95% A change in the CA 15Healthy women <2% 3 concentration is more Benign breast disease 9% predictive of cancer than is the absolute * Adapted from Gion M, Mione R, Nascimben 0, et al. The tumour-associated antigen CA concentration. Over 15-3 in primary breast cancer. Evaluation of time, tumor markers 667 cases. Br J Cancer. 1991;63: exhibit a steady state in the body, a balance between antigen production by the tumor and degradation and excretion. Changes in tumor burden (either increases or decreases) are reflected by changes in the tumor marker concentration. An increase in serum CA 15-3 concentration is associated with tumor recurrence. The percentage of patients with progressive disease compared with the magnitude of serum CA 15-3 changes is shown in Table 3. An increase of 25% or more indicates that tumor progression is 96% certain; nearly 100% of patients with a CA 15-3 that increases 40% or more will have disease progression31-34 (Table 3). Decreases in CA 15-3 Serum CA 15-3 decreases by more than 50% in 55% to 89% of patients with disease regression or those whose tumors respond to therapy. A decrease of 25% or more indicates that disease regression is 84% certain; a decrease of more than 50% indicates that disease regression is 100% certain TABLE 3. SENSITIVITY AND POSITIVE PREDICTIVE VALUE OF CHANGES IN CA 15-3 FOR PROGRESSIVE DISEASE Change in CA 15-3 % of Patients With Progressive Disease (Sensitivity) Likelihood of Progression (Positive predictive value) 96% 96% Increase >25% 100% Increase >40% Increase >50% 76% Increase >75% 48% Increase >100% 43% VOLUME 27, N UMBER 1 1 LABORATORY MEDICINE 763 on 01 October 2018 In patients with untreated, newly diagnosed prostate cancer, a serum PSA concentration of 10.0 ng/ml or less and absence of skeletal symptoms, the radionucleotide bone scan will be normal in all but 0.5% of cases.23 A staging bone scan therefore may not be necessary in these patients. If all of the prostate tissue is removed by radical prostatectomy, the serum PSA concentration should drop to an undetectable level (<0.2 ng/ml). In patients with a postprostatectomy serum PSA concentration of less than 0.2 ng/ml, 93% will have no clinical tumor recurrence.24 Prostatic acid phosphatase (PAP), the major acid phosphatase secreted by the prostate, has poor sensitivity in low-stage prostate cancer; only 13% of patients with elevated serum PSA concentration after radical prostatectomy have an elevated PAP concentration.24 Patients receiving androgen ablation therapy, however, may have a falsely-low PSA, but elevated PAP.24-25

5 References 1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, CA Cancer] Clin. 1996;46: Jacobsen SJ, Katusic SL, Bergstralh EJ, et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA. 1995;274: Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate-specific antigen in the early detection of prostate cancer: results of a multicenter trial of 6,630 men. / Urol. 1994;151: Krahn MD, Mahoney JE, Eckman MH, et al. Screening for prostate cancer. A decision analytic view. JAMA. 1994;272: Littrup PJ, Kane RA, Mettlin CJ, et al. Cost-effective prostate cancer detection. Reduction of low-yield biopsies. Cancer. 1994;74: Woolf SH. Screening for prostate cancer with prostatespecific antigen. N Engl J Med. 1995;333: Aziz DC, Barathur RB. 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Cancer. 1993;72: Mettlin C, Murphy GP, Lee F, et al. Characteristics of prostate cancers detected in a multimodality early detection program. Cancer. 1993;72: Y MEDICINE VOLUME 27, NUMBER Imai K, Ichinose Y, Kubota Y, Yamanaka H, Sato J. Diagnostic significance of prostate-specific antigen and the development of a mass screening system for prostate cancer. / Urol. 1995;154: Carter HB, Pearson JD, Mette J, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA. 1992;267: Kane RA, Littrup PJ, Babaian R, et al. Prostate-specific antigen level in 1,695 men without evidence of prostate cancer. Cancer. 1992;69: Bretton PR, Evans WP, Borden JD, Castellanos RD. The use of prostate-specific antigen density to improve the sensitivity of prostate-specific antigen in detecting prostate carcinoma. Cancer. 1994;74: Wolff JM, Boeckmann W, Effert PJ, Handt S, Jakse G. Evaluation of patients with diseases of the prostate using prostate-specific antigen density. Br J Urol. 1995;76: Carter HB, Pearson JD. PSA velocity for the diagnosis of early prostate cancer. Urol Clin North Am. 1993;20: Christensson A, Bjork T, Nilsson O, et al. Serum prostate specific antigen complexed to a-1-antichymotrypsin as an indicator of prostate cancer. / Urol. 1993;150: Catalona WJ, Smith DS, Wolfert RL, et al. Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA. 1995;274: Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges. JAMA. 1993;270: Oesterling JE, Chan DW, Epstein JI, et al. Prostate-specific antigen in the preoperative evaluation of localized prostate cancer treated with radical prostatectomy. / Urol. 1988;139: Beaver TR, Schultz AL, Fink LM, Andersen CA, Donohue RE. Discordance between concentrations of prostate-specific antigen and acid phosphatase in serum of patients with adenocarcinoma of the prostate. Clin Chem. 1988;34: Nystrom L, Rutqvist LE, Wall S, et al. Breast cancer screening with mammography: overview of Swedish randomized trials. Lancet. 1993;341: Figueroa JA, Yee D, McGuire WL. Prognostic indicators in early breast cancer. Am J Med Sci. 1993;305: Gion M, Mione R, Nascimben O, et al. The tumourassociated antigen CA 15-3 in primary breast cancer. Evaluation of 667 cases. Br J Cancer. 1991;63: O'Hanlon DM, Kerin MJ, Kent P, Maher D, Grimes H, Given HF. An evaluation of preoperative CA 15-3 measurement in primary breast carcinoma. Br J Cancer. 1995;71: Colomer R, Ruibal A, Genolla J, et al. Circulating CA 15-3 levels in the postsurgical follow-up of breast cancer patients and in nonmalignant diseases. Breast Cancer Res Treat. 1989;13: Hayes DF, Zurawski VR Jr, Kufe DW. Comparison of circulating CA 15-3 and carcinoembryonic antigen levels in patients with breast cancer. J Clin Oncol. 1986;4: Kallioniemi O-P, Oksa H, Aaran R-K, Hietanen T, Lehtin M, Koivula T. Serum CA 15-3 assay in the diagnosis and follow-up of breast cancer. Br J Cancer. 1988;58: Dnistrian AM, Schwartz MK, Greenberg EJ, Smith CA, Schwartz DC. CA 15-3 and carcinoembryonic antigen in the clinical evaluation of breast cancer. Clin Chim Acta. 1991;200: Depres-Brummer P, Itzhaki M, Bakker PJM, Hoek FJ, Veenhof KHN, de Wit R. The usefulness of CA 15-3, mucinlike carcinoma-associated antigen and carcinoembryonic antigen in determining the clinical course in patients with metastatic breast cancer. / Cancer Res Clin Oncol. 1995;121: on 01 October 2018 Conclusion No serum tumor marker is 100% sensitive and 100% specific. The use of PSA as a screening test for prostate cancer has had a striking effect on the incidence of the disease owing to the ability to detect prostate cancer earlier. The lack of specificity can be improved by determining the fraction of PSA that is unbound. In contrast, CA 15-3 is not sensitive or specific enough to be used in screening protocols for breast cancer. When CA 15-3 is used to monitor patients after surgery, the change in value is more important than the absolute concentration.