CE U P D A T E — T U M O R M A R K E R S II

Douglas C.Aziz, MD, PhD

Clinical Use of Tumor Markers Based on Outcome Analysis

Tumor markers are substances found in the serum or urine that can be used in cancer for case find­ing or screening, confirming diagnosis, estimating prognosis, monitoring response to therapy, or detecting recurrences. The first part of this series discussed the use of predictive values to determine the clinical use of tumor markers, in particular, prostate-specific antigen and CA 15-3. In this arti­cle, we discuss the clinical use of CA 125, carci-noembryonic antigen, CA 19-9, (3-human chori­onic gonadotropin, and a-fetoprotein.

CA 125 and Ovarian Cancer CA 125, a high-molecular-weight (>200 kd) mucinlike glycoprotein, is expressed on the sur­face of coelomic (body cavity) epithelium and human ovarian cancer cells. It is estimated that 26,700 new cases of ovarian cancer will be diag­nosed in 1996.' CA 125 is more sensitive in low-stage (stages I-II) ovarian cancer than is CA 15-3 in breast cancer, but due to the relatively low prevalence of ovarian cancer, CA 125 should not be used for case finding in screening the general population. The serum concentration of CA 125 is greater than 35 U/mL in about 80% of women with ovarian cancer,1"4 26% of women with benign ovarian tumors,3,4 and 66% of patients with nonneoplastic conditions, including the first trimester of pregnancy, menstruation, endometriosis, adenomyosis, uterine fibroids (leiomyomata), acute salpingitis, hepatic disease (eg, cirrhosis), and inflammation of the peri­toneum, pericardium, and pleura. Only 3% and 0.8% of healthy women have a concentration of CA 125 greater than 35 and 65 U/mL, respective­ly.5"8 In patients with cancer disseminated beyond the ovary (International Federation of Gynecology and Obstetrics System stages II, III, and IV), 90% have serum concentrations greater

ABSTRACT In ovarian cancer, the tumor marker CA 125 is best used to monitor patients for recurrent disease post-oophorectomy. Elevated concentrations ofCA 125 indicate a recurrence, but a negative value does not rule out recurrent disease, and a follow-up operation still is recommended. Carcinoembryonic antigen (CEA) lacks the specificity and sensitivity to be used as a screening test. CA 19-9 can be used before surgery to assess the resectability of a pancreatic tumor. (3-human chorionic gonadotropin ((3-hCG) is a nearly perfect tumor marker for the assessment of trophoblastic disease, and a high concentration indicates the presence of a choriocarcinoma or an invasive mole. In nonseminomatous germ cell tumors of the testes, assays for fi-hCG and a-fetoprotein (AFP) are useful for assessing patients postorchiectomy for the presence of a recurrence. Although tumor markers are not 100% sensitive and specific, with appropriate choice of cutoff values, they can be used to manage patients and thus affect patient outcome. This is the second article in a two-part series on tumor markers. 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, CA 125 in ovarian cancer, CEA in colon cancer, CA 19-9 in pancreatic cancer, and AFP and (3-hCG in patient management.

than 35 U/mL; only 50% of patients with cancer whose disease is confined to the ovary (stage I) have elevated CA 125.9

In women with a family history of ovarian cancer, it may be useful to prescreen them for CA 125 prior to referral for ultrasound. A cutoff point of 20 U/mL as the criterion for ultrasound referral would decrease costs, because only 25% of women would be referred. CA 125 prescreening would, however, miss 29% of the true-positive

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From Specialty Laboratories, Santa Monica, Calif.

Reprint requests to Dr Aziz, Specialty Laboratories, 2211 Michigan Ave, Santa Monica, CA 90404, or e-mail: special© ix.netcom.com

DECEMBER 1996 VOLU ME 27, NU M BER 1 2 LABOR ATORY MEDICINE 8 1 7

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TABLE 1. PREDICTION OF RECURRENCE IN DUKES' STAGE B2 AND C COLON CANCER PATIENTS, MEAN FOLLOW-UP 6 YEARS POSTSURGERY*

CEA Value1

(ng/mL)

<3

<5

< 10

<15

Positive Predictive Negative Predictive Value (%) Value (%)

57

72

89

96

77

75

72

69

* Adapted from Moertet CG, Fleming TR, MacDonald JS, Haller DG, Laurie JA, Tangen C. An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA. 1993;270:943-947.

cases detected by a strategy in which all patients are screened initially by ultrasound.10,1'

The most important use of CA 125 is to assess patients for recurrent disease after the removal of an ovary or ovaries (oophorectomy). Residual ovarian cancer is detected in 95% of patients with serum CA 125 concentrations greater than 35 U/mL who are monitored for recurrence. A nega­tive result is not conclusive, however; half the patients with such negative results have micro­scopic residual cancer.12 A follow-up procedure is necessary to rule out residual cancer. In most cases with a false-negative result, residual lesions are less than 15 mm in diameter.13,14 Patients are best monitored for recurrent ovarian cancer postsurgery through second-look operations and CA 125 monitoring. If either procedure is posi­tive, then adjuvant therapy should be instituted.

CA 125 is most useful in serous adenocarcino­ma, a-fetoprotein (AFP) is the best marker for endodermal sinus (yolk sac) tumors, and human chorionic gonadotropin (hCG) for germ cell tumors with trophoblastic components.15 Inhibin is a useful marker in granulosa cell tumors.16,17

Carcinoembryonic Antigen and Colon Cancer Carcinoembryonic antigen (CEA), discovered in 1965, is the prototypic tumor marker. Unfortunately, CEA is neither organ-specific nor tumor-specific; CEA concentrations are elevated (>3.0 ng/mL) in the serum specimens of patients with colorectal (57%), gastric (41%), liver (45%), pancreatic (59%), and biliary (59%) cancer.18

The serum concentration of CEA also can be ele­vated in benign diseases of the colorectum (inflammatory bowel disease, 17%), stomach (chronic gastritis and peptic ulcer, 14%), liver (cirrhosis and hepatitis, 17%), and pancreas

(pancreatitis, 21%).18 Although the sensitivity of CEA increases with stage, its relative insensitivity at low-stage disease precludes its use as a screen­ing test for colorectal cancer. Carcinoembryonic antigen is elevated in the serum (>3.0 ng/mL) in 10% to 28% of patients with Dukes' stage A, 45% of patients with Dukes' B, and 70% of patients with Dukes' C cancer of the colon.18,19

Carcinoembryonic antigen testing is used pri­marily to monitor patients after surgery for recurrent colorectal cancer. Because 20% of col­orectal cancers do not express CEA, immunohis-tochemistry of the resected tumor should be used to identify these cases and thereby avoid superflu­ous and misleading monitoring by CEA. Using a cutoff of 5.0 ng/mL, serum CEA testing is 60% to 95% sensitive in the detection of recurrences between 2 and 10 months prior to clinical detec­tion. The false-positive rates are 16% and less than 1% at cutoff values of 5.0 ng/mL and 15.0 ng/mL, respectively. The positive predictive value for the detection of recurrences increases with the CEA cutoff level20 (Table 1).

CA 19-9 and Pancreatic Cancer Treatment results for pancreatic cancer are dis­mal, and reports of 5-year survivors are rare (0.2%-3.4%).21 Resection of the pancreas shows a significant increase in the 5-year survival rate (21%-24%) in some series.22 Lymph node involvement, poor histologic differentiation, and increased tumor size are important prognostic factors. Most of these criteria, however, can only be assessed after surgery.

Serum CA 19-9 concentrations are elevated (>37 U/mL) in patients with pancreatic cancer (72%-100%), liver cancer (76%), and some patients with colorectal cancer (19%). In colorec­tal cancer, elevated concentrations of CA 19-9 are associated with extremely poor prognosis.23,24

Benign conditions that cause pancreatitis and jaundice also are associated with elevated concen­trations of CA 19-9 (18%), but most are below 75 U/mL (96%). Elevated CA 19-9 concentrations are extremely rare in control subjects.

CA 19-9 is the Lewisab (Leab) blood group antigen and, consequently, is not expressed in Lea-b- individuals, who comprise approximately 7% of the US population and 20% of the Japanese population. CA 19-9 testing therefore yields a false-negative result in these patients.25

The primary use of CA 19-9 testing is to deter­mine the resectability of pancreatic cancer, pre-operatively. Essentially all patients with a serum CA 19-9 concentration greater than 1,000 U/mL

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have tumors greater than 5 cm in diameter, and only 5% of patients in this group have a tumor that is resectable. Half the patients with a pre-treatment CA 19-9 concentration less than 1,000 U/mL have a resectable tumor.26'27 Most patients with a CA 19-9 concentration greater than 300 U/mL have unresectable tumors.28 Elevated CA 19-9 concentrations predict relapse of pancreatic cancer prior to clinical findings, but lack of effec­tive therapy precludes its use in monitoring.

ft-Human Chorionic Gonadotropin (3-human chorionic gonadotropin (P-hCG), a 40-kDa glycoprotein hormone produced by the placenta,29,30 normally is present in trace amounts (<1 ng/mL) in the serum. Positive results occur in men with solitary testes (24%) and in pregnant women.31

Gestational Trophoblastic Disease P-hCG is an almost ideal tumor marker for ges­tational trophoblastic disease (hydatidiform mole, invasive mole, or chorionic cancer).32 After evacuation for a molar pregnancy, the fi-hCG concentration is expected to decrease to normal levels after 21 days, at least by 8 to 12 weeks. Persistent elevation or a much slower rate of decline indicates that the patient has an invasive mole or chorionic cancer. A marked elevation (>8,000 ng/mL) indicates a high risk for chorionic cancer and a need for chemotherapy.33

Testicular Cancer (5-hCG is detectable in the serum of 70% of patients with nonseminomatous germ cell tumors.31 Combining tests for (3-hCG and AFP increases the sensitivity (0%-18% for stage I, 52%-82% for stage II, and 87%-100% for stage III).31,34"36 Following orchiectomy (excision of one or both testes), elevated [3-hCG concentra­tions indicate stage II or III spread, but a negative result does not rule out the presence of disseminated disease. Surveillance by serum (3-hCG and AFP assays after orchiectomy in stage I nonseminomatous testicular cancer detects relapse in 22% to 30% of patients using the tumor markers alone, in 19% to 36% using radiographic results alone, and in 45% to 70% when tumor markers and radiographic results are com­bined. 37,38 Pure seminoma can be positive for (5-hCG, but the concentrations usually are low (<40 ng/mL).39

n-Fetoprotein a-fetoprotein, a 70-kDa glycoprotein homolo­gous to albumin, normally is synthesized in the liver, yolk sac, and gastrointestinal tract of the fetus.30'40 Only 3% of control subjects have a serum concentration greater than 15 ng/mL, and essentially all control subjects have serum con­centrations less than 40 ng/mL. Elevated serum concentrations (>40 ng/mL) are found in patients with hepatocellular (72%), pancreatic (23%), gastric (18%), bronchogenic (7%), and colonic (5%) cancer, and testicular teratocarcino-ma (75%). Benign liver diseases such as viral hepatitis, (27%), and postnecrotic (24%), Laennec (15%), and primary biliary (5%) cirrho­sis can have elevated serum concentrations, but usually less than 500 ng/mL.30

Testicular Cancer In monitoring nonseminomatous germ-cell tumors of the testes for recurrence, AFP is more sensitive than is (B-hCG, which is elevated in only 10% of AFP-negative cases with disseminated disease.41

Liver Cancer In China, where the incidence of liver cancer is 24 cases per 100,000 persons, the positive predictive value of AFP is 0.74%. If screening is confined to patients with liver disease or hepatitis B surface antigen-positive chronic hepatitis, the positive pre­dictive value increases to 9% and 36%, respectively, using a cutoff value of 20 ng/mL. Patients who are positive for hepatitis B surface antigen and who have chronic active hepatitis or cirrhosis should be monitored every 3 to 4 months with serum AFP and every 4 to 6 months with ultrasound.42"44

Testing for lectin-reactive AFP can improve the specificity for the detection of liver cancer.44'45

Test Time! This installment con­cludes the two-part continuing education update series on tumor markers that began in November. Participants in the tumor markers exam, which follows this article, wil l earn two CMLE credit hours.

The exam is also available on the Internet at the ASCP Web site located at http://www.ascp.org where participants can view all installments of the series, take the exam, and e-mail it back to the ASCP for processing.

TABLE 2. TUMOR MARKERS AND THEIR USES*

Screening

Staging

Prognosis

Diagnosis

Detecting residual disease

Detecting recurrent disease

Monitoring therapy

PSA in prostate cancer

CA 19-9 in pancreatic cancer

CEA in colorectal cancer

P-hCG in gestational trophoblastic disease

CA 125 in ovarian cancer

PSA in prostate cancer

CA 15-3 in breast cancer

* PSA indicates prostate-specific antigen; CEA, carcinoembryonic antigen; hCG, human chorionic gonadotropin.

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Conclusion No tumor marker is 100% sensitive or 100% spe­cific for every clinical situation. Cutoff values can be adjusted to improve sensitivity at the cost of specificity, or vice versa. Clinical use depends on the particular tumor marker, the specific clinical situation, and the choice of cutoff value (see Table 2).

Knowing the predictive value of each tumor marker to approximate specific clinical outcome allows the physician to use these tests effectively and appropriately.©

References 1. Bast RC, Klug TL, St John E, et al. A radioimmunoassay

using a monoclonal antibody to monitor the course of epithe­lial ovarian cancer. N Engl I Med. 1983;309:883-887.

2. Mogensen O, Mogensen B, Jakobsen A. CA 125 in the diagnosis of pelvic masses. Eur J Cancer Clin Oncol. 1989;25:1187-1190.

3. Gadducci A, Ferdeghini M, Rispoli G, Prontera C, Bianchi R, Fioretti R Comparison of tumor-associated trypsin inhibitor (TATI) with CA 125 as a marker for diagnosis and monitoring of epithelial ovarian cancer. Scand J Clin Lab Invest. 1991;51(suppl207):19-24.

4. Gadducci A, Ferdeghini M, Prontera C, et al. The con­comitant determination of different tumor markers in patients with epithelial ovarian cancer and benign ovarian masses: relevance for differential diagnosis. Gynecol Oncol. 1992;44:147-154.

5. Zurawski VR, Sjovall K, Schoenfeld DA, et al. Prospective evaluation of serum CA 125 levels in a normal population, phase I: the specificities of single and serial determinations in testing for ovarian cancer. Gynecol Oncol. 1990;36:299-305.

6. Zurawski VR, Broderick SF, Pickens P, Knapp RC, Bast RC. Serum CA 125 levels in a group of nonhospitalized women: relevance for the early detection of ovarian cancer. Obstet Gynecol. 1987;69:606.

7. Kenemans P, Yedema CA, Bon GG, von Mensdorff-Pouilly S. CA 125 in gynecological pathology—a review. Eur J Obstet Gynecol Reprod Biol. 1993;49:115-124.

8. Alagoz T, Buller RE, Berman M, Anderson B, Manetta A, DiSaia P. What is a normal CA 125 level? Gynecol Oncol. 1994;53:93-97.

9. Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Intern Med. 1994;121:124-132.

10. Bourne TH, Campbell S, Reynolds K, et al. The poten­tial role of serum CA 125 in an ultrasound-based screening program for familial ovarian cancer. Gynecol Oncol. 1994;52:379-385.

11. Antoni J, Rakar S. Colour and pulsed Doppler US and tumour marker CA 125 in differentiation between benign and malignant ovarian masses. Anticancer Res. 1995;15:1527-1532.

12. Sliutz G, Tempfer C, Kainz CH, et al. Tissue polypeptide specific antigen and cancer associated serum antigen in the follow-up of ovarian cancer. Anticancer Res. 1995;15:1127-1130.

13. Gallion HH, Hunter JE, van Nagell JR, et al. The prog­nostic implications of low serum CA 125 levels prior to the second-look operation for stage III and IV epithelial ovarian cancer. Gynecol Oncol. 1992;46:29-32.

14. Tomas C, Kauppila A. Tumor markers of epithelial and stromal cell origin at second-look laparotomy in ovarian car­cinoma. Br J Cancer. 1993;45:279-283.

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15. Stenman U-H, Alfthan H, Vartiainen J, Lehtovirta P. Markers supplementing CA 125 in ovarian cancer. Ann Med. 1995;27:115-120.

16. Healy DL, Burger GH, Mamers P, et al. Elevated serum inhibin concentrations in postmenopausal women with ovar­ian tumors. N Engl J Med. 1993;329:1539-1542.

17. Lappohn RE, Burger GH, Bouma J, Bangah M, Krans M, de Bruijn WA. Inhibin as a marker for granulosa-cell tumors. N Engl J Med. 1989;321:790-793.

18. Kuusela P, Haglunk C, Roberts PJ. Comparison of a new tumour marker CA 242 with CA 19-9, CA 50 and carcinoem-bryonic antigen (CEA) in digestive tract diseases. Br ) Cancer. 1991;63:636-640.

19. Nilsson O, Johansson C, Glimelius B, et al. Sensitivity and specificity of CA242 in gastro-intestinal cancer. A com­parison with CEA, CA50 and CA 19-9. Br / Cancer. 1992;65:215-221.

20. Moertal CG, Fleming TR, MacDonald JS, Haller DG, Laurie JA, Tangen C. An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA. 1993;270:943-947.

21. Lundin J, Roberts PJ, Kuusela P, Haglund C. The prog­nostic value of preoperative serum levels of CA 19-9 and CEA in patients with pancreatic cancer. Br J Cancer. 1994;69:515-519.

22. Geer RJ, Brenna MR Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am ] Surg. 1993;165:68-73.

23. Diez M, Cerdani FJ, Pollan M, et al. Prognostic signifi­cance of preoperative serum CA 19-9 assay in patients with colorectal carcinoma. Anticancer Res. 1994;14:2819-2826.

24. Ueda T, Shimada E, Urakawa T. The clinicopathologic features of serum CA 19-9-positive colorectal cancers. Jpn J Surg. 1995;24:518-525.

25. Magnani JL, Steplewski Z, Koprowski H, Ginsburg V. Identification of the gastrointestinal and pancreatic cancer-associated antigen detected by monoclonal antibody 19-9 in the sera of patients as a mucin. Cancer Res. 1983;43:5489-5492.

26. Tian F, Appert HE, Myles J, Howard JM. Prognostic value of serum CA 19-9 levels in pancreatic adenocarcinoma. Ann Surg. 1992;215:350-355.

27. Sperti C, Pasquali C, Catalini S, et al. CA 19-9 as a prog­nostic index after resection for pancreatic cancer. / Surg Oncol. 1993;52:137-141.

28. Forsmark CE, Lambiase L, Vogel SB. Diagnosis of pan­creatic cancer and prediction of unresectability using the tumor-associated antigen CA 19-9. Pancreas. 1994;9:731-734.

29. Regelson W. Have we found the "definitive cancer bio-marker"? Cancer. 1995;76:1299-1301.

30. Bartlett NL, Freiha FS, Torti FM. Serum markers in germ cell neoplasms. Hematol Oncol Clin North Am. 1991;5:1245-1260.

31. Fowler JE Jr, Taylor G, Blom J, Stutzman RE. Experience with serum alpha-fetoprotein and human chorionic gonadotropin in non-seminomatous testicular tumors. / Urol. 1980;124:365-368.

32. Bagshawe KD. Choriocarcinoma. A model for tumour markers. Rev Oncol. 1992;5:99-106.

33. DuBeshter B, Berkowitz RS, Goldstein DP, Bernstein MR. Analysis of treatment failure in high-risk metastatic ges­tational trophoblastic disease. Gynecol Oncol. 1988;29:199-207.

34. Sailer B, Clara R, Spottl G, Siddle K, Mann K. Testicular cancer secretes intact human choriogonadotropin (hCG) and its free beta-subunit: evidence that hCG (+hCG-beta) assays are the most reliable in diagnosis and follow-up. Clin Chem. 1990;36:234-239.

35. Anderson T, Waldman TA, Javadpour N, et al. Testicular germ-cell neoplasms: recent advances in diagnosis and thera­py. Ann Intern Med. 1979;90:373-385.

36. Bosl GJ, Lange PH, Fraley EE, et al. Human chorionic gonadotropin and alphafetoprotein in the staging of non-seminomatous testicular cancer. Cancer. 1981;47:328-332.

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37. Williams MP, Husband JE, Heron CW. Stage I nonsemi-nomatous germ cell tumors of the testis: radiologic follow-up after orchidectomy. Radiology. 1987;164:671-674.

38. Thompson PI, Nixon J, Harvey JV. Disease relapse in patients with stage I non-seminomatous germ cell tumor of the testis on active surveillance. / Clin Oncol. 1988;6:1597-1603.

39. Riither U, Rothe B, Grunert K, et al. Role of human chorionic gonadotropin in patients with pure seminoma. Eur Urol. 1994;26:129-133.

40. Deutsch HE Chemistry and biology of a-fetoprotein. Adv Cancer Res. 1991;56:253-312.

41. Klepp O. Serum tumour markers in testicular and extragonadal germ cell malignancies. Ann Oncol. 1990;1:281-288.

42. Heyward WL, Lanier AP, McMahon BJ, Fitzgerald MA, Kilkenny S, Paprochi TR. Early detection of primary hepato­cellular carcinoma. Screening for primary hepatocellular car­cinoma among persons infected with hepatitis B virus. JAMA. 1985;254:3052-3054.

43. Lee H-S, Chung YH, Kim CY. Specificities of serum a-fetoprotein in HBsAg+ and HBsAg- patients in the diagnosis of hepatocellular carcinoma. Hepatology. 1991;14:68-72.

44. Sato Y, Nakata K, Kato Y, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl f Med. 1993;328:1802-1806.

45. Skiraki K, Takase K, Tameda Y, Hamada M, Kosaka Y, Nakano T. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the fol­low-up of cirrhotic patients. Hepatology. 1995;22:802-807.

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HSCIVCJIP1997

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M Wars o' Progress in ^Pathology and

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There is no better way to start your spring than with friends and colleagues at the ASCP/ CAP National Meeting April 5-10,1997!

Come join us in our hometown of Chicago as w e celebrate 75 years of progress in pathology and laboratory medicine at this Spring Meeting.

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