CANCER DIAGNOSIS AND MANAGEMENT MAURIE MARKMAN, M D Dr. Markman is chairman of the Department of Hematology/Wledical Oncology at the Cleveland Clinic, and an associate editor of the Cleveland Clinic Journal of Medicine. When and how to use serum tumor markers in clinical practice C We measure tumor markers mostly in following up patients who have cancer linicians have long wished for a simple blood or urine test that would be sensitive enough to detect cancer in its early stages when the tumor volume is small, yet specific enough to avoid large numbers of false-positive results. Such a test would measure tumor markers— substances that, in abnormal concentrations, suggest the patient has cancer. Unfortunately, no such ideal test exists, or is likely to. T h e problem is that the structural and biochemical differences between normal and malignant cells are remarkably limited, and the differences in the proteins and other substances that normal and malignant cells secrete are far more quantitative than qualitative. • ROLE OF T U M O R MARKERS IN CLINICAL PRACTICE Nevertheless, we do measure certain tumor markers in certain situations, mostly in following up patients who have cancer, in whom we want to monitor the course of the disease, assess the effect of treatment, and check for recurrence (TABLE). Increases or decreases in the serum levels of some tumor markers can influence therapeutic strategies. For example, a rising human chorionic gonadotropin ( H C G ) level in a patient with testicular cancer would indicate that the treatment needs to be changed. Other tumor markers provide prognostic information, although we may not know yet whether changing the therapy on the basis of these data can either improve quality of life or prolong survival. A n example would be a rising carcinoembryonic antigen ( C E A ) level after definitive surgery for colon cancer. Some tumor markers also find use as diagnostic tests, but because most are not specific for cancer, they do not by themselves prove that cancer is present, and are therefore used only in conjunction with other tests. Dangers of overinterpreting tumor marker levels It is important to not overinterpret changes in tumor marker levels, for several reasons. The value may be incorrect, due to tests being run on the wrong patient's serum, problems with laboratory technique, or transcription errors. The test may not be specific. Abnormal laboratory values can indicate a benign rather than malignant condition. For example, the prostate-specific antigen ( P S A ) level can be elevated in benign prostatic hyperplasia; the carbohydrate antigen 125 ( C A - 1 2 5 ) level can be elevated in endometriosis or pregnancy. Because the diagnosis of cancer or the documentation of disease recurrence or progression has great therapeutic, prognostic, and emotional significance, the burden of proof must be extremely high. Thus, in general, histologic analysis remains the "gold standard" for decision-making in oncology, while tumor markers play a supportive role. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 6 4 • NUMBER 1 Downloaded from www.ccjm.org on September 19, 2014. For personal use only. All other uses require permission. J A N U A R Y 1997 2 7 SERUM TUMOR MARKERS • MARKMAN TABLE TUMOR MARKERS AND THEIR CLINICAL USES Marker Abbreviation Normal limit Use Prostate-specific antigen PSA < 4.0 ng/mL Prostate can:er screening and follow-up Human chorionic gonadotropin HCG Undetectable Testicular cancer follow-up Alpha fetoprotein AFP < 10 ng/mL Testicular cancer follow-up Carcinoembryonic antigen CEA < 2.3 ng/mL Colorectal cancer follow-up Carbohydrate antigen 15-3 CA-15-3 < 29 U/mL Breast cancer follow-up Carbohydrate antigen 125 CA-125 < 35 U/mL Ovarian earner follow-up 5-Hydroxyindoie acetic acid 5-HIAA < 10 pg/mg creatinine* Carcinoid tunor diagnosis and follow-up ' M e a s u r e d in u r i n e CLINICALLY USEFUL T U M O R MARKERS The combination of a PSA test and a rectal examination appears to be an effective way to screen for prostate cancer Prostate-specific a n t i g e n (PSA) A s mentioned above, an elevated P S A level is not specific for prostate cancer. However, the combination of a P S A test and a rectal examination appears to be an effective way to screen for prostate cancer. In one study, P S A testing by itself had a positive predictive value of 3 1 . 5 % , vs 2 1 % for digital rectal examination and 4 8 % for the combination of the two. Several authorities propose a P S A level of 4 . 0 ng/mL as a normal limit in prostate screening studies. P S A is also of value in detecting the early recurrence of prostate cancer after surgery or radiation therapy. In this setting the P S A level is elevated in 9 0 % or more of cases, frequently more than a year before symptoms of disease progression appear. Unfortunately, the therapeutic options in this situation are limited and generally palliative in intent. A n o t h e r use of P S A testing is to monitor the effects of therapy in patients with metastatic prostate cancer. H u m a n chorionic g o n a d o t r o p i n (HCG) a n d alpha f e t o p r o t e i n (AFP) T h e s e two tumor markers are not sensitive enough to serve as screening tests for testicular cancer, but in a man known to have germ cell 2 8 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 1 JANUARY cancer, a confirmed elevation (ie, abnormal value on repeated tests) in either marker warrants starting therapy. Similarly, failure o f these marker levels to normalize after surgery or chemotherapy (depending on the status of the cancer) indicates t h e need to change the therapeutic strategy. T h e sensitivity of these tests for small volumes of testicular cancer makes it possible for carefully selected patients to be treated conservatively (ie, with more limited surgery or without chemotherapy). Such patients undergo frequent blood tests for several years and begin chemotherapy if these markers b e c o m e elevated, even without other signs or symptoms. T h e serum levels o f H C G and A F P at t h e start o f therapy, and their rate of decline during therapy, correlate well with tumor volume and the number of tumor cells killed, respectively. For this reason, these markers h a v e been used to evaluate different treatments in testicular cancer. Carcinoembryonic antigen (CEA) T h e serum C E A level is c o m m o n l y elevated in a number of malignant (eg, colorectal c a n c e r ) and nonmalignant conditions (eg, cigarette smoking). T h e CEA level is used most frequently to follow up patients with known colorectal cancer, whom a confirmed rise in the C E A level after definitive local therapy 1997 Downloaded from www.ccjm.org on September 19, 2014. For personal use only. All other uses require permission. (usually surgery with or without local radiotherapy) generally indicates recurrence. Unfortunately, for now, the therapeutic implications of a rising C E A level are limited, as chemotherapy in this setting is only palliative in intent. Some investigators suggest that monitoring the C E A level after definitive surgery may allow for more successful surgical removal of metastases (eg, in the liver). However, the clinical utility of such a strategy needs to be defined in well-designed clinical trials. Carbohydrate antigen 15-3 (CA-15-3) T h e serum level of this glycoprotein antigen has been demonstrated to correlate reasonably well with the total body burden of breast cancer. Thus, C A - 1 5 - 3 measurements have been used to monitor patients with breast cancer and to determine their response to chemotherapy. This antigen can also be used to demonstrate progression of disease after definitive local therapy. Carbohydrate antigen 125 (CA-125) C A - 1 2 5 is a cell-surface antigen secreted by both malignant and normal tissue. Although not specific for any malignant disease, it is most commonly elevated in cancer of the ovary. Like C A - 1 5 - 3 testing, C A - 1 2 5 testing is most frequently used to follow the progress of the disease, and especially the response to chemotherapy. Unfortunately, while an abnormal C A 125 level in a woman treated for ovarian cancer strongly indicates the cancer is still present (even in the absence of signs or symptoms), a normal value does not mean the cancer is gone. In fact, several studies demonstrated that 5 0 % of women with advanced ovarian cancer whose C A - 1 2 5 levels returned to normal by the end of chemotherapy still had microscopic or small-volume residual macroscopic disease within the abdominal cavity. 5-Hydroxyindole acetic acid (5-HIAA) T h e urinary 5 - H I A A level, used to detect carcinoid tumors, is perhaps the closest a tumor marker can come to being "diagnostic" for a particular cancer. Serotonin, which is secreted by carcinoid tumors, is degraded into 5 - H I A A which is secreted into the urine. 5 - H I A A levels can be monitored to follow the natural history of carcinoid tumor or its response to treatment. In addition, in a patient with histologically documented cancer in which the primary site is undetermined and in which carcinoid tumor is included in the differential diagnosis, an elevated 5 - H I A A level can confirm the diagnosis. • • SUGGESTED READING A m e r i c a n S o c i e t y o f C l i n i c a l O n c o l o g y . C l i n i c a l p r a c t i c e guidelines for t h e use o f t u m o r markers in breast and c o l o r e c t a l c a n cer. J C l i n O n c o l 1 9 9 6 ; 1 4 : 2 8 4 3 - 2 8 7 7 . B a t e s S . C l i n i c a l applications o f serum t u m o r markers. Intern Med 1991; Ann 115:623-638. C a t a l o n a W J , S m i t h D S , R a t l i f f T L , et al. M e a s u r e m e n t of prostate-specific a n t i g e n in serum as a screening test for prostate c a n c e r (published erratum appears in N Engl J M e d 1991; 3 2 5 : 1 3 2 4 ) . N Engl J M e d 1 9 9 1 ; 3 2 4 : 1 1 5 6 - 1 1 6 1 . M o e r t e l C G , F l e m i n g T R , M a c d o n a l J S , Haller D G , Laurie J A , Tangen C . A n evaluation of the carcinoembryonic antigen ( C E A ) test for m o n i t o r i n g p a t i e n t s w i t h resected c o l o n cancer. J A M A 1993; 2 7 0 : 9 4 3 - 9 4 7 . O e s t e r l i n g J E , M a r t i n S K , Bergstralh EJ, L o w e F C . T h e use o f prostate-specific a n t i g e n in staging patients w i t h newly diagnosed prostate cancer. J A M A 1 9 9 3 ; 2 6 9 : 5 7 - 6 0 . W o l f A M D , Nasser JF, W o l f A M , S c h o r l i n g J B . T h e impact o f Unfortunately, a normal CA-125 level does not mean that ovarian cancer is gone informed c o n s e n t o n p a t i e n t interest in prostate-specific a n t i g e n screening. A r c h Intern Med 1996; 156:1333-1336. A D D R E S S REPRINT REQUESTS t o M a u r i e M a r k m a n , M D , D e p a r t m e n t of Hematology/Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 1 Downloaded from www.ccjm.org on September 19, 2014. For personal use only. All other uses require permission. JANUARY 1997 3 5