CA 19-9 in Pancreatic Cancer

PANCREATIC CANCER

CA 19-9 IN PANCREATIC CANCER Roy E. Ritts, MD, and Henry A. Pitt, MD

Nearly two decades have passed since the tumor-associated antigen (TAA) CA 19-9 was described16and later identified as a Lewis blood group-related muin.'^,'^ Although the clinical application of CA 19-9 was initially suggested as a it subsequently became evident that the more monitor for colorectal ~arcinoma,'~ In the last 10 appropriate application of CA 19-9 was in pancreatic cancer.28,30,35 years, several hundred reports world-wide have attested to the clinical usefulness of CA 19-9 in the diagnosis, prognosis, and monitoring of pancreatic cancer. By imposing care in the use and interpretation of CA 19-9 with regard to (1)the reference value (RV or so-called cut-off level) chosen for positivity, (2) the Lewis phenotype, (3) icteric index of the patient, and (4) the combination of CA 19-9 with other diagnostic and clinical data, the assay for this TAA has become a valuable tool in the diagnosis and management of patients with pancreatic cancer (Table 1). As is the case with most tumor markers, the sensitivity of CA 19-9 in pancreatic cancer is not perfect. Nonetheless, CA 19-9 is clearly among the better cancer markers when intelligently applied and is superior to many markers routinely used, such as carcinoembryonic antigen (CEA), which, at best, should be reserved for second-look colon carcinoma patients. DIAGNOSIS

Any current appreciation of the clinical use of CA 19-9 in the diagnosis of pancreatic cancer should emphasize first that no data exist to support using this assay in screening for pancreatic or biliary malignancies. Furthermore, although massive serum levels of CA 19-9 are almost certainly confirmatory of pancreatic or biliary cancer in patients who bear such presumptive clinical suspicion, the proper role for CA 19-9 is as a diagnostic adjunct or simply as another piece of critical diagnostic information to be integrated into the diagnostic decision-making process. and the manufacturer's package insert when CA The first reports'5,28,30,35 From the Mayo Medical School, Mayo Clinic and Foundation (RER), Rochester, Minnesota, and the Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin (HAP) SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 7 . NUMBER 1. IANUARY 1998

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Table 1. FACTORS THAT INFLUENCE CA 19-9 INTERPRETATION reference (cut-off)level for "positivity" Lewis blood phenotype (-a, -b) degree of jaundice other diagnostic and clinical data prior interferon treatment

19-9 was first produced in the 1980s suggested a reference value of 37 to 40 U/ mL based on receiver operator character (ROC) analyses, which yielded a modest but acceptable sensitivity and specificity to detect most patients with pancreatic and Safi et however, both noted that much higher cancer. Steinberg et a134,35 serum levels (1000 U/mL or more) were essentially diagnostic for pancreatic cancer. The much decreased sensitivity at the levels of 1000 U/mL or higher imposed a concomitantly increased specificity, with resulting higher rates of false negativity and lower false positivity-not an ideal situation for any new proposed test as a stand-alone diagnostic, whether it be for syphillis, lupus, or cancer. Furthermore, at the time of first use in the early 1980s, the results of CA 19-9 assays departed from linearity > 90 to 100 U/mL because of the nature of the reagents and their assay configuration, so that both reference materials and patient specimens required multiple dilutions to determine high serum levels. This situation, in turn, incurred a modest loss in precision and occasional problems in day-to-day reproducibility seen with most largely carbohydrate TAAs. Despite the technical variabilities, however, the clinical interpretation of thousands of U/ mL was not in any way ambiguous, until it was recognized that jaundice, comparable to its effect on other glycoprotein TAAs, can cause a variably false increase The false increase is likely because of hepatic in serum levels of CA 19-9.5,22,26," insufficiency to degrade and excrete CA 19-9 metabolically. Although Pasquali et alz4did not observe the interfering effect of jaundice, caution in the use of CA 19-9 in patients with jaundice is generally understood, especially in the range of values of 40 to 120 U/mL. Moreover, these icteric patients are not so frequently a diagnostic dilemma for which CA 19-9 assays are indicated. For diagnostic use, a general consensus concerning a useful reference value has evolved from prospective and retrospective studies. What is lacking in the absence of a US Food and Drug Administration review and acceptance of CA 19-9 by a given professional group's considered recommendation is that a specific cut-off serum level for positivity has not been agreed upon. Nonetheless, accumulated results of CA 19-9 as a diagnostic adjunct indicate that a positive reference value of 100 U/mL should be used (Table 2), with nearly all reports citing significant patient accrual using 90 to 120 U/mL.6,1y,29,31,32,35 AS noted later, observations concerning prognosis, resectability, and postoperative monitoring report significant clinical correlations at different and occasionally much higher serum levels of CA 19-9. Understandably, the numbers of patients in these studies, except for

Table 2. CA 19-9 REFERENCE VALUE FOR DIAGNOSIS Level Accuracy (%)

From Forsmark C, Lambiase L, Vogel S: Diagnosis of pancreatic cancer and prediction of unresectability using tumor-associatedantigen CA 19-9. Pancreas 9:731-734, 1994; with permission.

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one by Kolb et al,14 are relatively small. However, it is probable that, like the interpretations of CEA and CA 125, more than one clinically relevant reference value will be pertinent for diagnosis, prognosis, and monitoring applications. To insist that a TAA must yield a definitive diagnosis of a condition or disease amenable to successful treatment, like an elevated serum electrolyte or serum metabolyte might do, before the TAA can be deemed appropriate for diagnostic use is a curious affectation. Perhaps this expectation reflects disappointment that all TAA moieties are not tumor-type or primary organ site specific or that they are not invariably present in all patients with a certain tumor or that they are not elaborated into the serum when tumors are quite small and surgically curable. Indeed, CA 19-9 is often present in patients with several different kinds of malignancies such as lung and ovarian cancers. Even in severe pancreatic infections, high CA 19-9 levels are noted.37Certainly, a pancreatic cancer patient with a Lewis (-a, -b) phenotype does not have positive CA 19-9 level in the absence of the phenotypically required precursors and synthetic pathway. Fortunately, this phenotype occurs in only approximately 15% of the population. On the other hand, some pancreatic cancer patients who are Lewis-positive with large pancreatic masses and distant metastases also can be CA 19-9 negative. In such circumstances, it is not certain whether antibody formation occurs and binds the CA 19-9 antigen to make CA 19-9 undetectable in the serum assay or whether the CA 19-9 is either not formed or not secreted into the circulation in quantities sufficient for detection because most tumors usually reveal CA 19-9 cellular localization. Patients who present for initial diagnosis are unlikely to have received interferon, but interferon significantly elevates CA 19-923as well as other TAAs.~Thus, the use of interferon can be confounding in experimental postoperative treatment protocols (see Table 1). CA 19-9 is not often positive in patients with early, small resectable pancreatic cancer. As a result, this group of patients remains difficult to detect, although the percentage of early-stage patients with positive CA 19-9 levels has been increasing in the last few years of reports, coincident with the assay becoming more commonly used as a diagnostic adjunct. Interferon may be an aid to amplify CA 19-9 serum levels in patients who are strongly suspected to have pancreatic cancer but whose imaging results are ambiguous. The four significant limitations of CA 19-9 in the diagnosis of pancreatic cancer (e.g., reference value, positive Lewis phenotype, icterus, and combination use of interferon) are not much different than other diagnostic modalities or tests commonly used for suspected cancer. Indeed, if diagnostic imaging procedures were held to the idealized criteria required of serologic tests, the sensitivity and specificity of CA 19-9 assays at reference values more than 100 U/mL appear to be equal or better than those of ultrasonography and CT in patients with pancreatic cancer. This statement is particularly true given the variation in the kinds and age of imaging equipment currently in use, different techniques, the difficulty in interpreting their results in some patients, and the differences in interpretation of the same images by multiple radiologists. Continuous technical improvements and scientific advances enhance the accuracy for diagnosis of both immunologic assays and imaging; but combining the two approaches provides a more effective diagnostic stratagem, given that the previously noted limitations of the CA 19-9 are observed. The combined use of CT and CA 19-9 in nonicteric patients provides a positive predictive value of 99% to 100% in the diagnosis of pancreatic cancer when a CA Comparable 19-9 reference value of 100 to 120 U/mL is used (Table 3).5,7,10,13,19,25,29 results using the CA 19-9 lower reference values of 37 U/mL were reported by Carlucci et a13 and DelMaschio et a14 (both groups using CT-guided fine needle percutaneous biopsy) and in a study by Niederau and Grendell.21Smaller, but similarly impressive negative predictive values of CA 19-9 to exclude pancreatic

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Table 3. CA 19-9 IN COMBINATION WITH OTHER TESTS FOR DIAGNOSIS Positive Predictive Value Without CA 19-9 (Oh)

CA 19-9 >40 (%)

Ca 19-9

>I00 (%)

ultrasound CT ERCP ERCP = endoscopic retrograde cholangiopancreatography. From Ritts R, Nagorney D, Jacobsen D, et al: Comparison of preoperative serum CA 19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease. Pancreas 9:707-716, 1994; with permission.

cancer have been reported in the accumulated reports from many countries, despite some differences in details. Among the published studies, the ultrasound results were comparable to CT when combined with CA 19-9, although ultrasonography has somewhat less individual sensitivity. The addition of other markers, such as CEA or CA 50, alone or in combination, offered no improvement in overall ~ e n s i t i v i t y . ~ ~ , ~Because ~ , ~ ~ , many ~ ~ , ~ patients ~ ~ ~ , ~ ~had , ~ ~both CT and ultrasonography in the course of their examinations and, depending on the institution and year also had endoscopic retrograde percutaneous cholangiography (ERPC) and percutaneous needle biopsies, most authors have observed that a single imaging CT or ultrasonographic examination plus a CA 19-9 assay offered a superior and cost-effective approach for diagnosis of pancreatic cancer. This approach saves time, discomfort, radiation exposure, and expense to the patient and further work by the medical staff. In addition to the concordance of their conclusions, it is interesting that most of these investigations began independently in the early 1990s. Although the observation periods and dates of the publications differ by 2 to 5 years, no comparable studies have been published after 1994 to the time of this summary in 1997. Despite the inherent simplicity and obviousness of the multimodality diagnostic approach, CA 19-9 has been disapproved twice in the past by the US FDA. The transcripts of the FDA advisory panel proceedings note that the assay results for CA 19-9 were not persuasive as an independent test for pancreatic cancer, and even if the assay were in combination with other modalities, it was inappropriate for use because early lesions were generally not revealed. Thus, no improvement in surgical cures would be observed because pancreatic cancer is rapidly fatal. In addition, the advisory panel suggested that if CA 19-9 were approved, all patient costs would increase because of the inappropriate application of the assay. The fear of an assay's excessive and inappropriate use, for example, in costly "diagnostic panels" of all available markers, is a realistic one. Indeed, the number of colon cancer surgical patients tested as second-look candidates (the approved consensus indication for CEA assay) is too few to command an average annual $70 million US market in CEA kits, even when most second-look patients are not surgically salvageable when CEA becomes elevated. Conversely, the reluctance to accept TAAs for their practical clinical utility, albeit limited in scope or for diseases of relatively low frequency, is especially unfortunate. The lack of an authoritative, official review and recommendations for the use of CA 19-9 delays not just an authorative reference value for the analyte but more significantly compromises the rigors of an assay performance standard, cogent recommendations for its clinical application, and specification of limitations.

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PROGNOSIS

Most of the previously cited authors, particularly S t e i n b ~ g )Haglund ~ and associate^,'^ and Safi and colleagues,3' presented preliminary data that CA 19-9

had prognostic value and might be useful in selecting patients for surgery and evolving radiation and chemotherapy programs. Satake et a133and Tian et a136both reported a correlation between CA 19-9 serum levels and tumor stage, with Tian et a1 observing that recurrent increases in CA 19-9 preceded by 2 to 9 months the progression of disease detectable by CT or clinical findings (Table 4). The prognostic application of CA 19-9, along with a few observations on monitoring, constitutes most of the more recent clinical reports, in which authors are in general agreement to validate the concept but use different cut-off serum levels of CA 199. In Japan, Yasue et a140used a reference value of 37 U/mL to report a preoperative sensitivity of 85% in 90 patients with advanced pancreatic cancer. Those patients with elevated levels of CA 19-9 or CEA (>5 ng/mL) had a poor prognosis; and in those patients who underwent operation, an elevation of CA 19-9 within 1 month after surgery significantly increased the hazard rate. In Italy, Plebani et alZ6 used 80 U/mL as the reference value and found a highly significant shortened survival in persons with elevated levels. Neither of these two investigative groups could correlate serum levels with size or spread of tumor, although van den Bosch et a138 reported that of 122 patients with pancreatic cancer, those with distant metastases at initial examination had a significantly higher CA 19-9 level than those without. In the postoperative period, a similarly significant correlation existed with elevated CA 19-9 and the development of distant metastases. In recent reports,14,17patients with resectable disease had a significantlybetter prognosis if their preoperative CA 19-9 levels were less than 100 U/mL. In persons with advanced disease prognosis was better if CA 19-9 levels were less than 3500 U/mL. Lundin et all7 and Kolb et all4 had comparable conclusions in studies of 347 pancreatic cancer patients, of whom 126 deemed to be resectable had a highly significant lower preoperative CA 19-9 level than the 221 unresectable patients with elevations >90 U/mL. After resection, CA 19-9 values quickly declined but normalized in 29% of stage I, 13% of stage 11, and 10% of stage I11 patients. Corresponding survival times were longer than in those patients whose CA 19-9levels had decreased but not returned below reference levels (33 months versus 11.3 months for stage I; 41 months versus 8.6 months for stage 11, and 28 months versus 10.8 months for stage 111).Eighty-eight percent of those with recurrent disease had elevations of CA 19-9. Similar data also have been reported recently by Safi et aP2 (Table 5). These reports from Japan, Sweden, Italy, the Netherlands, and Germany are

Table 4. CA 19-9 FOR PROGNOSIS Clinical Situation

CA 19-9 Level

<5 cm tumor resectable tumor unresectable tumor >5 cm tumor after resection tumor recurrence

120 U/mL 130 UImL 745 U/mL 750 U/mL decreases increases

From Tian, F, Alpert H, Myles J, et al: Prognostic value of serum CA 19-9 levels in pancreatic adenocarcinoma. Ann Surg 215:350-355, 1992; with permission.

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Table 5. CA 19-9 FOR RECURRENCE AFTER SURGERY

n

Stage

Diagnosis Without CA 19-9 (wk)

Recurrence (%)

Lead Time With CA 19-9 (wk)

From Safi, F, Kolb G, Beger H: Clinical relevance of CA 19-9 in diagnosing and monitoringpancreatic cancer with special reference to the Lewis phenotype. In Programs and Abstracts of the Annual Meeting of the American Association for Cancer Research, 1995, p A1 326; with permission.

different in many of the details, especially in using an established reference value and in the total number of patients being presented. Moreover, many fewer papers report on the prognostic use of CA 19-9 than on its use in diagnosis. However, the conclusions of the international prognosis papers are quite similar, suggesting a prognostic use for CA 19-9 preoperatively for resectability, for survival, and for postoperative recurrence, all of which confirm more anecdotal data on the assay's use in earlier diagnostic studies. The international reports are important, with conclusions that have useful clinical and economic significance. Nonetheless, one could hope for a confirmatory multicenter study with an agreed-upon protocol that would (1) standardize the several variables involved with the assay of CA 19-9, (2) include other potentially relevant tests, (3) set the criteria for patient eligibility, and (4) stratify the utility of other diagnostic modalities, types of surgery, and postoperative therapeutic trials. MONITORING

Several important observations using CA 19-9 to monitor combined modality treatments have been presented. Willet et aP9 examined CA 19-9 levels in 42 patients who received neoadjuvant treatment of external beam radiation and 5-fluorouracil. Patients were restaged with CT before laparotomy with either a Whipple procedure or intraoperative radiation. Nine of the 10 patients with increased CA 19-9 levels after radiation had distant metastases or localized disease extension identified by the restaging CT or surgery, in statistically significant contrast to 6 of 29 patients (21%)with declining CA 19-9 values (Table 6). In another study by Gattani et a1,8 9 unresectable anicteric and noninfected stage I1 and 25 stage I11 pancreatic cancer patients were treated with split-course radiation therapy and 5-fluorouracil, streptozotocin, and cisplatin. Their responses

Table 6. CA 19-9 FOR MONITORING NEOADJUVANT THERAPY CA 19-9 After Chemoradiation

n

Disease Progression (%)

increased decreased

10 29

90 21*

* P < 0.05 versus increased. From Willett C, Daly W, Warshaw A: CA 19-9 is an index of response to neoadjunctivechemoradiation therapy in pancreatic cancer. Am J Surg 172:350-352, 1996; with permission.

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were monitored by changes in CA 19-9, CEA, and CA 125. The markers were too variable in the 9 stage I1 patients to analyze, but of those with stage I11 disease, 16 patients with CA 19-9 levels less than 2000 U/mL had a median survival of 12.8 months. In significant contrast, eight patients with CA 19-9 levels more than 2000 U/mL had a median survival of 8 months (with one additional patient at >2000 U/mL surviving 1 year). CA 125 provided additional diagnostic return (in log rank and Wilcoxon statistical probability), but CEA yielded no correlations alone or in combination with the other two markers. The authors found that neither performance status nor tumor size were comparable prognostic variables for the stage I11 patients. Ishii et al" monitored CA 19-9 levels in 66 advanced pancreatic cancer patients who received chemotherapy. All patients had pretreatment levels of CA 19-9 more than 100 U/mL, and the authors defined a "responder" as a patient whose CA 19-9 level was reduced by 50% or more of their pretreatment level within 2 months of chemotherapy. Nine (13%)such patients had median survival times of 141days, compared with 88 days for the nonresponders. Cox regression analysis indicated a poor, relative risk of death for the latter group. Taken together, the three studies8,n,39 show an effective application of CA 19-9 for monitoring and risk assessment or possibly even patient selection for chemotherapy, notwithstanding the relatively modest numbers of such patients.

CONCLUSION

TAAs such as prostatic specific antigen (PSA), CA 125, CA 19-9, CEA, and other markers such as beta-hCG and alpha fetoprotein are helpful, albeit limited, diagnostic or monitoring aids in patients with different kinds of cancer. No tumorassociated antigen yet has the sensitivity and specificity that hCG has as a marker associated with trophoblastic disease. However, the literature is clear that TAAs, including CA 19-9, have an important role in managing patients, affecting decisions and outcomes, and potentially reducing costs and risks for patients, provided that the biology, reference levels, and limitations of the assays are obCA 19-9 has a somewhat unique role in serving as a diagnostic adjunct with CT or ultrasonography to provide a cost-effective, positively predictive value for pancreatic cancer. The combination can reduce the necessity for multiple imaging techniques and can assess patient survival and tumor resectability. In the future, more precise molecular probes and genetic markers are likely to enable improved clinical applications and decisions in the management of pancreatic cancer and other malignancies. Until these markers are described and validated, however, reasonable data from worldwide studies recommend the clinical use of CA 19-9 for patients with pancreatic cancer.

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Address reprint vequests to Henry A. Pitt, MD Department of Surgery Medical College of Wisconsin 9200 W. Wisconsin Ave. Milwaukee, WI 53226