Prognostic Value of Serum CA in Pancreatic Adenocarcinoma

19-9

Levels

FUZHOU TIAN, M.D.,* HUBERT E. APPERT, PH.D.,t JONATHAN MYLES, M.D.,t and JOHN M. HOWARD, M.D.*

Thirty-eight patients with histologically proven pancreatic adenocarcinoma were investigated to establish the utility of serum CA 19-9 as a prognostic indicator. CA 19-9 assays were performed serially during the course of the disease. In four patients with negative Lewis blood type, the CA 19-9 levels remained essentially normal throughout the disease course. In the remaining 34 patients, (1) CA 19-9 levels were significantly lower in patients with tumor size no larger than 5 cm in diameter, and in patients with resectable tumors than in those with tumor size larger than 5 cm or with unresectable tumors (p < 0.01). 2) CA 19-9 levels dropped sharply after resection in all 11 resectable patients, whereas no significant change was found after laparotomy without resection. (3) The average survival time in seven patients whose CA 19-9 levels returned to normal after resection was significantly longer than in those four patients with postoperative CA 19-9 levels that decreased but did not return to normal (21.9 versus 8.7 months, p < 0.05). (4) In 6 of 11 patients who underwent resection, recurrent elevation of CA 19-9 preceded changes detectable by computed tomography or clinical examination by 2 to 9 months. (5) In 23 patients who died of pancreatic carcinoma, 15 (65%) had an obvious rise in CA 19-9 level before death. There was a correlation between the doubling time of the CA 19-9 serum level and survival time (r = 0.5, p < 0.05). Because it can be demonstrated that the reduction of tumor burden by resection lowers serum CA 19-9 levels, serum CA 19-9 levels may be a useful indicator of whether other forms of treatment such as radiation therapy or chemotherapy also reduce the tumor burden.

S

INCE THE CA 19-9 monoclonal antibody was produced from a hybridoma cell line that was established by Koprowski et al.' in 1979, much has been written on its usefulness in patients with exocrine pancreatic adenocarcinoma.2-5 There are limitations, however, on its use for the initial diagnosis of the disease.6'7 Currently, attention is being focused on the utility of serum CA 19-9 in determining the prognosis of postoperative surgical patients with pancreatic adenocarcinoma and in monitoring postresection patients for recurrence Address reprint requests to John M. Howard, M.D., Harris McIntosh Towers, Suite 940, 2121 Hughes Drive, Toledo, OH 43606. Accepted for publication November 4, 1991.

350

From the Departments of Surgery and Pathology, tMedical College of Ohio, and *The Toledo Hospital. Toledo, Ohio

of the disease.8'9 It has been reportedl' that patients who are Lewis blood type negative (Lea-b-) do not express the CA 19-9 antigen, and thus, a negative Lewis blood type may be seen in a significant number of pancreatic patients who lack elevated serum CA 19-9 levels.'0 The present study is a clinical evaluation of the value of serial measurements of serum CA 19-9 levels in determining prog-

nosis in patients with pancreatic adenocarcinoma in patients that are Lewis blood type positive. Materials and Methods

Between January 1987 and November 1990, 38 patients (22 men and 16 women) with histologically proven pancreatic adenocarcinoma were studied. Each patient underwent laparotomy, at which time the longest diameter of the tumor was recorded. The patients were divided into two groups according to the tumor size (group 1, tumor size c 5 cm; group 2, tumor size > 5 cm). They were secondarily grouped by tumor resectability versus nonresectability. Serum CA 19-9 serum levels were determined serially by an immunoradiometric assay using the Centocor radioimmunoassay kit (Centocor, Inc., Malvern, PA). A value of 37 U/mL was used as the upper limit of normal. " Serum samples were collected from the patients 1 or 2 weeks before operation and approximately 1 week, 1 month, and every 3 months after operation. For patients with serum CA 19-9 levels lower than 500 U/mL, Lewis blood type was tested using blood grouping serum AntiLea and Anti-Leb (Ortho Diagnostic Systems, Inc., Raritan, NJ). Additional follow-up studies included clinical examination, routine biochemical and hematologic profiles, and computed tomography (CT) scans at 3-month intervals after operation. The rate of the increase of CA 19-9 levels was evaluated in terms of doubling time, the

VOl. 215.- NO. 4

SERUM CA 19-9 AND PANCREATIC ADENOCARCINOMA

time in days required for the CA 19-9 to double.'2 It was determined on the time axis between the two points that corresponded to the doubled serum CA 19-9 values.

Statistical Analysis Determination of statistical significance of comparisons in CA 19-9 values was calculated using Mann-Whitney U test because of the skewness in the distribution of the data.'3 For comparisons in survival time, the Student's t test was employed. The correlation between doubling time and survival time was calculated by linear regression using the least square method.

i

105-

I 104

-

c)

a)

0 -i

EI

103

.

0)

Patients Included in the Study Of the 38 patients, 35 had one or more preoperative CA 19-9 determinations. The CA 19-9 levels ranged from

0

I

.

0a E cn D

Results

T *

I

I

102 I

0

10 5.

L

0

0

S 104

Unresectable

FIG. 2. Comparison of CA 19-9 serum levels between 11 patients with resectable disease and 20 patients with unresectable disease. The bars represent median values (p < 0.01).

0

Ce

a)

a)

Resectable

103

0

-J

E E cn D CD)

0

%-

0)

i

1~

0 0

10Q2 0

Tumor Size < 5cm

Tumor Size > 5cm

(maximal diameter) FIG. 1. Serum CA 19-9 levels in 14 patients with tumor sizes of 5 cm or less compared with 17 patients with tumor sizes greater than 5 cm. Data in this figure and in all subsequent figures were taken from patients with Lewis-positive blood. The bars represent median values (p < 0.01).

21.9 months as shown in Figure 3A. Of these seven patients, four remain alive and well 13 to 29 months later with relatively stable, low levels of CA 19-9 and without any clinical evidence of recurrence or metastasis of the disease up to the time of this report. One showed a secondary elevation of CA 19-9 before hepatic metastasis was found by CT. In four patients whose CA 19-9 levels remained elevated after operation, the average survival time was 7.8 months, a significantly shorter time than the former group (p < 0.05) (Fig. 3B). Figure 5 shows the sequence of changes in CA 19-9 levels in two typical patients with different postoperative courses. In 26 patients who died of pancreatic cancer, three were Lewis-negative patients whose CA 19-9 remained a low value until death. Of the 23 Lewis-positive patients, 15 had an obvious rise in CA 19-9 level before death (65%). After a sudden rise in CA 19-9 levels, the patients' subsequent survival was approximately 2.9 to 13.8 times their CA 19-9 doubling time. A linear correlation (r = 0.5, p < 0.05) was established between these two times (Fig. 6).

5000 + 1000 CU)

a) -J C5) 0)

500 ±

1004E a)

Cn)

37.

N pre-operative CA 19-9

post-operative CA 19-9

5

15

FIG. 3. (A, left) Changes in serum CA 19-9 levels in 11 patients who underwent resection of pancreatic carcinoma. Shaded area represents normal of serum CA 19-9 levels. (B, right) Mean survival times of seven patients with normal serum CA 19-9 levels after operation versus four patients with elevated CA 19-9 levels. range

353

SERUM CA 19-9 AND PANCREATIC ADENOCARCINOMA

Vol. 215 * No. 4

103

105 CO)

------O-

-J

1 2

1 04 I E cnD 0

a)

103

co

a)

i

-J

O t 1p

Operation C)D

FIG. 5. Serum CA 19-9 levels in two typical patients with different courses of pancreatic carcinoma after tumor resection. Patient A (triangles), a 6 1-year-old man, died of liver metastasis at the time indicated by the vertical bar. Patient B (circles), a 50-year-old man, is alive and well.

102

con

pre-operative

post-operative

FIG. 4. Serum CA 19-9 levels before and after operation for unresectable pancreatic carcinoma in 9 patients who underwent biliary bypass for jaundice (closed circles) and in 11 patients without jaundice who underwent laparotomy (open circles).

Discussion Numerous investigators have reported on the utility of CA 19-9 in early and differential diagnosis of pancreatic adenocarcinoma. The sensitivity (69% to 93%) and specificity (78% to 98%) reported in various series were quite encouraging.' 3 14-16 Only a few reports, however, have appeared evaluating the utility of serum CA 19-9 deter-

mination in monitoring the course of the disease.8'9 This study has evaluated the usefulness of monitoring patients with known carcinoma of the pancreas by serial CA 199 radioimmunoassay. Previous investigators have noted that an elevation of serum CA 19-9 can be a measure of tumor progression.'7"'8 One of the important factors limiting the sensitivity of serum CA 19-9 assay is that some pancreatic cancers do not express this antigen to an appreciable extent. Exclusion of these patients is thus a prerequisite for the use of serum CA 19-9 antigen levels in the diagnosis and evaluation of the progress of the disease. Studies have shown that subjects with the Lea-b- blood group practically never produce CA 19-9 antigen.'0" 9 The CA 19-9 epitope is a complex carbohydrate that is a sialated Lewis (Lea) blood group antigen. The expression of the CA 19-9 epitope depends on the presence of the glycosyltransferase that sialates the Lewis antigen.20 The

TABLE 1. Lead Time of CA 19-9 Re-elevation vs. Clinical Evidence of Cancer Recurrence

Clinical Evidence of Cancer Progression

Patient

Age

Sex

Time of CA 19-9 Level Re-elevation (mo after operation)

1 2

56 59

M F

24 6

31 8

CT CT PE

3

50 61 67 65

F M M F

6 3 12 3

10 9 21 5

CT (-) Laparotomy CT CT CT

4 5 6

CT, computed tomography; PE, physical examination.

Time

Examination

Results

Pulmonary metastasis Local cancer recurrence Abdominal wall metastasis Hepatic metastasis Hepatic metastasis Hepatic metastasis Pulmonary metastasis

Lead Time of CA 19-9 Assay (mo) 7 2 4 6

9 2

354 350-

TIAN AND OTHERS

300c 250a

0

200. E0 o

- 150-

. 100-

cm

5000

i0

40 20 30 CAI19-9 Doubling. Time (Days)

50

FIG. 6. The linear correlation between survival time and doubling time of serum CA 19-9 levels in 15 patients with marked increases of CA 199 levels before death (r = 0.5, p < 0.05).

Lea-b- pancreatic cancer patients cannot express CA 199 because they do not have the oligosaccharide of the Lewis antigen to which sialic acid is added to form the CA 19-9 epitope. Approximately 5% of the population are Lewis type negative.2' Consequently it is reasonable to reject Lea-b- patients as candidates for serum CA 199 monitoring of their disease progression. In addition, poorly differentiated neoplasms may lack production of the CA 19-9 antigen.22 In the current series, 4 of 38 patients belonged to the Lea-b- group (1 1%). All CA 19-9 serum levels of these four patients, before and after operation, including their preterminal levels, were less than 61 U/mL. Excluding these four patients, the preoperative sensitivity of CA 19-9 assay improved, the median value rising from 330 to 360 U/mL. Our data in the 34 Lewis positive patients indicate that higher levels of serum CA 19-9 are correlated with larger tumor sizes even though much overlap existed. This supports the concept that CA 19-9 levels can be used as an indicator of tumor burden. Also, relatively low CA 19-9 levels suggest a likelihood of resectability of the pancreatic cancer, because in 6 of 11 Lewis-positive resectable patients, the preoperative CA 19-9 levels were below 200 U/ mL. Although only slightly elevated serum CA 19-9 levels can reflect a better prognosis for patients with pancreatic cancer, such values require that other diagnostic means be used to rule out nonmalignant pancreatic or biliary tract diseases.2"6

The comparison of the postoperative serum CA 19-9 levels with the preoperative level could, from our observation of 11 resectable Lewis-positive patients, provide information about the effectiveness of the operative resection. Each of the 11 patients who had their tumors removed had a sharp decrease in CA 19-9 serum concentration. Furthermore, the survival time in the seven patients in whom postoperative CA 19-9 dropped to the

Ann. Surg. * April 1992

normal range was significantly longer than in the four with persistently elevated CA 19-9 levels. Each ofthe latter four patients died of tumor recurrence or distant metastasis that had become evident much earlier than in the group with normal postoperative CA 19-9 levels. This suggests that the persistently elevated serum CA 19-9 level reflects the presence of a "critical volume" of cancer. By comparison, simple laparotomy and biopsy, without resection, resulted in no significant change in the CA 19-9 levels in patients without obstructive jaundice. Similarly, in nine patients with preoperative jaundice, biliary bypass resulted in only a slight decrease in CA 19-9 levels. Studies ofthe metabolic degradation ofthe CA 19-9 have not yet been reported in the literature. Serum CA 19-9 levels, however, decrease in the patients after biliary decompression, presumably as a result of improved hepatic function and biliary drainage rather than from any regression of the cancer per se.7'23 After the decrease of the CA 19-9 level after resection, a secondary rise is very suggestive that a clinically significant metastasis or local recurrence is evolving. Of resectable patients, six who subsequently developed recurrence or metastasis had a secondary elevation in CA 199 before the CT scan or clinical evaluation demonstrated the lesions. Five of the six died of the cancer. The lead time of CA 19-9 assay was from 2 to 9 months. One individual in the group of patients did not show a secondary elevation before death, even though he was verified as being Lewis positive. A review of the literature'2'24'25 indicates that survival time after diagnosis, expressed in multiples of doubling time of various serum tumor markers, can be used as a basis for prognosis and for evaluating the effect of various therapeutic modalities. Effectively treated cancer patients may survive up to 20 or more doubling times, as opposed to ineffectively treated patients, whose life expectancy may be only a few doubling times.'2 In our patients, the rate of the increase of CA 19-9 concentration could, to some extent, be correlated with the survival time both in resectable and in unresectable patients. The survival time ranged from 2.9 to 13.8 times the doubling time. Because many factors in clinical practice influence the survival time, an exact correlation could not be expected. In 23 patients, however, who died of their cancer, 15 (65%) revealed an increasing CA 19-9 level before death. A linear correlation between doubling time and survival time was found. This suggests that any therapeutic procedure that slows the rate of serum CA 19-9 increase should prove effective in prolonging the survival of patients with pancreatic carcinomas. From our data, we conclude that the serum CA 19-9 assay is useful for monitoring the progress of the disease in patients with either resectable or unresectable pancreatic adenocarcinomas. Serial examination of serum

Vol. 215 * No. 4

SERUM CA 19-9 AND PANCREATIC ADENOCARCINOMA

levels of this antigen in the Lewis-positive patient apparently reflects the tumor burden at any given time. Hopefully, as with the carcinoembryonic antigen level in the patient with cancer of the colon, a secondary rise in the CA 19-9 level may alert the physician to the need for careful re-evaluation of his patient's therapy. Conclusions Among 34 patients who were Lewis blood type positive, significantly lower serum CA 19-9 levels were found preoperatively in those patients with the smaller cancers and in those whose cancer proved resectable. After resection of the tumor, the serum concentration of CA 19-9 decreased. A secondary rise in the serum level preceded, by 2 to 9 months, the verification of recurrence or metastasis by other means. Among those patients whose CA 19-9 level decreased to the normal range after resection, the subsequent survival time was significantly longer than was the survival time of those patients whose CA 19-9 level remained higher than normal after resection. In the overall group, 23 of 34 Lewis-positive patients who died during the course ofthe study, 65% ofthe patients demonstrated an obvious rise in CA 19-9 level before death. Among the four patients ( 1%) who were Lewis blood type negative, none showed a significantly elevated CA 19-9 level during the course of their disease. Thus, in 89% of the patients who are Lewis blood type positive, the CA 19-9 serum antigen level provides a useful indicator of the prognosis and effectiveness of the treatment of cancer of the exocrine pancreas.

7.

8.

9. 10. 11.

12. 13. 14. 15.

16.

17.

18.

19.

References 1. Koprowski H, Steplewski Z, Mitchell K, et al. Colorectal carcinoma antigens detected by hybridoma antibodies. Somat Cell Genet 1979; 5:957-972. 2. Safi F, Roscher R, Beger HG. Tumor markers in pancreatic cancer: sensitivity and specificity of CA 19-9. Hepatogastroenterology

1989; 36:419-423. 3. Haglund C, Roberts PJ, Kuusela P, et al. Evaluation of CA 19-9 as a serum tumor marker in pancreatic cancer. Br J Cancer 1986; 53:197-202. 4. Safi F, Rascher R, Bittner R, et al. High sensitivity and specificity of CA 19-9 for pancreatic carcinoma in comparison to chronic pancreatitis: serological and immunohistochemical findings. Pancreas 1987; 2:398-403. 5. Pleskow DK, Berger HJ, Gyves J, et al. Evaluation of a serologic marker, CA 19-9, in the diagnosis of pancreatic cancer. Ann Intern Med 1989; 110:704-709. 6. Manabe T, Tobe T. Progress in the diagnosis and treatment of pan-

20. 21. 22.

23. 24. 25.

355

creatic cancer-the Kyoto University experience. Hepatogastroenterology 1989; 36:431436. Frebourg T, Bercoff E, Manchon N, et al. The evaluation of CA 199 antigen level in the early detection of pancreatic cancer. A prospective study of 866 patients. Cancer 1988; 62:2287-2290. Glenn J, Steinberg WM, Kurtzman SH, et al. Evaluation of the utility of a radioimmunoassay for serum CA 19-9 levels in patients before and after treatment of carcinoma of the pancreas. J Clin Oncol 1988; 6:462-468. Berretta E, Malessi A, Zerbi A, et al. Serum CA 19-9 in the post surgical follow-up of patients with pancreatic cancer. Cancer 1987; 60:2428-2431. Tempero MA, Uchida E, Takasaki H, et al. Relationship of carbohydrate antigen 19-9 and Lewis antigen in pancreatic cancer. Cancer Res 1987; 4:5501-5503. DelVillano BC, Zurawski VR. The carbohydrate antigenic determinant 19-9 (CA 19-9): a monoclonal antibody defined tumor marker. In Immunodiagnostics. New York: Alan R. Liss, 1983, pp 269-282. Pohl AL. Surveillance of cancer patients with tumor markers. Journal of Tumor Marker Oncology 1987; 2:1-14. Murphy E. Biopstatistics in Medicine. Baltimore: The Johns Hopkins University Press, 1982, pp 329-343. Satake K, Kanazawa G, Kho I, et al. A clinical evaluation of carbohydrate antigen 19-9 and carcinoembryonic antigen in patients with pancreatic cancer. J Surg Oncol 1985; 29:15-21. Steinberg WM, Gelfand R, Anderson KK, et al. Comparison of the sensitivity and specificity of the CA 19-9 and carcinoembryonic antigen assays in detecting cancer of the pancreas. Gastroenterology 1986; 90:343-349. Gupta MK, Arciago R, Bocci L, et al. Measurement of a monoclonalantibody defined antigen (CA 19-9) in serum of patients with malignant and nonmalignant diseases, comparison with carcinoembryonic antigen. Cancer 1985; 56:277-283. Del Villano BC, Brenna S, Brock P, et al. Radioimmunometric assay for a monoclonal antibody-defined tumor marker CA 19-9. Clin Chem 1983; 29:549-552. Yoshidawa T, Nishida D, Tanigawa M, et al. Carbohydrate antigenic determinant (CA 19-9) and other tumor markers in gastrointestinal malignancies. Digestion 1985; 31:67-76. Lan MS, Bast RC, Colnaghi MI, et al. Co-expression of human cancer-associated epitopes on mucin molecules. Int J Cancer 1987; 39:68-72. Appert HE. Composition and production of pancreatic tumor related antigens. Int J Pancreatol 1990; 7:13-23. Race RP, Sanger R. Blood groups in man. Oxford: Blackwell, 1975, pp. 323-349. Malesci A, Tommasini MA, Bonato C, et al. Determination of CA 19-9 antigen in serum and pancreatic juice for differential diagnosis of pancreatic adenocarcinoma from chronic pancreatitis. Gastroenterology 1987; 92:60-67. Atkinson BF, Ernst CS, Herlyn M, et al. Gastrointestinal cancerassociated antigen in immunoperoxidase assay. Cancer Res 1982; 42:4820-4823. Staab H-J, Anderer FA. Circulating carcinoembryonic antigen (CEA), a growth parameter in malignant disease. Cancer Detect Prevent 1983, 6:33-39. Brummendorf T, Anderer FA, Staab H-J, et al. Die dopplungszeit des zirkulierenden CEA als individuelles prognostisches kriterium bei rezidivierung in patienten mit gastrintestinalen karzinomen. Klin Wochenschr 1986; 64:63-69.