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Undetectable Preoperative Levels of Serum CA 19-9 Correlate with Improved Survival for Patients with Resectable Pancreatic Adenocarcinoma

From the Departments of Surgical Oncology (ACB, IMM, JCW, JPH) and Biostatistics (EAR), Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Correspondence: Address correspondence and reprint requests to: Adam C. Berger, MD, Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111; Fax: 215-728-2773; E-mail: a_berger{at}fccc.edu

	ABSTRACT

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Background: Serum levels of CA19-9 have been shown to correlate with both recurrence and survival in patients with pancreatic cancer. However, little is known about the prognosis for patients with undetectable levels of serum CA19-9.

Methods: One hundred twenty-nine patients with pancreatic cancer who underwent preoperative assessment of serum CA19-9 followed by resection with curative intent between 1990 and 2002 were retrospectively analyzed. Data collected included preoperative serum CA19-9 level (U/mL), age, pathologic staging, and survival. Data were analyzed with the SAS system according to four distinct preoperative serum CA19-9 levels: undetectable, normal (<37), 38–200, and >200 U/mL.

Results: Serum CA19-9 levels ranged from undetectable to 16,300 U/mL. Stage III/IV disease accounted for 86%, 67%, 59%, and 53% of patients in the four CA19-9 groups. The overall median and 5-year survivals were 19 months and 11%, respectively. Survival was similar between nonsecretors and those with normal CA 19-9 levels. However, both groups had statistically significant prolonged survival compared with the two groups with elevated CA 19-9 levels (P = .003). The only factors that were significant on univariate and multivariate analysis for overall survival were lymph node positivity (P = .015 and .002) and CA 19-9 grouping (P = .003 and P < .0001). Although this group of patients presented with predominately advanced-stage disease, their overall survival was superior.

Conclusions: These findings suggest that patients who present with undetectable preoperative CA19-9 levels and potentially resectable pancreatic cancer, regardless of advanced stage, should be considered candidates for aggressive therapy.

Key Words: CA 19-9 • Lewis blood group • Pancreatic cancer • Prognosis

	INTRODUCTION

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The tumor-associated antigen CA 19-9 was first described by Koprowski et al. in 1979¹ as a marker for colorectal cancer; since that time, it has become the most important tumor marker for pancreatic adenocarcinoma. Several hundred reports worldwide have attested to its clinical usefulness in the diagnosis, prognosis, and monitoring of pancreatic cancer. Recent evidence has shown that serum CA 19-9 is an independent predictor of recurrence and survival after resection,^2–4 and its levels correlate with tumor burden and metastatic disease. One study demonstrated that patients with resectable tumors had significantly lower CA 19-9 levels than those with unresectable tumors.⁵ Finally, in patients being treated with gemcitabine for advanced pancreatic cancer, a decrease of CA 19-9 by >20% was the strongest independent predictor of survival in multivariate analysis.⁶

CA 19-9 has also been identified as a monosialo-ganglioside/glycolipid and sialyl derivative of lacto-N-fucopenteose II (sialyl-Lewis[a], hapten of human Lewis[a] blood-group determinant).⁷ As such, CA 19-9 levels detected by conventional antibody tests may be affected by Lewis blood group phenotypes. In fact, pancreatic cancer patients with a Lewis negative (a^–, b^–) phenotype will have an undetectable CA 19-9 level.⁸ Fortunately, this phenotype occurs in only 7% to 10% of the population.⁹ Therefore, one cannot follow the serum CA 19-9 levels in Lewis-negative patients with pancreatic cancer; these patients may have undetectable CA 19-9 levels even in the face of metastatic or recurrent disease. Therefore, we set out to determine the characteristics and prognosis of pancreatic cancer in patients who are CA 19-9 nonsecretors in comparison with patients with normal CA 19-9 levels at diagnosis and those with elevated CA 19-9 levels. This is the first report in the literature looking specifically at these patients.

	MATERIALS AND METHODS

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We retrospectively reviewed the password-protected pancreatic cancer database at the Fox Chase Cancer Center to identify 129 patients who underwent preoperative assessment of serum CA 19-9 levels followed by resection with curative intent between 1990 and 2002. Hospital, clinic, and physician records were reviewed for pertinent information. Data collected included age, sex, date of diagnosis, date of surgery, use of induction adjuvant chemotherapy and radiation, serum CA 19-9 level, pathologic T stage, lymph node status, overall pathologic stage, margin status, and survival.

Serum CA 19-9 levels were determined with use of a CA 19-9 radioimmunoassay kit manufactured by Abbott Laboratories (Chicago, IL). The recommended normal value of 37 U/mL was used for the serum assays. Patients were divided into four groups based on their CA 19-9 level at diagnosis: undetectable, normal (<37 U/mL), 38–200 U/mL, and >200 U/mL. These groups comprised 5%, 16%, 34%, and 44% of the entire population. Lewis antigen testing was not performed for a couple of reasons. First of all, an assay was not available for the early part of this study. Second, our blood bank is unable to retrospectively perform the test because it can be performed on only fresh red blood cells. Overall survival (OS) was defined as date of diagnosis until time of death or last follow-up, and disease-free survival (DFS) was measured from time of operation to date of recurrence. Survival follow-up was complete for all patients, but 14 patients had incomplete data regarding time to recurrence and were thus left out of the DFS analysis.

Univariate analysis for categorical variables such as stage, lymph node status, and margin status was performed with log-rank analysis. OS and DFS were analyzed by the Kaplan-Meier method, and significance was determined by log-rank. Multivariate analysis was performed with the Cox proportional hazards model to examine the effects of CA 19-9 group accounting for positive univariate predictors. All data were analyzed with use of the SAS system (SPSS, Cary, NC).

	RESULTS

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Demographics
There were 59 males and 70 females, with an average age of 67 years (range, 41 to 85 years); 114 (88%) underwent pancreaticoduodenectomy, 4 (3%) underwent distal pancreatectomy, and 11 (8%) underwent subtotal or total pancreatectomy. On the basis of the American Joint Committee on Cancer Staging System,¹⁰ patients were pathologically staged as follows: 38 were stage I, 15 were stage II, 70 were stage III, and 6 were stage IV. Tumor stages included 20 patients with T1 lesions, 48 with T2 tumors, 56 patients with T3 lesions, and 5 with pathologic T4 tumors. Lymph nodes were positive in 78 patients (61%). Finally, margins were considered positive in 71 (55%) of the patients who underwent resection. Several patients also underwent induction treatment with chemotherapy and external beam radiotherapy (XRT); 33 patients received gemcitabine plus XRT; 13 received 5-FU, mitomycin C, and XRT as part of a phase II trial at FCCC; 4 patients received 5-FU combined with XRT; and 5 patients received other combinations (including carboplatin and taxol). Finally, 80 patients underwent some type of adjuvant therapy with 5-FU or gemcitabine, with or without radiation therapy.

Prognostic Factors
Several factors were analyzed to determine whether these impacted survival within these groups. Even though there were a higher percentage of stage 3 and 4 tumors in groups 1 and 2 (71% vs. 51%), stage itself had no impact on survival (P = .384). Neoadjuvant chemotherapy and radiation were frequently used in this group of patients, with 55 (43%) receiving treatment with this modality. Only one patient in group 1 received induction therapy, but otherwise these patients were evenly distributed between the groups; this modality had no impact on survival (P = .278). Adjuvant therapy was also frequently used, with 63% of patients receiving adjuvant treatment. Patients receiving adjuvant therapy were evenly distributed between the four CA 19-9 groups, and this modality had no impact on survival (P = .671).

Margin status was also evaluated as a possible factor effecting survival. Overall, 71 patients (55%) had margins that were considered to be positive or close (<1 mm). These patients were evenly distributed throughout the CA 19-9 groups (43%, 55%, 52%, and 60%). By univariate analysis, margin status showed a trend toward significance but did not reach statistical difference (P = .093), with median survival being 22 months for those with negative margins and 17 months for patients with positive margins. Median DFS for patients with negative margins was 15 months, compared with 10 months for those with positive margins (P = .059).

Lymph nodes were positive in the majority of patients in this series, with 78 patients (61%) having positive lymph nodes on final pathologic examination. It is interesting that six patients (86%) in the nonsecretor group had positive lymph nodes. In the other three groups, lymph nodes were positive in 60%, 59%, and 60% of patients. In this analysis, lymph node status was a significant prognostic indicator by both univariate and multivariate analysis. The median and 5-year survivals of patients with negative lymph nodes were 29 months and 16%. Patients with positive lymph nodes had a median survival of 17 months and 5-year survival of 8% (P = .015 on univariate analysis and P = .0022 by multivariate analysis). However, when disease-free survival was analyzed, lymph node positivity did not reach statistical significance. Patients with negative lymph nodes had a median DFS of 18 months, compared with 11 months for those with negative lymph nodes (P = .061).

CA 19-9 Analysis
CA 19-9 levels ranged from 0 to 16,300 U/mL; patients were divided into four groups based on their preoperative CA 19-9 level. Group 1 consisted of 7 patients (5%) and included those who were CA 19-9 nonsecretors; these patients always had an undetectable CA 19-9 level. Group 2 was composed of 21 patients (16%) whose CA 19-9 level at diagnosis was within the normal range (<37 U/mL). Groups 3 and 4 encompassed patients with CA 19-9 levels <200 or >200; these groups contained 44 patients (34%) and 57 patients (44%), respectively. Analysis of survival in these four groups showed that the median and 5-year survivals for groups 1 and 2 were significantly improved in comparison with groups 3 and 4 (P = .0026, Table 1, Fig. 1). There were no significant differences between the groups when patients were evaluated for recurrence. Even though the median and 5-year DFS were longer in groups 1 and 2 than in groups 3 and 4, these levels did not reach statistical significance (P = .232, Table 2, Fig. 2).

View larger version (21K): [in this window] [in a new window]   FIG. 1. Overall survival of patients with resected pancreatic cancer in relation to preoperative CA 19-9 value. Group 1 includes all patients with undetectable CA 19-9 levels, group 2 includes all patients with a normal CA 19-9 value (37 U/mL), group 3 contains patients with CA 19-9 values 200 U/mL, and group 4 is all patients with a preoperative CA 19-9 level >200 U/mL. For these patients, P = .005 on multivariate analysis with the Cox proportional hazards model.

View larger version (25K): [in this window] [in a new window]   FIG. 2. Disease-free survival of patients after resection of pancreatic adenocarcinoma in relation to preoperative CA 19-9 value. Group 1 includes all patients with undetectable CA 19-9, group 2 includes all patients with a normal CA 19-9 value (37 U/mL), group 3 contains patients with CA 19-9 values (200 U/mL), and group 4 is all patients with a preoperative CA 19-9 values >200 U/mL. For these patients, P = .125 on multivariate analysis with the Cox proportional hazards model.

	DISCUSSION

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Carbohydrate antigen (CA) 19-9 is a tumor-associated antigen found on the cell surface of many gastrointestinal tumors. It was first described by Koprowski et al.,¹ who immunized mice with a colorectal carcinoma cell line and then isolated the CA 19-9 monoclonal antibody from mouse splenocytes. Further research has shown that CA 19-9 is normally present in salivary mucus and exocrine pancreatic secretions.^10,11 Although it originated from a colorectal carcinoma cell line, CA 19-9 has found its greatest utility in the diagnosis and evaluation of patients with pancreatic adenocarcinoma.

Safi et al.¹² prospectively evaluated the utility of CA 19-9 in patients with pancreatic cancer versus those with benign diseases. They found that 92% of patients with pancreatic adenocarcinoma had a CA 19-9 level >37 U/mL, and 77% had levels >120 U/mL.¹² The median CA 19-9 level in patients with pancreatic cancer was 528 U/mL, compared with 18, 14, and 7 U/mL for patients with chronic pancreatitis, acute pancreatitis, and benign surgical diseases, respectively. In another group of patients with colorectal, gastric, esophageal, or extragastrointestinal malignancies, the majority of patients had CA 19-9 levels in the normal range.¹² In this series, the overall sensitivity, specificity, and accuracy were 92%, 85%, and 82%.

Several investigators have demonstrated the effectiveness of serial CA 19-9 measurements in following the course of patients with pancreatic adenocarcinoma. One of the earliest studies was at the National Cancer Institute in 1986. These investigators found that a return to normal CA 19-9 level after resection was associated with longer survival than among patients whose CA 19-9 level never returned to normal.² They also found that elevation of CA 19-9 to >95 U/mL or a fourfold increase from the lowest postoperative level predicted disease progression. Other investigators found that secondary elevations of CA 19-9 in the postoperative period preceded detectable CT scan or clinical examination changes by 2 to 9 months.¹³

In another study, Montgomery et al.⁴ found that postoperative CA 19-9 measurements were the best predictors of disease-free and overall survival. They found that patients whose CA 19-9 levels returned to normal by 3 to 6 months had a longer DFS and OS than those whose levels did not. In addition, the survival of patients whose postoperative CA 19-9 level was <180 U/mL at 1 to 3 months was similar to that of patients whose values normalized at 3 to 6 months.

Finally, CA 19-9 has been a useful predictor of response in patients with advanced pancreatic cancer undergoing chemotherapy with gemcitabine-containing regimens. In one study, the investigators found a significant decline in CA 19-9 levels in patients achieving a radiographic complete response and a decrease in CA 19-9 levels in those patients who had a partial response.¹⁴ Another study showed that a decrease of >20% of the baseline CA 19-9 level after 8 weeks of treatment resulted in a significantly better median survival. This CA 19-9 response was the strongest independent predictor of survival by multivariate analysis.⁶

Since the time that it was discovered, investigators have shown that the CA 19-9 antigen is also a sialylated Le^a blood group antigen.⁷ Magnani et al.¹⁵ discovered that the antigen is found in pancreatic tissue and salivary mucin from most normal individuals belonging to the Le(a⁺b^–) or Le(a^–b⁺) blood group and is not found in salivary mucin from normal individuals belonging to the Le(a^–b^–) blood group. About 5% to 7% of the population belong to the Le(a^–b^–) blood group and thus lack the fucosyltransferase that catalyzes the synthesis of the antigen detected by the CA 19-9 monoclonal antibody. As a consequence, Koprowski has hypothesized that patients with a Le(a^–b^–) phenotype should be unable to synthesize CA 19-9 and thus not express it in their secretions.¹⁶

However, there have been reports of some exceptional Le(a^–b^–) patients who demonstrated positive CA 19-9 values.¹⁷ Unfortunately, the Le blood group phenotype can be mistyped in patients with conditions such as pregnancy, alcoholic cirrhosis and pancreatitis, hydatid cysts, and cancer.¹⁸ This is probably because the absorption of Le-activated glycolipids to RBCs is inhibited in these patients, and the standard hemagglutination test results in a false-negative Le grouping. One possible explanation for this is that anti-Le antibodies are elevated in the sera of patients with cancer; these antibodies may perturb the glycolipid uptake by RBCs.¹⁹ Additionally, in many of these conditions, the serum lipoprotein level is elevated, and the Le antigen may be adsorbed onto the lipoprotein, resulting in a reduced amount of antigen and thus a false-negative Le(a^–b^–).¹⁹ This is the reason why some Le(a^–b^–) cancer patients are not genuinely Le-negative and thus have an elevated CA 19-9 value.²⁰ These false-negative Le(a^–b^–) patients usually become Le-positive after surgical resection and thus can be followed with regard to CA 19-9 values.

Because of this mistyping phenomenon, the Le-negative phenotype is more common among cancer patients (~20%) than among healthy individuals (~8%). Individuals who are genuinely Le-negative and genetically lack the enzyme never have a positive serum CA 19-9 value. This was clearly demonstrated in two different studies in Japan and Denmark.^20,21 It is important, therefore, to note that patients who do not secrete CA 19-9 are always Le-negative. On the other hand, Le-negative individuals may have elevated CA 19-9 levels in the conditions described above.

There have been very few studies reported in the literature concerning the prognosis of patients who are CA 19-9 nonsecretors. One would hypothesize that these patients may do worse because we lose the ability to monitor their levels and thus predict response to therapy and disease progression or recurrence. However, we have demonstrated in this study that these patients do just as well as patients with normal CA 19-9 levels at diagnosis. The median survivals of these two groups of patients were 32 and 35 months, respectively. Additionally, these patients had a statistically significantly better survival than patients with elevated CA 19-9 levels. This factor was significant by both univariate and multivariate analysis.

In fact, patients with undetectable CA 19-9 had a longer median disease-free survival than all other groups—27 months versus 14, 10, and 10, respectively—although this did not reach statistical significance. The only other positive predictor of overall survival by multivariate analysis was lymph node positivity, which has been seen in previous studies.²² Unfortunately, there were only seven patients in our nonsecretor groups, which comprised 5% of our study population and thus fits in with the frequency of Le(a^–b^–) patients in the population. Therefore, it is difficult to make any definitive conclusions based on this small number of patients. It is unclear why patients with undetectable CA 19-9 levels had better prognoses despite their lymph node positivity. It may be that Le-negativity is a marker for decreased metastatic potential or aggressiveness. However, these speculations will have to be borne out in larger studies before any conclusions can be drawn. Future studies will attempt to investigate the significance of an undetectable CA 19-9 level in the context of larger, multiinstitutional studies for which larger patient samples are available.

	FOOTNOTES

 
Presented as a poster at the 56th Annual Cancer Symposium of the Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.

Lewis-antigen-negative patients always have undetectable CA 19-9 levels. We show that these individuals have survival rates better than patients with elevated CA 19-9 levels and comparable to those of patients with normal preoperative CA 19-9 values.

Received for publication November 14, 2003. Accepted for publication March 12, 2004.

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