CA 19-9 was first described by Koprowski et al11
in 1979; since that time, it has become the most important tumor marker for pancreatic cancer. It is a carbohydrate tumor-associated antigen which was actually first isolated from a human colorectal cancer cell line. It is a derivative of lacto-N
-fucopenteose II (sialyl-Lewis[a], hapten of human Lewis[a] blood-group determinant).12
Because of this, CA 19-9 levels detected by conventional antibody tests may be influenced by Lewis blood group phenotypes. In fact, people with a Lewis negative phenotype will have an undetectable CA 19-9 level—this is present in 5% to 10% of the population.13
In a previous study from FCCC, this population comprised 5% of patients over a 12-year period.14
Several hundred reports worldwide have attested to the clinical usefulness of CA 19-9 in the diagnosis, prognosis, and monitoring of patients with pancreatic cancer. In particular, a few studies have demonstrated that serum CA 19-9 is an independent predictor of survival after resection. In a small study by Beretta et al,15
the authors found that in seven patients whose postresection CA 19-9 never returned to normal, no patient survived longer than 7 months (median, 4.8). However, in seven patients who had a normal postoperative CA 19-9 level, median survival was 17.3 months (P
< .005). In another study from the Surgery Branch of the National Cancer Institute, Glenn et al16
also demonstrated that a return to normal of the serum CA 19-9 level after surgery was associated with a significantly longer survival than those who never returned to normal range (P
This observation was taken further by Montgomery et al from FCCC. These authors studied 32 patients who underwent resection of pancreatic cancer over an 8-year period. They confirmed earlier findings by demonstrating that patients whose CA 19-9 values returned to normal between 3 and 6 months after surgery had a longer survival compared with those whose CA 19-9 did not (34 v
13 months; P
They then looked at the best threshold value for the 1- to 3-month time period postoperatively because this is when the majority of patients will begin their adjuvant therapy. This analysis revealed patients with CA 19-9 values lower than 180 U/mL in this time period had similar disease-free and overall survival to that of patients with normal CA 19-9 values measured between 3 and 6 months postoperatively.7
In another analysis of postoperative CA 19-9 levels, Ferrone et al from the Massachusetts General Hospital demonstrated that patients with a postoperative CA 19-9 higher than 200 U/mL had a significantly worse survival by univariate and multivariate analysis than those with CA 19-9 ≤ 200 U/mL.17
These same authors demonstrated that the strongest univariate predictor of overall survival was whether a patient's CA 19-9 decreased after surgery—this was also an independent predictor of improved survival.17
In this study, we did not evaluate preoperative CA 19-9 levels nor does the current analysis evaluate trends in CA 19-9 during the follow-up period. Based on the availability of these data, a future analysis may be performed.
While the significance of an elevated postoperative CA 19-9 is clear, the pathophysiology is not. These elevated levels could be due to tumor burden, spread of disease, or differences in the biologic behavior of tumors. In addition, there may be postoperative pancreatic inflammation or ductal irritation—indeed, Montgomery et al found that the time period in which CA 19-9 values returned to normal ranged from 2 months to 1 year. Finally, other factors related to the production, secretion, and metabolism of CA 19-9 probably play a role in these variations because a significant overlap between individual CA 19-9 values has been demonstrated.18
Another interesting observation from this trial was the unexpectedly high percentage of patients who were determined to be Lewis antigen negative. All patients who enrolled on RTOG 9704 had their RBC phenotype for Lewis A and Lewis B antigens determined by the laboratory/blood bank of the enrolling institution. If patients were determined to be positive at either the A or B locus, their serum was sent to the RTOG tissue bank (LDS Hospital in Utah) to have enzyme-linked immunosorbent assay performed for CA 19-9. If testing for A and B were both negative, the patient was determined to be Lewis antigen negative and thus have an undetectable CA 19-9.6
In this trial, the rate of Lewis Antigen–negative patients was 34% which is much higher than has ever been seen in any previous retrospective analysis. It is unclear whether this is a phenomenon of variations in testing for the Lewis A and B antigens in local laboratories (likely) or the percentage of Lewis Antigen patients is really close to 30% (less likely). For the purposes of data collection, patients were designated as either Lewis antigen positive or negative. We do not have data available as to the percentages of Lewis A and B positive, Lewis A negative B positive, and Lewis A positive B negative. The survival analysis shows that these patients had similar survival to those patients with CA 19-9 lower than 180 U/mL. This is contrary to the findings of Berger et al;14
however, this does represent a much larger and prospective cohort unlike the retrospective evaluation of seven patients. It is clear that future prospective trials that examine CA 19-9 as an end point should probably use a central laboratory for both determination of Lewis antigen status as well as CA 19-9 level.
When RTOG 9704 was conceived in the mid-1990s, the principal investigators made a conscious decision to make the evaluation of postoperative CA 19-9 as a secondary end point based on the previous work at FCCC. In January 2007, the results of an adjuvant chemotherapy trial from Germany were published. In this trial (CONKO-001), patients with a CA 19-9 level higher than 2.5 times the upper limit of normal (≈90) were deemed ineligible.5
With the results of this positive trial, an analysis of CA 19-9 less than 90 versus ≥ 90 U/mL was also undertaken. Briefly, the CONKO-001 trial was a randomized controlled phase III trial from Germany in which patients who had undergone curative resection for pancreatic cancer were randomly assigned to adjuvant gemcitabine (weekly, 1,000 mg/m2
, every 3 of 4 weeks for six cycles) or observation.5
The primary end point for this trial was disease-free survival, and this end point was met with a significant benefit in the treatment group (13.4 months) versus the control arm (6.9 months; P
< .001). There was not a significant difference in overall survival between the treatment (median, 22.1 months; 3 years, 34%) and control (median, 20.2 months; 3 years, 20.5%).5
Interestingly, the median and 3-year overall survival for patients on 9704 with CA 19-9 ≤ 90 U/mL was 23 months and 32% which compares favorably with these results.
The results of this analysis of postoperative CA 19-9 level are important because they clearly identify a subgroup of patients who have a much higher risk of death. When a CA 19-9 cutoff of 180 U/mL is used, there were 33 patients with CA 19-9 higher than 180, of whom, none survived 3 years. These patients were 3.52 times more likely to die of pancreatic cancer than patients with CA 19-9 lower than 180 U/mL. Using this cutoff point defines a population of patients with stage I and II disease (by the current staging system) who will need an intensification of their postoperative treatment to improve survival. Future adjuvant chemoradiotherapy trials should stratify patients by CA 19-9 level and/or possibly exclude patients with CA 19-9 ≥ 90 U/mL.
In summary, serum CA 19-9 is an important tumor marker for patients with pancreatic adenocarcinoma. In the postoperative setting, the CA 19-9 level can be used as a predictor of overall survival. Patients with a postoperative CA 19-9 level ≥ 180 U/mL have a significantly worse survival than those patients with CA 19 lower than 180 U/mL. These patients should be considered for alternative systemic therapy or chemoradiotherapy protocols. In addition, future phase III adjuvant trials should stratify patients by CA 19-9 values.