CA19-9 for detecting recurrence of pancreatic cancer

Abstract

CA19-9 values are regularly measured in patients with pancreatic cancer. Certainly, its potential as a biomarker has been compromised by false negative results in CA19-9 negative patients and false positive results in benign pancreatico-biliary diseases. For detection of PDAC recurrence, however, CA19-9 might play an important role. The aim of this study is to analyze the accuracy of CA19-9 for detecting recurrence of pancreatic cancer. All included patients were treated either at the University Medical Center Goettingen, or at the Department of Interdisciplinary Oncology and Pneumonology, DRK-Kliniken Nordhessen, Kassel. We analyzed data of 93 patients with pancreatic cancer in the training set and 41 in the validation set, both retrospectively. Pre- and postoperative CA19-9 values and results of imaging techniques were compared. We performed ROC-analysis. The association between longitudinally measured CA19-9 values and relapse was studied with a joint model between a random effects model for the longitudinal CA19-9 measurements and a Cox proportional hazards models for the survival data. In the test set (n = 93 patients) the median follow-up time was 644 days (22 months). Overall, 71 patients (76.3%) developed recurrence during follow-up. Patients with CA19-9 values of <10kU/l were considered as CA19-9 negative patients (n = 11) and excluded from further analysis. Among the rest, approximately 60% of the patients showed significantly elevated CA19-9 prior to detection of recurrence by imaging techniques. Recurrence was shown by 2.45 times elevated CA19-9 values with 90% positive predictive value. In the validation set, 2.45 times elevated CA19-9 values showed recurrence with 90% sensitivity and 83,33% specificity, with an area under the curve of 95%. Based on measured CA19-9 values during follow-up care, the joint model estimates in recurrence-free patients the probability of recurrence-free survival. CA19-9 elevation is an early and reliable sign for PDAC recurrence. On the strength of a very high accuracy in CA19-9 positive patients, it should be considered to use CA19-9 for therapy decision even without a correlate of imaging technics. Using the joint model, follow-up care of PDAC patients after curative therapy can be stratified.

Figure 1

Two examples for patients with recurrence of PC during follow-up with a CA19-9 elevation prior to detection in imaging techniques (CT, computed tomography).

Figure 2

CA19-9 in recurrence-free patients during follow-up. After surgery, the initially elevated CA19-9 value drops under 50 kU/l. One patient received neoadjuvant chemotherapy. Here, chemoradiotherapy started on day 15 till day 225, surgery was performed on day 262.

Figure 3

(A) CA19-9 values over all patients at baseline (before any therapy), after surgery (but before adjuvant chemotherapy), and at time point of recurrence are illustrated. CA19-9 negative patients are excluded. (B) Time interval between serological detection and evidence of recurrence in imaging in test set (red) and validation set (light blue).

Figure 4

(A) Initial set. Analyses of relative changes of CA19-9 values during follow-up with respect to relapse by a receiver operating characteristic (ROC) curve. Two different cutoff points with differences in sensitivity, specificity and predictive values are marked. 1.35xtimes elevation of CA19-9 shows recurrence with 72% sensitivity, 62% specificity, 85% positive predictive value and 42% negative predictive value (blue line). A 2.45 x times elevation of CA19-9 shows recurrence with 45% sensitivity, 85% specificity, 90% positive predictive value and 33% negative predictive value (red line). (B) Independent validation set. Analyses of relative changes of CA19-9 values during follow-up with respect to relapse by a receiver operating characteristic (ROC) curve. 1.35 x times elevation of CA19-9 shows recurrence with 100% sensitivity, 67% specificity, 83% positive predictive value and 100% negative predictive value. 2.45 x times elevation of CA19-9 shows recurrence with 90% sensitivity, 83,33% specificity.

Figure 5

Progression-free survival (PFS) during first line palliative chemotherapy in patients with an elevation of CA19-9 prior to detection of cancer recurrence (red line) versus PFS of patients with no prior CA19-9 elevation. The p-value is 0.008.

Figure 6

(A) Development of CA19-9 values of Patient 88 as an example for recurrence-free patients. (B) Based on measured CA19-9 values during follow-up, the joint model estimates in recurrence-free patients the probability of recurrence-free survival in the future. (C) The column “Time” represents the days after first diagnosis and the columns “Median”, “Lower” and “Upper” describe the probabilities of recurrence-free survival for this patients on that day. With every additional CA19-9 value measured the probabilities adjust.

Figure 7

Exemplary demonstration of the estimated recurrence free survival in case of three different subjects applying the joint model. Subject 2 has a comparatively good recurrence free survival (RFS) probability; subject 38 has a poorer prognosis. Subject 116 as an example for a patient with only few CA19-9 measurements shows a wide range between lower and higher probability of RFS.

Figure 8

(A) Kaplan-Meier Curve of the validation set using the Joint Model. Recurrence free survival time was estimated using Kaplan-Meier. (B) Estimated recurrence free survival probabilities (RFS) in the validation data.