The additive value of CA19.9 monitoring in a pancreatic cyst surveillance program

Abstract

Background: Surveillance of pancreatic cysts focuses on the detection of (mostly morphologic) features warranting surgery. European guidelines consider elevated CA19.9 as a relative indication for surgery. We aimed to evaluate the role of CA19.9 monitoring for early detection and management in a cyst surveillance population.

Methods: The PACYFIC-registry is a prospective collaboration that investigates the yield of pancreatic cyst surveillance performed at the discretion of the treating physician. We included participants for whom at least one serum CA19.9 value was determined by a minimum follow-up of 12 months.

Results: Of 1865 PACYFIC participants, 685 met the inclusion criteria for this study (mean age 67 years, SD 10; 61% female). During a median follow-up of 25 months (IQR 24, 1966 visits), 29 participants developed high-grade dysplasia (HGD) or pancreatic cancer. At baseline, CA19.9 ranged from 1 to 591 kU/L (median 10 kU/L [IQR 14]), and was elevated (≥37 kU/L) in 64 participants (9%). During 191 of 1966 visits (10%), an elevated CA19.9 was detected, and these visits more often led to an intensified follow-up (42%) than those without an elevated CA19.9 (27%; p < 0.001). An elevated CA19.9 was the sole reason for surgery in five participants with benign disease (10%). The baseline CA19.9 value was (as continuous or dichotomous variable at the 37 kU/L threshold) not independently associated with HGD or pancreatic cancer development, whilst a CA19.9 of ≥ 133 kU/L was (HR 3.8, 95% CI 1.1-13, p = 0.03).

Conclusions: In this pancreatic cyst surveillance cohort, CA19.9 monitoring caused substantial harm by shortening surveillance intervals (and performance of unnecessary surgery). The current CA19.9 cutoff was not predictive of HGD and pancreatic cancer, whereas a higher cutoff may decrease false-positive values. The role of CA19.9 monitoring should be critically appraised prior to implementation in surveillance programs and guidelines.

Keywords: CA19.9; GICA; biomarkers; early detection; follow-up; pancreatic cancer; pancreatic cysts; pancreatic lesions; surgical intervention; surveillance.

FIGURE 1

Flowchart of patient in‐ and exclusion, baseline information and follow‐up information. All PACYFIC participants were considered for inclusion in the current study. Participants without a recorded CA19.9 value as well as those with less than 12 months of follow‐up (with the exception of those participants for which a pathological cyst diagnosis was established within the first 12 months after the first recorded CA19.9 value) were excluded. Additionally, individuals with a history of PC or jaundice at baseline were excluded as these conditions may influence CA19.9 levels. CA19.9 values and (baseline) cyst growth were not included as absolute (AI) or relative (RI) indications for surgery; HGD, high‐grade dysplasia; PC, pancreatic cancer.

FIGURE 2

Clinical consequences of an elevated value at all visits, and at those visits with and without absolute (AI) or relative (RI) indications for surgery. For visits without AI or RI, an elevated CA19.9 value more often led to a shortened surveillance interval, as compared to a normal value <37 kU/L (χ ²‐test). Management was based on the decision of the physician after imaging. A general surveillance interval was 6 months' interval during the first year of surveillance and 12 months' interval during follow‐up afterward (as based on the recommendations in the European Guidelines ⁹ ).

FIGURE 3

The role of CA19.9 monitoring on treatment management. ((a)–(b)) Presence of relative indications for surgery other than (excl.) CA19.9 elevation (RI), absolute indications for surgery (AI) and elevated CA19.9 values over time for individuals who develop high‐grade dysplasia (HGD) or pancreatic cancer (PC; (a)) and other pathology‐proven lesions (b); (c) Overview of participants with two or more available CA19.9 values who did not undergo surgery, showing the high frequency of elevated values. IPMN, intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; NET, neuro‐endocrine tumor; PA‐proven, pathology proven; SPN, solid pseudopapillary neoplasm.

FIGURE 4

Subgroup analyses do not show differences in median CA19.9 values. However, CA19.9 is able to differentiate cases from controls with high specificity, yet low sensitivity. (a) The median CA19.9 value is not higher in cases with high‐grade dysplasia (HGD) or pancreatic cancer (PC) than controls; (b) Individuals with PC, HGD, low‐grade dysplasia (LGD), other pathologies (heterogeneous group of SPN, NET, SCN, lympho‐epithelial cyst, lymphangioma and pseudocyst); (c) The median CA19.9 level was not higher in individuals with absolute (AI) or relative (RI) indications for surgery, as compared to those without; (d) Receiver operator curve (ROC) of serum CA19.9 with three cut‐offs (37 kU/L and two selected based on visualized angles in the curve); (e) Diagnostic performance at the three cut‐offs. Described data do not have equal variances; therefore, nonparametric tests were used ((a)–(c)). 95% confidence intervals (CIs) are “exact” Clopper‐Pearson confidence intervals ((d)–(e)). AUC, area under the curve; NPV, negative predictive value.

FIGURE 5

Cox proportional hazards model. ((a)–(c)) The risk of developing high‐grade dysplasia (HGD) and pancreatic cancer (PC) for three different thresholds ((a), (b), (c); corrected for the presence of absolute indications for surgery (AI) and relative indications for surgery (RI) at baseline). Intervals are 95% confidence intervals.