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Review Article
The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal
1Department of Surgery, Maimonides Medical Center, Brooklyn, New York; 2Department of Surgery, Saint Barnabas Medical Center, Livingston, New Jersey, USA; 3Department of Surgery, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA; 4Saint George’s University School of Medicine, Grenada, West Indies
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Abstract
Background: Serum carbohydrate antigen (CA 19-9) is the most common tumor marker assessed in pancreatic cancer patients; nevertheless few articles have comprehensively evaluated the evidence for its utility in pancreatic cancer management.
Methods: Literature search was performed using Medline with keywords “pancreatic cancer” “tumor markers” “CA 19-9” “diagnosis” “screening” “prognosis” “resectability” and “recurrence”. All English language articles pertaining to the role of CA 19-9 in pancreatic cancer were critically analyzed to determine its utility as a biomarker for pancreatic cancer.
Results: Serum CA 19-9 is the most extensively validated pancreatic cancer biomarker with multiple clinical applications. CA 19-9 serum levels have a sensitivity and specificity of 79-81% and 82-90% respectively for the diagnosis of pancreatic cancer in symptomatic patients; but are not useful as a screening marker because of low positive predictive value (0.5-0.9%). Pre-operative CA 19-9 serum levels provide useful prognostic information as patients with normal levels (< 37 U/ml) have a prolonged median survival (32-36 months) compared to patients with elevated levels (> 37 U/ml) (12-15 months). A CA 19-9 serum level of < 100 U/ml implies likely resectable disease whereas levels > 100 U/ml suggest unresectablity or metastatic disease. Normalization or a decrease in post-operative CA 19-9 serum levels by ≥ 20-50% from baseline following surgical resection or chemotherapy is associated with prolonged survival compared to failure of CA 19-9 serum levels to normalize or an increase. Important limitations to CA 19-9 serum level evaluation in pancreatic cancer include poor sensitivity, false negative results in Lewis negative phenotype (5-10%) and increased false positivity in the presence of obstructive jaundice (10-60%).
Conclusion: CA 19-9 is the most extensively studied and validated serum biomarker for the diagnosis of pancreatic cancer in symptomatic patients. CA 19-9 serum levels can provide important information with regards to prognosis, overall survival, and response to chemotherapy as well as predict post-operative recurrence. However, non-specific expression in several benign and malignant diseases, false negative results in Lewis negative genotype and an increased false positive results in the presence of obstructive jaundice severely limit the universal applicability of serum CA 19-9 levels in pancreatic cancer management.
Key words
pancreatic cancer; tumor markers; CA 19-9; diagnosis; screening; prognosis; resectability; recurrence
J Gastrointest Oncol 2012;3(2):105-119. DOI: 10.3978/j.issn.2078-6891.2011.021
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Introduction
In the year 2010, the incidence of newly diagnosed
pancreatic cancer in USA was 43140 and deaths attributable
to pancreatic cancer were 18770 (1). Among recently
diagnosed pancreatic cancer patients, 65-70% will have
advanced disease (stage III-IV) at initial presentation.
Advanced pancreatic cancer has a very poor prognosis,
with a median survival of 2-6 months for stage IV disease
and 6-11 months for stage III disease. Overall, the 5-year survival among these patients is only 5-7% and the majority
of patients survive less than 1-2 years. Even among patients
who undergo surgery with curative-intent, > 90% develops
disease progression within 12-18 months. This poor
prognosis is attributable to late stage presentation, lack
of effective treatments, early recurrence and absence of
clinically useful biomarker(s) which can detect pancreatic
cancer in its precursor form(s) or earliest stages (2-4).
A wide-variety of tumor markers derived from serum,
pancreatic tissue, pancreatic juice, saliva and/or stool has
been proposed for early diagnosis as well as to predict
prognosis in pancreatic cancer patients. Nevertheless,
utility of those markers is often significantly limited by poor
sensitivity, high false positive rates and lack of large scale
validation (5).
Despite the vast number of potential pancreatic cancer
biomarkers, very few have been thoroughly evaluated and
none to the extent of carbohydrate antigen 19-9 (CA 19-9).
This review provides a comprehensive review on the utility
of serum CA 19-9 as a pancreatic cancer biomarker and
its value in screening, diagnosis, staging, determination
of resectability, early identification of recurrence and
predicting treatment response.
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Methods
A comphrensive literature search was performed using
PubMed with keywords “pancreatic cancer” “tumor
markers” “CA 19-9” “diagnosis” “screening” “prognosis”
“resectability” and “recurrence”. All English language
articles pertaining to the role of CA 19-9 in pancreatic
cancer for the years 1979-2010 were critically analyzed to
determine its utility as a biomarker for pancreatic cancer.
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Discussion
Koprowoski et al first described CA 19-9 in colorectal
cancer cell line (SW1116) using a monoclonal antibody
(1116-NS-19-9) i.e. hybridoma technology in 1979 (6). CA
19-9 is also identified in the tissue and sera of patients with
other gastrointestinal tumors including esophageal, gastric,
biliary and pancreatic cancer (7). CA 19-9 also termed as
sialyl Lewis-a (sLea), is expressed on the surface of cancer
cells as a glycolipid and as an O-linked glycoprotein. CA
19-9 is derived from an aberrant pathway during production
of its normal counterpart disialyl Lewis-a that has one extra
sialic acid residue attached through a 2→6 linkage. Normally,
Disialyl Lewis-a is expressed on the epithelial surface
of digestive organs, acts as a ligand for monocytes and
macrophages and helps in immunosurveillance. Epigenetic
silencing of the gene for 2→6 sialyl transferase during early stages of carcinogenesis leads to abnormal synthesis and
accumulation of sialyl Lewis-a (CA 19-9). sLea may also
play a role in cancer invasion/metastasis as it is known to be
a ligand for endothelial cell E-selectin responsible for cell
adhesion (7-11).
CA 19-9 is related to the Lewis blood group antigens
and only patients belonging to the Le (α-β+) or Le (α+β-)
blood groups will express the CA 19-9 antigen (7). Le (α-β-)
phenotypes occur in 5-10% of population which lack the
enzyme 1,4-fucosyl transferase required for antigen epitope
production, and as such limits the use of CA 19-9 as a
universally applicable biomarker (12-15).
Utility of CA 19-9 serum levels as a diagnostic and screening
marker for pancreatic cancer
An “ideal” tumor marker possesses high sensitivity enabling
it to identify the disease in a screening population without
symptoms. Several studies have explored the utility of
CA 19-9 serum levels as a screening tool for pancreatic
cancer in asymptomatic individuals as well as in patients
with symptoms suspicious for pancreatic cancer (Table 1)
(17-19). Kim et al assessed CA 19-9 serum levels in 70940
asymptomatic individuals and identified only 4 patients with
pancreatic cancer among 1063 patients with elevated CA
19-9 serum levels (> 37 U/ml, mean values 50.5 ± 16.8 U/
ml) (16), yielding a dismal positive predictive value (PPV)
of only 0.9%, although the sensitivity and specificity were
100 and 98.5% respectively. Satake et al analyzed CA 19-9
serum levels in 12840 asymptomatic and 8706 individuals
with symptoms suspicious for pancreatic cancer such as
weight loss, epigastric pain and jaundice. These authors
identified only 4 pancreatic cancers (1 resectable) among
18 asymptomatic patients (0.2%) with an elevated CA 19-9
serum level. Among the 8706 patients with symptoms
suspicious for pancreatic cancer, 198 patients (4.3%) had
elevated CA 19-9 serum levels. Following extensive work
up, 85 patients (1.8%) were found to have pancreatic cancer
of which 28 patients (0.4%) were resectable (16). Similarly,
Chang et al have screened 5343 asymptomatic individuals
for pancreatic cancer, and identified CA 19-9 serum level
elevation (> 37 U/ml) in 385 patients (7.2%) (18). Among
this group only 2 patients (0.004%) had pancreatic cancer
and their serum CA 19-9 levels were 88.4 U/ml and 46885
U/ml respectively. The PPV of an elevated serum CA 19-9
level in the asymptomatic population in this study was only
0.5%. False positive elevation of the CA 19-9 serum levels
was noted in 325 patients (6.1%) and a total of 58 other
cancers were identified (17).
As evident from aforementioned studies, given the
suboptimal sensitivity and poor predictive value of CA
19-9 serum levels and low prevalence of pancreatic cancer in the general population, routine serum CA 19-9 level
testing has no utility as a screening tool in asymptomatic
patients. Even among patients with symptoms suspicious
for pancreatic cancer, elevated CA 19-9 serum levels is a
poor predictor of pancreatic cancer with a predictive value
of 0.5-0.9%. Equally noted in all of the screening studies is
that a significant number of individuals with elevated CA
19-9 serum levels have actually harbored non-pancreatic
neoplastic patholog y which further undermines the
applicability of serum CA 19-9 levels as a screening tool.
Among patients who present with a pancreatic mass,
elevated CA 19-9 serum levels y ield a much higher
predictive value for diagnosing pancreatic cancer. Tessler
et al studied 150 patients undergoing surgery for suspected
pancreatic cancer without a preoperative tissue diagnosis.
Multivariate analysis identified that a combination of weight
loss > 20 lbs, bilirubin > 3 mg/dL, and CA 19-9 > 37 U/ml
provided an almost 100% specificity and positive predictive
value for pancreatic cancer regardless of the extent of
imaging abnormalities (19).
Two previous reviews have attempted to summarize the
diagnostic utility of CA 19-9 serum levels in patients with
pancreatic cancer (14,20). Steinberg analyzed diagnostic
value of CA 19-9 serum levels (37-40 U/ml) in 1040 patients
(24 case series) with symptomatic pancreatic cancer and
reported a median sensitivity and specificity of 81% and
90% respectively. The positive predictive value (PPV) and
negative predictive value (NPV) of an elevated serum CA
19-9 level was 72.3% and 95.8% respectively. If the serum
CA 19-9 threshold used to diagnose pancreatic cancer was
raised to 100 U/ml or 1000 U/ml, the specificity increased
to 98% and 99.8%, however the sensitivity decreased to 68%
and 41% respectively (20). More recently, Goonetilleke et al
analyzed the utility of CA 19-9 serum levels (37-40 U/ml)
to diagnose pancreatic cancer among 2283 symptomatic patients reported in 26 case-series. (16) In this report, the
sensitivity and specificity of an elevated serum CA 19-9
level was 79% and 82% with a PPV and NPV of 72% and
81% respectively. Overall, an elevated serum CA 19-9 level
has a sensitivity of 79-81% and a specificity of 82-90% for
diagnosing pancreatic cancer in symptomatic patients (14).
Utility of CA 19-9 serum levels in assessment of pancreatic
cancer stage and determination of surgical resectability
The value of pre-operative serum CA 19-9 levels to predict
pancreatic cancer stage and determine resectability has been
extensively studied (21-26)(Table 2). Kim et al evaluated
CA 19-9 serum levels in 114 pancreatic cancer patients who
underwent either pancreatic resection (N = 72) or palliative
bypass surgery (N = 42). These authors reported a positive
correlation between pancreatic cancer stage and mean
pre-operative CA 19-9 serum levels. In this study stage IA
patients had a mean serum CA 19-9 level of 40.05 U/ml,
stage IIA patients had mean serum levels of 469.64 U/ml,
stage IIB patients had mean serum levels of 747.79 U/ml,
stage III patients had mean serum levels of 709 U/ml, while
stage IV patients had a mean serum CA 19-9 levels of 3239
U/ml (25). Safi et al compiled preoperative CA 19-9 serum
levels in 126 patients with resectable pancreatic cancer (22).
In this study, 29 of 45 patients (64%) with stage I pancreatic
cancer had elevated CA 19-9 with a median level of 68
U/ml (range, 9.0-3018 U/ml). Eight of 10 patients (80%)
with stage II pancreatic cancer had elevated serum CA
19-9 level with a median levels of 72 U/ml (range, 8.4-5000
U/ml). Eighty one percent (47 out of 58) of patients with
stage III disease had an elevated CA 19-9 levels (median,
210 U/ml, range, 2-7496 U/ml) and 100% of patients (N =
13) with stage IV disease had an elevated CA 19-9 serum
levels (median 412 U/ml, range, 49.6-14600 U/ml). In an
effort to correlate advanced stage disease with higher CA 19-9 serum levels, these authors also noted that an elevated
pretreatment CA 19-9 serum level of ≥ 300 U/ml indicated
unresectable disease in 80% of patients. However the above
correlation between CA 19-9 serum levels and pancreatic
cancer resectability is not universal but undermined by
the fact that 5-10% of patients with pancreatic cancer will
not demonstrate elevated serum CA 19-9 serum levels
given their sialyl Lewis negative state and by false positive
elevations in obstructive jaundice (7). Moreover, CA 19-9
serum levels alone should not be the sole criteria used in
making decisions to proceed to surgery; rather CA 19-9
serum levels is one of several contributing factors used
in combination with clinical evaluation and information
obtained from radiological and endoscopic imaging.
Anatomic imaging provides vital information regarding
local invasiveness of pancreatic cancer and the presence
of metastatic disease. Recent advances in radiologic (CT
scan, Magnetic Resonance Imaging (MRI), Positron
Emission Tomography (PET scan) and endoscopic imaging
(Endoscopic Ultrasound (EUS), Endoscopic Retrograde
Cholangiopancreatography (ERCP)) and increased use
of staging laparoscopy have enabled better delineation
and staging of pancreatic cancer, which in turn has helped
to reduce the negative laparotomy rate (27,28). Despite
those advancements, up to 15% of patients with pancreatic
cancer are found unresectable at the time of surgery, which
is attributable to occult vascular invasion, presence of
undetected metastasis or positive peritoneal lavage cytology (25). Whether pre-operative CA 19-9 serum levels can be
used as a surrogate marker for tumor resectability has been
extensively evaluated (21,27-29) (Table 3). Schleiman
et al evaluated preoperative CA 19-9 serum levels in 89
pancreatic cancer patients prior to surgical exploration and noted that mean CA 19-9 serum levels were significantly
lower in resectable tumors compared to those with locally
advanced tumors (63 vs. 592 U/ml, p = 0.003) or with
metastatic disease (63 vs. 1387 U/ml, p < 0.001) (32)(Table
3). A pre-operative CA19-9 serum level of > 150 U/ml was associated with an 88% positive predictive value for
unresectability, whereas serum levels < 150 U/ml had a
negative predictive value of 64% (32). Kim et al evaluated
CA 19-9 serum levels in 72 patients treated surgically for
“resectable” pancreatic adenocarcinoma and 42 patients
treated with surgical palliation (bypass surgery). The
median CA 19-9 serum levels for patients achieving an R0
resection, R1 resection or R2 resection, was 49.66, 233.0
and 600 U/ml respectively. The median CA 19-9 serum
level for patients with peritoneal metastasis was 780.49 U/
ml. These authors concluded that a pre-operative CA 19-9 ≥
92.77 U/ml predicted an R1/2 resection or unresectability
with a 90.6% accuracy. It is important to note however
that lower pre-operative CA 19-9 serum levels predicted
the probability of an R0 resection in only 27.1% of patients
(25). In summary, these studies suggest that a median CA
19-9 serum level < 100 U/ml correlates with resectability
(41-80%) whereas levels > 100 U/ml suggest advanced or
metastatic pancreatic cancer (60-85%) (22,25,29-37)(Table
3). Nevertheless, 10-15% of patients with a low or normal
pre-operative CA 19-9 serum levels may harbor unresectable
disease identified at exploration, similarly 5-10% of patients
with elevated pre-operative CA 19-9 serum level will be
resectable (12,15). Halloran et al identified unresectable
disease in 17 out of 80 (21%) patients with low CA 19-9
serum levels (< 37 U/ml) who were deemed resectable by
radiologic criteria (37). While the pre-operative serum
CA 19-9 level provides a good prognostic information on
pancreatic cancer stage, however, it should not be the sole
criteria for determining resectability to avoid false negative
or false positive surgical exploration (15,27,28).
Utility of CA 19-9 serum levels as a biomarker of prognosis
in patients with pancreatic cancer
The value of serum CA 19-9 levels to provide meaningful
prognostic information and permit patient stratification
(survival groups) based on its serum level has been
extensively investigated (22,24,26,30,31,38-49)(Table 4).
Waraya et al performed a multivariate analysis of factors
predicting survival in 117 pancreatic cancer patients
undergoing surgical resection and reported that a low
preoperative CA 19-9 serum levels (28-30 U/ml) (p =
0.006, relative risk (RR), 2.16) and positive peripancreatic
margin (p = 0.04, RR, 1.62) independently predicted
survival (46). Moreover they noted that the higher the
preoperative CA19-9 serum level, the worse the prognosis.
Patients with a preoperative CA 19-9 serum levels of < 37
U/ml (N = 23) had a 5-year disease specific survival (DSS)
of 60.0% compared to 4.0% DSS among patients with
CA 19-9 serum levels > 37 U/ml (N = 66) (p = 0.0001).
Even more notable was the fact that 76.9% of stage III pancreatic cancer patients with a CA19-9 serum level of
< 37 U/ml survived more than 5 years (average DSS of
26.9 months). Barugola et al analyzed factors predictive
of early death (within 12 months) among 224 surgically
resected pancreatic cancer patients and reported that
an elevated preoperative CA 19-9 serum levels of > 200
U/ml, a high grade tumor, an R2 resection and prolonged
symptoms independently predicted early death (within 12
months) (46). Berger et al stratified 129 surgically resected
pancreatic cancer patients into 4 groups based on their
pre-operative CA 19-9 level ((undetectable, normal (< 37
U/ml), 38-200 U/ml, and > 200 U/mL)). Patients with
undetectable pre-operative CA 19-9 serum levels and those
with levels of < 37 U/ml had an improved median survival
(32 and 35 months, respectively) compared to patients with
CA 19-9 serum levels between 38-200 U/ml or > 200 U/ml
(22 and 16 months, respectively) (43). Smith et al evaluated
preoperative CA 19-9 serum levels in 109 pancreatic cancer
patients who underwent a pancreatoduodenectomy and
noted a median survival of only 10.4 months in patients
with a preoperative CA19-9 level > 150 U/ml (N = 64),
compared to a median survival of 22.1 months in patients
with a CA19-9 serum level ≤ 150 U/ml (N = 45, p = 0.012)
(45). Table 3 lists additional studies which have used
various cut-off levels for pre-operative CA 19-9 serum
levels in an effort to predict survival among pancreatic
cancer patients (22,24,26,30,31,38-49). These studies
support the conclusion that a normal (< 37 U/ml) or low
preoperative CA 19-9 serum level (< 100 U/ml) correlates
with early pancreatic cancer stage and independently
predicts improved overall survival, whereas an elevated CA
19-9 serum levels (> 100 U/ml) is associated with a poor
prognosis (38-49).
Several authors have reported on the prognostic
significance of the post-operative CA 19-9 serum levels in
predicting survival. Ferrone et al analyzed 111 pancreatic
cancer patients in whom pre- and post-operative CA 19-9
serum levels were measured. Post-operative CA 19-9 serum
levels of < 37 U/ml were associated with a mean survival of
2.4 years, a level of < 200 U/ml had a mean survival of 2.3
years, whereas a post-operative CA 19-9 serum levels of <
1000 U/ml and > 2000 U/ml had a mean survival of 9 and 5
months respectively. Overall a low postoperative serum CA
19-9 level (< 200 U/ml) was an independent predictor of
survival (24).
Kondo et al studied pre- and postoperative CA19-9
serum levels in 109 surgically treated pancreatic cancer
patients and identified that both a normal postoperative CA
19-9 serum level (37 U/ml) (Hazard Ratio (HR) 1.64, p =
0.004), and the addition of adjuvant chemotherapy were
independent predictors of prognosis (26). More specifically these authors identified that a post-operative CA 19-9
serum level measured at 2-5 weeks could independently
predict a prolonged 3- year survival rate. Post-operative CA
19-9 serum levels of < 37 U/ml, < 200 U/ml and > 500 U/ml
were associated with a 49%, 38%, and 0% 3-year survival
rates respectively. Elevated CA 19-9 (> 35 U/ml) in the
immediate post-operative period was also associated with
an R1 resection and lymph node metastases (p = 0.041)
(26). Montgomery et al assessed 40 pancreatic cancer
patients who had undergone surgical resection and found
that patients in whom the CA 19-9 serum levels returned
to normal within the first postoperative year had a longer
overall survival compared to patients in whom CA 19-9
serum levels remained elevated (34 vs.13 months, p < 0.04)
(50-52). Given the half life of CA 19-9 is approximately
14 hours, those authors suggested that post-operative CA
19-9 serum levels should be measured 4-6 weeks following
surgery and that patients with elevated levels are likely
to harbor residual tumor or sub-clinical metastases. In
summary, postoperative normalization or a downward trend
of the CA 19-9 serum level following pancreatic resection
is associated with prolonged survival whereas elevated or
failure of the CA 19-9 to decrease following pancreatic
resection reflects residual disease or occult metastasis and
portends a poor survival.
Utility of CA 19-9 serum levels to assess response to
chemotherapy in pancreatic cancer patients
Most patients with pancreatic cancer require chemotherapy
and/or radiation, either in the neo-adjuvant setting to
improve resectability or treat suspected micro-metastasis,
or in the adjuvant setting for locally advanced disease, high
grade tumor and when vascular invasion or lymph node
metastases are present. Whether serum CA 19-9 levels can
be used as a surrogate marker of response to chemotherapy
has been studied in a variety of clinical settings
(41,44,53-64). Willett et al measured CA 19-9 serum
levels in 42 resectable pancreatic cancer patients receiving
neoadjuvant treatment with 5-f lourouracil and external
beam radiation prior to planned pancreaticoduodenectomy.
Among 10 patients with an increased CA 19-9 serum level
following treatment, 9 (90%) had distant metastases or
local tumor progression. In contrast, only 6 of 29 patients
(21%) with a declining CA 19-9 serum level after neoadjuvant
chemo-radiotherapy had metastases or local
tumor progression on restaging CT scan or at laparotomy.
Whether the CA 19-9 serum level increased or decreased
during treatment, correlated significantly with disease
progression (p = 0.009) (65). Katz et al studied 119 patients
with pancreatic cancer who were treated with neoadjuvant
chemotherapy followed by pancreaticoduodenectomy. These authors found that a post-treatment CA 19-9
serum level of < 37 U/ml had an 86% PPV for successful
completion of the pancreatic resection, and a NPV of
only 33%. Post-treatment CA 19-9 serum levels < 61
U/ml also had a high 93 % PPV but a diminishing 28%
NPV in regards to predicting successful completion of
pancreaticoduodenectomy among resectable patients (49).
Although post-treatment CA 19-9 serum levels in the above
mentioned study had a high PPV in regards to likelihood of
resectability following neo-adjuvant chemotherapy, the low
NPV highlights the importance of re-staging radiographic
evaluation as well as laparoscopy prior to surgica l
exploration (34,49).
Several authors have reported on the use of CA 19-9
serum level trends to assess chemotherapy response using
such definitions as ≥ 20% or ≥ 50%-75% decline in CA 19-9
serum levels within the first 6–8 weeks of treatment. Nearly
all studies have demonstrated that a treatment related
decline in CA 19-9 serum levels is associated with prolonged
survival and is an independent predictor of overall survival
(41,44,53-64)(Table 5). Reni et al compared basal CA
19-9 serum levels in 247 advanced pancreatic cancer
patients enrolled in 5 consecutive chemotherapy trials (G,
gemcitabine; PEFG, cisplatin, epirubicin, 5-f luorouracil,
and gemcitabine; PDXG, cisplatin, docetaxel, capecitabine,
and gemcitabine) (60). The survival curves were plotted
based on a pre-defined decline in CA 19-9 serum levels
(Group 1, < 50% decrease, Group 2, 50% to 89% decrease
and Group 3, > 89% decrease). Patients with a higher
percent decline in CA 19-9 serum level following treatment
had improved overall survival (Group III-16.7 months
compared to Group II-10 months, p = 0.002, and Group II-
10 months vs. 6.5 months for Group -I, p = 0.002). Overall,
the median survival was 15.5 months among patients with
normal CA 19-9 levels, 11.9 months among 108 patients
with CA 19-9 serum levels between 38 U/ml and 1167 U/ml
and 8 months among 105 patients who had CA 19-9 serum
levels > 1167 U/ml (60).
Halm et al evaluated CA 19-9 serum levels in 36 patients
enrolled in gemcitabine chemotherapy trials and reported
that patients with a decline in CA 19-9 serum levels of >
20% from baseline after 8 weeks of treatment (N = 25)
had improved median survival compared to patients with
a rise or a decrease of < 20% (N = 11) (268 vs. 110 days, p
= 0.001) (55). Moreover, treatment related decline in CA
19-9 serum levels was the strongest independent predictor
of survival (p < 0.001) on multivariate analysis. Finally,
using a novel approach to compute log CA 19-9 kinetics
among 115 patients enrolled in first line pancreatic cancer
chemotherapy, Boeck et al demonstrated that log CA 19-9
kinetics was a significant predictor of both time to tumor progression (Hazard Ratio, HR 1.48, p < 0.001) and overall
survival (HR 1.34, p < 0.001) (66).
Utility of CA 19-9 serum levels to predict post-operative
recurrence
The predictive value of current methods (CT scan and
PET scan) to assess early post-operative recurrence
is sub-optimal given that pancreatic resection is often
associated with intense desmoplastic and post-operative
inf lammatory changes leading to dense fibrosis making
radiological detection difficult (15,41,60). The utility
of sequential post-operative CA 19-9 serum level
measurement to detect early recurrence in pancreatic
cancer patients has been well studied. Kang et al evaluated
factors predictive of post-operative recurrence in 61
pancreatic cancer patients and reported that an adjusted
CA 19-9 serum level (defined as a ratio of CA 19-9 serum
levels divided by serum bilirubin when higher than 2
mg/dl) of > 50 U/ml was associated with an increased
recurrence risk (twice) when compared to adjusted levels
of < 50 U/ml (67). Montgomery et al reported that a
significant and sustained post-operative elevations of
CA 19-9 serum levels preceded clinical or radiologic
detection of recurrence by 2 weeks to 5 months (median
3.5 months) and that an elevated post-operative CA 19-9
serum levels > 180 U/ml was associated with a disease
free survival of 12 months compared to 35 months for
patients with post-operative CA 19-9 serum levels < 180
U/ml (50). In this study, patients whose postoperative
CA 19-9 values normalized by 3 to 6 months (< 37 U/ml)
had a longer disease free survival (24 vs. 10 months, p <
0.04) and median survival (34 vs. 13 months, p < 0.04).
Hernandez et al analyzed data from 96 surgically resected
pancreatic cancer patients in whom CA 19-9 serum levels
were drawn at baseline, 4 weeks, and 12-week intervals
following surgery and for whom CA 19-9 velocity was
calculated (rate of change in CA 19-9 levels over a 4-week
period). These authors found that CA 19-9 velocity was a
better predictor of overall survival than baseline CA 19-9
serum levels (p < 0.001). Patients with disease progression
had a CA 19-9 velocity of 131 U/ml/4-weeks compared
to a velocity of 1 U/ml/4-weeks at 22 months for patients
without disease progression (p < 0.001) (51). In summary,
the above results imply that clinical or radiologic postoperative
recurrence is often preceded or associated with
elevated CA 19-9 serum levels by 2-6 months. Elevation
of post-operative CA 19-9 serum levels or failure of the
CA 19-9 serum levels to normalize in the post-operative
period suggest the presence of residual tumor or remnant
disease and is associated with a poor prognosis.
Limitations that undermine the utility of CA 19-9 serum
level as a preferred tumor marker for pancreatic cancer
Despite multiple clinical applications for CA 19-9 serum
levels in pancreatic cancer patients, the diagnostic utility
of CA 19-9 is limited due to a low or modest sensitivity
(79-81%) in symptomatic patients and a low PPV (0.9%)
which makes it suboptimal screening test (12,14,17-19).
Even among individuals at higher risk of pancreatic cancer
(hereditary pancreatitis, family history of pancreatic
cancer, Peutz-Jeghers syndrome), CA 19-9 serum levels
fail to identify early/small tumors or precancerous lesions
in 10-15% of patients (68), is elevated in only 80-85% of
pancreatic cancer patients (12,14,20). The CA 19-9 serum
levels are not predictive of tumor location or differentiation.
As noted earlier, CA 19-9 serum levels may be elevated
in a variety of non-pancreatic neoplastic conditions
resulting in a high false positive rate (10-30%). Benign
conditions associated with elevated serum CA 19-9 levels
include ovarian cyst, heart failure, hashimoto’s thyroiditis,
rheumatoid arthritis and diverticulitis (16-19,69-74)(Table
6). Marked elevations in CA 19-9 serum levels have also
been reported in numerous benign and malignant biliary
conditions (15-38.8%) such as choledocholithiasis,
gallbladder cancer and cholangiocarcinoma. Finally, CA
19-9 serum levels alone cannot differentiate between benign,
precursor lesions and malignant pancreatic conditions such
as acute and chronic pancreatitis, intraductal pancreatic
mucinous neoplasms (IPMN), pancreatic intra-epithelial
neoplasia (PANIN) and pancreatic cancer, as the former
are also associated with elevated CA 19-9 serum levels in
10-50% of cases (69-75).
Hyperbilirubinemia is also a significant confounding
factor since it is associated with an increased CA 19-9
serum level in cases of both benign and malignant biliary
obstruction (8,9,12,20). Although CA 19-9 serum levels
in the presence of obstructive jaundice may have higher
sensitivity, it is at the cost of decreased specificity and
accuracy. Mery et al studied 548 patients with obstructive
jaundice and reported a higher CA 19-9 serum level among
pancreatic cancer patients compared to those with other
hepatobiliary malignancies or benign diseases. These
authors noted that by increasing the cut-off level for CA
19-9 serum level from 37 to 90 U/ml they were better able
to differentiate malignant hepatobiliary diseases from
benign diseases (sensitivity 86% vs. 61% and specificity
39% vs. 86%) (75). Kau et al studied 86 resectable and
57 unresectable pancreatic cancer patients and reported
that a mean CA 19-9 serum levels of 191 ± 6 U/ml and
1203 ± 400 U/ml was associated with serum bilirubin
levels of < 7.3 mg/dl or > 7.3 mg/dl respectively (31).
Ong et al studied 83 patients presenting with abnormal CA19-9 serum levels and radiological or clinical features
suggestive of hepato-biliary-pancreatic (HPB) malignancy
who were subsequently found to have benign disease.
On multivariate analysis, these authors reported that
hyperbilirubinemia (serum bilirubin > 2 mg/dl) was an
independent factor predictive of CA 19-9 serum level (p =
0.028) (76,77).
Biliary drainage which results in a decrease in CA 19-9
serum levels may suggest benign conditions. Marrelli
et al studied 128 patients admitted with obstructive
jaundice including 87 patients with pancreatico-biliary
malignancy and 42 patients with benign diseases. CA 19-9
serum levels were elevated in 61% of benign causes and
86% of malignant causes, which resulted in a reduction
in accuracy to 61%. Following biliary drainage CA 19-9 serum levels decreased in nearly all benign cases (41 of 42
patients, 98%) but in only 19 out of 38 (50%) patients with
malignant biliary obstruction (78). Kau et al reported a 40%
reduction in CA 19-9 serum levels after relief of malignant
biliary obstruction. Several authors have postulated that
inflammation associated with obstructive jaundice increases
proliferation of biliary epithelial cells with a subsequent
increase in systemic absorption of CA 19-9. The CA 19-9
serum levels normalize after treatment of benign cholestasis,
whereas it remains elevated in malignant obstruction due
to persistent production of CA 19-9 by proliferating tumor
cells (31).
In an effort to increase the specificity and accuracy of CA
19-9 serum evaluation in the setting of hyperbilirubinemia,
several authors have suggested using higher cut-off levels for serum CA 19-9 or choosing a level determined by
receptor operator characteristic (ROC) curves associated
with higher specificity. Marrelli et al evaluated an increased
serum CA 19-9 cut-off level of 90 U/ml, and noted that the
specificity increased to 95%, while the sensitivity declined
to 61% (78). Similarly, using a CA 19-9 serum cut-off level
of > 1000 U/ml in the presence of hyperbilirubinemia,
Kim et al reported a specificity of nearly 100%, but a
sensitivity of less than 50% (25). Ortiz-Gonzalez et al
studied 26 patients with resectable pancreatic cancer and
found that the median adjusted CA 19-9 serum level was
significantly lower (p = 0.01) among patients with normal
biliary excretion than those with bilirubin levels > 2 mg/
dL (79). Kang et al assessed the value of adjusted CA 19-9
serum levels to predict post-operative recurrence in 61
patients who underwent pancreatic resection. Adjusted
preoperative CA 19-9 serum levels were significantly lower
compared to baseline CA 19-9 serum levels (129.4 ± 225.2
U/ml vs. 442.1 ± 645.5 U/ml, p < 0.0001). In this study an
adjusted preoperative CA 19-9 serum level of ≥ 50 U/ml (p
= 0.027) was an independent predictive factor for tumor
recurrence (67). Contrary to the above findings, a recent
article reported no effect of hyperbilirubinemia on CA 19-9
serum levels. Maithel et al studied 491 patients in whom
preoperative CA 19-9 serum level was evaluated to predict
presence of sub-radiographic unresectable disease at the
time of staging laparoscopy. These authors failed to find any
significant correlation between CA 19-9 serum levels and
elevated bilirubin levels (Pearson correlation coefficient
0.12) irrespective of tumor location (pancreatic head or
body/tail) (35).
Despite the anomalous report cited above, CA 19-9
serum levels are often significantly elevated in the setting of
obstructive jaundice, resulting in a further increase in false
positives in benign conditions thereby reducing the overall
accuracy and specificity of CA 19-9 as a diagnostic marker.
The use of adjusted CA 19-9 serum levels or using higher
CA 19-9 cut-off levels in the setting of hyper-bilirubinemia
and re-evaluation of CA 19-9 serum levels following the
treatment of obstruction should improve the diagnostic
utility.
Finally, as mentioned earlier, sialyl Lewis negative
phenotype seen in 5-10% of population is associated with
false negative results for CA 19-9 serum levels even in
the presence of advanced pancreatic cancer (7). Other
biomarkers such as duke pancreatic monoclonal antigen
type 2 (DUPAN-2), macrophage inhibitory cytokine
(MIC-1), regenerating islet derived (REG-4) which are
unaffected by Lewis blood group status may be more
effective for this population (7,80,81). Additional strategies
include simultaneous measurement of disialyl Lewis a (normal counterpart) during CA 19-9 evaluation. The ratio
of sLea (CA 19-9)/disialyl Lewis may provide an improved
serum diagnosis by averting undesired effect of a Lewisblood
group negative phenotype and reducing the falsepositive
rate (non-specific elevation) (7).
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Conclusion
Pancreatic cancer is associated with a dismal prognosis and
biomarkers that can detect pancreatic cancer in its earliest
stages should improve prognosis. Despite a large number
of putative biomarkers for pancreatic cancer, carbohydrate
antigen (CA 19-9) is the most extensively studied and
currently the gold-standard biomarker for pancreatic cancer
diagnosis in symptomatic patients. Pre-operative CA 19-9
serum levels provide important prognostic information
in pancreatic cancer patients, correlate with tumor stage
and independently predict overall survival. An increasing
postoperative CA 19-9 serum level or failure of the CA 19-9
serum levels to normalize post-operatively is associated
with a poor prognosis and suggests residual disease or
the presence of occult metastases, while a decline or
normalization of the post-operative CA 19-9 serum level,
is associated with improved survival. CA 19-9 serum levels
assessment can be used as a surrogate marker of response to
chemotherapy with a ≥ 20-50% decrease in CA 19-9 serum
levels following chemotherapy associated with a positive
tumor response and increased survival. Limitations such
as false negative results in sialyl Lewis negative individuals
and false positive elevation in the presence of obstructive
jaundice limit the universal applicability of serum CA
19-9 and the poor PPV of CA 19-9 serum level renders it
impotent as a screening tool.
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References
Cite this article as: Ballehaninna U, Chamberlain R. The clinical utility of serum CA 19-9 in the diagnosis, prognosis
and management of pancreatic adenocarcinoma: An evidence
based appraisal. J Gastrointest Oncol 2012;3(2):105-119. DOI:10.3978/j.issn.2078-6891.2011.021
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