Gastrointest Interv 2015; 4:15–20

Contents lists available at ScienceDirect

Gastrointestinal Intervention
journal homepage: www.gi-intervention.org

Invited Review Article

Management of malignant distal biliary obstruction

Lisa Cassani, Jeffrey H. Lee*

a b s t r a c t

The most common cause of malignant distal biliary obstruction is pancreatic cancer, as 70–90% of patients will develop jaundice during the course of their
disease. Pancreatic cancer is usually advanced at presentation, and curative resection is possible in < 15% of patients. If a patient is to undergo early
surgical resection, biliary drainage is not prerequisite. Early surgery without preoperative biliary drainage does not increase the risk of complications, as
compared with preoperative biliary drainage, followed by surgery. Postoperative complications do not differ significantly between the two approaches. In
light of no significant improvements in patient survival in large trials of a surgery-first followed by adjuvant therapy over the past 2 decades, there has
been a shift towards preoperative neoadjuvant chemotherapy in the setting of borderline resectable disease. Consequently, effective preoperative biliary
drainage has become a paramount concern in this setting. Multiple retrospective and prospective studies have compared the outcomes between covered
metal stents and uncovered metal stents in malignant biliary obstruction. In patients undergoing neoadjuvant chemoradiation or surgical resection, no
significant self-expanding metal stent-related complications or adverse events were seen. Additionally, no significant difference in overall survival was
seen between the two groups. Within the palliative realm, self-expanding metal stents have also become the stent of choice with greater duration of
patency. In an effort to deliver a survival benefit, there are many ongoing trials and developments in the realm of the therapeutic endoscopy. In this
review, we will examine what we have accomplished and further explore the potential benefits of endoscopic interventions on the horizon.
Copyright Ó 2015, Society of Gastrointestinal Intervention. Published by Elsevier. Open access under CC BY-NC-ND license.

Keywords: biliary brushings, cholangiocarcinoma, endoscopic retrograde cholangiopancreatography, pancreatic cancer, self-expanding metal stent

Introduction Screening

Malignant biliary strictures most commonly arise from either Approximately 10–20% of pancreatic cancers may have an un-
pancreatic cancer or cholangiocarcinoma. Often the first presen- derlying genetic predisposition.3,4 Although screening would not
tation of these cancers is with jaundice and biliary obstruction. be appropriate for the general population, consideration of
Unfortunately most of these also present in the late stages of the screening in high-risk individuals may be useful if a highly sensitive
disease. The most recent Surveillance, Epidemiology, and End Re- and cost-effective test is identified. Groups with known genetic
sults data show the overall 5-year survival rate of pancreatic cancer syndromes that predispose them to an increased risk of pancreatic
at 6–7%. If detected early with only local disease (reported as cancer are most likely to benefit from screening. The highest risk
approximately 10% of cases), the survival rates are better but still patients include those with Peutz–Jeghers syndrome (STK11/ LKB1
abysmal at approximately 25%.1 Similarly, the 5-year survival with mutation), familial atypical multiple mole melanoma (p16/CDKN2A
extrahepatic biliary cancer after resection was approximately 30% mutation), Lynch syndrome (MLH1, MSH2, MSH6, and PMS2 mu-
but 0% in those cases that were unresectable.2 Given these sobering tations), hereditary breast and ovarian cancer syndrome (BRCA1/2
statistics, the goal with early stage disease is to proceed to therapy mutations), and hereditary pancreatitis (PRSS1 mutation). Addi-
in an efficient and timely manner, specifically to get to surgical tionally those with a strong family history of pancreatic cancer
resection, as this is the only hope for cure. Palliative therapy by (familial pancreatic cancer) may also be appropriate for screening.
contrast focuses on relief of symptoms and delay of disease Those patients with three or more first-degree relatives are at a 32-
progression. fold increased lifetime risk of pancreatic cancer. Mutations in PALB2
This review discusses the rationale for screening high risk pa- have been associated with familial pancreatic cancer.3
tients, the diagnosis of malignant strictures, the endoscopic therapy Multiple studies have assessed imaging modalities for screening
currently available for these strictures, and possible future thera- of pancreatic cancer.3,5 A large study across five United States in-
pies in the pipeline. stitutions compared computed tomography (CT), magnetic reso-

Department of Gastroenterology, Hepatology, and Nutriton, MD Anderson Cancer Center, TX, USA
Received 1 October 2014; Revised 19 January 2015; Accepted 1 February 2015
* Corresponding author. Department of Gastroenterology, Hepatology, and Nutriton, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 79703, USA.
E-mail address: jefflee@mdanderson.org (J.H. Lee).

2213-1795 Copyright Ó 2015, Society of Gastrointestinal Intervention. Published by Elsevier. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.gii.2015.02.001
16 Gastrointestinal Intervention 2015 4(1), 15–20

nance imaging (MRI), and endoscopic ultrasound (EUS) in 225 Studies of results with endobiliary forceps biopsies have shown
asymptomatic high-risk adults and showed that EUS was the best increased sensitivities, on average around 60%, but this method is
modality to detect a pancreatic abnormality (11%, 33.3%, and 42.6% time consuming and technically difficult and therefore not used on
respectively).6 Currently there are no specific guidelines as to how a routine basis.12
to screen and what age to start this process, but EUS or MRI seems In a prospective comparison of ERCP with biopsies or brushings
to be the best currently available modality for early detection in and EUS-guided fine needle aspiration (FNA) in patients with both
these high risk patients. biliary and pancreatic pathology, ERCP-based techniques were su-
Development of new technology for better screening for perior for the subgroup with biliary tumors (ERCP 75% vs. EUS 25%),
pancreatic cancer is needed. Evaluation of optical markers in the and EUS-FNA guided biopsy was better in the subgroup with
periampullary duodenum with low-coherence enhanced back- pancreatic masses (EUS 60% vs. ERCP 38%).15 A more recent study
scattering has been reported to discriminate between healthy published in Gastrointestinal Endoscopy in July 2014 compared EUS-
controls and patients with pancreatic adenocarcinoma with 95% guided FNA to ERCP tissue sampling with brushings and forceps
sensitivity, 71% specificity, and 85% area under the receiver oper- biopsy. This was a prospective, single-blinded trial of same session
ator characteristic curve. Additionally these numbers were not EUS and ERCP for malignant biliary strictures. The overall sensi-
affected when looking specifically at resectable stage disease.7 tivity and accuracy was 94% and 94% respectively for EUS compared
Further study is underway to better elucidate the utility of this to 50% and 53% for ERCP sampling. This study also confirmed
technology and assess whether it may be a promising technique for comparable sensitivity for biliary masses but superior sensitivity
screening. for EUS-FNA over ERCP in strictures related to pancreatic masses.16
FNA needle size has been investigated to determine sample
Diagnosis adequacy. A meta-analysis of 22-gauge needles versus 25-gauge
needles for FNA of solid pancreatic masses showed that 25-gauge
Distinguishing between malignant and benign strictures in an needles were more sensitive than 22-gauge needles for the diag-
efficient manner may portend a better chance for cure for local nosis of malignancy (93% versus 85%).17 In another study, the 25-
disease but also for those patients with borderline resectable dis- gauge needles were again superior over 22-gauge but also over
ease. Imaging studies as well as stricture sampling provide com- 19-gauge Trucut core biopsy needles as well.18 Additional core bi-
plementary information regarding both the etiology of the stricture opsy needles have been developed as well. A 22-gauge core needle
but also the extent of disease. in one small study did not show superior diagnostic results over the
Multiple imaging modalities have been studied to assess the 22-gauge FNA needle.19 Most recently a 25-gauge core biopsy
best method of detection and differentiation between malignant needle was studied and produced high sensitivities on each of three
and benign strictures. passes (83%, 91%, and 96%) despite low histological core biopsy
A prospective study assessing magnetic resonance chol- yields (32%).20 Randomized studies comparing the 25-gauge core
angiopancreatography (MRCP) compared to CT, endoscopic retro- needles and standard FNA needles are needed.
grade cholangiopancreatography (ERCP), and percutaneous Finally, the combination of sampling methods appears to in-
transhepatic cholangiography for the diagnosis of malignant biliary crease the yield of diagnosis. A study of 133 patients undergoing
strictures versus benign strictures showed comparable sensitivities ERCP for jaundice underwent trimodal tissue sampling by brushing,
and specificities for ERCP versus MRCP (sensitivity 85% for both and endobiliary forceps biopsy, and fine-needle aspiration cytology. 104
specificity of 75% for ERCP and 71% for MRCP). CT had lower patients had a malignant stricture with (46 pancreatic, 30 chol-
sensitivity and specificity compared to both ERCP and MRCP.8 angiocarcinoma, 13 ampullary, and 15 metastatic). The highest
Although MRCP was comparable, ERCP provides the ability to yield of sampling regardless of type was seen with ampullary
sample the stricture as discussed below, which may make it a more cancers. The combination of techniques was superior to any one
attractive study despite the invasiveness of the test. alone.21
The sensitivity and specificity of fludeoxyglucose-positron Despite the investigation of numerous adjunctive tests to
emission tomography (18FDG-PET) to distinguish malignant from routine cytology and histology, only fluorescence in-situ hybridi-
benign strictures has varied widely across studies and for different zation (FISH) has seen consistently optimistic results. This tech-
anatomic locations (intrahepatic versus perihilar versus extrahe- nique uses fluorescently labeled DNA probes to assess for polysomy
patic). In one study of 93 patients with cholangiocarcinoma un- on certain predetermined chromosomal loci. In a study by Fritcher
dergoing preoperative 18FDG-PET scans, the sensitivity and et al,22 498 brushings from pancreaticobiliary strictures were
specificity for intrahepatic versus extrahepatic lesions was 95% and assessed with FISH versus routine cytology. The sensitivity of pol-
100% versus 69.2% and 66.7% respectively.9 An additional study ysomy FISH was 42.9%, which was significantly higher than routine
comparing 18FDG-PET with conventional imaging modalities (CT cytology (20.1%). Specificity approached 100% for both.22 Additional
and MRI) showed no statistically significant advantage in favor of studies have confirmed this result and in fact exceeded the sensi-
18
FDG-PET for diagnosis but did show higher accuracy over CT in tivity value.23–25 Given these findings, the use of FISH in the setting
the diagnosis of regional and distant metastases, suggesting that of negative or indeterminate routine cytology has been recom-
18
FDG-PET should be an adjunct to other modalities for staging mended in recent guidelines by The Papanicolaou Society of
purposes.10 The use of 18FDG-PET for not only diagnosis but also Cytopathology.26
staging and follow-up for cholangiocarcinoma has been reviewed
separately beyond the details above.11 Endoscopic therapy
Studies on the yield of biliary brushings during ERCP have
shown a wide range of sensitivities from approximately 30% to Stenting
60%.12 Performing multiple brushings has been shown to increase
sensitivity, and after three consecutive negative brushings, the Previously it was thought that preoperative drainage was
probably of malignancy is very low.13 Sensitivity does not seem to beneficial as, theoretically, drainage was thought to decrease
increase with dilation.14 Improvement in sensitivities with some of complications related to cholestasis including cholangitis, impaired
these methods is thought to be related to disruption of the biliary clotting and immunological response, and fat malabsorption.
epithelium, yielding better access to malignant cells. Despite lack of evidence for it,27 preoperative drainage has been
 Lisa Cassani and Jeffrey H. Lee / Management of malignant distal biliary obstruction 17

Fig. 1. The algorithm for management of malignant distal biliary obstruction.

incorporated into most centers’ algorithms for care of these pa- plastic stents.37 Further studies compared types of SEMSdcovered
tients. However, if a patient is to undergo early surgical resection versus partially covered versus fully covered. The majority of these
for resectable pancreatic cancer, biliary drainage is not necessary. In studies have shown no differences between these stents as far as
2010 a randomized, multicenter trial was done to compare pre- time to recurrent obstruction (Table 2).38–46
operative biliary drainage with plastic stenting for 4–6 weeks In patients undergoing neoadjuvant chemoradiation or surgical
versus early surgery (within 1 week) in patients with resectable resection, no significant SEMS-related complications or adverse
pancreatic cancer. Serious complications occurred in 39% of the events were seen, and no significant difference in overall survival
early surgery group versus 74% of the biliary drainage group. was seen between the covered and uncovered metal stent
Cholangitis and stent related complications were the main com- groups.38–40
plications in the biliary drainage group.28 There were a number of In these studies, covered SEMS were more frequently associated
criticisms with the paper including a high rate of initial ERCP failure with migration and uncovered SEMS were more frequently asso-
(25%) and excessively high ERCP complication rate (46%).29 ciated with tumor ingrowth.38–40
Throughout the past 2 decades, the approach of an operation Metal stents have been associated with higher rates of post-
first, followed by adjuvant therapy failed to show any significant ERCP pancreatitis compared to plastic stents.47 The frequency be-
improvements in patient survival. Over the past 6 years, there has tween covered and uncovered stents has shown mixed results in
been a shift towards preoperative neoadjuvant chemotherapy and studies with either similar pancreatitis rates or increased rates with
radiation in the setting of borderline resectable disease (Table 1).30– covered stents.39,47 Additionally, the rate of acute cholecystitis has
34
Neoadjuvant therapy efficiently delivers early treatment of been higher with the covered stents than uncovered.40,48,49
micrometastic disease. Although the longer preoperative interval These studies clearly suggest that metal stents are superior over
was not associated with local tumor progression during the pre- plastic stents but comparison of covered versus uncovered stents
operative therapy, it required durable biliary decompression. has been difficult. Comparison across studies has been challenging
Consequently, effective preoperative biliary drainage has become a due to the use of different brands of stents with different metal
paramount concern in this setting. struts and coatings. Additional controlled randomized studies are
Additionally, the use of plastic stents in for biliary drainage in needed to assess the newer stents for time to recurrent obstruction
this setting has also become less desirable as self-expandable and rates of complications. Taking into consideration the issues
metallic stents (SEMS) have been shown to be superior as far as discussed above, the algorithm for management of malignant distal
rates of occlusion and cholangitis with minimal intra- or post- biliary obstruction is shown in Fig. 1.
operative complications.35,36 Finally, given the success of drug eluding stents in the vascular
SEMS have also been shown to be better than plastic stents for arena, a natural transition would be to utilize this technology with
palliative stenting as well. A Cochrane database review evaluated biliary stents if a suitable drug could be identified. Intravenous
nine studies that compared the stent materials. This showed a risk paclitaxel in combination with gemcitabine is considered first line
ratio for recurrent biliary obstruction of 0.48, favoring metal over therapy for metastatic pancreatic cancer. Additionally, paclitaxel

Table 1 Summary of Trials of Preoperative Chemoradiation for Resectable Pancreatic Cancer

Study No. of patients Preoperative regimen Resection % r1 Median survival Local recurrence
rate (%) resected patients (mo) rate (%)

Evans et al (1992)34 28 5-FU þ XRT 50.4 Gy 61 d 18 d

Pisters et al (1998)32 35 5-FU þ XRT 30 Gy 57 10 25 10
Pisters et al (2002)33 37 Paclitaxel þ XRT 30 Gy 54 32 19 d
Evans et al (2008)31 86 Gem þ XRT 30 Gy 75 12 34 11
Varadhachary et al (2008)30 90 Gem/Cis then Gem þ XRT 30 Gy 58 4 31 25

5-FU, fluorouracil; Cis, cisplatin Gem, gemcitabine; XRT, radiotherapy.

18 Gastrointestinal Intervention 2015 4(1), 15–20

Table 2 Sample of Selected Comparative Studies of Covered Versus Uncovered Self-expandable Metallic Stents (SEMS)

Study SEMS used % with recurrent Patency rates (%) Time to recurrent Adverse Events
obstruction obstruction (mo)

Lee et al (2013)39 Zilver/Flexxus/ U: 38 d U: 26.3 U: 1% migration; 1% cholecystitis; 1%

Niti-S/Wallstent/ C: 35 C: 15.4 pancreatitis; 5% cholangitis
Wallflex C: 7% migration; 0% cholecystitis; 6%
pancreatitis; 2% cholangitis
Li et al (2012)45 Nitinol U: 64 U: 85, 68, 43 U: 5.3 U: 0% migration; 0% cholecystitis; 11%
C: 51 C: 86, 83, 60 C: 8.4 cholangitis; 2% pancreatitis
(3 mo, 6 mo, 12 mo) C: 9% migration; 3% cholecystitis; 20%
cholangitis; 3% pancreatitis
Kawakubo et al Wallstent/ComVi/ U: 38 U: 77, 58, 29 U: 3.7 U: 0% migration; 5% cholecystitis; 0%
(2011)46 Diamond/ C: 11 C: 94, 82, 73 C: 7.4 pancreatitis; 0% cholangitis
Wallflex/JOSTENT SelfX/ (3 mo, 6 mo, 12 mo) C: 4% migration, 0% cholecystitis; 14%
SMART/ZEO pancreatitis; 7% cholangitis
Telford et al Wallstent U: 18 d U: 23.4 U: 0% migration; 2% pancreatitis, 7%
(2010)40 PC: 29 PC: 11.7 cholecystitis
PC: 12% migration, 0% pancreatitis; 7%
cholecystitis
Kullman et al Nitinol U: 23 U: 97, 87, 78, 56 U: 6.5 U: 0% migration; 1% cholecystitis; 2%
(2010)38 C: 24 C: 95, 83, 74, 50 C: 5.0 pancreatitis; 6% cholangitis
(1 mo, 3 mo, 6 mo, 12 mo) (25% stents occluded) C: 3% migration; 1% cholecystitis; 1.5%
pancreatitis; 4% cholangitis
Gwon et al Nitinol/Zilver/Sentinol U: 33 U: 98, 83, 72, 57, 57 U: 5.6 U: 0% migration; 0% cholecystitis
(2010)44 PC: 12 PC: 98, 98, 91, 76, 76 C: 4.9 PC: 3% migration; 2% cholecystitis
(1 mo, 3 mo, 6 mo, 9 mo,
12 mo)
Yoon et al Wallstent U: 37 U: 83, 66, 54, 36 U: 10.4 U: 2% migration; 0% cholecystitis; 0%
(2006)41 C: 25 C: 83, 78, 67, 54 C: 13.0 pancreatitis
(100 d, 200 d, 300 d, C: 8% migration; 3% cholecystitis; 0%
400 d) pancreatitis
Park et al Wallstent U: 19 U: 92, 77, 54, 37 U: 4.7 U: 0% migration; 1% cholecystitis; 2%
(2006)42 C: 21 C: 92, 72, 56, 37 C: 4.9 pancreatitis
(1 mo, 3 mo, 6 mo, C: 6% migration; 1% cholecystitis; 6%
12 mo) pancreatitis
Isayama et al Diamond stents U: 38 U: 81, 68, 55 U: 5.5 U: 0% cholecystitis; 2% pancreatitis
(2004)43 C: 14 C: 100, 91, 74 C: 10.0 C: 4% cholecysitits; 9% pancreatitis
(3 mo, 6 mo, 12 mo)

C, covered; PC, partially covered U, uncovered.

has been shown to inhibit cell proliferation in several in vitro uncovered metal). Choledochoscopy confirmed coagulation ne-
models pertinent to stent reocclusion and tumor ingrowth.50 Given crosis in three patients.53 Although these studies of small pop-
the above, local drug therapy with paclitaxel within biliary stents ulations suggest potential benefit with this treatment, further
may provide improved rates of stent patency. This has been eval- larger randomized studies are needed to document meaningful
uated in limited human studies. In a prospective, randomized pilot utility and, particularly, safety.
study out of South Korea, 52 patients were randomizedd26 to drug
eluting stents and 26 to covered metal stents as the control group.
Injection therapy
Forty-nine patients were included in the final analysis (24 in
intervention group and 25 in the control group). Although study
Although theoretically encouraging, improvement in outcomes
size was a limitation, stent patency duration and survival time were
with injection of antitumor therapy or placement of radioactive
not significantly different between the two groups.51 Further larger
seeds, specifically for pancreatic cancer, has unfortunately been
studies of this drug may be warranted or additional drug investi-
disappointing despite proven administration safety. Potential in-
gation may prove more fruitful to lower the rates of reocclusion.
jection treatments have attempted stimulation of the immune
system with lymphocyte culture, tumor necrosis factor-a, or den-
Ablation dritic cells, use of viruses, or local administration of chemothera-
peutic agents or radioactive therapy.
Radiofrequency ablation (RFA) has been an established treat- Injection of allogenic mixed lymphocyte culture (Cytoimplant)
ment for malignant or premalignant conditions such as Barrett’s directly into the tumor causes release of cytokines and induction of
esophagus and hepatocellular carcinoma. Endobiliary RFA has been tumor regression. One small Phase I study with eight participants
studied as a palliative adjunct to biliary stenting in patients with had two patients with partial responses and one with a minor
unresectable disease to decrease the rate of tumor ingrowth and response, and there was no correlation with survival.54
epithelial hyperplasia within the stent. One initial study showed TNFeradeBiologic is an adenovector that expresses human
promising results with excellent 90-day patency rates (18 of 21 tumor necrosis factor-a under the control of a promotor inducible
patients had patent stents) as well as an excellent safety profile. All by chemoradiation. A small randomized trial of TNFerade with
treated patients received uncovered metal stents post RFA treat- standard of care (fluorouracil combined with radiotherapy) versus
ment.52 Further study has confirmed safety of this treatment and standard of care alone in patients with locally advanced pancreatic
additionally showed a significant increase in post treatment bile cancer showed a longer median survival (14.7 months vs. 11.1
duct diameter. All treated patients again underwent stent place- months) in the treatment group.55 The final results of the multi-
ment post RFA (6 plastic, 13 partially or fully covered metal, and 1 center trial were reportedly not as encouraging.56
 Lisa Cassani and Jeffrey H. Lee / Management of malignant distal biliary obstruction 19

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Pathol. 2011;136:442–9.
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All contributing authors declare no conflicts of interest. Fluorescence in situ hybridisation in the cytological diagnosis of pan-
creatobiliary tumours. Pathology. 2011;43:335–9.
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