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. Author manuscript; available in PMC: 2013 Nov 1.
Published in final edited form as: Cancer J. 2012 Nov-Dec;18(6):584–590. doi: 10.1097/PPO.0b013e3182745ad4

Endoscopic Palliation of Pancreatic Cancer

Gregory A Coté 1, Stuart Sherman 1
PMCID: PMC3551340  NIHMSID: NIHMS415047  PMID: 23187846

Abstract

Endoscopy has an increasingly important role in the palliation of patients with pancreatic ductal adenocarcinoma. Endoscopic biliary drainage is still requested in the majority of patients who present with obstructive jaundice, and the increased use of self-expandable metallic stents has reduced the incidence of premature stent occlusion. First-line use of metallic stents is expected to be utilized more frequently as neoadjuvant protocols are improved. The efficacy of endoscopy for palliating gastroduodenal obstruction has advanced with the development of through-the-scope, self-expandable gastroduodenal stents. There have been advances in pain management, with endoscopic ultrasound-guided celiac plexus neurolysis reducing opiate requirements and pain for patients with unresectable malignancy. Future applications of endoscopy in pancreatic cancer may include fine needle injection of chemotherapeutic and other agents into the lesion itself. This review will summarize the evidence of endoscopy in the management of patients with pancreatic cancer.

Keywords: pancreatic cancer, endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, stent

Introduction

Therapeutic endoscopic interventions for patients with pancreatic ductal adenocarcinoma (PDAC) have expanded from biliary drainage to include gastroduodenal stent placement for gastric outlet obstruction and endoscopic ultrasound (EUS) guided celiac plexus neurolysis for pain management. Future endoscopic therapies may include ultrasound-guided injection of chemotherapeutic or immunologic agents and local tumor ablation. The majority of this review will discuss techniques of endoscopic palliation and consider the evidence for each of these procedures. We will conclude by discussing potential future directions for endoscopy in the palliation of patients with PDAC.

Biliary obstruction

PDAC typically causes a distal bile duct obstruction which should be considered separately from perihilar obstruction (Klatskin tumor), where the efficacy and durability of endoscopic biliary drainage are lower. Furthermore, the impact of preoperative biliary drainage (PBD) on postoperative outcomes varies depending on the location of biliary obstruction. Perihilar obstruction will not be addressed in this review.

Endoscopic approaches to biliary drainage

Endoscopic retrograde biliary drainage is generally preferred in favor of percutaneous, transhepatic biliary drainage since patients prefer to avoid having a percutaneous drain when possible. When performed by experienced providers, endoscopic biliary drainage has favorable (80–90%) short term (< 90 day) success rates in the setting of distal bile duct obstruction, even when combined with diagnostic EUS and fine needle aspiration.1 Still, complications may occur in up to 10% of cases and include cholangitis, perforation, bleeding and post-ERCP pancreatitis. Biliary obstruction may be treated via plastic or metallic stents. Plastic stents are comparatively inexpensive and easily removed during future endoscopy or surgery. On the other hand, self-expandable metallic stents (SEMS) have a larger diameter than plastic stents since their diameter (8–10mm) are not constrained by the size of the working channel of the duodenoscope (4.2mm). While more expensive than plastic stents, SEMS are less likely to occlude, with a relative risk reduction compared to plastic stents after four months of 0.44, (95% CI 0.3, 0.63).2 [Editor's note: Metallic biliary endoprosthesis can be removed at surgery, if the patient comes to resection and the bile duct is divided for biliary reconstruction].

Locally advanced or metastatic PDAC

The goals of biliary drainage in the setting of locally advanced or metastatic PDAC are to palliate obstructive jaundice and normalize serum bilirubin prior to systemic chemotherapy. In addition to resolving jaundice and associated pruritis, biliary drainage improves anorexia, indigestion, and quality of life.3, 4Endoscopic biliary drainage is safer than surgical bypass, with endoscopic placement of a plastic stent having a lower relative risk of complications (0.60, 95% CI 0.45–0.81); on the other hand, biliary obstruction is more likely to recur with an endoscopic/plastic stent approach (relative risk (RR) 18.59, 5.33–64.86). As a result, for patients who are expected to live at least three to six months, SEMS are increasingly preferred over plastic stents due to their superior patency rates.5–9 Use of a SEMS in this setting minimizes short term morbidity while optimizing the durability of nonoperative biliary drainage. If a patient's life expectancy is shorter than 3 months, the role of biliary drainage altogether is questionable since palliation of jaundice will be limited. Nevertheless, in patients with such a short life expectancy, placement of a 10Fr plastic stent is reasonable.

Potentially resectable PDAC

In the United States, the majority of patients with potentially resectable PDAC undergo PBD despite evidence failing to demonstrate its impact on reducing postoperative complications.10–12 This is probably explained by the delayed timing of surgical consultation and pancreatoduodenectomy (PD), which often dictate PBD first and a less urgent surgical consultation second.12

What are the goals of biliary drainage in the preoperative setting?

The purpose of biliary drainage in a patient who is expected to undergo resectional surgery is twofold: first, to resolve jaundice; second, to permit administration of full-dose neoadjuvant chemotherapy. While hyperbilirubinemia may be a predictor of postoperative complications,13–16 the benefit of PBD is questionable.11, 12, 17–21 Experimental studies have demonstrated the benefits of biliary drainage in terms of improved nutritional status22, immune function23 and reducing endotoxinemia.24 In older studies, increased serum bilirubin has been correlated with a greater incidence of infectious, renal and nutritional complications, as well as postoperative mortality.25–29 Studies evaluating the role of PBD are typically limited to patients without marked hyperbilirubinemia (often defined as a serum total bilirubin ≥ 10–15mg/dL), where the potential benefits of PBD will be minimal. Furthermore, the duration between PBD and surgery is often less than 4 weeks despite evidence which shows normalization of hepatocyte function after 6 weeks of decompression.30

Although there have been several studies evaluating the benefit of PBD in patients with periampullary tumors and mild elevation in serum total bilirubin,11, 12, 17, 18, 21 there have been no prospective trials specifically evaluating the impact of PBD on patients with severe hyperbilirubinemia (i.e., “deep jaundice”). Therefore, the role for PBD in patients with marked hyperbilirubinemia and distal bile duct obstruction who are expected to undergo surgical resection remains uncertain.

Endoscopic biliary drainage in a patient who may undergo surgery

Plastic stents are typically composed of polyethylene or polyurethane and derived from internal stents developed in the 1970s for deployment via a percutaneous approach.31 These stents are relatively inexpensive ($200–400 per stent), range in diameter from 7 to 11.5Fr and can be removed intraoperatively or during follow-up ERCP without difficulty. Since their diameter is limited by the size of the working channel of the endoscope, patency rates are limited: 10Fr plastic stents have median patency rates of approximately three months.32 After stent placement, bacterial translocation into the bile duct leads to the development of a biofilm along the internal surface of the stent, increasing the viscosity of bile (with formation of microscopic and occasionally macroscopic sludge) and its consequential precipitation (figure 1). Prophylactic antibiotics, stents coated with antimicrobial materials, variations in stent design, and deployment location (e.g., fully internalizing the stent in the bile duct) have failed to meaningfully improve patency rates in clinical studies.33–35 Increased diameter up to 10Fr is the only stent characteristic that significantly reduces the frequency of stent occlusion.36 Placement of multiple plastic stents in parallel increases the functional diameter across the stricture and permits biliary drainage between the stents (a.k.a., “wicking”). This technique is usually employed in the serial dilation of benign biliary strictures but probably improves patency rates compared to single plastic stents; prospective data evaluating this strategy in the setting of malignant, distal bile duct obstruction are lacking. For patients with resectable PDAC and biliary obstruction who are expected to undergo surgery within three months, a 10Fr plastic stent is definitely recommended over smaller diameter alternatives given their superior patency rates.

Figure 1. Occlusion of a plastic bile duct stent.

Figure 1

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Due to their limited diameter, plastic stents may occlude after 2–3 months due to the development of a bacterial biofilm and precipitation of bile/sludge along the internal margin of the stent. For this reason, use of a 10Fr stent is preferred in the setting of malignant biliary obstruction when surgery is anticipated in the next three months.

Compared to plastic stents, SEMS have superior patency rates due to their greater diameter (8–10mm), and do not have to be replaced every 3 months. However, increased device cost (~ $2–3,000 each) and limited endoscopic or intraoperative removability are potential disadvantages of SEMS compared to PS. Original SEMS were composed of a stainless steel mesh that would embed into the bile duct mucosa, leading to a hyperplastic reaction and interfering with removal during subsequent endoscopy. To optimize patency and minimize ingrowth with tumor and hyperplastic tissue, newer designs utilize more flexible metal alloys and offer a partial or fully covered, nonporous membrane composed of a silicone-like material in certain models. These “covered” or “partially covered” SEMS can be removed during subsequent endoscopy more easily, although they are not currently FDA-approved for this use.37–40 In the setting of malignant biliary obstruction, clinical trials of these coated variants have shown similar or superior patency rates compared to uncovered SEMS for malignant biliary obstruction.41–44 However, numerous studies confirm the superior patency of SEMS when compared to PS, typically in patients with locally advanced or metastatic PDAC.5–9

Limited data suggest no impact on postoperative complications when patients undergo pancreatoduodenectomy after SEMS placement.45–47 If surgery remains a possibility, we recommend deploying the SEMS > 2cm below the hepatic bifurcation to minimize interference with the subsequent creation of a biliary-enteric anastomosis during surgery (figure 2A–B). Data do not strongly favor covered over uncovered SEMS in the setting of malignant obstruction. There is a theoretical risk of occluding the cystic duct with a covered SEMS in patients with an intact gallbladder; rates of cholecystitis are variable in the literature, but the majority of cases typically occur from malignant obstruction of the cystic duct insertion and are not due to the stent itself.48 That said we usually try to deploy the proximal margin of the stent below the cystic duct insertion whenever possible.

Figure 2A–B. Distal bile duct obstruction: Deployment of a self-expandable metallic stent (SEMS).

Figure 2A–B

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Cholangiogram confirms a distal bile duct stricture (A). A self-expandable metallic stent (SEMS) is deployed (note contrast flow immediately following deployment), with the proximal margin of the stent > 2cm below the hepatic bifurcation (B). This permits safe creation of a choledochojejunostomy if surgery is performed at a later date.

Accurate staging of PDAC is challenging: in a recent landmark prospective, randomized clinical trial comparing PBD followed by surgery, 30% of all patients deemed resectable preoperatively could only undergo palliative bypass at the time of surgical exploration.12 Postoperative complications were particularly high in this subgroup that had previously undergone PBD. Based on the recent evidence, if surgical resection is definitely planned within two months and PBD is requested, placement of a single, 10Fr plastic stent is recommended. However, if surgical resection is delayed indefinitely or neoadjuvant therapy is planned, we recommend first-line placement of a fully covered SEMS in an effort to minimize the probability of having to perform a second ERC with stent placement later.46 Despite compelling models favoring these recommendations, SEMS are currently only FDA approved for use in patients with unresectable, malignant biliary obstruction.2, 7, 49 Our practice is outlined in figure 3.

Figure 3. Recommended algorithm for biliary drainage in patients with PDAC.

Figure 3

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PDAC = pancreatic ductal adenocarcinoma; SEMS = self-expandable metallic stents; PDAC

†SEMS are currently approved by the FDA for use in patients who have an inoperable, malignant bile duct stricture.

¥Surgical resection without preoperative biliary drainage is reasonable if the procedure can be arranged in a timely fashion and the patient has no significant symptoms related to biliary obstruction (e.g., cholangitis, pruritis refractory to medical therapy).

Gastroduodenal obstruction

Historically, nonsurgical palliation of gastric outlet obstruction was limited to balloon dilation and intraluminal tumor ablative techniques such as bipolar current and argon plasma coagulation. These approaches conferred limited short term benefit and often required re-intervention. Advances in device development, particularly the advent of SEMS, has extended the role of endoscopy to the palliation of gastric outlet obstruction in patients with PDAC. Since patients with PDAC and concomitant gastric outlet obstruction often have unresectable disease, an endoscopic intervention may obviate the need for surgery altogether. The flexibility of the SEMS deployment system and use of fluoroscopy permits palliation of strictures that cannot be traversed endoscopically (figure4A–E). Trials comparing surgical bypass with endoscopic deployment of a gastroduodenal stent have confirmed the superiority of endoscopy in terms of symptom relief, length of hospitalization and costs.50–54 Similar to biliary drainage, surgical bypass of the gastroduodenal obstruction (typically open or laparoscopic gastrojejunostomy) confers a more durable benefit at the cost of greater short term morbidity and longer time for symptom resolution.55

Figure 4A–E. Endoscopic deployment of a gastroduodenal stent.

Figure 4A–E

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An obstructing malignant stricture is visualized in the duodenal sweep (A) and demarcated using fluoroscopy (B). A previous biliary metallic stent is only seen on fluoroscopy. A balloon catheter is used to advance a 0.035” stiff guidewire across the stricture, aided by a combination of endoscopy and fluoroscopy (C). The endoscope is withdrawn to the antrum, where the stent catheter is advanced over the guidewire and centered across the stricture (D). The stent is deployed by slowly withdrawing its sheath, allowing its proximal margin to flare in the antrum (E).Reproduced, permission pending, from Cote GA and Edmundowicz SA56

Gastroduodenal stent placement may be complicated by perforation, bleeding and stent migration. In addition, if biliary drainage is not assured prior to deployment of the enteral stent, secondary bile duct obstruction may ensue.56, 57 Since the gastroduodenal stent usually traverses the major papilla, we recommend endoscopic biliary drainage prior to deployment of a gastroduodenal stent whenever possible. If this is not technically feasible, it is possible to attempt endoscopic biliary drainage through the interstices of the enteral stent; however, success rates with this approach are lower, based on limited observation and experience.57

In certain cases the enteral stent may not fully expand in the first 24–72 hours due to inadequate radial forces opposing the obstructing tumor or severe angulation of the obstructed bowel loop. Balloon dilation may facilitate initial expansion but has limited durability. Placement of a second stent within the first is typically reserved for cases of stent migration or stent re-stenosis; risk factors for migration include patients who have a robust response to systemic chemotherapy whereas re-stenosis from tumor ingrowth is more likely to occur in those with longer survival, occurring in up to 18% of patients over time.58 Restenosis may also occur from food particles obstructing the lumen; we generally advise patients to remain on a liquid diet for several days after deployment to permit expansion of the stent. Thereafter, a low residue diet is advisable indefinitely. Covered gastroduodenal stents have been developed in an effort to reduce re-stenosis rates; these have higher migration rates and are not currently available in the United States.

EUS-guided celiac plexus neurolysis

Despite the mantra of “painless jaundice” being the textbook presentation for patients with pancreatic cancer, many individuals present with significant upper abdominal and back pain as a result of their disease. For patients who are not expected to undergo imminent surgical resection, early and aggressive titration of analgesics and opiates to achieve pain control should be a priority for the treating physician. EUS-guided celiac plexus neurolysis with injection of combination local anesthetic (e.g., bupivacaine) and highly concentrated alcohol may facilitate pain management with fewer side effects than opiates.59 The procedure is technically straightforward since the celiac axis is typically located within a few centimeters of the gastric wall. When the celiac ganglia can be visualized, the efficacy of the injection is superior, having 15-fold greater odds of response(figure 5).60 Otherwise, an FNA needle is inserted anterior to the celiac axis in one or two locations followed by injection under endosonographic guidance. Some advocate a broader region of injection to include the space anterior to the superior mesenteric artery.61 There are no other factors associated with a better response, but direct tumor invasion of the celiac axis corresponds with reduced efficacy.62

Figure 5. EUS-guided celiac neurolysis.

Figure 5

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A 22 gauge needle is inserted into a celiac ganglion identified by endoscopic ultrasound. Factors associated with a better response include direct injection of celiac ganglia (when visualized) and absence of tumor invasion of the celiac plexus.

Severe complications from EUS-guided neurolysis are rarely reported but may include hemorrhage and spinal cord infarction.63 More common sequelae are a transient increase in pain for several days post-procedure and self-limited diarrhea. Patients may develop self-limited hypotension within hours of the injection that can be managed with an intravenous fluid bolus. Pain reduction can be expected in 75–85% of patients within two weeks of the procedure, and a minority of patients can stop opiates altogether.59, 64, 65 Early use of EUS-guided neurolysis is associated with less pain up to three months later compared, is to medical management alone while also reducing opiate requirements.66 Given its reasonable efficacy and favorable safety profile, we recommend early consideration of EUS-guided neurolysis for patients with unresectable PDAC who have abdominal pain requiring regular use of opiates. In select cases, this can be performed during the initial diagnostic procedure when a preliminary cytology confirms malignancy.

New directions

Targeted therapy

PDAC represents a systemic disease, yet much of its morbidity and mortality derive from complications related to its regional spread. Therefore, efforts to control its growth locally present an opportunity for endoscopy as the vehicle to deliver therapies. A current example is the use of endoscopically-directed markers to localize radiation therapy. Potential future applications include the endoscopic delivery of local chemotherapeutic and immunologic agents.

Stereotactic radiation permits the administration of higher concentrations to the targeted lesion while minimizing collateral tissue damage and systemic side effects. EUS-guided placement of fiducial markers into pancreatic tumors is technically feasible with a safety profile on par with fine needle aspiration; these markers can now be deployed using a 22 gauge needle, reducing technical complexity for lesions in the pancreatic head and uncinate.67–70

EUS-guided tumor ablation via photodynamic therapy and radiofrequency probes along with injection of chemotherapeutic or immunologic agents may permit targeted therapy with fewer side effects compared to systemic chemotherapy.71 The strongest evidence is limited to precancerous cysts of the pancreas treated with injection of ethanol in combination with paclitaxel.72 Early experience with intratumoral injection of TNFerade™, a biologic that combines tumor necrosis factor-alpha with an adenovirus vector, shows promise in improving the radiosensitivity of PDAC.73

Pancreatic duct stenting

PDAC causes pain through several mechanisms, one of which is posited to be obstruction of the pancreatic duct. Similar to “obstructive” chronic pancreatitis where the object of endoscopic or surgical therapy is often drainage of the pancreatic duct, placement of a larger diameter (10Fr) pancreatic duct stent may improve pain and exocrine insufficiency related to PDAC.74 Clinical trials are lacking, but this would be a logical intervention at the time of endoscopic biliary decompression in patients with pancreatic head lesions. The added risks of attempting pancreatic duct stent placement, particularly incomplete drainage, should be considered in any clinical trial evaluating this palliative intervention. [Editor's note: Pancreatic duct stenting is currently rarely used in this setting, and should not be considered standard of care.]

Summary

With future advances in nonsurgical therapies for PDAC, endoscopy is expected to serve an important role in the palliation of biliary, gastroduodenal and perhaps pancreatic duct obstruction. Endoscopic palliation is expected to increase, as endoscopic approaches are logical conduits for the delivery of local agents to the primary tumor. In addition to safety and efficacy, the cost implications of any new endoscopic interventions will significantly influence their implementation, considering the anticipated changes in the U.S. health care system. The added procedure-related costs should be offset by reductions in the length and frequency of hospitalization as well as measurable improvements in quality of life. For patients with PDAC, the decision to proceed with any endoscopic intervention should derive from a multidisciplinary discussion that includes the patient as well as experts in surgery, medical and radiation oncology, and gastroenterology.

Acknowledgments

Conflicts of Interest and Source of Funding: Gregory Coté is currently receiving grants from the National Institute of Health (5R21DK090708-02 and 1K23DK095148-01) and has received honoraria from Boston Scientific Corp. and Olympus America. Stuart Sherman has received honoraria from Olympus America, Boston Scientific Corp., Cook Medical and Repligen Corporation.

Abbreviations

PDAC

pancreatic ductal adenocarcinoma

EUS

endoscopic ultrasound

PBD

preoperative biliary drainage

ERCP

endoscopic retrograde cholangiopancreatography

SEMS

self-expandable metallic stents

RR

relative risk

PD

pancreatoduodenectomy

Footnotes

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