Technical and Clinical Outcomes

EUS-guided PFC drainage has shown a technical success rate of more than 90% and a clinical success rate of 75–90% [7]. Depending on the type of collection, the treatment outcomes can vary. A recent study reported a treatment success rate of 93.5% for pseudocysts, but only 63.2% for WON with plastic stents [8]. This may be due to the small diameter of PS and the presence of solid debris in WON that is more difficult to drain through the fistula tract.

Consequently, straight biliary FcSEMS have been tried in patients with PFCs given theoretical advantages of improved drainage due to larger stent caliber. A study assessed the efficacy of these metal stents for pseudocyst drainage and the overall treatment success was excellent (85–95%) [6].

A randomized study failed to demonstrate superiority of FcSEMS over PS for pseudocyst drainage (clinical success 87% vs. 91%, p = 0.97) [9]. The only advantage of FcSEMS was shorter procedure time (15 min vs. 29.5 min).This was further confirmed in a meta-analysis that found no difference in overall treatment success rates between patients with pseudocysts treated with PS or with metal stents (85% vs. 83%, respectively) [10].

On the other hand, FcSEMS do seem to have superior rates of treatment success compared to PS when used to drain WON [11]. But the straight FCSEMS are prone to migration. Hence, LAMS with a unique “dumbbell” design that bring the walls of the lumen and the PFC close together were introduced. The early reported data have been impressive, with overall technical success rates exceeding 90% and clinical success rates of 85–91%, with many patients achieving complete resolution of WON without the need for DEN. Complications have been observed in 10–15% of patients, while very few patients have gone on to require surgery [12, 13]. Furthermore, migration of LAMS occurred in only 5% of patients,29 and their insertion required significantly shorter procedure times when compared to PS (25 min vs. 43 min, p = 0.01) [14]. A recent study found superior resolution rates of WON at 6-month follow-up when drainage had been performed with metal stents (both straight FcSEMS and LAMS) than with PS [12]. However, to date, no significant difference in efficacy has been shown between straight FcSEMS and the new LAMS, with long-term success rates of 95% vs. 90%, respectively [15].

As with plastic stents, treatment outcomes for pancreatic pseudocysts and WON with LAMS also differ. A recent study evaluated the outcomes of PFC drainage with LAMS. It found that endoscopic therapy by using the LAMS was successful in 12 out of 12 patients (100%), with pancreatic pseudocysts compared with 60 of 68 patients (88.2%) with WON [16].

Two randomized trials that compared EUS-guided PPC drainage and conventional endoscopy-guided PPC drainage demonstrated that EUS-guided transmural approach is superior to conventional endoscopy-guided drainage in terms of technical success and complications [17, 18]. Several observational studies have investigated the efficacy of EUS-guided drainage of pseudocysts and abscesses. They all resulted in high technical and clinical success rates, ranging from 89% to 100% and 82% to 100%, respectively [19–21]. Ng et al [22] recently demonstrated that, although EUS-guided drainage of pseudocysts was technically successful in 93% of patients, the treatment success rate was 75% and the complication rate was 5%. Varadarajulu et al [18], in a comparison of the efficacy of EUS-guided and non-EUS-guided pseudocyst drainage, found that the technical success rate was 100% with EUS, but only 33% with the non-EUS-based approach. A recent randomized, controlled trial of EUS-guided versus surgical cystogastrostomy for pseudocyst drainage determined that there were no differences in terms of treatment success rate, complications, or recurrence, but there was a significantly shorter hospital stay (median, 2 d vs 6 d; p < 0.001) and lower costs in the endoscopic group [23]. An earlier randomized study by the same group yielded similar conclusions [24]. Therefore, the endoscopic approaches seem to be the preferred method for drainage of PFCs.

Adverse Events

A number of adverse events may occur when performing endoscopic management of PFCs including bleeding, perforation, secondary infection, and stent migration. The use of EUS may help to reduce the risk of bleeding by visualizing any intervening vessels. One prospective study reported a 13% rate of bleeding with conventional endoscopic drainage compared to no bleeding with EUS-guided interventions [18]. However, even with EUS guidance, bleeding remains an important adverse event, particularly when metal stents are used [12]. Stent migration is a well-described complication for both PS and FcSEMS, which can occur externally into the GI tract or internally into the PFC. The risk of stent migration is in the range: 1–15% [8, 25]. Internal migration of a stent into the PFC cavity can result in bleeding if the stent erodes into a large blood vessel. Infection of PFCs after endoscopic intervention can occur in up to 20% of cases, often resulting in need for DEN or even surgical intervention. Indeed, a recent retrospective study showed a higher rate of adverse events with PS compared to FcSEMS (31% vs. 16%, p = 0.006), predominantly due to secondary infection that occurs when the stents become blocked and/or the drainage tract closes [26]. As a result, patients with PS were 2.9 times more likely to experience an adverse event compared to those with FcSEMS (odds ratio, 2.9; 95% confidence interval, 1.4–6.3) on multivariable analysis.

Duration of Stenting

Duration of stenting is an important, yet unresolved issue. PFCs have been shown to recur in 10–38% of patients [27, 28]. There are no data to confirm the long-term safety of leaving these stents in place. Prolonged stent placement (using PSs) was shown to be superior to protocolized stent removal by a prospective trial that randomized 28 patients to removal of the stents 2 weeks after PFC resolution or to keeping them in place. At 14 months, the recurrence rate was 38% in the stent-removal group compared to no recurrence in the long-term stent group, with no complications experienced by patients with prolonged stenting [28]. However, the patients who should benefit from prolonged transluminal stenting are those with a viable body or tail of the pancreas with a disrupted PD. In this “disconnected pancreatic duct syndrome (DPDS),” pancreatic secretions from the disconnected body and/or tail leak from the disrupted PD, resulting in persistence or recurrence of a pseudocyst. Long-term plastic stent has been demonstrated by multiple centers to be a safe and an effective solution in more than 90% of patients with DPDS [29–31]. A significant consideration when deciding upon the duration of transluminal stent placement is whether double pigtail PSs or a metal stent are in place. There are concerns about increased risks of delayed bleeding from a collapsed WON collection when a metal stent is in place, which is why stent removal is advised after the PFC resolves if an FcSEMS is in place, except for cases of DPDS.

Role of DEN

DEN consists of debridement of WON using a gastroscope that is inserted directly into the collection via the stomach or duodenum through the cystogastrostomy or cystoduodenostomy fistula tract. The tract is dilated to enable passage of the endoscope and then the necrotic debris is slowly removed from the WON and pulled back into the lumen using a variety of endoscopic tools.

The GEPARD trial evaluated outcomes with DEN [32]. It was a multicenter study of 93 patients with WON who underwent transluminal endoscopic debridement of peripancreatic and pancreatic necrosis, achieving an 80% success rate. Despite these encouraging results, complications were common, occurring in 26% of patients, with 7.5% mortality. Similar outcomes have been observed in subsequent studies [33, 34] A recent meta-analysis found pooled rates of treatment success, adverse events, and mortality of 81%, 35%, and 6%, respectively [35] Reported adverse events include perforation, air embolism, and bleeding, which occurs in 3–21% of patients [32–35]. Therefore, despite the fact that DEN may contribute to accelerated patient recovery and clinical resolution of infected WON, the morbidity and mortality associated with the procedure should limit its use to circumstances in which patients have failed to improve after appropriate transluminal drainage, with a target treatment endpoint of clinical resolution of significant symptoms, not radiological resolution.

Conclusion

EUS-guided intervention is an important component of the treatment of PFCs and currently is the first-line approach for most patients. Recent advances have significantly improved the efficacy and safety of endoscopic PFC drainage procedures. The endoscopic management of pseudocysts has high rates of success regardless of what type of stent is used. On the other hand, WON remains a therapeutic challenge that poses significant morbidity and mortality. In these cases, EUS-guided placement of an FcSEMS, and in particular an LAMS, may provide clinical benefit over the use of double pigtail PSs.

Introduction

Endoscopic retrograde pancreatography (ERP ) is considered the first-line, standard treatment for treating main pancreatic duct (MPD) obstruction, stricture, or disruption. Endoscopic-ultrasound-guided pancreatic duct intervention (EUS-PDI) allows access and intervention to the MPD for patients with failed ERP or with surgically altered anatomy. It is technically demanding with a high risk for complications, but can serve as an alternative to surgical treatment. Proper patient selection is important, and indication and relative contraindications must be carefully assessed.

Technique

EUS-PDI can be divided into two main approaches: EUS-guided antegrade drainage and EUS-guided rendezvous technique.

EUS-PDI Procedure

The MPD is visualized and carefully assessed with a linear echoendoscope. Under combined fluoroscopic and EUS guidance, access into the MPD through the stomach or duodenum is achieved using a 19-gauge needle. Subsequentl, y a pancreatogram is performed and a guidewire can be passed into the MPD.

The rendezvous technique is performed after the guidewire is advanced across the papilla or anastomosis and coiled in the small intestine. The echoendoscope is removed leaving the guidewire in place. Depending on the anatomy, a standard therapeutic duodenoscope, colonoscope, or balloon-assisted enteroscope is then advanced to the papilla or the anastomosis, where the PD can be accessed with the guidance of the EUS placed wire to perform retrograde interventions.

For antegrade PD drainage, the echoendoscope is used throughout the procedure for placement of a stent into the MPD via the stomach or the duodenum. Once guidewire access is achieved into the MPD, dilation of the transmural tract is performed using tapered catheters, dilators, cystotomes or balloons. After tract dilatation, the stent can be deployed.

Outcomes

Although there are several studies reporting outcomes using EUS-PDI, overall the data are quite limited.

A systematic review of studies that focused only on EUS-guided PD access identified 222 patients who underwent EUS-PDI and demonstrated a 77% rate of technical success with a clinical success rate of 70% using either the antegrade or rendezvous technique. Adverse events developed in 19% of the patients, and included abdominal pain (7.7%), pancreatitis (3.1%), bleeding (1.8%), perforation (0.9%), peripancreatic abscess (0.9%), stripping of the guidewire coating (0.9%), and one patient each who developed fever, pneumoperitoneum, pseudocyst, pseudocyst with an aneurysm, and perigastric fluid collection (0.5%) [39].

An international, multicenter, retrospective study on the safety and efficacy of EUS-PDI after failed ERP showed a technical success rate of 89% and clinical success rate of 81%. The transpapillary or trans-anastomotic approaches to stent placement via rendezvous wire access seemed to be the more successful technique. There was an increased likelihood of complete symptom resolution with the rendezvous technique but was not statistically significant. Immediate adverse events (AEs) (<24 hours) occurred in 20% of patients, with 15% experiencing major complications (6 patients with post-ERCP pancreatitis, 4 who developed pancreatic fluid collections, one with a MPD leak, and one with an intestinal perforation. Delayed AEs (>24 hours) occurred in 11% of patients (all of whom also had immediate AEs—2 pancreatitis, 1 MPD leak, and 4 abscesses treated with antibiotics). The method of approach (antegrade vs. rendezvous) was not a predictor of immediate or delayed AE [40].

A recent international, multicenter, retrospective study was performed to compare EUS PDI and ERP in terms of technical success, clinical success, and adverse event rates in patients with post-Whipple anatomy. A total of 66 patients underwent 75 procedures (40 EUS-PDI and 35 ERP). Technical success of EUS-PDI was 92.5% compared with 20% in the ERP group (odds ratio [OR], 49.3; p < 0.001). Clinical success was achieved in 87.5% of EUS-PDI procedures compared with 23.1% in the ERP group (OR, 23.3; p < 0.001). However, adverse events occurred more commonly in the EUS-PDI group (35% vs. 2.9%, p < 0.001) [41].

Potential contributing factors of treatment failure include small PD diameter, fibrotic pancreatic parenchyma, short length for guidewire insertion, lack of dedicated devices, lack of technical standard, and failure to navigate the guidewire through the site of obstruction, across the papilla or PJA [42].

It is difficult to determine the need for reintervention and to predict long-term clinical outcomes after initial successful intervention. Will et al. reported that 29% of patients having EUS-PDI ultimately required surgical intervention during a follow-up period of 4 weeks to 3 years [43].

Conclusions

Although the technical and clinical success rates of EUS-PDI are improving, it remains a challenging procedure with a high risk of adverse events. Considering the major limitations in alternative treatment options after failed ERP, EUS-PDI has the potential to become standard-of-care by avoiding more invasive and involved surgical interventions.

Introduction

The availability of real-time assessment of anatomical details, precise needle advancement coupled with Doppler ultrasonography to avoid major vasculature has led EUS to leap from a diagnostic to the unparalleled era of therapeutic interventions. In recent years, EUS guided antitumor therapy has emerged as an exciting realm and has undergone various phases of experimentation in terms of its feasibility, safety, and efficacy. It can be broadly classified into direct and indirect methods. Direct methods include EUS-guided radio-frequency ablation, ethanol injection, photodynamic therapy, and brachytherapy. Indirect methods include EUS guide fine needle injection (FNI), fiducial placement. In indirect methods, EUS-guided intervention would allow determination of precise anatomical location, which is followed by a second process that has antitumor effects, for example, locally acting chemotherapeutic agents or external beam-guided stereotactic irradiation.

To date, majority of the above EUS-guided antitumor therapy has been targeting on pancreatic tumors. Adenocarcinoma of the pancreas carries a dismal prognosis, its deep seated anatomical location, aggressive tumor biology, and significant peritumoral desmoplastic reaction often entails suboptimal response to systemic chemotherapeutic agents, with an overall <7% survival despite optimal therapy. On the other end of the spectrum, the prevalence of pancreatic cystic lesion has been increasing, owing to the increase in availability and accuracy of cross-sectional imaging. Surgical resection remained the gold standard for lesions with malignant potential; however, curative resection is accompanied with significant morbidly and mortality, which might not be feasible among our aging patient population with significant comorbidities. This eloquently explained why pancreas has been the organ of interest in majority of the EUS-guided therapeutic interventions. Various direct and indirect EUS-guided therapeutic interventions have been attempted in both solid and cystic pancreatic tumors.

Treatment of Solid Pancreatic Tumor

Treatment of Pancreatic Cystic Lesion

Introduction

Celiac plexus neurolysis (CPN ) is the chemical ablation of the celiac ganglia and corresponding neural pathways. This is performed by injecting local anesthetic followed by absolute alcohol into the ganglia, resulting in moderate neuronal degeneration and fibrosis, hence inhibiting pain transmission from upper abdominal organs. The first percutaneous celiac plexus neurolysis was reported by Kappiset al [54] in 1914; since then, the procedure has been performed under fluoroscopic, ultrasound, and computed tomography (CT) guidance. The first endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) was reported in 1996 by Wiersema et al. [55] and Faigel et al. [56]; the technique has been popularized as it allows real-time, accurate assessment of the anatomical details. Safety profile of the procedure is further enhanced with the use of Doppler ultrasonography, which avoids puncturing the interposing vasculature.

The celiac plexus is the largest plexus of the sympathetic nervous system, located in the retroperitoneal space around the origin of the celiac axis and superior mesenteric artery. It comprises a dense network of ganglia with considerable variation in size (0.5–4.5 cm) and number [57]. The preganglionic sympathetic fibers of the celiac plexus constitute the greater (T5-10), lesser (T10-11), and the least (T12) splanchnic nerves, and the plexus also receives parasympathetic fibers from the celiac branch of the right vagus nerve. The left celiac plexus is located more caudally than its counterpart on the contralateral side. The celiac plexus innervates organs in the upper abdomen including stomach, pancreas, liver, spleen, adrenal glands, kidneys, abdominal aorta, mesentery, small bowel, and right colon.

Indication

Celiac plexus neurolysis provides an attractive adjunct in the management of intractable pain from the upper abdominal organs. Current pain management follows the stepwise approach suggested by the World Health Organisation [58], where we commence with the use of nonopioid analgesics and then gradually step up the use of opioids such as morphine. However, escalating dosage of opioid analgesics is often limited by its side effects: nausea, vomiting, constipation, drowsiness, confusion, addiction, and dependence. The use of CPN is particularly pronounced in the management of pancreatic cancer. The aggressive tumor biology and late manifestations entails that only 20% of the patient has resectable disease at the time of diagnosis, with a dismal 5% overall survival over 5 year. Moreover, up to 70–80% of the patients experience intractable pain over the course of the disease [57, 59]; hence, CPN becomes a promising adjunct in the course of tumor pain management.

Chronic pancreatitis is another disease entity where CPN plays an important role in pain management. Despite the benign nature of disease, the recurrent bouts of acute pancreatitis lead to progressive and irreversible destruction of pancreatic parenchyma, leading to gradual loss of endocrine and exocrine functions. The exact mechanism of pain is not understood; a postulated pathophysiological mechanism attributes to increase in pressure either within the pancreatic duct or in the pancreatic parenchyma, which leads to ischemia and the inflammation of pancreatic tissue. This process is further coupled with infiltration of neural inflammatory cells leading to alteration in the neural plasticity of the pancreas [60, 61], leading to the relentless bouts of deep, dull neuropathic pain, which is often opioid resistant.

Techniques of CPN

The two commonly used techniques for EUS CPN are, namely, the central technique and the bilateral technique. The central technique involves injection of neurolytic agent at the origin of the celiac artery. In bilateral technique, both sides of the celiac artery are injected.

Anesthetic agents, such as 0.25–0.75% bupivaciane, are usually injected prior to neurolytic agent to prevent transient exacerbation of pain. Ethanol is the most widely used neurolytic agent, while phenol could be used in patients with ethanol intolerance. It is generally considered that the transient pain exacerbation associated with ethanol injection does not occur with phenol, because it has an immediate local anesthetic effect. A retrospective case cohort by Ishiwateri et al. [62] showed no significant difference in the positive response rate (phenol 83% versus ethanol 69%) among the phenol group of six patients as compared to the ethanol group of 16 patients. Moreover, no significant difference was found in the frequencies of complication and duration of pain relief.

In central technique , the echoendoscope is advanced till the aorta is identified at the level of the diaphragm in the posterior wall of the gastric fundus; the celiac plexus was targeted at the point where the celiac artery (CA) originates from the aorta. The neurolytic agent is injected till the echogenic cloud is sufficiently widespread.

In the bilateral technique , the celiac artery is identified where it originates from the aorta, the echoendoscope is rotated clockwise until the celiac artery (CA) and superior mesenteric artery (SMA) is no longer seen, the needle is advanced to a point where SMA takes off from the aorta, half portion of the neuroleptic agent is injected, the echoendoscope is then rotated counterclockwise until both arteries are no longer seen, the needle is advanced to the right lateral base of the SMA, and the remaining portion of the agent is injected.

Efficacy

The initial report by Wiersema and Wiersema et al. [55] in 1996 showed significant improvement in pain control in 58 patients receiving EUS-CPN in up to 12 weeks following the procedure: among them, 45 patients (78%) experienced a decrease in pain score independently of narcotic use. In the systemic review by Nagels et al. [65], significant pain reduction was noted at weeks 2, 4, 8, and 12 with a mean difference in pain score of −4.26 [95%CI: −5.53-(−3.00)], −4.21 [95%CI: −5.29-(−3.13)], −4.13 [95%CI: −4.84-(−3.43)], −4.28 [95%CI: −5.63-(−2.94)], respectively. This is consistent with result from meta-analysis by Puli et al., [66] which showed a pain reduction in 80% [95%CI: 74.44–85.22] of the patients following EUS-CPN for pancreatic cancer and a 59% [95%CI: 54.51–64.30] of the patients receiving EUS-CPN for chronic pancreatitis. Despite the favorable effects in pain control, EUS-CPN is not associated with significant reduction in opioid use; many patients require same or less than baseline usage of narcotics.

According to a recent review by Yasuda and Wang et al. [67], the choice between central versus bilateral technique is still controversial: the meta-analysis by Puli et al. [66] showed superior result in pain relief among patients treated with bilateral procedure (84.54%; 95% CI = 72.15–93.77) as compared to those received central procedure(45.99%; 95% CI = 37.33–54.78). However, such result was not shown in subsequent RCT by Leblanc et al. [68], where there is no significant difference in pain relief between the central and bilateral techniques (central: 69% vs bilateral: 81%; p = 0.340). Hence, the choice of central or bilateral technique is still a matter of debate.

Though the initial report by Levy et al. [63] showed promising result with regard to the use of EUS-CGN; the only RCT was a comparison between EUS-CGN versus EUS unilateral CPN, which showed substantial greater pain relief in the CGN group (73.5% vs 45.5%, p = 0.026) [69] with similar adverse events; however, conclusion with regards to superiority should await the availability of RCT comparing EUS-CGN with EUS bilateral CPN.

Adverse Events

Complications commonly associated with EUS-CPN are related to blockade of sympathetic efferent activity with parasympathetic overflow. Self-limiting diarrhea occurred in up to 23% of the patients, while transient hypotension is noted in 11–20% of the patients. About 29–34% of the patients may experience transient exacerbation of pain [59, 60, 64–67]. There have been reports of inebriation among Japanese patients [62], a phenomenon which may be due to high proportions of patients with aldehyde dehydrogenase (ALDH2) deficiency among Asian population.

Despite the theoretical enhancement in safety profile associated with better visualization and precision, there have been reports of major complications. Bacteremia and abscess formation may be induced as a needle is pierced through the gastrointestinal tract during the procedure; there have been reports of retroperitoneal abscess [70–72] in three patients receiving EUS-guided bilateral CPN for chronic pancreatitis. Therefore, antibiotic prophylaxis is recommended especially when steroid is used. Two cases of retroperitoneal bleeding [64, 67] have also been reported using the same technique. Three cases of paraplegia were noted, the postulated mechanism may be related to the high volume of alcohol injected to the celiac region, which diffused via intercostal artery toward the anterior spinal artery causing spinal infarction, another mechanism may be related to thrombosis or spasm of the artery of Adamkiewicz, which arises from the aorta at T7 to L4, anatomically in close relation to the celiac ganglion, it supplies the lower two-thirds of the anterior spinal artery.

Fatal ischemic complications have been reported. It is postulated that the sclerosing effect of alcohol led to acute thrombosis of the celiac trunk, resulting in pneumatosis of the stomach, duodenum, small bowel, and ascending colon in a patient receiving bilateral EUS-guided CPN for chronic pancreatitis. Vasospasm of the celiac artery as a result ethanol diffusion has resulted in infarction of liver, spleen, stomach, and small intestine in patients with pancreatic metastasis from lung cancer [73, 74].