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Original article Clinical endoscopy: Editorial| Volume 83, ISSUE 5, P921-923, May 2016

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Endosonography-guided ablation of pancreatic cystic tumors: Is it justified?

      Abbreviations:

      CT (computerized tomography), MRI (magnetic resonance imaging), EEL (EUS-guided ethanol cyst lavage), MPD (main pancreatic duct), PET (Positron emission tomography), IRB (Institutional Review Board)
      The prevalence of pancreatic cysts has been estimated to be around 2% in the general population and may increase up to 9.5% in elderly people.
      • Laffan T.A.
      • Horton K.M.
      • Klein K.P.
      • et al.
      Prevalence of unsuspected pancreatic cysts on MDCT.
      Improvements in imaging techniques, like CT or magnetic resonance imaging (MRI), occurring in recent decades, have resulted in increased numbers of diagnoses of pancreatic cystic lesions that are difficult to characterize and treat.
      • De Jong K.
      • Nio C.Y.
      • Hermans J.J.
      • et al.
      High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations.
      These factors are likely responsible for the “epidemic” of pancreatic cysts that we are now observing. Although consensus guidelines have been published in recent years to facilitate the treatment of these patients,
      • Tanaka M.
      • Fernandez del Castillo C.
      • Adsay V.
      • et al.
      International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
      • Vege S.S.
      • Ziring B.
      • Jain R.
      • et al.
      American Gastroenterological Association Institute Guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.
      a decision on which cysts deserve treatment and which should be better surveyed is yet to be defined. Because pancreas surgery is associated with significant rates of morbidity and mortality, some authors have proposed less-invasive therapies like EUS-guided ethanol cyst lavage (EEL) for tumor ablation.
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      EEL produces lysis of the cyst membrane, protein denaturation, and vascular occlusion, resulting in tumor ablation.
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      This type of therapy has been used in patients who are unfit for surgery or who have a lesion with a low potential for malignancy.
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      The clinical usefulness of EEL in this setting remains controversial.
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      Complete cyst resolution after EEL ranges from 33% to 79%.
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      The differences observed between studies may be due to differences in method (sample size, ethanol concentration ranging from 5% to 99%, use of ethanol alone or in combination with other drugs like paclitaxel), distinct survival time, and absence of reliable markers of tumor response.
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      To assess the effectiveness of EEL, studies have relied on cyst size as determined by CT.
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      Unfortunately, this surrogate marker does not show whether the pancreatic cyst epithelium has been completely ablated. Reports of patients undergoing surgery after ethanol ablation have shown a low rate of epithelial ablation with EEL (0% to 100% complete pathologic response rate).
      • Gan S.I.
      • Thompson C.C.
      • Lawyers G.Y.
      • et al.
      Ethanol lavage of pancreatic cystic lesions: initial pilot study.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      Therefore, in our opinion, CT does not seem to be an adequate method of evaluating response to EEL.
      These limitations make it premature to advocate for the use of EEL at present. To further advance this field, we need to solve these deficiencies and obtain conclusive, reliable, and reproducible data. Otherwise, the future of this attractive technique does not seem to be very optimistic. The study by Gómez et al
      • Gómez V.
      • Takahashi N.
      • Levy M.J.
      • et al.
      EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video).
      in this issue of Gastrointestinal Endoscopy represents, in our opinion, a step in the right direction because the technique for EEL has been standardized and we believe it may serve as a reference for future studies in this area. This is probably the major strength of the study. The protocol includes 3 important points for preventing adverse events: (1) to use routine antibiotic prophylaxis to reduce the risk of infections and (2) to avoid puncturing the main pancreatic duct (MPD) and (3) to exclude those cysts communicating with the MPD to prevent post-EEL acute pancreatitis. To assess this last point, the authors left the needle inside the cyst after EUS-guided cyst aspiration, and then radiographic iodinated contrast medium was injected through the needle to confirm that there was no leakage to the pancreatic parenchyma or communication with the MPD. This method is likely to be more reliable than EUS or MRI images for this specific issue. From the 33 patients initially enrolled, 6 patients (18%) did not undergo EEL because of communication with the MPD (n = 3), leakage to pancreatic parenchyma (n = 2), or the possibility of puncture of the MPD (n = 1). These concerns about safety may probably explain the low rate of adverse events in this study, and we therefore believe they should be probably replicated in future studies on this field. Only 1 patient (4.3%) experienced a mild acute interstitial pancreatitis within the first 24 hours after EEL. The rate of adverse events in this study may be considered especially low, mainly because 5 patients (21.7%) underwent more than 1 session of EEL (range, 2 to 3 sessions). Whether the use of radiographic contrast medium immediately before ethanol injection might have reduced exposure of the pancreatic cyst epithelial lining to the ablative agent and whether such use may have a negative impact on the results of EEL remain unclear, but these possibilities should be kept in mind.
      Another important issue from the EEL protocol adopted in the study by Gómez et al
      • Gómez V.
      • Takahashi N.
      • Levy M.J.
      • et al.
      EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video).
      is that the amount of ethanol injected in the cyst was routinely calculated and depended on the volume of the cyst. This type of practice may certainly provide more reproducible results when EEL is performed. The cyst volume was calculated by taking into account the measures of cross-sectional imaging studies (CT, MRI, EUS), the known FNA needle dead space volume (∼ 2 mL), and the amount of fluid aspirated and injected for lavage. This fact may be responsible, at least in part, for the low rate of adverse events and the poor ablation rate observed in the study (9% complete resolution, and 52% of patients with an 80% reduction in size as estimated by imaging techniques).
      Another point that should be taken into consideration to improve EEL efficacy is to optimize the ablative agent used. Dealing with this issue, De Witt et al
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      demonstrated a few years ago in a prospective, comparative study that ethanol was more effective than saline solution serum for EEL. Unfortunately, despite some optimistic reports,
      • DeWitt J.M.
      • McGreevy K.
      • Schmidt C.M.
      • et al.
      EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized double-blind study.
      • DiMaio C.J.
      • DeWitt J.M.
      • Brugge W.R.
      Ablation of pancreatic cystic lesions: the use of multiple endoscopic ultrasound-guided ethanol lavage sessions.
      most studies, like the study by Gómez et al,
      • Gómez V.
      • Takahashi N.
      • Levy M.J.
      • et al.
      EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video).
      have shown disappointing results for EEL ablation with ethanol. Because there is room for improvement in this area, other agents, like paclitaxel, have been tested for pancreatic cyst ablation.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • Oh H.Y.
      • Seo D.W.
      • Song T.J.
      • et al.
      Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.
      Paclitaxel, a chemotherapeutic agent administered in conjunction with ethanol during EEL, appears to be safe and does not increase the risk of systemic side effects.
      • Oh H.C.
      • Seo D.W.
      • Lee T.Y.
      • et al.
      New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection.
      • Oh H.Y.
      • Seo D.W.
      • Song T.J.
      • et al.
      Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.
      However, it is unclear whether it provides an ablation rate that is superior to that of ethanol alone. A few years ago, Oh et al
      • Oh H.Y.
      • Seo D.W.
      • Song T.J.
      • et al.
      Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.
      described a cohort of 47 patients with incidentally discovered pancreatic cysts that underwent treatment with alcohol lavage and paclitaxel injection. After a median follow-up time of 21.7 months, the authors reported a 62% rate of complete resolution. Whether these results improve cyst lavage with ethanol alone remains to be proved because no comparative study has been reported. Furthermore, serious concerns are still present in patients treated with ethanol and paclitaxel, as highlighted by Fernandez del Castillo.
      • Fernandez del Castillo C.
      EUS treatment of pancreatic cysts: let’s keep the alcohol (and the chemotherapy) locked in the cupboard.
      The main concern about this technique, as for EEL with ethanol alone, is that the epithelial lining of the cyst cannot be assessed by conventional imaging techniques, and we therefore cannot be sure about the effectiveness of this combined therapy. This concern is supported by the fact that in the study by Oh et al,
      • Oh H.Y.
      • Seo D.W.
      • Song T.J.
      • et al.
      Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.
      3 of the 4 patients (treated by EEL with ethanol and paclitaxel) who finally underwent surgical resection had at least 50% of the epithelial lining intact at surgical specimen. Unfortunately, in those cases, the risk of tumorigenesis will remain intact after EUS-guided ablation. These results strongly suggest that the combination of ethanol and paclitaxel is not the answer for effective treatment of these patients. If we aim to offer this therapy to patients with pancreatic cysts, we certainly need to find more efficient agents to completely ablate the epithelium of the cyst. Whether EUS-guided injection of other agents (eg, newer chemotherapy agents, immunotherapy, monoclonal antibodies specifically directed against the epithelium of the cyst) or EUS-directed radiofrequency ablation may become an effective alternative therapy in these patients remains unknown at present. Further research in this direction should be conducted.
      Another area that may help improve results of EEL is the refinement of indications for therapy. A better selection of candidates who may benefit more from EEL may potentially have an impact on patient outcome. Even though its clinical usefulness remains to be proved, experts in the field have classically proposed this type of therapy as a palliative measure restricted only to patients who refuse surgery or who are high-risk candidates for surgery.
      • Fernandez del Castillo C.
      EUS treatment of pancreatic cysts: let’s keep the alcohol (and the chemotherapy) locked in the cupboard.
      Although this appears to be reasonable, one may argue that on the basis of the published results we may be consuming significant human and economic resources for an indication that is at least questionable. By contrast, we have to state that we are in strong disagreement with the indications for EEL proposed by Oh et al
      • Oh H.Y.
      • Seo D.W.
      • Song T.J.
      • et al.
      Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.
      : cysts increasing in size during follow-up and cysts larger than 2 cm, with 6 or fewer locules, that fail to show communication with the pancreatic duct. These indications for EEL have also been severely criticized by experts in the field
      • Fernandez del Castillo C.
      EUS treatment of pancreatic cysts: let’s keep the alcohol (and the chemotherapy) locked in the cupboard.
      because there is no evidence supporting such recommendation. Studies demonstrating that this subgroup of patients is more likely to respond and have fewer adverse events than other patients are needed before one may assume such recommendations. Regarding the selection of patients for EEL, it should also be noted that it is often difficult and sometimes not possible to be sure which type of cyst we are treating (eg, serous, mucinous).
      • Tanaka M.
      • Fernandez del Castillo C.
      • Adsay V.
      • et al.
      International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
      • Vege S.S.
      • Ziring B.
      • Jain R.
      • et al.
      American Gastroenterological Association Institute Guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts.
      Improvements in diagnostic tools to differentiate patients with an increased risk for malignancy from those at low or no risk are also required. Otherwise, we may be treating patients who do not need therapy; even worse, we may be incompletely treating patients with a high risk for malignancy and have an erroneous feeling of tumor ablation. Certainly, improvements in serologic markers of the cyst fluid that allow one to adequately diagnose the underlying cause of the cyst are required in the near future.
      Finally, improvements in surveillance after EEL are required as well. It has been previously mentioned that complete ablation of cyst epithelium is reached in a minority of cases.
      • Oh H.Y.
      • Seo D.W.
      • Song T.J.
      • et al.
      Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.
      Nonsurgical mechanisms of control of the effectiveness of EEL are required, and CT does appear to be sensitive enough. The usefulness of dynamic techniques targeting the cyst epithelium after EEL (eg, contrast-enhanced EUS, positron emission tomography, catheter-based confocal laser endomicroscopy probes) has not been evaluated to date. We believe that a better control of the degree of epithelium ablation is mandatory to ascertain the degree of response to therapy and to tailor subsequent sessions of EEL if needed. We believe confocal laser endomicroscopy probes, which may be advanced through a 19-gauge needle previously introduced into the cyst area, represent the technique more likely to be helpful for this task. It may provide real-time monitoring of the effectiveness of EUS-guided ablation. Studies in this direction are anxiously awaited.
      In summary, at present, EEL is not an effective treatment for pancreatic cysts. Specific areas for improvement in this technique have been clearly identified, and an attempt to standardize EEL and scientifically quantify the amount of alcohol or other agent required to be injected is definitively a step ahead in this technique. Research in this field is definitely warranted, and prospective, multicenter, controlled, institutional review board—approved studies, with a long-term follow-up, is the only way to obtain definitive answers to the many questions raised in this field.

      Disclosure

      All authors disclosed no financial relationships relevant to this publication.

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