Secretin-Stimulated MRCP to Optimally Select Patients for Pancreatic Endotherapy?

Abstract

See “Administration of secretin (RG1068) increases the sensitivity of detection of duct abnormalities by magnetic resonance cholangiopancreatography in patients with pancreatitis,” by Sherman S, Freeman ML, Tarnasky PR, et al, on page 646. See “Administration of secretin (RG1068) increases the sensitivity of detection of duct abnormalities by magnetic resonance cholangiopancreatography in patients with pancreatitis,” by Sherman S, Freeman ML, Tarnasky PR, et al, on page 646. In the initial evaluation of acute pancreatitis, comprehensive history, routine laboratory testing, transabdominal ultrasonography, and computed tomography reveal the etiology of pancreatitis in most patients. Gallstones and alcohol are the cause in the majority, and when the risk factor is removed, the disease generally does not recur. For those patients without a clearly defined etiology, or for the 20%–30% with recurrent episodes of pancreatitis, additional imaging to identify an etiology and appropriately direct treatment is critical to prevent the morbidity of recurrent disease and the development of chronic pancreatitis. In this issue of Gastroenterology, Sherman et al1Sherman S. Freeman M.L. Tarnasky P.R. et al.Administration of secretin (RG1068) increases the sensitivity of detection of duct abnormalities by magnetic resonance cholangiopancreatography in patients with pancreatitis.Gastroenterology. 2014; 147: 646-654Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar explore the role of secretin stimulated magnetic resonance cholangiopancreatography (S-MRCP) for patients with acute and/or recurrent pancreatitis. The primary goal of the trial, designed to obtain US Food and Drug Administration (FDA) approval for the synthetic human secretin manufactured by the sponsor, was to prove that S-MRCP is superior to standard MRCP for the imaging of the pancreatic ductal anatomy, using ERCP in combination with other imaging as the “gold standard.” Trials such as this one are designed with the FDA with the primary purpose of regulatory approval of a pharmaceutical product and the methodologic rigor mandated by the regulatory authority often narrows the population studied. In this case, only those patients who underwent the gold standard imaging procedure, in this case endoscopic retrograde cholangiopancreatography (ERCP) with pancreatography could be included. The study was designed to assess the value of S-MRCP compared with MRCP—and was not a trial of its clinical impact for the management of the target population, so one must cautiously generalize the results to current clinical practice. ERCP has evolved from its inception as a diagnostic procedure to its current role nearly exclusively as a therapeutic one. Safety has driven this evolution, because complications of ERCP remain a critically important consideration despite recent progress in reducing the risk of post-ERCP pancreatitis.2Dumonceau J.M. Andriulli A. Deviere J. et al.European Society of Gastrointestinal Endoscopy (ESGE) Guideline: prophylaxis of post-ERCP pancreatitis.Endoscopy. 2010; 42: 503-515Crossref PubMed Scopus (239) Google Scholar Until this risk is eliminated, careful selection of patients for ERCP therapy using less invasive approaches remain the standard for current, advanced endoscopy practice. The inclusion criteria of this trial required a history of acute or acute recurrent pancreatitis and patients had to have an ERCP with pancreatography planned for diagnosis and/or treatment. The population studied must have excluded patients with well-defined biliary pancreatitis and obvious chronic pancreatitis without a target for therapy. Pancreatography should not be an intentional part of an ERCP examination for patients undergoing biliary endotherapy, and inadvertent pancreatic manipulation and injection should prompt the use of indomethacin to reduce the risk of procedure-related pancreatitis.3Elmunzer B.J. Higgins P.D.R. Saini S.D. et al.Does rectal indomethacin eliminate the need for prophylactic pancreatic stent placement in patients undergoing high-risk ERCP? Post hoc efficacy and cost-benefit analyses using prospective clinical trial data.Am J Gastroenterol. 2013; 108: 410-415Crossref PubMed Scopus (81) Google Scholar The focus of the paper was the quality of pancreatic ductal imaging. The final clinical diagnoses of the patients are not provided; but not surprisingly, 40% of the ducts were completely normal and 25% of the patient’s had pancreas divisum. Although not explicitly discussed, some of the patients with normal ducts may have been studied with manometry to identify sphincter of Oddi dysfunction (SOD) as a potential cause of idiopathic recurrent acute pancreatitis. Further exploring the results, subtle findings of chronic pancreatitis were found in about one quarter of the ducts, a finding of uncertain impact on patient management. Turning to the ERCP prevention index, an estimate defined by the authors exploring the ability of noninvasive imaging to spare the patient the risk of the more invasive procedure, S-MRCP confirmed 75% of patients did not require ERCP, compared with 48% with standard MRCP. However, it is important to keep in mind that this index proposed by the authors includes divisum as well as duct stricture or disruption as an indication for pancreatic endotherapy—and although the data are not granular enough to be certain, diagnostic accuracy for divisum may drive the endpoint difference. This raises key questions regarding the overall role of endotherapy for unexplained/recurrent pancreatitis. Debate regarding the importance of pancreas divisum as a cause of pancreatitis continues among experts.4Roberts J.R. Romagnuolo J. Endoscopic therapy for acute recurrent pancreatitis.Gastrointest Endosc Clin North Am. 2013; 23: 803-819Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Because as many as 1 in 7 humans have this congenital variant, it cannot be the sole risk factor for the condition, prompting further restraint regarding the value of endotherapy for these patients. It is most likely that divisum is a risk factor that lowers the threshold for development of pancreatitis in a genetically predisposed individual, as does alcohol and smoking (alone or in combination).5Bertin C. Pelletier A. Vullierme M. et al.Pancreas divisum is not a cause of pancreatitis by itself but acts as a partner of genetic mutations.Am J Gastroenterol. 2012; 104: 311-317Crossref Scopus (145) Google Scholar For patients with divisum and established chronic pancreatitis, as well those with chronic pain, results of minor sphincterotomy are markedly inferior to those with normal glands.6Kanth R. Samji S. Inaganti A. et al.Endotherapy in symptomatic pancrea divisum: a systematic review.Pancreatology. 2014; (In press)Crossref PubMed Scopus (41) Google Scholar Endoscopic ultrasonography (EUS) is the most sensitive test for chronic pancreatitis changes, although the specificity of current scoring systems is in question given the lack of a histologic gold standard.7Stevens T. Parsi M.A. Endoscopic ultrasound for the diagnosis of chronic pancreatitis.World J Gastroenterol. 2010; 16: 2841-2850Crossref PubMed Scopus (18) Google Scholar I would expect MRCP and S-MRCP to be less sensitive but perhaps more specific for confirming chronic pancreatitis than EUS, although well-designed studies are lacking. However, EUS is less sensitive then MRCP for divisum.8Rana S.S. Gonen C. Vilmann P. Endoscopic ultrasound and pancreas divisum.JOP. 2012; 13: 252-257PubMed Google Scholar Studies to examine the role of S-MRCP compared with EUS, for example, to identify small duct chronic pancreatitis and predict the outcome of endotherapy for pancreas divisum would be a welcome addition to the literature. Even greater debate can be engendered for SOD as a cause of recurrent pancreatitis. Investigators have studied S-MRCP to predict the condition and direct sphincterotomy; however, the data remain highly controversial, with evidence that S-MRCP cannot predict SOD and endotherapy response.9Aisen A.M. Sherman S. Jennings S.G. et al.Comparison of secretin-stimulated magnetic resonance pancreatography and manometry results in patients with suspected sphincter of Oddi dysfunction.Acad Radiol. 2008; 15: 601-609Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar It is important to keep in mind that pancreatic sphincterotomy can induce recurrent pancreatitis as well as sphincter stenosis—so the intervention can be a double-edged sword. Adding to the complexity in this area is evidence that recurrent/chronic pancreatitis itself can induce scarring in the pancreatic sphincter which raises pressure, prompting an intervention that can sometimes help but sometimes induce further pancreatitis. My view is that many patients with idiopathic pancreatitis and “pancreatic-SOD” have additional genetic predispositions to pancreatitis, similar to those with divisum. These concepts should provide equipoise in using S-MRCP over MRCP or EUS to select patients for SOD evaluation until convincing data support treatment success. ERCP has a central role not only for stone/sludge-induced pancreatitis that can be cured by sphincterotomy and ductal decompression, but parasitic as well as ampullary neoplastic obstruction that is amenable to endoscopic cure. MRCP, however, is not the only high-resolution imaging approach to evaluate patients with unexplained pancreatitis. EUS, in addition to its accuracy for identification of occult chronic pancreatitis, at the same time can provide high-quality imaging of the bile duct for stones as well as endoscopic and ultrasound assessment of ampullary lesions, small tumors, ductal strictures, as well as pancreas divisum. Although EUS, like MRCP, is operator dependent, it is generally less costly than MRCP (with or without secretin). Quantifying procedure “cost” however is not a simple matter. At our University Hospital, MRCP charges (professional and facility fees) are approximately $5700, with EUS less than half ∼$2500. Medicare reimbursement, however, is ∼$1600 for EUS while only ∼$650 for MRCP. Commercial payers reimburse MRCP closer to 50% of charges, far exceeding EUS charges and reimbursement. If anesthesiology services are used for either procedure, costs will escalate. EUS is invasive and requires patients to provide an accompanying driver, however, some patients request sedation for MRCP due to claustrophobia. While life threatening allergic reactions to gadolinium are very rare, one study reported nearly 2% of patients prematurely terminated their MRI exams due to claustrophobia.10Eshed I. Althoff C.E. Hamm B. et al.Claustrophobia and premature termination of magnetic resonance imaging examinations.Magn Reson Imaging. 2007; 26: 401-404Crossref PubMed Scopus (106) Google Scholar So, when should a clinician select EUS and when MRCP—and if MRCP, should secretin be given? Until recently, this question in the United States was essentially an academic exercise. The only manufacturer in the United States, ChiRhoClin, Inc, received approval from the FDA on April 5, 2002, to manufacture and market Synthetic Porcine Secretin. Two years later, the same company received approval from the FDA on April 9, 2004, to manufacture and market ChiRhoStim (Synthetic Human Secretin for injection; ChiRhoClin, Burtonsville, MD). The drug has orphan drug status and was approved for the following indications: Stimulation of pancreatic secretions, including bicarbonate to aid in the diagnosis of exocrine pancreas dysfunction, stimulation of gastrin secretion to aid in the diagnosis of gastrinoma and stimulation of pancreatic secretions to facilitate the identification of the ampulla of Vater and accessory papilla during ERCP.10Eshed I. Althoff C.E. Hamm B. et al.Claustrophobia and premature termination of magnetic resonance imaging examinations.Magn Reson Imaging. 2007; 26: 401-404Crossref PubMed Scopus (106) Google Scholar As reported on the ChiRhoClin, Inc, website,11Evaluate. ChiRhoStim (human secretin for injection) is now available Evaluate [updated 2012 Sep 25]. Available: http://evaluategroup.com/Universal/View.aspx?type=Story&id=335204.Google Scholar their contract manufacturer also manufactured an antibiotic at its facility. According to FDA regulations, a β-lactam antibiotic must be made in a separate facility to avoid any cross-contamination with other products, stopping production of secretin. The company identified a new manufacturing site and proceeded to go through all the safety steps, but encountered similar problems. This has led to lack of clinical availability of the product over the past year. The company now reports on their website that ChiRhoStim is now commercially available. Batch #0636149 was manufactured in June 2013 in a new manufacturing facility and has met all product release and sterility tests, but the FDA must approve the new facility before more batches can be manufactured. In the interim, the agency is permitting the release of batch #0636149, provided there is an additional level of assurance to protect against any theoretical possibility of microbiological contamination. All medical personnel administering ChiRhoStim are to use the Millex-GV syringe microbial filter unit (0.22 μm, PVDF, 33 MM, GAMMA STERILIZED) prior to administering ChiRhoStim batch #0636149. The acquisition cost of a vial of secretin to the University of Michigan is $496 (more than the professional reimbursement for EUS), so the incremental cost of a drug to enhance imaging must be carefully considered. Reimbursement for the drug in the United States is insurer dependent and in some cases may be passed on to the patient, so clearly the use of S-MRCP may be difficult to justify on a routine basis for all pancreatitis patients. The Repligen secretin product studied by Sherman et al1Sherman S. Freeman M.L. Tarnasky P.R. et al.Administration of secretin (RG1068) increases the sensitivity of detection of duct abnormalities by magnetic resonance cholangiopancreatography in patients with pancreatitis.Gastroenterology. 2014; 147: 646-654Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar has faced its own set of regulatory challenges. The authors designed the study with the FDA imaging branch; however, the current study is from a reanalysis of images collected during an earlier study (RG1068-16). The authors state, “This re-evaluation was prompted after a detailed audit of the read conduct by the original central imaging laboratory in Study RG1068-16 uncovered multiple deviations from the study protocol Read Charter, which may have affected image interpretation and study analyses but were not expected to have adversely impacted the quality of the imaging studies themselves.”1Sherman S. Freeman M.L. Tarnasky P.R. et al.Administration of secretin (RG1068) increases the sensitivity of detection of duct abnormalities by magnetic resonance cholangiopancreatography in patients with pancreatitis.Gastroenterology. 2014; 147: 646-654Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Although the data are convincing to this editorialist, the FDA and the European Medicines Agency had other views.12ChiRhoStim (Human Secretin for Injection) [updated 2014]. Available: http://human-secretin.com/html/index.aspx?page=home.Google Scholar, 13Repligen receives complete response letter from FDA for RG1068 NDA. Waltham, MA: Repligen Corporation; 2012. Available: http://corporate.repligen.com/Mobile/file.aspx?IID=4325751&FID=13702970.Google Scholar Given their concerns about the trial design and criticism of the patient population studied, the agencies did not accept the trial as a single pivotal trial, resulting in nonapproval for product registration. Thus, no secretin product is current labeled for MRCP, although the current product available in the United States has been used for this purpose. Globally, other secretin products are available. Repligen has currently abandoned clinical development of the product and given the costs involved with further trials, it has not been licensed to another company at the present. How should a clinician decide between S-MRCP or EUS as the optimal test to select those patients with acute pancreatitis for ERCP therapy? Because there are no trials to directly inform this question, it remains a well-defined, unmet research need. The answer is currently subject to ones interpretation of the literature and expertise. S-MRCP seems to be superior to MRCP, but how this impacts therapy needs further refinement. MRCP is likely superior to EUS for identifying divisum, and seems to be similar for finding solid and cystic tumors as well as strictures. EUS is far superior to MRCP to detecting ampullary tumors. Further studies to define the cost effectiveness as well as clinical outcomes of patients directed to an EUS versus S-MRCP diagnostic strategy are essential to optimally address this complex patient population. Currently, approaches reflect the availability of experts in EUS versus MRCP as well as secretin. Although there is little doubt that pancreatic ductal imaging is enhanced over MRCP alone, the availability of EUS and continued questions of whether the ductal findings seen on S-MRCP predict robust clinical outcomes with ERCP-directed therapy are needed. Only a trial comparing EUS– and S-MRCP–directed pancreatic endotherapy will be able to provide clear recommendations on test selection. Although a daunting study to undertake, National Institutes of Health–funded, multicenter trials have recently answered key questions in ERCP,14European Medicine Agency. Withdrawal assessment report for SecreFlo. Bonn, Germany: European Medicine Agency; 2012. Available: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2012/11/WC500135621.pdf.Google Scholar, 15Cotton P.B. Durkalski V. Romagnuolo J. et al.Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial.JAMA. 2014; 311: 2101-2109Crossref PubMed Scopus (146) Google Scholar and this topic should be considered a future research priority. The author thanks Drs Grace Elta and B. Joseph Elmunzer for their critical review of the manuscript. Administration of Secretin (RG1068) Increases the Sensitivity of Detection of Duct Abnormalities by Magnetic Resonance Cholangiopancreatography in Patients With PancreatitisGastroenterologyVol. 147Issue 3PreviewAdministration of secretin improves noninvasive imaging of the pancreatic duct with magnetic resonance cholangiopancreatography (MRCP). We performed a large prospective study to investigate whether synthetic human secretin (RG1068)-stimulated MRCP detects pancreatic duct abnormalities with higher levels of sensitivity than MRCP. Full-Text PDF