International Journal of Surgery

Transcription

1 International Journal of Surgery 7 (2009) Contents lists available at ScienceDirect International Journal of Surgery journal homepage: Review Surgical therapy of chronic pancreatitis: Indications, techniques and results Oliver Strobel, Markus W. Büchler, Jens Werner * Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Germany article info abstract Article history: Received 18 May 2009 Accepted 24 May 2009 Available online 6 June 2009 Keywords: Chronic pancreatitis Inflammatory mass Ductal obstruction Ductal hypertension Pain Neuropathy Surgical therapy Drainage Resection Duodenum-preserving pancreatic head resection In chronic pancreatitis (CP) a benign inflammatory process in the pancreas results in progressive structural changes with replacement of functional exocrine and endocrine parenchyma by a fibrotic and inflammatory tissue, often evident as an inflammatory mass. The consequences are diabetes mellitus, exocrine insufficiency, and severe recurrent upper abdominal pain, often resulting in a significant reduction in the quality of life. The inflammatory process or the formation of pseudocysts can cause local complications such as obstruction of the pancreatic duct, bile duct or the duodenum. In spite of intensive research there is still no specific therapy for CP. Medical pharmacologic treatment is the basis of therapy in CP and aims at pain relief and treatment of exocrine and endocrine insufficiency. However, many patients require additional therapy for effective pain relief or treatment of local complications. Whereas a lot of these patients undergo repetitive endoscopic interventions, surgical drainage results in better long-term outcome. In patients with an inflammatory mass of the pancreatic head, surgical resection procedures provide good short and long-term results, especially in terms of pain relief. This article summarizes indications and potential of endoscopic/interventional and surgical therapy and gives an overview of surgical techniques with special focus on organ-sparing procedures such as the duodenumpreserving pancreatic head resection and its variants. Whereas exocrine and endocrine insufficiency may progress, adequate surgical therapy can provide effective long-term pain relieve and improvement in the quality of life in patients with CP. Ó 2009 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. 1. Definition, epidemiology and etiology of chronic pancreatitis Chronic pancreatitis (CP) is a benign, inflammatory process of the pancreas which leads to progressive and irreversible loss of functional parenchyma and replacement with fibrotic tissue and ductal metaplasia. 1 The ductal system displays stenoses and dilatations. CP can result in either an atrophy of the gland or in the formation of an inflammatory mass, as often observed in European series. 2,3 Furthermore, CP can result in intraductal and/or parenchymal calcifications. Clinically, the disease is characterized by recurrent episodes of severe and uncontrollable upper abdominal pain and by a loss of exocrine function (diarrhea, steatorrhea) and endocrine function (diabetes mellitus). Histologically, CP is characterized by inflammatory infiltration, acinar atrophy, formation of metaplastic ductal lesions (Tubular complexes and Pancreatic Intraepithelial Neoplasia), extended fibrosis, and in some cases by focal necrosis and cysts. 4 Further neural hypertrophy and perineural inflammation can frequently be observed and are the correlate of neuropathic pain as discussed below. 5 * Corresponding author. Tel.: þ ; fax: þ address: jens.werner@med.uni-heidelberg.de (J. Werner). Incidence and prevalence of CP vary between continents and countries. Most European studies show comparable incidence and prevalence rates around 7 per 100,000 and 28 per 100,000, respectively. 6 8 The numbers reported from Asia are markedly higher with a rapidly rising incidence up to 14 per 100,000. 9,10 The etiologic factors associated with CP are commonly summarized using the TIGAR-O classification: Toxic metabolic (alcohol and tobacco are the main reasons is Western countries associated with up to 80 90% of cases), Idiopathic, Genetic (e.g. PRSS1, CFTR, or SPINK1 gene mutations), Autoimmune, Recurrent and severe acute pancreatitis or Obstructive (e.g. pancreas divisum, sphincter oddi dysfunctions or neoplasms). 11 The tropical CP is a common entity in India, southern Africa and parts of South America and typically affects younger patients; tropical CP is often classified as idiopathic but may in fact have a mixed etiology, including nutritional, metabolic and genetic factors Pathophysiology and clinical presentation The pathophysiology of CP remains a matter of debate. Over the last decades several theories focusing on different etiologic and pathomorphological aspects have been proposed (primary ductal inflammation, ductal obstruction, oxidative stress, toxic metabolic, /$ see front matter Ó 2009 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi: /j.ijsu

2 306 O. Strobel et al. / International Journal of Surgery 7 (2009) necrosis-fibrosis). The SAPE (sentinel acute pancreatitis event) hypothesis proposes a sentinel event of acute pancreatitis initiating the inflammatory process which is then sustained by a combination of the mechanisms mentioned above. 13,14 Clinically the course of chronic pancreatitis is characterized by recurrent episodes of upper abdominal pain, which represents the most common indication for endoscopic and surgical intervention. Additionally, patients may present with symptoms of endocrine insufficiency (diabetes mellitus) and exocrine insufficiency (diarrhea, steatorrhea, malnutrition and weight loss). In the natural course of CP, as the gland burns out, episodes of pain may occur less frequently and be less severe whereas endocrine and exocrine insufficiency frequently increase Local complications Depending of the morphologic changes of the pancreas, patients often have symptoms due to local complications (Fig. 1). The inflammatory ductal changes and intraductal calculi (pancreatolithiasis) result in obstruction of the pancreatic duct itself, which can result in multiple ductal stenoses and dilatations and aggravate the process in the distal part of the gland. Additionally, the intrapancreatic portion of the bile duct can be obstructed. An inflammatory mass of the pancreatic head, as it is regularly observed in European series, 2 frequently results in obstruction of the duodenum and compression and subsequent thrombosis of the splenic, superior mesenteric or portal veins. Development of pancreatic pseudocysts represents another local complication which results in obstruction, abscess formation or in ascites/pleural effusions in case of rupture. A rare but severe local complication of chronic pancreatitis is vascular erosion presenting as gastrointestinal hemorrhage or less frequently as intraabdominal bleeding. Finally, CP is a risk factor for the development of pancreatic cancer; Patients with CP have a 4-fold higher risk of cancer than individuals without CP. 16,17 Especially in the management of patients with an inflammatory mass this risk has to be taken in account Pancreatic pain Whereas all these local complications can per se cause upper abdominal pain, the main mechanism of pain in CP is thought to be a parenchymal hypertension due to ductal obstruction. This mechanism is the rationale for endoscopic treatment as well as surgical drainage procedures. However, recent studies demonstrate that to a large extent the pain in patients with chronic pancreatitis is the consequence of neural alterations, namely a hypertrophy and an inflammatory infiltration of peripheral intra- and peripancreatic nerves. 5 Thus, pancreatic neuropathic pain is the consequence of pancreatic neuritis, which represents a common clinical feature of CP and pancreatic cancer and appears to be associated with upregulation of specific proteins. 18,19 This pancreatic pain is frequently observed in patients with an inflammatory mass in the pancreatic head and can be effectively relieved by pancreatic head resection (see Table 5). 3. Diagnostic work-up for chronic pancreatitis A thorough medical history and physical examination is pivotal for the diagnosis and adequate therapy of patients with CP (Table 1). In the medical history, evaluation of etiologic factors (especially alcohol) and of pancreatic pain is crucial to select patients for the different therapeutic options as discussed below. Besides routine parameters, laboratory data should include cholestasis parameters, and tumor markers for pancreatic adenocarcinoma. In order to adequately inform patients about the course of their disease and possible consequences of surgery (e.g. need of insulin), the endocrine and exocrine function have to be evaluated. Exocrine function test are often provided by gastroenterologists but not required for surgical decision-making, except for patients with uncertain diagnosis due to atypical clinical presentation. For tailored therapy and especially for planning of surgical therapy, imaging studies play a central role in the diagnostic workup of patients with CP. Most patients with CP first consult general practitioners and gastroenterologists. For the general practitioner abdominal ultrasound is an effective screening method, which may help to establish the diagnosis in patients with a thickened pancreas or head mass, a dilated duct, or pseudocysts. Gastroenterologists frequently use endoscopic ultrasound, which is more sensitive and specific than transabdominal ultrasound. Many patients undergo multiple endoscopic retrograde cholangio-pancreatographies (ERCP) for diagnosis and therapeutic intervention. The gold standard of imaging for diagnosing CP and for the design of surgical therapy is cross section imaging by contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). The superiority of CT or MRI is still a matter of debate, but either imaging study is adequate if Table 1 Preoperative diagnostic work-up in chronic pancreatitis. Thorough medical history: & Physical exam Laboratory work-up: Helpful but not mandatory: - Etiologic factors: especially alcohol, smoking - Symptoms: pain, signs of exocrine and endocrine insufficiency, weight loss - Previous treatment: analgesics, endoscopy - Routine laboratory parameters including liver and cholestasis parameters - Tumor markers (CEA, CA19-9) - Endocrine and exocrine function test (oral glucose tolerance, fecal elastase etc.) Imaging procedures: mandatory: - computed tomography (CT) or magnetic resonance imaging (MRI) Fig. 1. Local complications of chronic pancreatitis. Fibrosis and the inflammatory mass can result in stenosis and prestenotic dilatation of the pancreatic duct, the common bile duct and the duodenum. Intraductal concrements result in ductal obstruction. Formation of pseudocysts result in local compression of neighboring structures. Not shown: Parenchymal calcifications and portal vein thrombosis. Often provided by referring gastroenterologist and helpful, but not mandatory: Not needed: - Endoscopic retrograde cholangiopancreaticography (ERCP) a Endoscopic ultrasound (EUS) - Preoperative tissue diagnosis a Either ERCP or MRI with MRCP have to be performed for reliable evaluation of the pancreatic duct.

3 O. Strobel et al. / International Journal of Surgery 7 (2009) performed with sufficient quality. If a patient presents without ERCP, the MRI offers the additional possibility to evaluate the ductal system by MR cholangiopancreatography. Only ERCP or MRCP allows for evaluation according to the Cambridge-classification, which is at present still the only broadly accepted classificationsystem. 20 The advantage of CT is the better visualization of parenchymal calcifications. It has recently been proposed that positron emission tomography (FDG-PET) is helpful to differentiate between CP and pancreatic cancer. 21 In fact, it is a difficult task to rule out cancer in a chronically inflamed pancreatic head. As indicated by a recent review the indication for surgery for a pancreatic mass should not be based on preoperative tissue diagnosis because of frequent false negative results due to sampling problems. 22 We believe that patients with cancer as differential diagnosis should undergo surgical exploration and resection. 4. Tailored therapy of chronic pancreatitis 4.1. Conservative therapy Conservative treatment is the basis of any adequate managment of CP and includes (i) reduction of etiologic risk factors, including abstinence from alcohol and nicotine consumption, (ii) substitution for exocrine and endocrine insufficiency and nutritional supplements, as well as (iii) pain therapy according to the WHO-scheme 23 (Table 2). In autoimmune CP, a special entity which often presents as diffuse gland enlargement but may present as focal lesion, immunosuppression by corticosteroid treatment represents an effective specific causal therapy resulting in both morphologic resolution (imaging) and relief of symptoms. If autoimmune CP is suspected, a corticosteroid-therapy should be tried and monitored clinically and by radiologic imaging Endoscopic and interventional treatment options Many patients with CP require additional therapy for effective pain relief or treatment of local complications. Most of these patients are primarily referred to gastroenterologists and undergo endoscopic treatment. Endoscopic treatment options and their indications are summarized in Table 3. Pancreatic ductal obstruction by stenoses and/or calculi are the most frequent reasons for Table 2 Conservative and supportive treatment of chronic pancreatitis. Causal therapy: Special entity: Suspected autoimmune pancreatitis: Adjunct treatment: Pain therapy: Therapy of exocrine insufficiency: Therapy of endocrine insufficiency: Reduction of risk factors: abstinence from alcohol and smoking Corticosteroid treatment and re-evaluation! - Antioxidant therapy: promising results, needs further evaluation - Reduction of etiologic factors - Diet and treatment of exocrine insufficiency - Analgesia according to the WHO-scheme a - Diet - Substitution with pancreatic enzymes - Diet - Oral antidiabetics - Insulin therapy a Caution with opioids in patients with alcoholic chronic pancreatitis because of risk of addiction. Table 3 Interventional & endoscopic therapy: options and indications. Interventional external drainage: Interal drainage: Endoscopic cystogastrostomy/ Endoscopic cytoduodenostomy Endoscopic ductal drainage: ept ept þ dilation þ stenting of pancreatic duct ept þ Lithotripsy & stone extraction ept þ bile duct stenting Caution: Poor outcome of endoscopic treatment if Temporary treatment of pancreatic abscess, infected pseudocyst - often followed by definitive surgical treatment - if internal drainage is not possible Effective therapy of pseudocysts. No RCTs with comparison to surgery - if anatomically possible: less invasive than surgery - Problems with recurrence and catheter dislocation Pancreas divisum, sphincter of Oddi-dysfunction Proximal stenosis of pancreatic duct Pancreatolithiasis Bile duct stenosis - distal stenosis of pancreatic duct - parenchymal calcifications - no successful management after 1 year RCT: Randomized-controlled trial, ept: endoscopic papillotomy. endoscopic therapy and the treatment modalities aim to decompress and drain the pancreatic ductal system. However, in almost all patients endocopic treatments, such as stone extraction, dilations, stenting etc. have to be repeated on a regular basis. In consequence, the patients have to remain in endoscopic therapy and are frequently re-hospitalized. Two recent randomized controlled trials demonstrated the superiority of surgical vs. endoscopic therapy in primary success rate, pain relief and quality of life in patients with proximal duct obstruction. 25,26 On the other hand a large multicentre study in 1018 patients reports a success rate of endocopic therapy (multiple sessions) in 65% and necessity of surgery in only 24% of patients. 27 A study in 61 patients with bile duct stenosis due to CP reported a 1-year success-rate of 59% of endoscopic stenting with stent replacement every three months, but failure of endoscopic therapy in the majority of cases with presence of calcifications (7.7% success rate). 28 Moreover, 49% of patients without successful therapy after one year finally underwent surgery. 28 In patients with symptomatic pseudocysts without ductal obstruction, endoscopic drainage procedures may be equally safe and effective as surgical drainage and superior to external drainage, as reported in a recent retrospective study. 29 However, this remains to be confirmed in larger scale randomized trials. These data allow the following recommendations concerning endoscopic vs. surgical treatment of CP: (i) Patients with proximal stenosis without calcifications and without inflammatory mass may be treated endoscopically. If repetitive endoscopic treatment fails, the option of surgery has to be evaluated. (ii) In patients with distal obstruction, calcifications or inflammatory mass surgery is superior to endoscopic treatment and patients should undergo surgery early in the course of the disease. (iii) Pancreatic pseudocysts can be treated endoscopically. If endoscopic treatment fails, a surgical drainage procedure should be performed. If endoscopic treatment does not result in effective pain relief, patients should undergo surgical therapy early, because persistent pancreatic pain may become pancreas-independent over time.

4 308 O. Strobel et al. / International Journal of Surgery 7 (2009) Table 4 Surgical therapy: techniques and indications. Indications for surgery in chronic pancreatitis: Intractable pain Symptomatic local complications Unsuccessful endoscopic management Suspicion of malignancy Surgical techniques Indications and recommendations Pure drainage operations: Cystojejunostomy (Fig. 2a) 4.3. Surgical therapy: Indications and techniques Surgical procedure of choice for isolated pseudocysts Caution: intraoperative frozen section to exclude cystic neoplasm! Laterolateral Ductal dilation > 7 mm, without pancreaticojejunostomy:partington- inflammatory mass Rochelle-procedure (Fig. 2b) Caudal drainage/puestow-procedure: Rare indications, replaced by other procedures Resection procedures: Pancreatic head resections (Fig. 3) PD and pppd (Fig. 3a) DPPHR techniques: DPPHR, Beger (Fig. 3b) DPPHR, Bern (Fig. 3d) DPPHR, Frey (Fig. 3c) V-shaped excision: Pancreatic left resection Segmental resection Total pancreatectomy Always include a ductal drainage Procedures of choice if inflammatory mass in the head of the pancreas All techniques have comparable results (see Table 5) Procedure of choice in suspected malignancy and in irreversible duodenal stenosis Caution: intraoperative frozen section to exclude malignancy! Procedures of choice if inflammatory mass in the head of the pancreas Bern technically less difficult than Beger but equal long-term outcome Patients with ductal obstruction in the head and tail and a smaller inflammatory mass in the head Small duct disease (diameter of pancreatic duct < 3mm) Rare cases, e.g. isolated CP in the tail (e.g. posttraumatic) Rare cases of large pseudocysts in the tail Rare cases, e.g. isolated ductal stenosis in the body (e.g. posttraumatic) in patients without diabetes. Rare cases with severe changes in the entire pancreas and pre-existing IDDM PD: pancreatoduodenectomy, pppd: pylorus-preserving pancreatoduodenectomy, DPPHR: duodenum-preserving pancreatic head resection, IDDM: insulin-dependent diabetes mellitus. An overview about the common surgical procedures and the indication for surgery are listed in Table 4. Pain remains the most important and most frequent indication for surgery in CP, followed by the local complications of CP as shown in Fig. 1. Suspicion of malignancy is another important indication for surgery. Surgical procedures in CP can be divided in drainage operations (Fig. 2) and resections (Fig. 3) Pure drainage procedures In patients with isolated pancreatic pseudocysts, as frequently observed in patients with a history of a severe episode of acute pancreatitis, a drainage procedure in form of a cysto-jejunostomy with Roux-en-y reconstruction (Fig. 2a) is still the surgical procedure of choice. A pancreatic left resection may be a good alternative in cases with large cysts in the pancreatic tail. In patients with a ductal dilation without inflammatory mass in the pancreatic head, a laterolateral pancreaticojejunostomy Fig. 2. Drainage procedures in chronic pancreatitis. a) If the cyst wall is thick enough, a pancreatic pseudocyst can be safely and effectively treated by drainage with a cystojejunostomy and Roux-en-Y reconstruction. b) In rare patients with a dilation of the pancreatic duct of > 7 mm without inflammatory mass, a laterolateral pancreatojejunostomy Partington Rochelle-procedure may be performed. (Partington-Rochelle-procedure) represents an effective drainage operation (Fig. 2b), which replaced the previously performed caudal drainage procedures. Whereas these ductal drainage operations have good primary success rates, 30,31 their long-term outcome is poor. 32 Moreover, these procedures are only promising if the duct is substantially dilated (>7 mm) which is the case in only about 25% of cases. 33 For these reasons, pure drainage procedures have been replaced by techniques which combine resection and drainage Resections The vast majority of patients present with a ductal obstruction located in the pancreatic head, frequently associated with an inflammatory mass. In these patients pancreatic head resection is the procedure of choice. The available techniques of pancreatic head resection are shown in Fig. 3. The partial pancreatoduodenectomy (Kausch-Whipple-procedure), in its classical or pylorus-preserving variant, has been the procedure of choice for pancreatic head resection in CP for many years. 34,35 The duodenum-preserving pancreatic head resections and its variants (Beger-procedure, 36,37 Frey-procedure, 38,39 and Bern-procedure 40 ) represent less invasive, organ-sparing techniques with equal long-term results (see Table 5). In patients without circumscript mass in the pancreatic head and small duct disease (diameter of the pancreatic duct <3 mm) a V-shaped excision of the anterior aspect of the pancreas is a safe approach with effective pain management. 41 In the rare cases in which a patient presents with segmental CP in the pancreatic body or tail, e.g. due to posttraumatic ductal stenosis, a middle segment pancreatectomy or a pancreatic left resection can represent the best approach. Similarly, a total pancreatectomy may be necessary in selected cases with severe inflammation involving the entire pancreas and has to be evaluated especially in patients with pre-existing insulin-dependent diabetes mellitus Techniques of pancreatic head resection for chronic pancreatitis Partial pancreatoduodenectomy: Kausch-Whipple-procedure The extent of resection in the Kausch-Whipple pancreatoduodenectomy (PD) includes pancreatic head with duodenum and the lower third of the stomach. PD was initially designed for malignancies in the pancreatic head and associated with high morbidity and mortality. With increasing safety the procedure has also been used for patients with CP. 43 With the pylorus-preserving pancreatoduodenectomy (pppd) a less invasive procedure for

5 O. Strobel et al. / International Journal of Surgery 7 (2009) Fig. 3. Techniques of pancreatic head resection for chronic pancreatitis. Resections are shown on the left, reconstructions on the right side. a) Partial pancreatoduodenectomy (here shown as pylorus-preserving procedure). The pancreatic head is removed with the duodenum. The reconstruction is performed by a pancreatojejunostomy, hepaticojejunostomy and a duodenojejunostomy (if pylorus-preserving). b) Duodenum-preserving pancreatic head resection: Beger-procedure. The pancreas is dissected on the level of the portal vein. The pancreatic head is excavated and the duodenum is preserved with a thin layer of pancreatic tissue. If the bile duct is obstructed it can be opened and a internal anastomosis with the excavated pancreatic head can be performed (not shown). The reconstruction is performed with two anastomoses, of the pancreatic tail remnant and of the excavated pancreatic head with a Roux-en-Y jejunal loop. c) Duodenum-preserving pancreatic head resection: Frey-procedure. The Frey-procedure combines a circumscript excision in the pancreatic head with longitudinal dissection of the pancreatic duct toward the tail. Reconstruction is performed with an anastomosis with a Roux-en-Y jejunal loop. Compared to the Begerprocedure the extent of resection of the pancreatic head is smaller, however, reconstruction is easier as it only requires one anastomosis to the pancreas. d) Duodenum-preserving pancreatic head resection: Bern modification. The Bern modification is a technical simplification of the Beger-procedure. The extent of resection of the pancreatic head is comparable to the Beger-procedure. However, the pancreas is not dissected on the level of the portal vein. Thus, reconstruction can be performed with one single anastomosis of the pancreas with a Roux-en-Y jejunal loop. The bile duct can be opened and a internal anstomosis can be performed (as shown).

6 310 O. Strobel et al. / International Journal of Surgery 7 (2009) resection of cancer or CP was introduced, in which the stomach is preserved (Fig. 3a). 44 In experienced hands PD and pppd are safe and effective procedures with an operative mortality of 2 5% and lasting pain relief in about 80% of patients. 33,34 Furthermore, PD provides the benefit of adequate resection of an unrecognized pancreatic adenocarcinoma, which may arise and presents a differential diagnosis in some patients with CP. 33 However, in contrast to patients with pancreatic cancer, resection of the duodenum is not necessary in the majority of patients with CP Duodenum-preserving pancreatic head resection: Procedure according to Beger Beger et al. introduced the duodenum-preserving pancreatic head resection (DPPHR) as a less radical and organ-sparing procedure designed specifically for patients with CP and an inflammatory mass in the head of the pancreas. 2,36,37,45 Similar to PD the pancreas is divided at the level of the portal vein (Fig. 3b). However, in contrast to PD, the pancreatic head is excavated with preservation of the duodenum and a layer of pancreatic tissue. The reconstruction is performed by two anastomoses with a jejunal loop to drain the pancreatic remnant and to coverand drain the defect in the pancreatic head. During this procedure the common bile duct can be opened and drained with an internal anastomosis to treat bile duct obstruction. The DPPHR has gained wide acceptance and has become the procedure of choice for most patients with CP in Europe. However, maybe because the technique is technically more demanding than PD, it is not commonly used outside Europe Duodenum-preserving pancreatic head resection: Procedure according to Frey Frey et al. developed a modification of DPPHR which represents a hybrid technique between the Beger- and Partington-Rochelle procedures. 38,39,46 Compared to the Beger-procedure the resection in the pancreatic head in the Frey-modification is smaller and combined with a laterolateral pancreaticojejunostomy to drain the entire pancreatic duct towards the tail (Fig. 3c). In contrast to the Beger-procedure reconstruction can be performed with one single anastomosis. This procedure is not suitable in patients with a large inflammatory mass in the pancreas without stenosis of the leftsided pancreatic duct, as often observed in the European series. However, it appears advantageous in patients with less severe inflammation in the head combined with an obstruction in the leftsided pancreatic duct Duodenum-preserving pancreatic head resection: Bern modification The Bern modification of the DPPHR represents a technical simplification of the Beger-procedure with equal outcome. 40,47 49 The excavation of the pancreatic head can be performed with identical extent compared to the Berger-procedure (Fig. 3d). However, in contrast to the Beger-procedure the pancreas is not divided at the level of the portal vein, which is often difficult because of inflammation and portal hypertension. The reconstruction can be performed by one single anastomosis between a jejunal loop and the continuous pancreatic resection rim. 40 As in the Beger-procedure, Table 5 Randomized controlled trials comparing techniques of pancreatic head resection for CP. Author [ref.] (year) Technique- n results RCTS comparing PD vs. DPPHR Klempa 55 (1995) Beger 21 Beger: shorter hospital stay, less exocrine insufficiency, less need of analgesics pppd 22 Büchler 51 (1995) Beger 20 Beger: less impaired glucose metabolism, higher gain of weight, more frequent pain relief pppd 20 Müller 56 (1997) Beger 10 pppd: more frequent delayed gastric empting, more frequent pathologic secretion of enteral hormons pppd 10 Müller 57 (2008) Beger 20 equal in pain relief, exocrine & endocrine function equal in QoL pppd 20 Izbicki 54 (1998) Frey 31 Frey: lower morbidity, better QoL better professional rehabilitation equal in pain relief pppd 30 Strate 59 (2008) Frey 23 equal in pain relief and QoL, equal in exocrine & endocrine function pppd 23 RCTs comparing different techniques of DPPHR Izbicki 52 (1995) Beger 20 comparable in pain relief, QoL, exocrine & endocrine function, management of local complications Frey 22 Izbicki 53 (1997) Beger 38 comparable in pain relief, QoL, professional rehabilitation, exocrine & endocrine function Frey 36 Strate 58 (2005) Beger 34 comparable in pain relief, QoL, exocrine & endocrine function. Frey 33 Köninger 47 (2008) Beger 32 Bern: shorter operative time & hospital stay comparable in QoL Bern 33 RCT: Randomized-controlled trial, PD: pancreatoduodenectomy, pppd: pylorus-preserving pancreatoduodenectomy, DPPHR: duodenum-preserving pancreatic head resection, QoL: Quality of life.

7 O. Strobel et al. / International Journal of Surgery 7 (2009) a bile duct obstruction can be managed by internal bile duct anastomosis. The Bern-modification of DPPHR appears ideal for patients with an inflammatory mass and without stenosis in the left-sided duct. Adequate drainage of the pancreatic duct has to be verified by probing. If a stenosis is discovered, the resection can be extended towards the left similar to the Frey/Partingtin-Rochelle procedures until adequate drainage is achieved. However, in our series this is necessary in only 2 3% of cases. 49 Independent of the technique of DPPHR, an intraoperative frozen section has to be obtained to rule out pancreatic adenocarcinoma. If the frozen section is suspicious for malignancy or if a cancer is suspected already preoperatively, a PD represents the oncologically adequate approach PD and DPPHR in chronic pancreatitis: Results and evidence Irrespective of the technique, if carried out by experienced hands pancreatic head resection is a safe and effective therapy with good short- and long-term results in patients with CP and an inflammatory mass in the head of the pancreas. 35,36,39,45,48 50 The above-mentioned techniques of pancreatic head resection were compared in several randomized-controlled trials (RCTs) (Table 5), 47,51 59 in which their safety and efficacy was confirmed. The RCTs comparing PD and DPPHR 51,54 57,59 as well as a recent metaanalysis 60 demonstrate comparable mortality and efficacy in terms of pain relief as well as endocrine insufficiency; however, the less invasive DPPHR was superior in hospital stay, exocrine insufficiency, weight gain and quality of life in medium-term follow-up. In even more recent studies with long-term follow-up these metabolic advantages appear to be lost over time and longterm results of PD and DPPHR are equal in terms of pain management and quality of life as well as endocrine and exocrine function (compare results reported in the initial trials and the latest follow-ups in Table 5). 51,54 57,59 Of interest, the resection techniques remain effective in terms of pain relief and quality of life but cannot stop the progress of exocrine and endocrine insufficiency on the long-term. 48,59 One explanation may be that resection effectively treats the obstruction and hypertension, but does not completely stop continued cellular damage and parenchymal loss. 33 Certainly these observations stress the importance of continued conservative treatment by with reduction of etiologic factors, substitution for exocrine and endocrine insufficiency and probably antioxidant therapy. 61 The RCTs comparing different techniques of DPPHR demonstrate equal outcome in both pain control/quality of life and metabolic parameters after Beger vs. Frey and Beger vs. Bern technique (Table 5). 47,52,53,58 However, with equal outcome, the Bern modification of DPPHR represents a technically simpler alternative, as reflected by a significantly (by 46 minutes) shorter operative time as well as a significantly shorter hospital stay (11 vs. 15 days). 47 Recent reports confirm that the Bern modification of DPPHR can be performed without severe complications or mortality in smaller series. 62,63 Thus, the Bern technique represents a modification of DPPHR which may find broader acceptance due to technical and economic advantages. 5. Conclusions The adequate therapy of chronic pancreatitis is adjusted to the symptoms of the patient, the stage of the disease and the morphology of the pathological changes of the pancreas. Conservative therapy is the basis of treatment in all patients and has to accompany both interventional and surgical therapy. Endoscopic therapy appears to be effective for internal drainage of pseudocysts and in proximal ductal stenoses in patients without calcifications. However, endoscopic therapy requires frequent reinterventions and if it is not sufficiently effective after one year, the patient should be referred to surgery. The surgical technique has to be adjusted to the pathomorphological changes of the pancreas. This article gives an overview of the most common surgical options for therapy of CP and their typical indications. Recent data proposes that regional differences in the surgical strategy and preferred surgical techniques for pancreatic head resection may in fact be based on differences in the anatomic pathology between patient series. 3 For patients with CP and an inflammatory mass in the head of the pancreas the DPPHR is less invasive than a PD with comparable long-term results and should thus be considered as treatment of choice. The Bern modification of DPPHR represents a technical variation which is equally effective but technically less demanding. Whereas surgical therapy provides effective long-term pain-relief and improvement of quality of life, it does not stop a decrease in both endocrine and exocrine function. Thus, endocrine and exocrine function should currently not be considered to define a successful therapy in CP. Instead, strategies for improvement or maintenance of endocrine and exocrine function remain an important field of research. Conflict of interest None. Funding None. Ethical approval None. References 1. Sarles H, Adler G, Dani R, Frey C, Gullo L, Harada H, et al. The pancreatitis classification of Marseilles-Rome Scand J Gastroenterol 1989;24: Beger HG, Buchler M, Bittner R. The duodenum preserving resection of the head of the pancreas (DPRHP) in patients with chronic pancreatitis and an inflammatory mass in the head. An alternative surgical technique to the Whipple operation. Acta Chir Scand 1990;156: Keck T, Marjanovic G, Fernandez-del Castillo C, Makowiec F, Schafer AO, Rodriguez JR, et al. The inflammatory pancreatic head mass: significant differences in the anatomic pathology of German and American patients with chronic pancreatitis determine very different surgical strategies. Ann Surg 2009;249: Kloppel G. Chronic pancreatitis, pseudotumors and other tumor-like lesions. Mod Pathol 2007;20(Suppl. 1):S Ceyhan GO, Bergmann F, Kadihasanoglu M, Altintas B, Demir IE, Hinz U, et al. Pancreatic neuropathy and neuropathic pain a comprehensive pathomorphological study of 546 cases. Gastroenterology 2009;136: Dite P, Stary K, Novotny I, Precechtelova M, Dolina J, Lata J, et al. Incidence of chronic pancreatitis in the Czech Republic. Eur J Gastroenterol Hepatol 2001;13: Lankisch PG, Assmus C, Maisonneuve P, Lowenfels AB. Epidemiology of pancreatic diseases in Luneburg County. A study in a defined german population. Pancreatology 2002;2: Levy P, Barthet M, Mollard BR, Amouretti M, Marion-Audibert AM, Dyard F. Estimation of the prevalence and incidence of chronic pancreatitis and its complications. Gastroenterol Clin Biol 2006;30: Otsuki M, Tashiro M. 4. Chronic pancreatitis and pancreatic cancer, lifestylerelated diseases. Intern Med 2007;46: Wang LW, Li ZS, Li SD, Jin ZD, Zou DW, Chen F. Prevalence and clinical features of chronic pancreatitis in China: a retrospective multicenter analysis over 10 years. Pancreas 2009;38: Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120: Mohan V, Premalatha G, Pitchumoni CS. Tropical chronic pancreatitis: an update. J Clin Gastroenterol 2003;36: Whitcomb DC. Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 1999;45: Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronic pancreatitis: an evidence-based review of past theories and recent developments. Am J Gastroenterol 2004;99: Lankisch PG. Natural course of chronic pancreatitis. Pancreatology 2001;1:3 14.

8 312 O. Strobel et al. / International Journal of Surgery 7 (2009) Pedrazzoli S, Pasquali C, Guzzinati S, Berselli M, Sperti C. Survival rates and cause of death in 174 patients with chronic pancreatitis. J Gastrointest Surg 2008;12: Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20: Ceyhan GO, Bergmann F, Kadihasanoglu M, Erkan M, Park W, Hinz U, et al. The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 2007;56: Ceyhan GO, Deucker S, Demir IE, Erkan M, Schmelz M, Bergmann F, et al. Neural fractalkine expression is closely linked to pain and pancreatic neuritis in human chronic pancreatitis. Lab Invest 2009;89: Sarner M, Cotton PB. Definitions of acute and chronic pancreatitis. Clin Gastroenterol 1984;13: van Kouwen MC, Jansen JB, van Goor H, de Castro S, Oyen WJ, Drenth JP. FDG- PET is able to detect pancreatic carcinoma in chronic pancreatitis. Eur J Nucl Med Mol Imaging 2005;32: Hartwig W, Schneider L, Diener MK, Bergmann F, Buchler MW, Werner J. Preoperative tissue diagnosis for tumours of the pancreas. Br J Surg 2009;96: Warshaw AL, Banks PA. Fernandez-del Castillo C. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115: Finkelberg DL, Sahani D, Deshpande V, Brugge WR. Autoimmune pancreatitis. N Engl J Med 2006;355: Cahen DL, Gouma DJ, Nio Y, Rauws EA, Boermeester MA, Busch OR, et al. Endoscopic versus surgical drainage of the pancreatic duct in chronic pancreatitis. N Engl J Med 2007;356: Dite P, Ruzicka M, Zboril V, Novotny I. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003;35: Rosch T, Daniel S, Scholz M, Huibregtse K, Smits M, Schneider T, et al. Endoscopic treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term follow-up. Endoscopy 2002;34: Kahl S, Zimmermann S, Genz I, Glasbrenner B, Pross M, Schulz HU, et al. Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study. Am J Gastroenterol 2003;98: Johnson MD, Walsh RM, Henderson JM, Brown N, Ponsky J, Dumot J, et al. Surgical Versus Nonsurgical Management of Pancreatic Pseudocysts. J Clin Gastroenterol; Duval Jr MK. Caudal pancreaticojejunostomy for chronic pancreatitis; operative criteria and technique. Surg Clin North Am; 1956: Partington PF. Chronic pancreatitis treated by Roux type jejunal anastomosis to the biliary tract. AMA Arch Surg 1952;65: Markowitz JS, Rattner DW, Warshaw AL. Failure of symptomatic relief after pancreaticojejunal decompression for chronic pancreatitis. Strategies for salvage. Arch Surg 1994;129: Buchler MW, Warshaw AL. Resection versus drainage in treatment of chronic pancreatitis. Gastroenterology 2008;134: Jimenez RE, Fernandez-del Castillo C, Rattner DW, Chang Y, Warshaw AL. Outcome of pancreaticoduodenectomy with pylorus preservation or with antrectomy in the treatment of chronic pancreatitis. Ann Surg 2000;231: Jimenez RE, Fernandez-del Castillo C, Rattner DW, Warshaw AL. Pyloruspreserving pancreaticoduodenectomy in the treatment of chronic pancreatitis. World J Surg 2003;27: Beger HG, Witte C, Krautzberger W, Bittner R. [Experiences with duodenumsparing pancreas head resection in chronic pancreatitis]. Chirurg 1980;51: Beger HG, Krautzberger W, Bittner R, Buchler M, Limmer J. Duodenumpreserving resection of the head of the pancreas in patients with severe chronic pancreatitis. Surgery 1985;97: Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas 1987;2: Frey CF, Amikura K. Local resection of the head of the pancreas combined with longitudinal pancreaticojejunostomy in the management of patients with chronic pancreatitis. Ann Surg 1994;220: Gloor B, Friess H, Uhl W, Buchler MW. A modified technique of the Beger and Frey procedure in patients with chronic pancreatitis. Dig Surg 2001;18: Yekebas EF, Bogoevski D, Honarpisheh H, Cataldegirmen G, Habermann CR, Seewald S, et al. Long-term follow-up in small duct chronic pancreatitis: A plea for extended drainage by "V-shaped excision" of the anterior aspect of the pancreas. Ann Surg 2006;244: Muller MW, Friess H, Kleeff J, Dahmen R, Wagner M, Hinz U, et al. Is there still a role for total pancreatectomy? Ann Surg 2007;246: Traverso LW, Kozarek RA. The Whipple procedure for severe complications of chronic pancreatitis. Arch Surg 1993;128: Traverso LW. The pylorus preserving Whipple procedure for the treatment of chronic pancreatitis. Swiss Surg 2000;6: Beger HG, Krautzberger W, Bittner R, Buchler M, Block S. [Duodenum-sparing pancreas head resection in chronic pancreatitis results after 10 years use]. Langenbecks Arch Chir 1984;362: Frey CF, Bodai BI. Surgery in chronic pancreatitis. Clin Gastroenterol 1984;13: Koninger J, Seiler CM, Sauerland S, Wente MN, Reidel MA, Muller MW, et al. Duodenum-preserving pancreatic head resection a randomized controlled trial comparing the original Beger procedure with the Berne modification (ISRCTN No ). Surgery 2008;143: Muller MW, Friess H, Leitzbach S, Michalski CW, Berberat P, Ceyhan GO, et al. Perioperative and follow-up results after central pancreatic head resection (Berne technique) in a consecutive series of patients with chronic pancreatitis. Am J Surg; Strobel O, Buchler MW, Werner J. [Duodenum-preserving pancreatic head resection: Technique according to Beger, technique according to Frey and Berne modifications.]. Chirurg 2009;80: Buchler MW, Friess H, Bittner R, Roscher R, Krautzberger W, Muller MW, et al. Duodenum-preserving pancreatic head resection: Long-term results. J Gastrointest Surg 1997;1: Buchler MW, Friess H, Muller MW, Wheatley AM, Beger HG. Randomized trial of duodenum-preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg 1995;169: Izbicki JR, Bloechle C, Knoefel WT, Kuechler T, Binmoeller KF, Broelsch CE. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized trial. Ann Surg 1995;221: Izbicki JR, Bloechle C, Knoefel WT, Kuechler T, Binmoeller KF, Soehendra N, et al. [Drainage versus resection in surgical therapy of chronic pancreatitis of the head of the pancreas: a randomized study]. Chirurg 1997;68: Izbicki JR, Bloechle C, Broering DC, Knoefel WT, Kuechler T, Broelsch CE. Extended drainage versus resection in surgery for chronic pancreatitis: a prospective randomized trial comparing the longitudinal pancreaticojejunostomy combined with local pancreatic head excision with the pylorus-preserving pancreatoduodenectomy. Ann Surg 1998;228: Klempa I, Spatny M, Menzel J, Baca I, Nustede R, Stockmann F, et al. [Pancreatic function and quality of life after resection of the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study after duodenum preserving resection of the head of the pancreas versus Whipple s operation]. Chirurg 1995;66: Muller MW, Friess H, Beger HG, Kleeff J, Lauterburg B, Glasbrenner B, et al. Gastric emptying following pylorus-preserving Whipple and duodenumpreserving pancreatic head resection in patients with chronic pancreatitis. Am J Surg 1997;173: Muller MW, Friess H, Martin DJ, Hinz U, Dahmen R, Buchler MW. Long-term follow-up of a randomized clinical trial comparing Beger with pyloruspreserving Whipple procedure for chronic pancreatitis. Br J Surg 2008;95: Strate T, Taherpour Z, Bloechle C, Mann O, Bruhn JP, Schneider C, et al. Longterm follow-up of a randomized trial comparing the beger and frey procedures for patients suffering from chronic pancreatitis. Ann Surg 2005;241: Strate T, Bachmann K, Busch P, Mann O, Schneider C, Bruhn JP, et al. Resection vs drainage in treatment of chronic pancreatitis: long-term results of a randomized trial. Gastroenterology 2008;134: Diener MK, Rahbari NN, Fischer L, Antes G, Buchler MW, Seiler CM. Duodenumpreserving pancreatic head resection versus pancreatoduodenectomy for surgical treatment of chronic pancreatitis: a systematic review and metaanalysis. Ann Surg 2008;247: Bhardwaj P, Garg PK, Maulik SK, Saraya A, Tandon RK, Acharya SK. A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis. Gastroenterology 2009;136: Andersen DK, Topazian MD. Pancreatic head excavation: a variation on the theme of duodenum-preserving pancreatic head resection. Arch Surg 2004;139: Farkas G, Leindler L, Daroczi M, Farkas Jr G. Organ-preserving pancreatic head resection in chronic pancreatitis. Br J Surg 2003;90:29 32.