Resection vs Drainage in Treatment of Chronic Pancreatitis: Long-term Results of a Randomized Trial

GASTROENTEROLOGY 2008;134:1406 1411 Resection vs Drainage in Treatment of Chronic Pancreatitis: Long-term Results of a Randomized Trial TIM STRATE,* KAI BACHMANN,* PHILIPP BUSCH,* OLIVER MANN,* CLAUS SCHNEIDER,* JENS P. BRUHN,* EMRE YEKEBAS,* THOMAS KUECHLER, CHRISTIAN BLOECHLE,* and JAKOB R. IZBICKI* *Department of General Surgery, University Hospital Hamburg Eppendorf, Hamburg, Germany; and Department of Medical Psychology, University Hospital Kiel, Kiel, Germany See Dietrich CF et al on page 590 in CGH. See editorial on page 1605. Background & Aims: Tailored organ-sparing procedures have been shown to alleviate pain and are potentially superior in terms of preservation of endocrine and exocrine function as compared with standard resection (Whipple) for chronic pancreatitis with inflammatory pancreatic head tumor. Long-term results comparing these 2 procedures have not been published so far. The aim of this study was to report on long-term results of a randomized trial comparing a classical resective procedure (pylorus-preserving Whipple) with an extended drainage procedure (Frey) for chronic pancreatitis. Methods: All patients who participated in a previously published randomized trial on the perioperative course comparing both procedures were contacted with a standardized, validated, quality of life and pain questionnaire. Additionally, patients were seen in the outpatient clinic to assess endocrine and exocrine pancreatic function by an oral glucose tolerance test and fecal chymotrypsin test. Results: There were no differences between both groups regarding quality of life, pain control, or other somatic parameters after a median of 7 years postoperatively. Correlations among continuous alcohol consumption, endocrine or exocrine pancreatic function, and pain were not found. Conclusions: Both procedures provide adequate pain relief and quality of life after long-term follow-up with no differences regarding exocrine and endocrine function. However, short-term results favor the organ-sparing procedure. In cases of severe disease with intractable pain and organ complication that cannot be treated by endoscopic sphincterotomy and stenting, there is little doubt as to the need for surgical intervention in patients suffering from chronic pancreatitis. This was further supported by the recent report of Cahen et al, who revealed surgery for chronic pancreatitis to be more effective than endoscopic stenting. 1 This interesting study, however, compared patients without pathology in the pancreatic head. Therefore, the present study focuses on patients with inflammatory enlargement of the pancreatic head, causing not only severe pain but also organ complications such as segmental portal hypertension. 2 4 Over the years, extensive resection (Whipple procedure) or triple bypass has dominated the surgical approach in patients suffering from chronic pancreatitis and enlargement of the pancreatic head. 5,6 Only recently, organsparing procedures have gained wide acceptance. 7,8 If the organ-sparing procedure is equally effective in terms of pain control, quality of life, and definite control of organ complication, it bears a potential benefit because better exocrine and endocrine function may be achieved because of tissue preservation. This has already been shown by our group in a previously published randomized trial. 9 The current study is a follow-up of this randomized trial and provides answers to the following question: Does the organ-sparing extended drainage procedure (Frey) have any long-term benefits compared with the radical resection (pylorus-preserving pancreatoduodenectomy [PPPD]) in terms of pain control, quality of life, exocrine and endocrine function, and mortality in patients with inflammatory enlargement of the pancreatic head? Materials and Methods Patients The presented data are results of a long-term follow-up of a closed randomized trial that was approved by the Ethics and Research Committee of the Hamburg Medical Association. 9 The design of the randomized trial, inclusion and exclusion criteria as well as patient assessment, treatment assignment, technical aspects of the operative procedures, in-hospital morbidity and mortality, and early postoperative results (follow-up at 24 months), is reported elsewhere. 9 All patients suffered from pathology in the pancreatic head. Abbreviation used in this paper: PPPD, pylorus-preserving pancreatoduodenectomy. 2008 by the AGA Institute 0016-5085/08/$34.00 doi:10.1053/j.gastro.2008.02.056

May 2008 TREATMENT OF CHRONIC PANCREATITIS 1407 In summary, the original study enrolled patients from January 1995 to January 1997. Inclusion criteria were an inflammatory mass in the head of the pancreas of more than 35 mm in diameter, history of at least 1 pain attack per month requiring opiates, history of pain for at least 1 year, or coexisting complications from adjacent organs. Disease-related exclusion criteria were chronic pancreatitis without involvement of the pancreatic head, small duct disease, pseudocysts without duct pathology, and portal vein thrombosis. A total of 64 patients were randomized, but 3 patients had to be excluded because of adenocarcinoma that was detected during surgery. As a result, 61 patients were included in the original trial (Frey, n 31; PPPD, n 30). Both patient groups were comparable in terms of incidence of complications from adjacent organs, pancreatic morphology, and clinical features. 9 All patients had an enlargement of the pancreatic head averaging 56 mm and recurrent intractable pain. A total of 34 patients suffered from bile duct stenosis, and 5 patients had duodenal stenosis. All patients displayed pancreatic duct abnormalities according to the Cambridge classification. 10 Prior to surgery, 43 patients underwent multiple endoscopic stenting procedures and lithotripsy. The remaining 18 patients were found to be inappropriate for endoscopic treatment by a panel of gastroenterologists and surgeons. The primary end points of the study were pain assessed by a validated pain score 11,12 and improvement of quality of life. Quality of life was measured by the European Organization for Research and Treatment of Cancer s Quality of Life Questionnaire 13 and an additional module of 20 specific items incorporating a disease-specific symptom scale, a treatment strain scale, and an overall hope and confidence scale. This scoring system has previously been validated for patients with chronic pancreatitis. 11 Secondary criteria were definitive control of complications arising from adjacent organs, mortality and morbidity rates, exocrine and endocrine pancreatic function, and occupational rehabilitation. 14 Therefore, the current study population consisted of 61 patients (PPPD, n 30; Frey, n 31). One patient in the extended drainage group died postoperatively because of myocardial infarction so that 60 patients were available for short-term follow-up after 24 months. These patients were reassessed after a median of 7 years postoperatively by investigators who were unaware of group allocation. Patients were contacted by mail to fill out the quality-of-life questionnaire and pain score forms. In addition, patients were asked to report to our outpatient clinic to sample stool for the assessment of exocrine pancreatic function (fecal chymotrypsin, normal value: 40 g/g feces). 15,16 In all patients who were not on oral antidiabetic agents or insulin, an oral glucose tolerance test was performed, and the results were classified as normal or diabetes mellitus according to the criteria established by the German Diabetes Society in 2002 in accordance with World Health Organization criteria of 1997. Diabetes mellitus was defined as blood glucose levels 200 mg/dl (11.1 mmol/l) 2 hours after oral glucose tolerance test. Continuous alcohol consumption was defined as average daily consumption of 12 g alcohol. 17,18 The family practitioner and the local administration were contacted for all patients who did not answer by mail to assess whether the patient had died. Patients who were not retrieved by these methods were declared as lost to follow-up. Surgical Procedures The procedures have been described elsewhere. 7,19 Basically, PPPD is the pylorus-preserving variant of the classical Kausch Whipple procedure. 6 It consists of the complete removal of the pancreatic head and uncinate process with the cut margin above the superior mesenteric vein, the duodenum, and the common bile duct. Limited pancreatic head excision with extended drainage (Frey procedure) accomplishes drainage of the main pancreatic duct by combining a Partington Rochelle procedure 20 with an additional limited excision of the pancreatic head (average, 5.7 g tissue). 21 With this procedure, the gastroduodenal and bilioenteric passage remains intact. Statistical Analysis SPSS 11.0 (SPSS Inc, Chicago, IL) was used for statistical analysis. The power calculation for the original study is described as follows: Based on literature review and personal experience, an educated guess was made setting the probability of improvement of global quality of life by 100% of the baseline value to 40% for the resection group and to 80% for extended drainage group. On the premise of an error of 5% and a error of 15%, the size was set to 30 patients per group. 9 Quality of life scores, including functional and symptom scales, and pain scores were evaluated using the Mann Whitney U test. All other data were compared using the 2 test. Statistical analysis was performed on an intention-to-treat basis. Results Hospital course and early postoperative results, with a median follow-up of 24 months, are reported elsewhere. 9 Follow-Up and Mortality Ten patients died during follow-up (6/30 Frey; 4/30 PPPD; ns). Among the 50 patients, 47 were available for continuing follow-up after a median of 7 years (24/30 Frey; 23/30 PPPD). Three patients were lost during follow-up (PPPD). The majority of patients died of chronic

1408 STRATE ET AL GASTROENTEROLOGY Vol. 134, No. 5 Table 1. Death During Follow-Up and Causes Procedure n Sex Causes PPPD (n 27) 4 M Unknown M Unknown F Decompensated cirrhosis M Plasmocytoma Frey (n 30) 6 M Myocardial infarction M Continuous alcohol abuse F Pneumonia F Unknown M Oropharyngeal carcinoma M Unknown pancreatitis-unrelated causes, although in 4 patients the reasons remained unclear (Table 1). Pain and Quality of Life All but 1 patient (Frey) filled out the respective questionnaires. This one patient also refused to answer the questions regarding quality of life and pain but provided detailed information about other features. In surviving patients, there was no difference between the 2 groups regarding quality of life and pain score (Tables 2 4). Comparing the quality of life and pain scores regarding the distribution of ranks using cross tables ( 2 test), there were no significant differences between the groups. Control of Complications From Adjacent Organs In 2 patients (Frey), a reintervention was necessary because of distal common bile duct stenosis (n 1) and relapse of chronic pancreatitis in the tail of the pancreas (n 1). The patient with bile duct stenosis refused to undergo a second operation. His symptoms were alleviated by endoscopic stenting. The patient with relapse of chronic pancreatitis underwent distal splenopancreatectomy (Table 5). Exocrine and Endocrine Insufficiency Almost all patients were exocrine insufficient in both groups (PPPD, 96%; Frey, 86%; ns). The rate of diabetic patients was slightly lower after Frey s procedure with no significant difference between the 2 groups (PPPD, 65%; Frey, 61%; ns) (Tables 5 7). Three patients of the Frey group did not come to the outpatient clinic to check for exocrine and endocrine insufficiency. Of these, 2 patients were diabetic and required antidiabetic medication. Therefore, the sample size is smaller in this group, 21 instead of 24 patients regarding exocrine insufficiency and 23 instead of 24 patients regarding endocrine insufficiency. Occupational Rehabilitation Only 19 patients were employed full-time at follow-up (PPPD, 9/23; Frey, 10/24). Of the other patients, 4 were unemployed (PPPD, 3; Frey, 1; ns). All other patients retired early, before the ages of 65 and 62 years for men and women, respectively (Table 5). Continuous Alcohol Consumption Eleven patients admitted to continuous alcohol consumption (PPPD, 6; Frey, 5; ns) (Table 5). If the pain score is compared between alcohol consumers and nonalcohol consumers, no difference is found in subgroups, total score, or pain score. The same holds true for comparison between the 2 groups regarding functional and symptom scales with the exception of 2 symptom scores (consumers vs nonconsumers: sleep disturbance: 100 (0 100) vs 33.3 (0 100); P.011 and financial strain: 100 (0 100) vs 0 (0 100); P.009). There was no correlation between alcohol consumers and pain score (Table 8). Alcohol consumption did not contribute to exocrine and endocrine insufficiency or to the necessity for a reintervention because of pancreas-related problems (2 patients requiring reintervention did not consume alcohol). Discussion The recent publication of Cahen et al indicates that surgery has a higher potential to alleviate severe symptoms arising from chronic pancreatitis as compared with endoscopic treatment alone, even though these results can not be generalized because of several limitations (eg, small sample size). 1 The authors found lower pain score, better physical health summary score, and better pain relief 24 months after the operation when compared with endoscopic treatment. When analyzing the patients cohort from the Dutch group, it is remarkable that only patients with normal-appearing pancreatic head were included. However, a significant number of patients suffering from chronic pancreatitis have some pathology in the pancreatic head, the least being inflammatory enlargement. 2 4 Therefore, one focus of this analysis is to determine the effectiveness of the 2 antipodes in pancreatic surgery for chronic pancreatitis with inflammatory pancreatic head tumor: limited excision or extensive resection. Table 2. Follow-Up Results of the Pain Score of Surviving Patients PPPD (n 23) Frey (n 23) Pain VAS 25 (0 100) 20 (0 100).669 Frequency of pain 25 (0 100) 25 (0 100) 1 Pain medication 0 (0 100) 0 (0 100).455 Inability to work 0 (0 100) 0 (0 100).914 Total 75 (0 400) 45 (0 400).634 Pain score 18.75 (0 75) 17.5 (0 100).821 NOTE. Values are median and range.

May 2008 TREATMENT OF CHRONIC PANCREATITIS 1409 Table 3. Results of Long-term Follow-Up Functioning Scale Scores of Surviving Patients Functioning scale and/or items a Items b PPPD (n 23) Frey (n 23) Physical status 1 5 100 (0 100) 100 (0 100).77 Working ability 6, 7 50 (0 100) 100 (0 100).363 Cognitive functioning 20, 25 100 (0 100) 83.3 (0 100).187 Emotional functioning 21 24 83.3 (0 100) 66.6 (0 100).365 Social functioning 26, 27 83.3 (0 100) 66.65 (0 100).535 Global quality of life 29, 30 50 (0 100) 58.35 (0 83.4).974 NOTE. Median and range of sums of single median values divided by numbers of items. a Scores range from 0 to 100, with a higher score representing a higher level of functioning. b Numbers correspond to the item numbers in the questionnaire. 10 To compare the efficacy of operative procedures for chronic pancreatitis addressing the pancreatic head, 4 randomized trials have been initiated, and early results have been reported. 3,9,22 Up to now, there have been no long-term results available aside from one trial comparing the duodenum preserving pancreatic head excision according to Beger vs the Frey procedure, 12 in which no differences were detected by our group. The uniform finding of all trials comparing the organ-sparing procedures with standard resection showed favorable results regarding endocrine and exocrine function as well as quality of life shortly after the operation. Therefore, longterm results are warranted. Continued alcohol abuse has been held responsible for persisting pain after surgery. 23 26 Other groups presented data about the relationship of pain and continuous alcohol consumption in the natural course of pancreatitis. 27,28 However, in our analysis, no definite correlation between alcohol abuse and pain could be established (Table 8). One explanation could be the different type of operation in the other study populations because pure drainage procedures prove to be less effective. It is even more important to address that the other authors did not use a validated pain score, which makes it harder to compare different data sets. Both procedures were equally effective in controlling symptoms arising from adjacent organs, even though the only 2 patients who underwent a reintervention were both patients in the Frey group. When analyzing the data on Frey and Beger s procedures, 12 there were only 3 patients who needed to undergo a reintervention, all in the Beger group. Altogether this might account for potentially better control of adjacent organs in the PPPD group when compared with the organ-sparing group as a whole. However, this comparison is incorrect because the study population was different in the 2 randomized trials. Still, this finding has led us to slightly modify the technique of Charles Frey. To minimize recurrences regarding adjacent organ complications, we recommend a more extensive resection of the head of the pancreas, especially above the intrapancreatic bile duct (Hamburg procedure). In our study population, there was no relation between pain and exocrine or endocrine insufficiency (Tables 6 Table 4. Results of Long-term Follow-Up Symptom Scale Scores of Surviving Patients Symptom scale and/or items a Items b PPPD (n 23) Frey (n 23) Fatigue 10, 12, 18 66.6 (0 100) 33.3 (0 100).53 Nausea and vomiting 14, 15 0 (0 100) 0 (0 100).57 Pain 9, 19, 38, 41 46 0 (0 100) 0 (0 100).191 Loss of appetite 13, 39 0 (0 100) 0 (0 100).656 Dyspnea 8 0 (0 66.6) 0 (0 100).435 Sleep disturbance 11 66.6 (0 100) 33.3 (0 100).701 Constipation 16 0 (0 100) 0 (0 66.6).147 Diarrhea 17 33.3 (0 100) 0 (0 100).111 Financial strain 28 0 (0 100) 33.3 (0 100).368 Loss of body weight 33 33.3 (0 100) 0 (0 100).058 Fever or shivering 34 0 (0 33.3) 0 (0 100).096 Jaundice 35 0 (0) 0 (0 66.6).153 Bloating 36 0 (0 100) 33.3 (0 100).326 Thirst 37 66.6 (0 100) 0 (0 100).11 Itching 40 0 (0 100) 0 (0 100).312 Treatment strain 47 50 (0 100) 50 (0 100).203 Hope and confidence 50 83.4 (0 100) 66.7 (0 100).146 NOTE. Median and range, as applicable sums of single median values divided by numbers of items. a Scores range from 0 to 100, with a higher score representing a higher degree of symptoms. b Numbers correspond to the item numbers in the questionnaire. 10

1410 STRATE ET AL GASTROENTEROLOGY Vol. 134, No. 5 Table 5. Results of Long-term Follow-Up of Surviving Patients PPPD (n 23) Frey (n 24) ( 2 test) Reintervention (pancreas related) 0/23 2/24.489 Exocrine insufficiency 22/23 18/21.335 Endocrine insufficiency 15/23 13/23.672 Occupational rehabilitation 9/23 10/24.765 Continuous alcohol consumption 6/23 5/24.73 and 7). Although we found a considerable amount of exocrine and endocrine insufficiency in our patients, the reported quality of life was good, regardless of pancreatic insufficiency. This underlines the impact of chronic pain on the patients quality of life. It also implies the effectiveness of both procedures in addressing the pancreatic head as the main factor in the development of pain. This also emphasizes the fact that the development of pancreatic insufficiency probably develops independent of the surgical procedure 29 and seems to be related to the chronic feature of the disease. Malka et al, for example, report on their experience in 500 patients with chronic pancreatitis and found 83% to be endocrine insufficient after 25 years of clinical onset. 29 The rate of endocrine insufficient patients was lower in our study population, but, even if we added up to 10 years of presurgical symptoms, our observational period would not reach 25 years. This leaves our data analysis most likely in accordance with this long-term follow-up of a large patient population, which probably reflects the natural course of the disease. An overall mortality rate of approximately 30% (28.8% 30%) and a pancreatitis-related death rate of approximately 15% (12.8% 19.8%) in patients with chronic pancreatitis without surgical intervention during a similar follow-up period has been reported by other investigators. 15,27,28,30 This leaves approximately 15% of patients dying of pancreatitis-unrelated causes, which parallels the mortality rate in our study population. Even though we do not have information about Table 6. Follow-Up Results of the Pain Score of Surviving Patients Comparing Patients With Exocrine Insufficiency vs Normal Function Exocrine insufficient (n 40) Normal (n 4) Pain VAS 20 (0 100) 25 (0 50).768 Frequency of pain 25 (0 100) 12.5 (0 50).595 Pain medication 0 (0 100) 0 (0).490 Inability to work 0 (0 100) 12.5 (0 25).679 Total 72.5 (0 399) 50 (0 125).768 Pain score 18.125 (0 99.75) 12.5 (0 31.25).768 NOTE. Values are median and range. Table 7. Follow-Up Results of the Pain Score of Surviving Patients (Median and Range) Comparing Patients With Diabetes Mellitus vs Normal Diabetes (n 28) Normal (n 18) Pain VAS 22.5 (0 100) 0 (0 100).322 Frequency of pain 25 (0 100) 0 (0 75).228 Pain medication 0 (0 100) 0 (0 15).261 Inability to work 0 (0 100) 0 (0 25).814 Total 72.5 (0 399) 20 (0 185).410 Pain score 19.375 (0 99.75) 5 (0 46.25).311 NOTE. Values are mean and range. One diabetic patient did not fill out the pain score. the cause of death in 4 patients, all other patients died of causes that were unrelated to chronic pancreatitis. Therefore, one might conclude that either complete resection of the pancreatic head (PPPD) or limited excision (Frey) results in a very low pancreas-related death rate because it controls the disease effectively after long-term follow-up. However, one factor should be taken into account: Short-term results favor the organ-sparing operation, 9 and, additionally, it is the easier operation to learn and perform. Even though the long-term results are equal, one should still favor the organ-sparing procedure to let the patient benefit from better short-term results. Furthermore, there is although no single scale is statistically significant a slight tendency to better overall quality of life associated with the Frey procedure even in the long-term follow-up. In conclusion, both the standard (extensive) resectional procedure (PPPD) and the organ-sparing extended drainage procedure (Frey) ensure comparable quality of life and pain control after long-term follow-up. These surgical procedures were found to be equally effective in Table 8. Follow-Up Results of the Pain Score of Surviving Patients Comparing Alcohol Consumers vs Nonalcohol Consumers Alcohol (n 11) Nonalcohol (n 36) Pain VAS 40 (0 100) 20 (0 100).346 Frequency of pain 50 (0 75) 25 (0 100).175 Pain medication 0 (0 15) 0 (0 100).476 Inability to work 0 (0 50) 0 (0 100).685 Total 100 (0 230) 25 (0 399).167 Pain score 25 (0 75) 11.25 (0 99.75).201 NOTE. Values are median and range. One nonalcohol consumer did not fill out the pain score.

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Gastroenterology 2000;119:1324 1332. 30. Lankisch PG. Natural course of chronic pancreatitis. Pancreatology 2001;1:3 14. Received October 22, 2007. Accepted January 31, 2008. Address requests for reprints to: Tim Strate, MD, Department of General Surgery, University Hospital Hamburg Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. e-mail: strate@uke.unihamburg.de; fax: (49) 040 42803 4995. The authors thank Suzette Block for her assistance in editing this manuscript. Conflicts of interest: No conflicts of interest to disclose.