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Pancreatic duct stones in chronic pancreatitis: Criteria for treatment intensity and success
Pancreatic duct stones in chronic pancreatitis: criteria for treatment intensity and success Michael J. Farnbacher, MD, Christoph Schoen, Thomas Rabenstein, MD, Johannes Benninger, MD, Eckhart G. Hahn, MD, H. Thomas Schneider, MD Erlangen-Nuremberg, Germany
Background: The aim of the study was to evaluate interventional endoscopic management of pancreatic duct stones in patients with chronic pancreatitis by describing therapeutic methods and defining factors that predict technical success. Methods: Records were retrospectively analyzed for 125 patients with symptoms caused by chronic pancreatitis with pancreatic duct stones (single 43, multiple 82) treated by interventional endoscopy, including extracorporeal shockwave lithotripsy. Results: Technical success was achieved in 85% of patients (11 patients by mechanical lithotripsy, 114 by piezoelectric extracorporeal shockwave lithotripsy). There were no serious complications from lithotripsy. Univariate analysis disclosed a statistically significant association between treatment success and patient age as well as prepapillary location of stones. A greater therapeutic effort was necessary in patients with stones located in the tail of the pancreas, 2 or more stones, a stone 12 mm or more in diameter, or who have had a longer duration (>8 years) of the disease. However, with exception of the last parameter, correction for multiple testing of data removed statistical significance. Conclusions: Extracorporeal shockwave lithotripsy enhances endoscopic measures for treatment of pancreatic duct stones when mechanical lithotripsy fails. Middle-aged patients in the early stages of chronic pancreatitis with stones in a prepapillary location proved to be the best candidates for successful treatment. Unfavorable patient-related or morphologic factors can be compensated for through more intense efforts at therapy. (Gastrointest Endosc 2002;56:501-6.)
The natural course of chronic pancreatitis (CP) is often complicated by the occurrence of stones within the main pancreatic duct (MPD), followed by ductal obstruction, an increase in intraductal as well as parenchymal pressure, and ischemia.1 These factors are thought to be responsible for pancreatic pain.1,2 Currently, the rationale for interventional endoscopic treatment of obstructing pancreatic calculi is based on the observation that pain subsides as soon as the stone(s) is removed and drainage of pancreatic secretion is restored.3,4 Smaller calculi within the MPD usually can be extracted endoscopically.5 However, for large or impacted stones, or an MPD stenosis, endoscopic removal is usually impossible.6 In these patients extracorporeal shockwave lithotripsy (ESWL) has proved efficacious for disintegrating stones into small fragments before clearance of the duct can be Received August 10, 2001. For revision September 25, 2001. Accepted July 9, 2002. Current affiliations: Department of Medicine I, FriedrichAlexander-University Erlangen-Nuremberg, Germany. Reprint requests: Professor Dr. med. H. Thomas Schneider, Medizinische Klinik II, Klinikum Fuerth, Jakob-Henle-Straße 1, D-90766 Fürth, Germany. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy 0016-5107/2002/$35.00 + 0 37/1/128162 doi:10.1067/mge.2002.128162 VOLUME 56, NO. 4, 2002
achieved.7 Numerous reports describe ESWL as a low-risk, technically successful method with fragmentation rates of up to 100%. Nevertheless, complete clearance of the MPD can only be achieved in 40% to 60% of patients.8-16 Yet stone fragmentation in particular appears to be essential for complete removal of calculi, and the complete removal of the stones seems to increase the probability of longterm response.15,16 The present study investigated the value of interventional therapy, including ESWL, in patients with pancreatic duct stones to establish factors that predict technical success. PATIENTS AND METHODS A retrospective review of medical records identified 183 patients with CP treated by interventional endoscopy between January 1991 and December 1996. Of these patients, 125 (101 men, 24 women; mean [SD] age 48 years [12], range 25-88 years) presented with pancreatic duct stones obstructing the MPD. Alcohol was the most common etiologic factor (66%). The mean time between diagnosis of CP and initiation of therapy was 71 (76) months (range 0-368 months). Thirty patients (24%) had chronic pain and 77 (62%) had episodic pain. Attacks of pain occurred at least several times a week, often daily, in almost two thirds of the patients (n = 48). Six patients reported no pain at the onset of treatment. Another 18 of the 125 patients (14%) with chronic calcifying pancreatitis had not experienced any pain. All available clinical GASTROINTESTINAL ENDOSCOPY
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Figure 1. Retrograde pancreatogram showing pancreatic duct stones before ESWL. data were assessed retrospectively including radiographic images, medical records during treatment, follow-up appointments, and information obtained by telephone interview. The follow-up interval was defined as the time between the end of the first hospitalization, during which interventional therapy was carried out, and the end of observation, surgery, or death. Treatment Before endoscopic treatment all patients underwent diagnostic endoscopic retrograde pancreatography (ERP). Based on circumstances in individual patients, endoscopic biliary or pancreatic sphincterotomy was performed and an attempt was made to disintegrate and remove the stones using a Dormia basket. If this failed, ESWL was performed with a piezoelectric shockwave lithotripter with capability for visualization of the stones ultrasonographically (Piezolith 2300, R. Wolf, Knittlingen, Germany) or with alternating US and radiographic visualization (Piezolith 2500, Piezolith 2501-economy; Wolf). These lithotripters develop a maximal shockwave pressure of 120 to 150 mega-pascals in a focus area of 3 11 mm2 at a pulse repetition rate of 1 to 2 Hertz.10 ESWL was performed with the patient prone after intravenous administration of analgesic (meperidine, 50-200 mg) and/or sedative (diazepam, 520 mg) medications. Based on our experience, a maximum of 3 ESWL sessions per treatment course were scheduled before the next endoscopic procedure to remove fragments that did not clear spontaneously. In case of complete duct clearance, the next ERP was scheduled 3 months later. If residual fragments were detected, another series of 3 to 5 ESWL sessions was performed during the same hospital stay. If duct clearance was incomplete after this second attempt, an endoprosthesis was inserted to improve pancreatic duct drainage and therapy was continued, but no sooner than 3 months later. Because previous studies found that fragmentation is essential for stone removal,15,16 lithotripsy was rated successful if stone disintegration resulting in complete or partial duct clearance was achieved regardless of further endoscopic measures (Figs. 1 and 2). Clinical success was defined as complete relief of pain. All further endoscopic procedures, such as dilation of pancreatic duct strictures and/or inser502
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Figure 2. Retrograde pancreatogram showing complete duct clearance after ESWL and endoscopic removal of fragments. tion of an endoprosthesis, were performed according to the clinical circumstances in the individual case. To define factors potentially suitable for predicting technically successful lithotripsy, the following patient and morphologic factors were evaluated: age; gender; duration of CP before therapy; etiology of CP; number, size, and location of stones; and the concurrent presence of MPD strictures. The number of shockwave pulses and sessions needed for successful stone fragmentation by piezoelectric ESWL were determined (excluding 11 patients in whom mechanical lithotripsy was successful). Statistical methods For apparently normal quantitative data, the summary statistics are the mean, standard deviation (SD), and range. If normal distribution is not assumed, data are presented as median (interquartile range). Statistical analysis between 2 qualitative parameters was calculated with the Pearson chisquare test with the Yates correction for continuity where necessary, or the Fisher exact test when fewer than 20 data points were considered. The Mann-Whitney U test was used to compare quantitative data in 2 groups without assumption of normal distribution, whereas the Kruskal-Wallis H test was used if more than 2 groups were compared. To enhance discriminative power, the prognostic factors were assessed exclusively by univariate analysis of groups that differed by only one factor. Results for each of the individual hypothesis tests are stated; however, because there were several tests of hypotheses performed on data arising from individual patients, it was necessary to indicate where statistical significance would be removed by recognition of the multiple testing of data. The Bonferroni method was used to correct significant p values and it is noted where this correction removed statistical significance. For analysis of follow-up parameters, Kaplan-Meier curves were constructed to adequately take into account the differing lengths of follow-up. These data are presented as median (interquartile range).
RESULTS Before therapy, 324 intraductal stones were counted in the 125 patients evaluated. More than VOLUME 56, NO. 4, 2002
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half of these patients presented with only 1 (34%) or 2 stones (21.6%), whereas 17.6% had 3 and 26.4% 4 or mores stones were detected in the MPD. The stones were located more often within the head of the pancreas (46.6%) or the prepapillary segment (24.7%) of the MPD; about one third (28.7%) of the patients had stones within the body and/or tail of the pancreas. The mean maximum diameter of the stones was 8.6 mm (4.2) (range 2-31 mm). In 70 patients (56%), a stricture of the MPD was present, predominantly within the head or the prepapillary segment (81.9%). A mean of 8 (2-12) ERP sessions were performed. In anticipation of further endoscopic therapy, pancreatic sphincterotomy or needle-knife incision toward the pancreatic duct was carried out in 88 of the 125 patients (70%).17 In 11 patients (9%), calculi were disintegrated mechanically and fragments completely removed by using a Dormia basket alone. However, these maneuvers failed to clear the duct of stones in the majority of patients (91%). These stones were treated by piezoelectric ESWL in a median of 2.5 (interquartile range 2-4) sessions, mean 3600 (3000-4500) pulses per session, over a median treatment period of 4.6 months (interquartile range 0.45-14.3 months). To ensure pancreatic duct drainage and to simplify localization of the stones during ESWL, a nasopancreatic tube was temporarily placed in 47 patients before ESWL. Because of MPD strictures, a total of 234 plastic stents (5-12F, length 30-200 mm) were placed. These were left in situ for a median of 2.25 months (interquartile range, 1-3 months) and were exchanged on a regular basis in 70 patients. In advance, the strictures were dilated with bougies or high-pressure balloons (4-8 mm diameter) 33 times in 24 patients. Fifty-seven endoprostheses (24.3%) occluded in 27 patients (38.6%) after a mean of 2.7 months. Migration of the endoprosthesis into the pancreatic duct occurred in 2 patients at 1.6 and 2 months after insertion. In another 4 patients, spontaneous dislocation of the stents into the duodenum was documented. Technical success As mentioned, MPD stones were completely removed by using a Dormia basket in 11 patients. In 94 patients, disintegration of MPD stones was achieved after ESWL, leading to a complete or partial duct clearance in, respectively, 39 and 55 patients. During the initial treatment series, mechanical extraction and ESWL were unsuccessful in clearing the stones in only 20 patients. ESWL was continued in 21 patients. In 19 of these patients, the initial treatment series had VOLUME 56, NO. 4, 2002
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Table 1. Pain before therapy and long-term clinical benefit after interventional therapy (n = 84) Before therapy
Clinical success during follow-up: No pain Pain relapse
Recurrent pain attacks n = 56
Chronic pain n = 26
No pain n=2
28/56 (50%) 28/56 (50%)
11/26 (42%) 15/26 (58%)
1/2 (50%) 1/2 (50%)
achieved partial duct clearance, whereas in 2 the initial treatment proved to be completely unsuccessful. In 20 of these patients (95%), complete (n = 14) or partial (n = 6) duct clearance was achieved. Continued lithotripsy failed in only 1 patient. At the conclusion of all therapeutic measures, stone fragmentation was achieved in a total of 106 of the 125 patients (85%), with complete duct clearance in 64 (51%) and partial clearance in 42 (34%) patients. Despite all measures, treatment was unsuccessful in 19 patients (15%). In 32 of 62 patients (48%) who could be followed and in whom interventional therapy resulted in a complete clearance of the MPD, there was no stone recurrence. The “stone-free survival time,” calculated with the Kaplan-Meier method, for these patients was a median of 18.5 months (interquartile range 3.0-29.2 months). In the remaining 30 patients, at least 1 recurrent stone was found at a mean followup of 7.4 months (6.0) (range, 2.0-22.8 months). In almost three fourths of the cases (22/30, 73.3%), stone recurrence was diagnosed within the first 9 months after successful treatment. Twenty-five of the patients with recurrent stones underwent further ESWL, leading to complete duct clearance in 14 patients (56%) and partial clearance in 8 (32%). Treatment was completely unsuccessful in only 3 cases (12%). The technical success rate (88%) for treatment of recurrent stones was comparable with that of initial therapy. Clinical success Of the 101 of 125 patients presenting with acute pain immediately before interventional therapy, 94 (93%) became completely pain-free after completion of the therapeutic measures. The majority of these patients (n = 84) were followed (mean 29 months, [20]; range 2.3-73.2 months), and 40 (48%) remained pain-free throughout the follow-up period. The remaining 44 patients (52%) experienced relapses of pain and were hospitalized again for treatment (Table 1). In more than half of these latter patients (23/44; 52%) recurrent MPD stones and/or occlusion GASTROINTESTINAL ENDOSCOPY
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Table 2. Technical success and long-term clinical benefit after interventional therapy (n = 84) Clearance of main pancreatic duct
Clinical success during follow-up No pain Pain relapse
Complete n = 39
Partial n = 43
None n=2
22/39 (56%) 17/39 (44%)
17/43 (39%) 26/43 (61%)
1/2 (50%) 1/2 (50%)
as well as dislocation of the endoprosthesis into the duodenum were found to be the most likely reasons for recurrence of pain. Treatment of recurrent stones resulted in immediate and complete relief in 21 of the 23 patients (91%). All 11 patients with stent-related complications (occlusion 10, dislocation 1) managed by stent removal or exchange became pain-free again. In 7 patients with MPD strictures, stent placement was continued and led to immediate clinical relief of pain in all 7. In the remaining 3 patients, no particular cause, either disease- or therapy-related, was identified for the relapse of pain. Two of these patients, treated conservatively, became free of pain. Thus, the overall clinical success rate for continued endoscopic treatment was 93%, which was similar to the response rate after the initial treatment course. No significant association was found between continued consumption of alcohol during follow-up and relapse of pain. Of the 24 of 125 patients who did not have pain before therapy, only 1 had abdominal pain during follow-up. Among the 84 patients for whom follow-up data were available, pain relapse was less frequent in those with complete as opposed to partial duct clearance (Table 2), although this association did not reach statistical significance (p = 0.184). Nine patients (7.8%) died during follow-up (mean 30.5 months, [19.9]; range 1.3-73.2 months). The cause of death was unclear for 5 patients. One patient committed suicide, another developed a pleural mesothelioma, and 2 patients died of multiorgan failure caused by acute pancreatitis. Surgical intervention became necessary in 15 patients (13%) because of intractable pain after unsuccessful endoscopic treatment (hemipancreatectomy, 3; Whipple’s operation, 2; pancreaticojejunostomy, 6; cystojejunostomy, 2). In 2 patients, dislocated, endoscopically irretrievable endoprostheses had to be removed surgically from the pancreatic duct. Success factors and therapeutic effort The technical success of interventional endoscopic therapy for pancreatic duct stones was signif504
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icantly better in patients 50 to 59 years of age (98%) compared with older (80%) and younger (78%, p = 0.03) patients, and also significantly better in patients with stones located in the head of the pancreas or prepapillary segment (94%) compared with patients with calculi in the body or tail (50%, p = 0.045). Both of these parameters, however, were not significant after correction for multiple testing. There was no association between successful fragmentation of stone(s) and any of the following: MPD stricture (stricture [94%] vs. no stricture [90%]; p = 0.49), number of stones (single stone [88%] vs. {≥2 stones [70%]; p = 0.26), stone diameter (2-5 mm [100%] vs. 6-15 mm [91%]; p = 0.77), time interval from onset of symptoms caused by CP and therapy (≤8 years [87%] vs. >8 years [79%]; p = 0.26), gender (male [85%] vs. female [83%]; p = 0.84), and etiology of CP (alcohol [82%] vs. no alcohol [89%]; p = 0.34). The associations between therapeutic effort to achieve fragmentation and patient-related as well as morphologic factors are outlined in Table 3. DISCUSSION Stones within the pancreatic duct system are found in 50% to 90% of patients presenting with CP.18 Depending on stone size and duct diameter, drainage of pancreatic secretions is obstructed, resulting in upstream dilation. This obstruction is assumed to be a factor in the development of pain, which leads to heavy usage of analgesic drugs, loss of weight, inability to work, and reduced quality of life.19-21 Before the introduction of ESWL in 1989, surgery was the only therapeutic option and resulted in pain relief in approximately 85% of patients with endoscopically nonremovable stones.7 Nevertheless, even after duodenum-preserving resection of the head of the pancreas, presently considered the best surgical treatment for CP and inflammatory mass in the head, almost 25% of patients experience recurrences of pain. Additionally, surgical intervention has a considerable procedure-related morbidity rate of 20% to 47% and mortality rate of 1% to 5%.3,22-24 Therefore, interventional endoscopy, including ESWL, has been increasingly used in the treatment of chronic calcifying pancreatitis during the last 10 years, with clinical results that are almost equal to conventional surgery.6-16 For prepapillary stones, stones proximal to strictures of the MPD, and impacted stones that prevent retrograde cannulation, ESWL has become essential. Regardless of the method of shockwave generation (electrohydraulic, electromagnetic, piezoelectric)25 ESWL provides immediate pain relief in more than 90% of cases.8-16 As with pancreatic surgery, however, long-term relief is achieved in only about VOLUME 56, NO. 4, 2002
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Table 3. Therapeutic effort and individual/morphologic factors in ESWL treatment of pancreatic duct stones in chronic pancreatitis Mean No. shock wave pulses*
Parameter Location of stones No. of stones Size of stones Age Symptoms before therapy Risk factors
Prepapillary Body/tail 1 stone ≥2 stones 2-10 mm 12-15 mm <50 y ≥50 y ≤8 y >8 y Alcohol No alcohol
6495 18,750 6661 11,567 4666 9129 8892 7335 7070 10,435 6723 10,191
Significance p = 0.049† p = 0.01† p = 0.006† p = 0.22 p = 0.002 p = 0.036†
Mean No. treatment sessions* 2.0 4.5 2.0 2.8 1.4 2.8 2.5 2.1 2.1 2.9 2.0 2.8
Significance p = 0.048† p = 0.052 p = 0.013† p = 0.11 p = 0.004 p = 0.03†
*No. of shockwave pulses and treatment sessions necessary to achieve fragmentation. †Correction for multiple testing of data removes that significance.
30% to 50% of patients. But in contrast to surgery, endoscopic therapy can be performed repeatedly in response to recurrences of pain, and has a high clinical success rate that is similar to that for initial therapy. Moreover, patient age is not significant as a risk factor for procedure-related morbidity and mortality.26 Because the complication rate is low (0%36%) and deaths associated with the procedure are uncommon, endoscopic management appears to be a safe as well as successful alternative to surgery. Unfortunately, lithotripters are not available in every hospital because of their high cost, especially the preferred machines that incorporate devices for fluoroscopic and US localization. Furthermore, for most pancreatic duct stones, greater experience and effort are needed to achieve a sufficient degree of fragmentation compared with lithotripsy of gallbladder stones.27 There is evidence that complete removal of the stones promotes immediate and long-term recovery15,16 and that fragmentation is often essential for complete duct clearance. In the present study, a significantly increased fragmentation rate was noted for stones within the head of the pancreas including those close to the papilla, and in patients in the fifth decade of life, although significance was removed after correction for multiple testing of data. These findings are confirmed by other analyses (univariate and multivariate) of prognostic morphologic factors.4,8,12,16 In contrast to the observations of Dumonceau et al.,16 who maintain that patients without a proximal stenosis of the MPD respond best to ESWL, there was no correlation in the present study between technical success and the presence of a pancreatic duct stricture. Furthermore, stone number and size, gender, regular consumption of alcohol, and time interval between onset of symptoms of CP VOLUME 56, NO. 4, 2002
and initiation of therapy did not influence the success of treatment. Interestingly, Dumonceau et al.16 identified ESWL as the only independent criterion for successful fragmentation. The therapeutic efforts required to achieve fragmentation were significantly greater for patients with 2 or more stones, stones 12 mm or more in diameter, and stones within the body and/or tail of the pancreas; however, correction for multiple testing of data removed significance for all of these parameters. The intensified schedule of treatment in our patient group accounts for the fact that neither number nor size of stones is associated with the technical success of the procedure. Complete endoscopic clearance of stones from the MPD leads to immediate pain relief significantly more often than partial or no clearance.11,15,16 Therefore, the goal of endoscopic therapy for chronic calcifying pancreatitis should be complete removal of all stones and fragments. Even if this is not achieved initially, despite intense therapeutic efforts, the present study demonstrates that complete clearance can be obtained in more than two thirds of patients with partial duct clearance after an initial treatment series when interventional therapy is continued. Treatment should be initiated as soon as possible after diagnosis because this reduces costs and increases the probability of long-term clinical benefit. REFERENCES 1. Di Sebastiano P, Friess H, Di Mola FF, Innocenti P, Buechler MW. Mechanisms of pain in chronic pancreatitis. Ann Ital Chir 2000;71:11-6. 2. Pitchumoni CS. Chronic pancreatitis: pathogenesis and management of pain. J Clin Gastroenterol 1998;27:101-7. 3. Sakorafas GH, Farnell MB, Farley DR, Rowland CM, Sarr MG. Long-term results after surgery for chronic pancreatitis. Int J Pancreatol 2000;27:131-42. GASTROINTESTINAL ENDOSCOPY
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4. Sherman S, Lehman GA, Hawes RH. Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc 1991;37:511-7. 5. Schneider MU, Lux G. Floating pancreatic duct concrements in chronic pancreatitis. Endoscopy 1985;17:8-10. 6. Kozarek RA, Ball TJ, Patterson DJ. Endoscopic approach to pancreatic duct calculi and obstructive pancreatitis. Am J Gastroenterol 1992;87:600-3. 7. Sauerbruch T, Holl J, Sackmann M, Paumgartner G. Extracorporeal shockwave lithotripsy of pancreatic stones. Gut 1989;30:1406-11. 8. Delhaye M, Vandermeeren A, Baize M, Cremer M. Extracorporeal shockwave lithotripsy of pancreatic calculi. Gastroenterology 1992;102:610-20. 9. Sauerbruch T, Holl J, Sackmann M, Paumgartner G. Extracorporeal shock wave lithotripsy of pancreatic duct stones in patients with pancreatitis and pain: a prospective follow up study. Gut 1992;33:969-72. 10. Schneider HT, May A, Benninger J, Rabenstein T, Hahn EG, Katalinic A, et al. Piezoelectric shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol 1994;89:2042-8. 11. van der Hul R, Plaiser P, Jeekel J, Terpstra O, den Toom R, Bruining H. Extracorporeal shock wave lithotripsy of pancreatic duct stones: immediate and long-term results. Endoscopy 1994;26:573-8. 12. Smits ME, Rauwes EA, Tygat GNJ, Huibregtse K. Endoscopic treatment of pancreatic stones in patients with chronic pancreatitis. Gastrointest Endosc 1996;43:556-60. 13. Ohara A, Hoshino M, Hayakawa T, Kamiya Y, Miyaji M, Takeuchi T, et al. Single application extracorporeal shock wave lithotripsy is the first choice for patients with pancreatic duct stones. Am J Gastroenterol 1996;91:1388-94. 14. Costamagna G, Gabrielli A, Mutignani M, Perri V, Pandolfi M, Boscani M, et al. Extracorporeal shockwave lithotripsy of pancreatic stones in chronic pancreatitis: immediate and medium-term results. Gastrointest Endosc 1997;46:231-6. 15. Adamek HE, Jakobs R, Buttmann A, Adamek MU, Schneider AR, Riemann JF. Long-term follow-up of patients with chronic pancreatitis and pancreatic stones treated with extracorporeal shock wave lithotripsy. Gut 1999;45:402-5.
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16. Dumonceau JM, Deviere J, Le Mione O, Delhaye M, Vandermeeren A, Baize M, et al. Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-term results. Gastrointest Endosc 1996;43:547-55. 17. Ell C, Rabenstein T, Schneider HT, Ruppert T, Nicklas M, Bulling D. Safety and efficacy of pancreatic sphincterotomy in chronic pancreatitis. Gastrointest Endosc 1998;48:244-9. 18. Ammann RW, Muench R, Otto R, Buechler H, Freiburghaus AU, Siegenthaler W. Evolution and regression of pancreatic calcification in chronic pancreatitis. A prospective long-term study of 107 patients. Gastroenterology 1988;95:1018-28. 19. Apte MV, Keogh GW, Wilson JS. Chronic pancreatitis: complications and management. J Clin Gastroenterol 1999;29:225-40. 20. Jansen JB, Kuijpers JH, Zitman FJ, van Dongen R. Pain in chronic pancreatitis. Scand J Gastroenterol 1995;30:117-25. 21. Ammann RW, Müllhaupt B. The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999;116: 1132-40. 22. Beger HG, Schlosser W, Friess HM, Buechler MW. Duodenumpreserving head resection in chronic pancreatitis changes the natural course of the disease: a single-center 26-year experience. Ann Surg 1999;230:512-9. 23. Berney T, Rudisuhli T, Oberholzer J, Caulfield A, Morel P. Long-term metabolic results after pancreatic resection for severe chronic pancreatitis. Arch Surg 2000;135:1106-11. 24. Schlosser W, Beger HG. Organ-preserving surgery in chronic pancreatitis: the duodenum-preserving pancreatic head resection. Ann Ital Chir 2000;71:65-70. 25. Schneider HT, Fromm M, Ott R, Janowitz P, Swobodnik W, Neuhaus H, et al. In vitro fragmentation of gallstones: comparison of electrohydraulic, electromagnetic and piezoelectric shockwave lithotripters. Hepatology 1991;14:301-5. 26. Rabenstein T, Schneider HT, Hahn EG, Ell C. 25 years of endoscopic sphincterotomy in Erlangen: assessment of the experience in 3498 patients. Endoscopy 1998;30(Suppl 2): A194-201. 27. Ell C, Kerzel W, Schneider HT, Wirtz P, Domschke W, Hahn EG. Piezoelectric lithotripsy: Stone disintegration and followup results in patients with symptomatic gallbladder stones. Gastroenterology 1990;99:1439-44.
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Background: The aim of the study was to evaluate interventional endoscopic management of pancreatic duct stones in patients with chronic pancreatitis by describing therapeutic methods and defining factors that predict technical success. Methods: Records were retrospectively analyzed for 125 patients with symptoms caused by chronic pancreatitis with pancreatic duct stones (single 43, multiple 82) treated by interventional endoscopy, including extracorporeal shockwave lithotripsy. Results: Technical success was achieved in 85% of patients (11 patients by mechanical lithotripsy, 114 by piezoelectric extracorporeal shockwave lithotripsy). There were no serious complications from lithotripsy. Univariate analysis disclosed a statistically significant association between treatment success and patient age as well as prepapillary location of stones. A greater therapeutic effort was necessary in patients with stones located in the tail of the pancreas, 2 or more stones, a stone 12 mm or more in diameter, or who have had a longer duration (>8 years) of the disease. However, with exception of the last parameter, correction for multiple testing of data removed statistical significance. Conclusions: Extracorporeal shockwave lithotripsy enhances endoscopic measures for treatment of pancreatic duct stones when mechanical lithotripsy fails. Middle-aged patients in the early stages of chronic pancreatitis with stones in a prepapillary location proved to be the best candidates for successful treatment. Unfavorable patient-related or morphologic factors can be compensated for through more intense efforts at therapy. (Gastrointest Endosc 2002;56:501-6.)
The natural course of chronic pancreatitis (CP) is often complicated by the occurrence of stones within the main pancreatic duct (MPD), followed by ductal obstruction, an increase in intraductal as well as parenchymal pressure, and ischemia.1 These factors are thought to be responsible for pancreatic pain.1,2 Currently, the rationale for interventional endoscopic treatment of obstructing pancreatic calculi is based on the observation that pain subsides as soon as the stone(s) is removed and drainage of pancreatic secretion is restored.3,4 Smaller calculi within the MPD usually can be extracted endoscopically.5 However, for large or impacted stones, or an MPD stenosis, endoscopic removal is usually impossible.6 In these patients extracorporeal shockwave lithotripsy (ESWL) has proved efficacious for disintegrating stones into small fragments before clearance of the duct can be Received August 10, 2001. For revision September 25, 2001. Accepted July 9, 2002. Current affiliations: Department of Medicine I, FriedrichAlexander-University Erlangen-Nuremberg, Germany. Reprint requests: Professor Dr. med. H. Thomas Schneider, Medizinische Klinik II, Klinikum Fuerth, Jakob-Henle-Straße 1, D-90766 Fürth, Germany. Copyright © 2002 by the American Society for Gastrointestinal Endoscopy 0016-5107/2002/$35.00 + 0 37/1/128162 doi:10.1067/mge.2002.128162 VOLUME 56, NO. 4, 2002
achieved.7 Numerous reports describe ESWL as a low-risk, technically successful method with fragmentation rates of up to 100%. Nevertheless, complete clearance of the MPD can only be achieved in 40% to 60% of patients.8-16 Yet stone fragmentation in particular appears to be essential for complete removal of calculi, and the complete removal of the stones seems to increase the probability of longterm response.15,16 The present study investigated the value of interventional therapy, including ESWL, in patients with pancreatic duct stones to establish factors that predict technical success. PATIENTS AND METHODS A retrospective review of medical records identified 183 patients with CP treated by interventional endoscopy between January 1991 and December 1996. Of these patients, 125 (101 men, 24 women; mean [SD] age 48 years [12], range 25-88 years) presented with pancreatic duct stones obstructing the MPD. Alcohol was the most common etiologic factor (66%). The mean time between diagnosis of CP and initiation of therapy was 71 (76) months (range 0-368 months). Thirty patients (24%) had chronic pain and 77 (62%) had episodic pain. Attacks of pain occurred at least several times a week, often daily, in almost two thirds of the patients (n = 48). Six patients reported no pain at the onset of treatment. Another 18 of the 125 patients (14%) with chronic calcifying pancreatitis had not experienced any pain. All available clinical GASTROINTESTINAL ENDOSCOPY
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Figure 1. Retrograde pancreatogram showing pancreatic duct stones before ESWL. data were assessed retrospectively including radiographic images, medical records during treatment, follow-up appointments, and information obtained by telephone interview. The follow-up interval was defined as the time between the end of the first hospitalization, during which interventional therapy was carried out, and the end of observation, surgery, or death. Treatment Before endoscopic treatment all patients underwent diagnostic endoscopic retrograde pancreatography (ERP). Based on circumstances in individual patients, endoscopic biliary or pancreatic sphincterotomy was performed and an attempt was made to disintegrate and remove the stones using a Dormia basket. If this failed, ESWL was performed with a piezoelectric shockwave lithotripter with capability for visualization of the stones ultrasonographically (Piezolith 2300, R. Wolf, Knittlingen, Germany) or with alternating US and radiographic visualization (Piezolith 2500, Piezolith 2501-economy; Wolf). These lithotripters develop a maximal shockwave pressure of 120 to 150 mega-pascals in a focus area of 3 11 mm2 at a pulse repetition rate of 1 to 2 Hertz.10 ESWL was performed with the patient prone after intravenous administration of analgesic (meperidine, 50-200 mg) and/or sedative (diazepam, 520 mg) medications. Based on our experience, a maximum of 3 ESWL sessions per treatment course were scheduled before the next endoscopic procedure to remove fragments that did not clear spontaneously. In case of complete duct clearance, the next ERP was scheduled 3 months later. If residual fragments were detected, another series of 3 to 5 ESWL sessions was performed during the same hospital stay. If duct clearance was incomplete after this second attempt, an endoprosthesis was inserted to improve pancreatic duct drainage and therapy was continued, but no sooner than 3 months later. Because previous studies found that fragmentation is essential for stone removal,15,16 lithotripsy was rated successful if stone disintegration resulting in complete or partial duct clearance was achieved regardless of further endoscopic measures (Figs. 1 and 2). Clinical success was defined as complete relief of pain. All further endoscopic procedures, such as dilation of pancreatic duct strictures and/or inser502
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Figure 2. Retrograde pancreatogram showing complete duct clearance after ESWL and endoscopic removal of fragments. tion of an endoprosthesis, were performed according to the clinical circumstances in the individual case. To define factors potentially suitable for predicting technically successful lithotripsy, the following patient and morphologic factors were evaluated: age; gender; duration of CP before therapy; etiology of CP; number, size, and location of stones; and the concurrent presence of MPD strictures. The number of shockwave pulses and sessions needed for successful stone fragmentation by piezoelectric ESWL were determined (excluding 11 patients in whom mechanical lithotripsy was successful). Statistical methods For apparently normal quantitative data, the summary statistics are the mean, standard deviation (SD), and range. If normal distribution is not assumed, data are presented as median (interquartile range). Statistical analysis between 2 qualitative parameters was calculated with the Pearson chisquare test with the Yates correction for continuity where necessary, or the Fisher exact test when fewer than 20 data points were considered. The Mann-Whitney U test was used to compare quantitative data in 2 groups without assumption of normal distribution, whereas the Kruskal-Wallis H test was used if more than 2 groups were compared. To enhance discriminative power, the prognostic factors were assessed exclusively by univariate analysis of groups that differed by only one factor. Results for each of the individual hypothesis tests are stated; however, because there were several tests of hypotheses performed on data arising from individual patients, it was necessary to indicate where statistical significance would be removed by recognition of the multiple testing of data. The Bonferroni method was used to correct significant p values and it is noted where this correction removed statistical significance. For analysis of follow-up parameters, Kaplan-Meier curves were constructed to adequately take into account the differing lengths of follow-up. These data are presented as median (interquartile range).
RESULTS Before therapy, 324 intraductal stones were counted in the 125 patients evaluated. More than VOLUME 56, NO. 4, 2002
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half of these patients presented with only 1 (34%) or 2 stones (21.6%), whereas 17.6% had 3 and 26.4% 4 or mores stones were detected in the MPD. The stones were located more often within the head of the pancreas (46.6%) or the prepapillary segment (24.7%) of the MPD; about one third (28.7%) of the patients had stones within the body and/or tail of the pancreas. The mean maximum diameter of the stones was 8.6 mm (4.2) (range 2-31 mm). In 70 patients (56%), a stricture of the MPD was present, predominantly within the head or the prepapillary segment (81.9%). A mean of 8 (2-12) ERP sessions were performed. In anticipation of further endoscopic therapy, pancreatic sphincterotomy or needle-knife incision toward the pancreatic duct was carried out in 88 of the 125 patients (70%).17 In 11 patients (9%), calculi were disintegrated mechanically and fragments completely removed by using a Dormia basket alone. However, these maneuvers failed to clear the duct of stones in the majority of patients (91%). These stones were treated by piezoelectric ESWL in a median of 2.5 (interquartile range 2-4) sessions, mean 3600 (3000-4500) pulses per session, over a median treatment period of 4.6 months (interquartile range 0.45-14.3 months). To ensure pancreatic duct drainage and to simplify localization of the stones during ESWL, a nasopancreatic tube was temporarily placed in 47 patients before ESWL. Because of MPD strictures, a total of 234 plastic stents (5-12F, length 30-200 mm) were placed. These were left in situ for a median of 2.25 months (interquartile range, 1-3 months) and were exchanged on a regular basis in 70 patients. In advance, the strictures were dilated with bougies or high-pressure balloons (4-8 mm diameter) 33 times in 24 patients. Fifty-seven endoprostheses (24.3%) occluded in 27 patients (38.6%) after a mean of 2.7 months. Migration of the endoprosthesis into the pancreatic duct occurred in 2 patients at 1.6 and 2 months after insertion. In another 4 patients, spontaneous dislocation of the stents into the duodenum was documented. Technical success As mentioned, MPD stones were completely removed by using a Dormia basket in 11 patients. In 94 patients, disintegration of MPD stones was achieved after ESWL, leading to a complete or partial duct clearance in, respectively, 39 and 55 patients. During the initial treatment series, mechanical extraction and ESWL were unsuccessful in clearing the stones in only 20 patients. ESWL was continued in 21 patients. In 19 of these patients, the initial treatment series had VOLUME 56, NO. 4, 2002
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Table 1. Pain before therapy and long-term clinical benefit after interventional therapy (n = 84) Before therapy
Clinical success during follow-up: No pain Pain relapse
Recurrent pain attacks n = 56
Chronic pain n = 26
No pain n=2
28/56 (50%) 28/56 (50%)
11/26 (42%) 15/26 (58%)
1/2 (50%) 1/2 (50%)
achieved partial duct clearance, whereas in 2 the initial treatment proved to be completely unsuccessful. In 20 of these patients (95%), complete (n = 14) or partial (n = 6) duct clearance was achieved. Continued lithotripsy failed in only 1 patient. At the conclusion of all therapeutic measures, stone fragmentation was achieved in a total of 106 of the 125 patients (85%), with complete duct clearance in 64 (51%) and partial clearance in 42 (34%) patients. Despite all measures, treatment was unsuccessful in 19 patients (15%). In 32 of 62 patients (48%) who could be followed and in whom interventional therapy resulted in a complete clearance of the MPD, there was no stone recurrence. The “stone-free survival time,” calculated with the Kaplan-Meier method, for these patients was a median of 18.5 months (interquartile range 3.0-29.2 months). In the remaining 30 patients, at least 1 recurrent stone was found at a mean followup of 7.4 months (6.0) (range, 2.0-22.8 months). In almost three fourths of the cases (22/30, 73.3%), stone recurrence was diagnosed within the first 9 months after successful treatment. Twenty-five of the patients with recurrent stones underwent further ESWL, leading to complete duct clearance in 14 patients (56%) and partial clearance in 8 (32%). Treatment was completely unsuccessful in only 3 cases (12%). The technical success rate (88%) for treatment of recurrent stones was comparable with that of initial therapy. Clinical success Of the 101 of 125 patients presenting with acute pain immediately before interventional therapy, 94 (93%) became completely pain-free after completion of the therapeutic measures. The majority of these patients (n = 84) were followed (mean 29 months, [20]; range 2.3-73.2 months), and 40 (48%) remained pain-free throughout the follow-up period. The remaining 44 patients (52%) experienced relapses of pain and were hospitalized again for treatment (Table 1). In more than half of these latter patients (23/44; 52%) recurrent MPD stones and/or occlusion GASTROINTESTINAL ENDOSCOPY
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Table 2. Technical success and long-term clinical benefit after interventional therapy (n = 84) Clearance of main pancreatic duct
Clinical success during follow-up No pain Pain relapse
Complete n = 39
Partial n = 43
None n=2
22/39 (56%) 17/39 (44%)
17/43 (39%) 26/43 (61%)
1/2 (50%) 1/2 (50%)
as well as dislocation of the endoprosthesis into the duodenum were found to be the most likely reasons for recurrence of pain. Treatment of recurrent stones resulted in immediate and complete relief in 21 of the 23 patients (91%). All 11 patients with stent-related complications (occlusion 10, dislocation 1) managed by stent removal or exchange became pain-free again. In 7 patients with MPD strictures, stent placement was continued and led to immediate clinical relief of pain in all 7. In the remaining 3 patients, no particular cause, either disease- or therapy-related, was identified for the relapse of pain. Two of these patients, treated conservatively, became free of pain. Thus, the overall clinical success rate for continued endoscopic treatment was 93%, which was similar to the response rate after the initial treatment course. No significant association was found between continued consumption of alcohol during follow-up and relapse of pain. Of the 24 of 125 patients who did not have pain before therapy, only 1 had abdominal pain during follow-up. Among the 84 patients for whom follow-up data were available, pain relapse was less frequent in those with complete as opposed to partial duct clearance (Table 2), although this association did not reach statistical significance (p = 0.184). Nine patients (7.8%) died during follow-up (mean 30.5 months, [19.9]; range 1.3-73.2 months). The cause of death was unclear for 5 patients. One patient committed suicide, another developed a pleural mesothelioma, and 2 patients died of multiorgan failure caused by acute pancreatitis. Surgical intervention became necessary in 15 patients (13%) because of intractable pain after unsuccessful endoscopic treatment (hemipancreatectomy, 3; Whipple’s operation, 2; pancreaticojejunostomy, 6; cystojejunostomy, 2). In 2 patients, dislocated, endoscopically irretrievable endoprostheses had to be removed surgically from the pancreatic duct. Success factors and therapeutic effort The technical success of interventional endoscopic therapy for pancreatic duct stones was signif504
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icantly better in patients 50 to 59 years of age (98%) compared with older (80%) and younger (78%, p = 0.03) patients, and also significantly better in patients with stones located in the head of the pancreas or prepapillary segment (94%) compared with patients with calculi in the body or tail (50%, p = 0.045). Both of these parameters, however, were not significant after correction for multiple testing. There was no association between successful fragmentation of stone(s) and any of the following: MPD stricture (stricture [94%] vs. no stricture [90%]; p = 0.49), number of stones (single stone [88%] vs. {≥2 stones [70%]; p = 0.26), stone diameter (2-5 mm [100%] vs. 6-15 mm [91%]; p = 0.77), time interval from onset of symptoms caused by CP and therapy (≤8 years [87%] vs. >8 years [79%]; p = 0.26), gender (male [85%] vs. female [83%]; p = 0.84), and etiology of CP (alcohol [82%] vs. no alcohol [89%]; p = 0.34). The associations between therapeutic effort to achieve fragmentation and patient-related as well as morphologic factors are outlined in Table 3. DISCUSSION Stones within the pancreatic duct system are found in 50% to 90% of patients presenting with CP.18 Depending on stone size and duct diameter, drainage of pancreatic secretions is obstructed, resulting in upstream dilation. This obstruction is assumed to be a factor in the development of pain, which leads to heavy usage of analgesic drugs, loss of weight, inability to work, and reduced quality of life.19-21 Before the introduction of ESWL in 1989, surgery was the only therapeutic option and resulted in pain relief in approximately 85% of patients with endoscopically nonremovable stones.7 Nevertheless, even after duodenum-preserving resection of the head of the pancreas, presently considered the best surgical treatment for CP and inflammatory mass in the head, almost 25% of patients experience recurrences of pain. Additionally, surgical intervention has a considerable procedure-related morbidity rate of 20% to 47% and mortality rate of 1% to 5%.3,22-24 Therefore, interventional endoscopy, including ESWL, has been increasingly used in the treatment of chronic calcifying pancreatitis during the last 10 years, with clinical results that are almost equal to conventional surgery.6-16 For prepapillary stones, stones proximal to strictures of the MPD, and impacted stones that prevent retrograde cannulation, ESWL has become essential. Regardless of the method of shockwave generation (electrohydraulic, electromagnetic, piezoelectric)25 ESWL provides immediate pain relief in more than 90% of cases.8-16 As with pancreatic surgery, however, long-term relief is achieved in only about VOLUME 56, NO. 4, 2002
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Table 3. Therapeutic effort and individual/morphologic factors in ESWL treatment of pancreatic duct stones in chronic pancreatitis Mean No. shock wave pulses*
Parameter Location of stones No. of stones Size of stones Age Symptoms before therapy Risk factors
Prepapillary Body/tail 1 stone ≥2 stones 2-10 mm 12-15 mm <50 y ≥50 y ≤8 y >8 y Alcohol No alcohol
6495 18,750 6661 11,567 4666 9129 8892 7335 7070 10,435 6723 10,191
Significance p = 0.049† p = 0.01† p = 0.006† p = 0.22 p = 0.002 p = 0.036†
Mean No. treatment sessions* 2.0 4.5 2.0 2.8 1.4 2.8 2.5 2.1 2.1 2.9 2.0 2.8
Significance p = 0.048† p = 0.052 p = 0.013† p = 0.11 p = 0.004 p = 0.03†
*No. of shockwave pulses and treatment sessions necessary to achieve fragmentation. †Correction for multiple testing of data removes that significance.
30% to 50% of patients. But in contrast to surgery, endoscopic therapy can be performed repeatedly in response to recurrences of pain, and has a high clinical success rate that is similar to that for initial therapy. Moreover, patient age is not significant as a risk factor for procedure-related morbidity and mortality.26 Because the complication rate is low (0%36%) and deaths associated with the procedure are uncommon, endoscopic management appears to be a safe as well as successful alternative to surgery. Unfortunately, lithotripters are not available in every hospital because of their high cost, especially the preferred machines that incorporate devices for fluoroscopic and US localization. Furthermore, for most pancreatic duct stones, greater experience and effort are needed to achieve a sufficient degree of fragmentation compared with lithotripsy of gallbladder stones.27 There is evidence that complete removal of the stones promotes immediate and long-term recovery15,16 and that fragmentation is often essential for complete duct clearance. In the present study, a significantly increased fragmentation rate was noted for stones within the head of the pancreas including those close to the papilla, and in patients in the fifth decade of life, although significance was removed after correction for multiple testing of data. These findings are confirmed by other analyses (univariate and multivariate) of prognostic morphologic factors.4,8,12,16 In contrast to the observations of Dumonceau et al.,16 who maintain that patients without a proximal stenosis of the MPD respond best to ESWL, there was no correlation in the present study between technical success and the presence of a pancreatic duct stricture. Furthermore, stone number and size, gender, regular consumption of alcohol, and time interval between onset of symptoms of CP VOLUME 56, NO. 4, 2002
and initiation of therapy did not influence the success of treatment. Interestingly, Dumonceau et al.16 identified ESWL as the only independent criterion for successful fragmentation. The therapeutic efforts required to achieve fragmentation were significantly greater for patients with 2 or more stones, stones 12 mm or more in diameter, and stones within the body and/or tail of the pancreas; however, correction for multiple testing of data removed significance for all of these parameters. The intensified schedule of treatment in our patient group accounts for the fact that neither number nor size of stones is associated with the technical success of the procedure. Complete endoscopic clearance of stones from the MPD leads to immediate pain relief significantly more often than partial or no clearance.11,15,16 Therefore, the goal of endoscopic therapy for chronic calcifying pancreatitis should be complete removal of all stones and fragments. Even if this is not achieved initially, despite intense therapeutic efforts, the present study demonstrates that complete clearance can be obtained in more than two thirds of patients with partial duct clearance after an initial treatment series when interventional therapy is continued. Treatment should be initiated as soon as possible after diagnosis because this reduces costs and increases the probability of long-term clinical benefit. REFERENCES 1. Di Sebastiano P, Friess H, Di Mola FF, Innocenti P, Buechler MW. Mechanisms of pain in chronic pancreatitis. Ann Ital Chir 2000;71:11-6. 2. Pitchumoni CS. Chronic pancreatitis: pathogenesis and management of pain. J Clin Gastroenterol 1998;27:101-7. 3. Sakorafas GH, Farnell MB, Farley DR, Rowland CM, Sarr MG. Long-term results after surgery for chronic pancreatitis. Int J Pancreatol 2000;27:131-42. GASTROINTESTINAL ENDOSCOPY
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4. Sherman S, Lehman GA, Hawes RH. Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc 1991;37:511-7. 5. Schneider MU, Lux G. Floating pancreatic duct concrements in chronic pancreatitis. Endoscopy 1985;17:8-10. 6. Kozarek RA, Ball TJ, Patterson DJ. Endoscopic approach to pancreatic duct calculi and obstructive pancreatitis. Am J Gastroenterol 1992;87:600-3. 7. Sauerbruch T, Holl J, Sackmann M, Paumgartner G. Extracorporeal shockwave lithotripsy of pancreatic stones. Gut 1989;30:1406-11. 8. Delhaye M, Vandermeeren A, Baize M, Cremer M. Extracorporeal shockwave lithotripsy of pancreatic calculi. Gastroenterology 1992;102:610-20. 9. Sauerbruch T, Holl J, Sackmann M, Paumgartner G. Extracorporeal shock wave lithotripsy of pancreatic duct stones in patients with pancreatitis and pain: a prospective follow up study. Gut 1992;33:969-72. 10. Schneider HT, May A, Benninger J, Rabenstein T, Hahn EG, Katalinic A, et al. Piezoelectric shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol 1994;89:2042-8. 11. van der Hul R, Plaiser P, Jeekel J, Terpstra O, den Toom R, Bruining H. Extracorporeal shock wave lithotripsy of pancreatic duct stones: immediate and long-term results. Endoscopy 1994;26:573-8. 12. Smits ME, Rauwes EA, Tygat GNJ, Huibregtse K. Endoscopic treatment of pancreatic stones in patients with chronic pancreatitis. Gastrointest Endosc 1996;43:556-60. 13. Ohara A, Hoshino M, Hayakawa T, Kamiya Y, Miyaji M, Takeuchi T, et al. Single application extracorporeal shock wave lithotripsy is the first choice for patients with pancreatic duct stones. Am J Gastroenterol 1996;91:1388-94. 14. Costamagna G, Gabrielli A, Mutignani M, Perri V, Pandolfi M, Boscani M, et al. Extracorporeal shockwave lithotripsy of pancreatic stones in chronic pancreatitis: immediate and medium-term results. Gastrointest Endosc 1997;46:231-6. 15. Adamek HE, Jakobs R, Buttmann A, Adamek MU, Schneider AR, Riemann JF. Long-term follow-up of patients with chronic pancreatitis and pancreatic stones treated with extracorporeal shock wave lithotripsy. Gut 1999;45:402-5.
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16. Dumonceau JM, Deviere J, Le Mione O, Delhaye M, Vandermeeren A, Baize M, et al. Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-term results. Gastrointest Endosc 1996;43:547-55. 17. Ell C, Rabenstein T, Schneider HT, Ruppert T, Nicklas M, Bulling D. Safety and efficacy of pancreatic sphincterotomy in chronic pancreatitis. Gastrointest Endosc 1998;48:244-9. 18. Ammann RW, Muench R, Otto R, Buechler H, Freiburghaus AU, Siegenthaler W. Evolution and regression of pancreatic calcification in chronic pancreatitis. A prospective long-term study of 107 patients. Gastroenterology 1988;95:1018-28. 19. Apte MV, Keogh GW, Wilson JS. Chronic pancreatitis: complications and management. J Clin Gastroenterol 1999;29:225-40. 20. Jansen JB, Kuijpers JH, Zitman FJ, van Dongen R. Pain in chronic pancreatitis. Scand J Gastroenterol 1995;30:117-25. 21. Ammann RW, Müllhaupt B. The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999;116: 1132-40. 22. Beger HG, Schlosser W, Friess HM, Buechler MW. Duodenumpreserving head resection in chronic pancreatitis changes the natural course of the disease: a single-center 26-year experience. Ann Surg 1999;230:512-9. 23. Berney T, Rudisuhli T, Oberholzer J, Caulfield A, Morel P. Long-term metabolic results after pancreatic resection for severe chronic pancreatitis. Arch Surg 2000;135:1106-11. 24. Schlosser W, Beger HG. Organ-preserving surgery in chronic pancreatitis: the duodenum-preserving pancreatic head resection. Ann Ital Chir 2000;71:65-70. 25. Schneider HT, Fromm M, Ott R, Janowitz P, Swobodnik W, Neuhaus H, et al. In vitro fragmentation of gallstones: comparison of electrohydraulic, electromagnetic and piezoelectric shockwave lithotripters. Hepatology 1991;14:301-5. 26. Rabenstein T, Schneider HT, Hahn EG, Ell C. 25 years of endoscopic sphincterotomy in Erlangen: assessment of the experience in 3498 patients. Endoscopy 1998;30(Suppl 2): A194-201. 27. Ell C, Kerzel W, Schneider HT, Wirtz P, Domschke W, Hahn EG. Piezoelectric lithotripsy: Stone disintegration and followup results in patients with symptomatic gallbladder stones. Gastroenterology 1990;99:1439-44.
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