Long-term Results of Extracorporeal Shockwave Lithotripsy and Endoscopic Therapy for Pancreatic Stones

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: Long-term Results of Extracorporeal Shockwave Lithotripsy and Endoscopic Therapy for Pancreatic Stones HIROSHI TADENUMA, TAKESHI ISHIHARA, TAKETO YAMAGUCHI, SHOUICHI TSUCHIYA, AKITOSHI KOBAYASHI, KAZUYOSHI NAKAMURA, REIKO SAKURADA, and HIROMITSU SAISHO Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan Background & Aims: The aim of this study was to evaluate the short- and long-term results of extracorporeal shockwave lithotripsy (ESWL) and endoscopic therapy for pancreatic stones. Methods: A total of 117 patients with pancreatic stones underwent ESWL and endoscopic treatment in our institute. Seventy patients who were followed-up for over 3 years after treatment were evaluated retrospectively. Results: Immediate pain relief was achieved in 97% and complete removal of stones was achieved in 56%. During the long-term follow-up evaluation, 49 of 70 patients continued to be asymptomatic. Pain recurred more frequently in patients with incomplete removal than in those with complete removal (P <.05). Twenty-one patients who became symptomatic during the follow-up period underwent additional therapy, and pain relief was attained without surgery in all of them. Both endocrine and exocrine function deteriorated after the long-term follow-up period (P <.05). Conclusions: ESWL and endoscopic treatment of pancreatic stones proved to be effective for long-term pain relief, especially in patients in whom stones were removed completely at initial therapy. Chronic pancreatitis (CP) is characterized by a progressive loss of pancreatic parenchymal tissue, and after a subclinical phase of variable duration, recurrent attacks of abdominal pain occur, and exocrine and endocrine insufficiency becomes apparent. 1 In most patients with CP, pain is the predominant symptom 2 and ductal hypertension caused by stones and strictures is believed to be the major cause of pain in CP. 1,3 Thus, treatment of pain in CP has been directed toward pancreatic duct decompression. Surgical drainage is safer and preferable to preserve pancreatic function than resection of the pancreas. 4 However, surgical drainage is associated with a mortality rate of up to 5%, and long-term prognosis is not good because pain may recur in up to 50% of the patients within 5 years after the surgery. 5 In recent years, extracorporeal shockwave lithotripsy (ESWL) and endoscopic treatment were introduced to remove pancreatic stones, 6 8 and their effectiveness regarding stone removal and pain relief has been shown. 9 Because these procedures are noninvasive, some investigators regarded ESWL and endoscopic treatment as the first-line treatment for pancreatic stones. 3 To our knowledge, most reports were based on short- and medium-term results, and there have been few reports on the usefulness of ESWL and endoscopic treatment after long-term follow-up evaluation. Therefore, we reviewed our long-term results of ESWL and endoscopic treatment for pancreatic ductal stones in addition to our short-term results. Materials and Methods Patients From May 1991 to December 2003, 117 consecutive patients (85 men, 32 women; mean age, 47.8 y; range, y) with pancreatic duct stones were treated in our hospital. The cause of CP was alcohol in 79 patients and other factors in 38. All the patients had abdominal or back pain associated with pancreatitis. The patients who had undergone pancreatic surgery and/or had been diagnosed with pancreatic cancer were excluded. Table 1 shows the characteristics of the patients. Written informed consent was obtained from all patients who underwent ESWL and endoscopic treatment. Definition Before therapy, all patients underwent endoscopic retrograde pancreatography (ERP). Stone characteristics (number, maximum diameter, and location) and the presence of a main pancreatic duct (MPD) stricture were assessed. The MPD stricture was defined as a linear stricture ( 1 mm) on ERP without malignant findings (confirmed by brushing cytology or computed tomography). The maximum diameter of the MPD was measured at the body of the pancreas before and immediately after therapy with ultrasound. Fragmentation of stones was considered successful if each fragment was 3 mm or less in diameter judged by ultrasound and plain radiograph Abbreviations used in this paper: BT-PABA, N-benzoyl-L-tyrosilparaaminobenzoic acid; CP, chronic pancreatitis; ERP, endoscopic retrograde pancreatography; ESWL, extracorporeal shockwave lithotripsy; MPD, main pancreatic duct by the American Gastroenterological Association /05/$30.00 PII: /S (05)

2 November 2005 ESWL AND ENDOSCOPIC THERAPY 1129 Table 1. Clinical and Morphologic Characteristics of Patients With Pancreatic Stones Sex Male 85 Female 32 Age (y) Mean 48 Range Cause Alcohol 79 Others 38 Stones Number Single 37 Multiple 80 Location Head 100 Body/tail 17 Maximum diameter (mm) Mean 11.2 Range 3 37 MPD stricture 57 (48.7%) films. Complete removal of stones was defined as no filling defect in the MPD on ERP. Incomplete removal of stones was defined as the presence of remaining filling defect(s) in the MPD on ERP. Treatment Initial treatment. After hospitalization, ESWL was performed as the first-line treatment and those in whom stones were not removed by ESWL were subjected to endoscopic treatment. The treatment goal was complete removal of stones. ESWL was performed with a piezoelectric lithotriptor (LT-01, 02; EDAP International Inc., Paris, France, or Piezolith 2500; Richard Wolf, Inc., Knittlingen, Germany). Targeting of pancreatic stones was performed by radiograph or ultrasound. Patients were treated with ESWL twice a week until each fragment was 3 mm or less in diameter. When removal of pancreatic stones was insufficient, endoscopic pancreatic sphincterotomy and basket extraction were performed to remove the stones at post-eswl ERP. Those who had an MPD stricture underwent balloon dilation of the stricture. In patients with impacted stones at the MPD, laser lithotripsy under peroral pancreatoscopy was performed. Patients in whom ERP after pancreatic stone treatment showed a poor excretion of contrast agents because of MPD stricture underwent pancreatic duct stenting. Patients who had MPD stricture but a good excretion of contrast agents did not undergo pancreatic duct stenting. We used 7F, 8.5F, and 10F plastic stents. The stents were changed every 3 6 months, but were not replaced if the strictures were found to have improved on ERP. Additional treatment. The patients who felt pain after the initial therapy underwent additional treatment. All the patients underwent conservative therapy, and if they did not respond to conservative therapy, ESWL and endoscopic treatment was repeated. Evaluation of Clinical Symptoms Clinical data were collected until June On their first visit to outpatient clinics, patients were interviewed by doctors regarding the presence of pain, the use of analgesics, and previous hospitalizations. These results were included in the clinical notes. When clinical testing for a patient (including blood test, ultrasound, computed tomography, and endoscopy) showed that the cause of pain was unrelated to the pancreas, the patient was excluded from the group assessed for remaining pain. During the follow-up period, the patients were requested to visit the clinic every 6 months. Pain scores were determined in August 2004 based on those clinical records. Pain was assessed retrospectively according to a 4-grade scale: none, mild (no use of analgesics, including discomfort), moderate (requiring analgesics), and severe (requiring hospitalization). Remaining pain was moderate or severe, and pain relief was defined as none or mild pain. Pain relapse was defined as moderate or severe pain that appeared after pain relief had been obtained. N-benzoyl-L-tyrosil-paraaminobenzoic acid (BT-PABA) test was used to evaluate pancreatic exocrine function. N-benzoyl-Ltyrosil-paraaminobenzoic acid is administered in this test, and Chymotrypsin cleaves N-benzoyl-L-tyrosil-paraaminobenzoic acid, yielding p-aminobenzoic acid, which is absorbed and can be measured in urine. Diabetes was evaluated according to the American Diabetes Association. 10 Post-ERCP and ESWL pancreatitis was defined according to consensus criteria. 11 Follow-up Evaluation For short-term results, stone removal, pain relief, complete removal of stones as a prognostic factor, and complications were evaluated in all cases. Long-term results were assessed in those patients who were followed-up for 3 years or more after the initial therapy. Pain relief, pain relapse as a prognostic factor, pancreatic function, and survival rate were evaluated. The effectiveness of pancreatic stenting also was evaluated in patients with an MPD stricture. Pain was assessed by interview at several time points: 1 year before treatment, and 1 year, 1 2, 2 3, 3 5, 5 7, and 7 10 years after treatment. Statistical Analysis The results are presented as the mean value SD. For the statistical analysis of quantitative parameters, the 2 test or the Fisher exact test was used. The Mann Whitney U test was used to compare the difference between 2 groups. The Wilcoxon paired signed-rank test was used to compare the change in each group. To determine the risk factors for pain relapse, we used the Cox proportional hazards regression model. For the analysis of longterm results after successful or unsuccessful treatment and survival rates, we used Kaplan Meier curves and the log-rank test. A P value of less than.05 was considered statistically significant. Results Short-term Results Fragmentation of the stones was achieved in 113 patients (96.6%) and complete removal of stones was achieved in 65 patients (55.6%). Table 2 shows technical and clinical results. A total of 114 patients (97.4%) had

3 1130 TADENUMA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 11 Table 2. Technical and Clinical Results Patients Pain relief Complete removal (100%) Incomplete removal (100%) No fragmentation 4 1 (25%) immediate pain relief after treatment, however, 3 of 4 patients without fragmentation had no pain relief; 2 remained in moderate pain and 1 in severe pain. Of 117 patients who underwent ESWL, 65 patients (56%) required additional endoscopic therapy after ESWL. Seven patients required laser lithotripsy. ESWL and endoscopic therapy were required for sessions and sessions, respectively. The MPD diameter before and after treatment is shown in Figure 1. The mean MPD diameter decreased significantly from mm to mm (P.001). Table 3 shows prognostic factors for a successful treatment. Age; sex; cause of CP; number, location, and maximum diameter of stones; and the presence of an MPD stricture were analyzed for their influence on the patient s prognosis. The complete removal of stones was attained more frequently in patients with a single stone (P.05) and without an MPD stricture (P.05). Complications. Complications related to ESWL occurred in 5 of the 107 patients (4.7%): mild pancreatitis in 4 and neuropathy in 1, and complications related to endoscopic treatment occurred in 5 of the 65 patients (7.7%): mild pancreatitis in 2, moderate pancreatitis in 1, and bleeding after sphincterotomy in 2. All of the patients recovered after conservative treatment and no severe complications were noted. Table 3. Prognostic Factors for Complete Removal of Stones (n 117) Prognostic factors Complete removal % P value Sex Male 47/ Female 18/ Age 50 y 31/ y 34/ Alcohol induced 42/ Nonalcohol induced 23/ Single stone 27/ Multiple stones 38/ Stones in head 54/ Stones in body/tail 11/ Stone diameter 10 mm 26/ mm 39/ Stricture in MPD 25/ No stricture 40/ Long-term Results Long-term outcome of pain. Long-term outcome of pain was assessed in 70 patients followed-up for months (Figure 2). Of these 70 patients, 57 patients had severe pain before treatment and pain relapse occurred in 21 (36.8%) approximately months after treatment. The number of patients with moderate or severe pain decreased significantly during the first year after treatment (P.001); 49 patients (70%) experienced pain relief. At 3, 5, and 10 years after treatment, pain relief was obtained in 57 of 70 (81.4%), 35 of 42 (83.3%), and 13 of 13 (100%) of the patients, respectively. Pain relapse occurred in 21 of 57 patients (36.8%) approximately months after treatment. In the complete removal group 7 of 30 patients (23.3%) had pain relapse, whereas in the incomplete removal group 15 of 27 patients (55.6%) had pain relapse. Figure 2 shows cumulative rates of pain relapse in groups with complete Figure 1. MPD diameter (mm) before and after therapy. The MPD diameter was mm before therapy and mm immediately after therapy (P.001). The box represents the interquartile range, which contains 50% of the values. The whiskers are lines that extend from the box to the highest and lowest values, excluding outliers. The line across the box indicates the median. Figure 2. Cumulative rates of pain relapse in relation to removal of stones. The thick line indicates the cumulative rates of pain relapse in the complete removal group and the thin line indicates the cumulative rates of pain relapse in the incomplete removal group.

4 November 2005 ESWL AND ENDOSCOPIC THERAPY 1131 or incomplete removal of stones. In the complete removal group, pain relapse occurred significantly less frequently than in the incomplete removal group (P.001). The prognostic factors for pain relapse during longterm follow-up evaluation are shown in Table 4. Pain relapse occurred more frequently in the group with incomplete removal of the stones after the initial therapy (hazard ratio, 3.719; P.0067) and in those with an MPD stricture (hazard ratio, 3.387; P.0178) as assessed by univariate analysis; both factors were found to be significant risk factors by multivariate analysis (P.05). In alcohol-induced CP, the rate of recurrence was high compared with nonalcohol-induced CP (41.0% vs 27.8%), but the difference did not reach statistical significance. In the patients with an MPD stricture, the rate of recurrence was lower in the stenting group (5 of 14, 35.7%) compared with the nonstenting group (11 of 18, 61.1%), but the difference was not statistically significant either. As for pain relapse, no difference was observed in alcohol intake between the continuation group and the abstinence group. Of the 21 patients with pain relapse, 15 were in the incomplete removal group and 6 were in the complete removal group after initial therapy. Pain relapse was associated with the presence of pancreatic stones in all patients. In 7 patients, pain ameliorated after conservative therapy of hospitalization. In 14 patients, repeated ESWL and/or endoscopic treatment (once in 9 patients, twice in 3 patients, and 3 times or more in 2 patients) was required to attain pain relief. None of the patients underwent surgery. Table 4. Prognostic Factors for Pain Relapse Prognostic factors Pain relapse Hazard ratio (95% confidence interval) P value Male 16/ (Female) (5/14) ( ) Age 50 y 13/ (Age 50 y) (8/30) ( ) Alcohol induced 16/ (Nonalcohol induced) (5/18) ( ) Multiple stones 14/ (Single stone) (7/17) ( ) Stones in head 19/ (in body/tail) (2/8) ( ) Stone diameter 10 mm 15/ ( 10 mm) (6/21) ( ) Stricture in MPD 16/ (No stricture) (5/25) ( ) Incomplete removal of stones 15/ (Complete removal) (6/30) ( ) Continuance of alcohol 9/ (Abstinence) (7/15) ( ) NOTE. n 57. Table 5. Long-term Outcome of BT-PABA Tests (% Urinary PABA Recovery) in Relation to Removal of Stones Before therapy (%) At long-term follow-up evaluation (%) Complete removal (n 18) Incomplete removal (n 12) Total (n 30) Long-term outcome of exocrine function. The BT-PABA test was performed in 30 patients at 2 time points: before treatment and after the long-term follow-up period (mean, mo; range, mo). The mean rates of urinary PABA recovery before treatment and after the long-term follow-up period were and , respectively, and the rates decreased significantly (P.05). When assessed in relation to stone removal, the urinary PABA recovery rates were found to be decreased in both groups (Table 5), but only in the incomplete removal group was the difference significant (P.05). As for the influence of CP cause, the urinary PABA recovery rates were decreased significantly after the longterm follow-up period only in the alcohol-induced CP group (P.05). Moreover, when the alcohol-induced CP group was divided into the continued drinking group and the abstinence group, the recovery rates were found to be decreased significantly in the continuance group (P.05) (Table 6). Long-term outcome of endocrine function. Longterm follow-up evaluation of endocrine function was possible in 70 patients. The follow-up period was months (range, mo). Diabetes was observed in 35.7% of the patients before treatment, but at the long-term follow-up evaluation it increased significantly in 57.1% (P.05). The results of endocrine function evaluation in the complete removal group and the incomplete removal group at follow-up evaluation are shown in Table 7. Although in the percentage of patients with diabetes between the complete and incomplete removal groups Table 6. Long-term Outcome of BT-PABA Tests (% Urinary PABA Recovery) in Relation to Cause Before therapy (%) At long-term follow-up evaluation (%) Nonalcohol induced (n 12) Alcohol induced (n 18) Abstinence (n 11) Continuance (n 7)

5 1132 TADENUMA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 11 Table 7. Long-term Outcome of Endocrine Function in Relation to Removal of Stones Before therapy At long-term follow-up evaluation Diabetes Insulin required Diabetes Insulin required Complete removal (n 37) 13 (35.1%) 0 (0%) 20 (54.1%) 5 (13.5%) Incomplete removal (n 33) 12 (36.4%) 4 (12.1%) 20 (60.6%) 13 (39.4%) Total (n 70) 25 (35.7%) 4 (5.7%) 40 (57.1%) 18 (25.7%) NOTE. Data represent number (% of patients in group). there was no significant difference, more patients required insulin in the incomplete removal group (39.4%) than in the complete removal group (13.5%). As for the frequency of diabetes in relation to CP cause, the rate of diabetic patients was higher in the alcohol-induced CP group (45.5% before therapy and 70.5% at the long-term follow-up evaluation) (Table 8). Moreover, when divided into the drinking continuation group and the abstinence group, the rate of diabetic patients was significantly higher in the continuance group (P.01). Survival rate. Eighty-seven (92.6%) of 94 patients who were followed-up for more than 3 years after the initial treatment were included in the evaluation of long-term survival. The other 7 patients were lost to follow-up evaluation. The mean duration of follow-up evaluation was months (range, mo). Ten patients (11.5%) died. The average age at the time of death was years (range, y), and the average age at the time of the initial treatment was years (range, y). The causes of death were esophageal cancer, pharyngeal cancer, and rectal cancer in 1 patient each, cardiac diseases in 4 patients, renal insufficiency in 1 patient, and acute obstructive suppurative cholangitis in 2 patients. None of the patients developed pancreatic cancer. The probability of 5- or 10-year survival after the initial treatment was 90.8% and 85.1%, respectively (Figure 3). Discussion Short-term Results In this series, fragmentation of pancreatic stones, complete removal of stones, and immediate pain relief were observed in 96.6% (113 of 117), 55.6% (65 of 117), and 97.4% (114 of 117) of the patients, respectively. According to the literature, fragmentation, complete removal, and immediate pain relief are observed in 72% 100%, 41% 75%, and 79% 100% of the patients, respectively. 3,5,12 21 The success rates of fragmentation and complete removal were almost equivalent to those of previous reports. As for complete removal, however, the rates differ among the institutions. This discrepancy was considered to be owing to several causes such as the type of lithotriptor used, the power setting and number of shocks delivered, and differences regarding the definition of complete removal of pancreatic stones among institutions. As for the definition of complete removal, we used ERP as the gold standard to define the clearance of intraductal stones. Some investigators reported that the judgment of complete removal was based on plain radiograph films, whereas others did not refer to the methods used. Schneider and Lux 7 reported that floating pancreatic duct concrements more than 2 mm in diameter can be detected by ERP; therefore, it may be judged as complete removal on ERP even if some pieces of fragments remain in the MPD. It is possible that evaluation of complete removal will be more accurate if we use more sensitive diagnostic methods (ie, intraductal ultrasound as the gold standard). In this study, complete removal of stones was attained more frequently in patients with a single stone and without an MPD stricture. There are some reports that a single stone 5,16,21 and no MPD stricture 3,5,16 are prognostic factors of complete removal of stones. In patients with multiple stones or with an MPD stricture it is difficult to remove all intraductal stones. Table 8. Long-term Outcome of Endocrine Function in Relation to Cause Before therapy At long-term follow-up evaluation Diabetes Insulin required Diabetes Insulin required Nonalcohol induced (n 26) 5 (19.2%) 1 (3.8%) 9 (34.6%) 6 (23.1%) Alcohol induced (n 44) 20 (45.5%) 3 (6.8%) 31 (70.5%) 12 (27.3%) Abstinence (n 18) 7 (38.9%) 2 (11.1%) 10 (55.5%) 8 (44.4%) Continuance (n 26) 13 (50.0%) 1 (3.8%) 21 (80.8%) 4 (15.4%) NOTE. Data represent number (% of patients in group).

6 November 2005 ESWL AND ENDOSCOPIC THERAPY 1133 Figure 3. Cumulative survival rate of patients with pancreatic stones treated by ESWL and endoscopic therapy. The Kaplan Meier curve shows that the 5- and 10-year survival rates were 90.8% and 85.1%, respectively. The number of individuals followed at 5 and 10 years after therapy were 63 and 21, respectively. Immediately after the therapy the maximum diameter of the MPD detected by ultrasound was decreased significantly compared with that before therapy. Some investigators also reported that the MPD diameter decreased significantly after therapy. 3,5,13 Warshaw et al 4 reported that marked improvement of pain apparently was correlated with the resolution of pathologic pancreatic duct dilation. Brand et al 5 found a statistical correlation between the decrease in MPD diameter and pain relief. Among the multiple causes of pain in patients with chronic calcifying pancreatitis, intraductal hypertension plays an important role. 9 In the present study, immediate pain relief was achieved in almost all the patients, including those with incomplete removal of stones. Various factors may account for the relief of pain such as improvement of pancreatitis by the treatment provided during hospitalization and a positive psychologic effect derived from the therapy; a possible assumption may be that the ameliorated excretion of pancreatic juice to some extent resulted in pain relief even if stone removal was incomplete. Complications of ESWL and endoscopic treatment were observed in 4.7% and 4.3% of the patients, respectively. They were comparable in frequency with those of other reports. 3,5,12 21 Long-term Results Studies on the long-term prognosis of CP showed a complete relief of pain in 76% 79% of patients for an average of months observation. 3,13,22 In this study, 44 of 70 patients (62.9%) never experienced pain relapse during the follow-up period. Historic records were searched to compare them with our results. There have been no reports regarding the natural course of pain in patients with CP treated conservatively, and many reports included surgically treated patients. Ammann et al 23 reported that of 145 patients with alcohol-induced chronic calcifying pancreatitis, including surgically treated patients (data not shown), 85% obtained pain relief within a median time of 4.5 years from onset. On the other hand, Lankisch et al 24 reported that of 275 patients with chronic calcifying pancreatitis, including surgically treated patients (data not shown), 44% had pain relief during the long-term follow-up period (mean, 11.3 y). Because the patients backgrounds differed, it was difficult to compare these data. But even so, our results seemed better when compared with historic records. Approximately one third of the patients experienced pain relapse during the follow-up period. All patients with pain relapse had intraductal pancreatic stones, suggesting that the main cause of pain relapse was pancreatic stones. When divided into the complete removal group and the incomplete removal group, pain relapse was observed more frequently in the incomplete removal group. van der Hul et al 19 and Sauerbruch et al 25 also reported that pain relapse occurred more frequently in the incomplete removal group. On the other hand, Adamek et al 12 and Schneider et al 14 reported that there was no difference in pain relapse rates between the complete and incomplete removal groups. However, they did not refer to the recurrence of pancreatic stones. Adamek et al 12 suggested that pain relapse might be related to the multifactorial causes of pain in CP. Pain relapse in patients with complete removal of stones at initial therapy may be attributed to undetectable remaining stones in the MPD. It is important to confirm the existence of stones at the time of pain relapse. It is considered that complete removal of stones at initial treatment reduces the pain relapse. Incomplete removal of stones and MPD stricture proved to be risk factors for pain relapse. Both are supposed to be involved in the increase of MPD pressure. It is supposed that increased pressure in the MPD is one of the major causes of pain relapse. Among patients with MPD stricture, those who were treated by pancreatic stent tended to have pain relapse less frequently than the patients without pancreatic stent. The possibility of pancreatic stenting is relatively limited because it is necessary to monitor the patient carefully to prevent stent obstruction and/or dislocation. Further studies are needed to clarify the long-term effectiveness of pancreatic stenting. In this study the patients who had pain relapse underwent additional therapy and all of them became asymptomatic again. In this study surgery was performed only in 1 patient. In previous reports, surgery was per-

7 1134 TADENUMA ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 11 formed in 1.4% 35.3% of patients. 3,12 20 Additional therapy including ESWL and endoscopic treatment proved to be effective in patients with pain relapse. Pancreatic exocrine function is supposed to deteriorate to some degree in CP during the course of the disease. Lankisch et al 24 reported no change of exocrine pancreatic insufficiency in 46.2% of patients and deterioration in 42.6%, although Ammann et al 23 reported that severe exocrine insufficiency developed within 5.65 years in 86.6% of the cases. In the present study, pancreatic exocrine function of the patients who had undergone ESWL and endoscopic treatment proved to deteriorate after long-term follow-up evaluation. Exocrine function of the pancreas deteriorated more significantly in the incomplete removal group. Adamek et al 12 reported that there were no differences in the long-term outcome of exocrine function between the complete and incomplete removal group, as evaluated by the frequency of fatty stool. In the present study, the BT-PABA test was used to evaluate the exocrine function of the pancreas. The gold standard to evaluate exocrine pancreatic function is the secretin and cholecystokinin pancreozymin test under duodenal intubation. The BT-PABA test is a tubeless test with a reported sensitivity of 85% and a specificity of 90%. 1 Lankisch et al 26 investigated the frequency of fatty stool and BT-PABA as pancreatic function tests, and reported a sensitivity of 51% and 89% compared with the secretin and cholecystokinin pancreozymin test, respectively, and concluded that the sensitivity of BT-PABA was higher than that of fatty stool. Lankisch et al 24 reported that there were no differences between the alcohol-induced CP group and the nonalcohol-induced CP group, or between the abstinence group and the continuance group. In this study pancreatic exocrine function in the continuance group significantly deteriorated at the end of the follow-up period. To preserve the exocrine function it is important to remove the stones completely and to abstain from alcohol. Ammann et al 23 found that 74.5% of the patients had diabetes after 5.72 years of observation, and Lankisch et al 24 reported 78% of their patients had diabetes after 10 years of follow-up evaluation. In the present study the pancreatic endocrine function of the patients treated for pancreatic stones deteriorated after long-term follow-up evaluation. No significant difference in the rates of diabetes after long-term follow-up evaluation was observed between the complete removal group and the incomplete removal group. For diabetes requiring insulin treatment, however, the number of patients was significantly lower in the complete removal group compared with the incomplete removal group. Adamek et al 12 reported that no improvement of endocrine function was observed in the successfully treated group of patients. More patients had diabetes in the group of patients that continued drinking alcohol than in the nonalcoholic group and the abstinence group, after long-term follow-up evaluation. Our findings are in accordance with those of Lankisch et al, 24 who reported endocrine pancreatic insufficiency was more frequent and severe in alcohol-induced than in nonalcohol-induced CP. We considered that abstinence was necessary to preserve pancreatic endocrine function. The 10-year mortality rate in the natural history of CP was reported to be 25% 35% 23,27,28 and the mortality of patients with pancreatic stones was reported at 31.0%. 23 In Japan, the 4-year mortality rate of patients with CP was 11.8%. 29 In this study the long-term follow-up (mean, 74.3 mo) mortality was 11.5% and the 10-year probability of survival as assessed by the Kaplan Meier method was 85.1% and better than historic records. There are some reports showing that the mortality of patients with pancreatic stones treated by ESWL and endoscopy was 6% 9% after follow-up evaluation for months, 12,15,21 and was equivalent to that found in this study. Regarding the cause of death in CP, there is a high rate of cancer and cardiovascular disease in relation to alcohol abuse and cigarette smoking. 24,27 Lowenfels et al 28 claimed that smoking and drinking were the major predictors of mortality in patients with CP. In the present study the main causes of death were cardiovascular disease and cancer, which were related to drinking and smoking. However, none of our patients developed pancreatic cancer. CP is regarded as a risk factor for pancreatic cancer. This may be attributed to cellular dysfunction and glandular destruction and increased cell turnover caused by inflammation. Lowenfels et al 30 reported the cumulative risk for pancreatic cancer at 10 and 20 years after diagnosis of pancreatitis was estimated to be 1.8% and 4.0%, respectively. Talamani et al 31 documented a significant increase in the incidence of pancreatic cancer (SIR, 18.5; 95% confidence interval, 10 30; P.0001). In Japan, 17 of 1073 patients (1.6%) died of pancreatic cancer during a 4-year observation period. 29 On the other hand, there have been no cases of pancreatic cancer after ESWL and endoscopic treatment for pancreatic stones among patients followed-up for a long period of time; 80 patients were followed-up by Adamek et al, patients were followed-up by Farbacher et al, 15 and 58 patients were followed-up by Dumonceau et al. 21 In the present study, none of the patients developed pancreatic cancer either. Further studies also are needed, however, to clarify that

8 November 2005 ESWL AND ENDOSCOPIC THERAPY 1135 ESWL and endoscopic treatment for pancreatic stones reduce the risk for pancreatic cancer. In conclusion, short-term pain relief was attained even in patients with incomplete removal of pancreatic stones. After long-term follow-up evaluation, however, pain relapse was observed more frequently in patients with incomplete removal of stones than in the complete removal group. Complete removal of stones at the initial therapy contributes to improving the prognosis of the patients regarding pain in CP. References 1. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med 1995;332: Mitchell RMS, Byrne MF, Baillie J. Pancreatitis. Lancet 2003; 461: Ohara H, Hoshino M, Hayakawa T, et al. Single application extracorporeal shock wave lithotripsy is the first choice for patients with pancreatic duct stones. Am J Gastroenterol 1996;91: Warshaw AL, Banks PA, Fernandes-Del Castillo C. AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115: Brand B, Kahl M, Sidhu S, et al. Prospective evaluation of morphology, function, and quality of life after extracorporeal shockwave lithotripsy and endoscopic treatment of chronic calcifying pancreatitis. Am J Gastroenterol 2000;95: Fuji T, Amano H, Harima K, et al. Pancreatic sphincterotomy and pancreatic endoprosthesis. Endoscopy 1985;17: Schneider MU, Lux G. Floating pancreatic duct concrements in chronic pancreatitis. Endoscopy 1985;17: Sauerbruch T, Holl J, Sackmann M, et al. Disintegration of a pancreatic stone with extracorporeal shock waves in a patient with chronic pancreatitis. Endoscopy 1987;19: Guda NM, Partington S, Freeman ML. Extracorporeal shock wave lithotripsy in the management of chronic calcific pancreatitis: a meta-analysis. Journal of Pancreas 2005;6: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20: Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc 1991;37: Adamek HE, Jakobs R, Buttmann A, et al. Long term follow up of patients with chronic pancreatitis and pancreatic stones treated with extracorporeal shock wave lithotripsy. Gut 1999;45: Delhaye M, Vandermeeren A, Baize M, et al. Extracorporeal shock-wave lithotripsy of pancreatic calculi. Gastroenterology 1992;102: Schneider HT, May A, Benninger J, et al. Piezoelectric shock wave lithotripsy of pancreatic stones. Am J Gastroenterol 1994;89: Farbacher MJ, Schoen C, Rabenstein T, et al. Pancreatic duct stones in chronic pancreatitis: criteria for treatment intensity and success. Gastrointest Endosc 2002;56: Sherman S, Lehmann GA, Hawes RH, et al. Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc 1991;37: Smits ME, Rauws EAJ, Tytgat GNJ, et al. Endoscopic treatment of pancreatic stones in patients with chronic pancreatitis. Gastrointest Endosc 1996;43: Costamagna G, Gabberielli A, Mutignani M, et al. Extracorporeal shock wave lithotripsy of pancreatic stones in chronic pancreatitis: immediate and medium-term results. Gastrointest Endosc 1997;46: van der Hul R, Plaisier P, Jeekel J, et al. Extracorporeal shockwave lithotripsy of pancreatic duct stones: immediate and longterm results. Endoscopy 1994;26: Kozarek RA, Brandabur JJ, Ball TJ, et al. Clinical outcomes in patients who undergo extracorporeal shock wave lithotripsy for chronic calcific pancreatitis. Gastrointest Endosc 2002;56: Dumonceau JM, Devière J, Moine OL, et al. Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: longterm results. Gastrointest Endosc 1996;43: Rösch T, Daniel S, Scholz M, et al. Endoscopic treatment of chronic pancreatitis: a multicenter study of 1000 patients with long-term follow-up. Endoscopy 2002;34: Ammann RW, Akovbiantz A, Largiader F, et al. Course and outcome of chronic pancreatitis. Gastroenterology 1984;86: Lankisch PG, Löhr-Happe A, Otto J, et al. Natural course in chronic pancreatitis; pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 1993;54: Sauerbruch T, Holl J, Sackmann M, et al. Extracorporeal lithotripsy of pancreatic stones in patients with chronic pancreatitis and pain: a prospective study. Gut 1992;33: Lankisch PG, Otto J, Brauneis J, et al. Detection of pancreatic steatorrhea by oral pancreatic function test. Dig Dis Sci 1988; 33: Cavallini G, Frulloni L, Pederzoli P, et al. Long-term follow-up of patients with chronic pancreatitis in Italy. Scand J Gastroenterol 1998;33: Lowenfels AB, Maisonneuve P, Cavallini G, et al, and the International Pancreatitis Study Group. Prognosis of chronic pancreatitis: an international multicenter study. Am J Gastroenterol 1994;89: Otsuki M. Chronic pancreatitis in Japan: epidemiology, prognosis, diagnosis, criteria, and future problems. J Gastroenterol 2003;38: Lowenfels AB, Maisonneuve P, Cavallini G, et al, and the International Pancreatitis Study Group. Pancreatitis and the risk factor of pancreatic cancer. N Engl J Med 1993;328: Talamani G, Falconi M, Bassi C, et al. Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999;94: Address requests for reprints to: Hiroshi Tadenuma, MD, Department of Medicine and Clinical Oncology, Chiba University, 1-8-1, Inohana, Chuoku, Chiba , Japan. tade@staysea.nir.jp; tadenum@yahoo.co.jp; fax: (043)