ORIGINAL ARTICLE
Success of Extracorporeal Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management A Meta-Analysis and Systematic Review Harsha Moole, MD,* Amy Jaeger, MD,* Matthew L. Bechtold, MD,† David Forcione, MD,‡ Deepak Taneja, MD,§ and Srinivas R. Puli, MD|| Objectives: This is a meta-analysis and systematic review to assess the overall utility and safety of Extracorporeal shock wave lithotripsy (ESWL) in chronic calcific pancreatitis. Primary outcomes are pain relief, narcotic usage, ductal clearance, quality of life, and pancreatic exocrine and endocrine function. Methods: Studies involving ESWL in chronic calcific pancreatitis with main pancreatic duct stones greater than 5 mm and patients that failed conservative pain management were included. Fixed and random effects models were used to calculate the pooled proportions. Results: Initial search identified 1471 reference articles, in which 184 articles were selected and reviewed. Data were extracted from 27 studies (N = 3189) which met the inclusion criterion. The pooled proportion of patients with absence of pain at follow-up was 52.7% (95% confidence interval [95% CI], 50.85–54.56) and mild to moderate pain at follow-up was 33.43% (95% CI, 31.40–35.50). Quality of life improved in 88.21% (95% CI, 85.43–90.73) and complete ductal clearance was 70.69% (95% CI, 68.97–72.38) in the pooled patients. Conclusions: The ESWL is an effective and safe management option in patients with chronic calcific pancreatitis patients with main pancreatic duct stone size greater than 5 mm who did not get adequate pain relief with conservative management. Key Words: extracorporeal shock wave lithotripsy, chronic pancreatitis, meta-analysis, systematic review (Pancreas 2016;45: 651–658)
E
xtracorporeal shock wave lithotripsy (ESWL) was first described by Chaussy et al1 in 1980, who used it to disintegrate renal calculi. Since then, it has been in use for a wide array of clinical applications. Its use in chronic pancreatitis was first described in 1987 by Sauerbrunch et al.2 Chronic pancreatitis is a progressive inflammatory condition of pancreas associated with parenchymal tissue loss with fibrosis, recurrent episodes of abdominal pain, and exocrine and endocrine dysfunction.3 These patients also develop pancreatic ductal strictures and pancreatic parenchymal and ductal calcifications (calculi) causing retrograde ductal hypertension.4 Alcoholic pancreatitis is the most common etiology for chronic calcific pancreatitis (CCP); however, idiopathic and hereditary etiologies From the *Division of General Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL; †Division of Gastroenterology and Hepatology, University of Missouri-Columbia, Columbia, MO; ‡Interventional Endoscopy Services, Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA; §Division of Pulmonary Medicine, Department of Medicine, Saint Francis Medical Center, Peoria, IL; and ||Division of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL. Received for publication May 7, 2015; accepted July 20, 2015. Reprints: Harsha Moole, MD, Department of Internal Medicine, University of Illinois College of Medicine Peoria, 530 NE Glen Oak Ave, Peoria, IL 61637 (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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contribute to a significant number of cases.5,6 On long-term follow-up, it was observed that close to 90% of alcoholic CCP patients have pancreatic duct (PD) stones.7 Exact pathology of PD stone formation is unclear.8 Abdominal pain in CCP has multifactorial etiology: impacted stones and strictures causing elevated ductal pressure seem to be the primary contributors, although tissue necrosis, perineural inflammation, pseudocysts, and fibrosis of pancreatic parenchyma can cause pain.9–12 Because of these reasons, the treatment modalities focused on improving the PD drainage by removing the stones/dilating the strictures to attain clinical improvement. Historically, surgical approaches used to treat CCP were associated with increased mortality (up to 5%) due to the invasive nature of the procedures, also, these procedures were associated with increased pain recurrence at follow-up (in up to 50% of the patients).13 Endoscopic approaches, including sphincterotomy, basket stone removal, stricture dilatation, PD stent placement, mechanical lithotripsy, and intraductal lithotripsy, have been tried and tested. Success of these procedures by far depended on the size of the stone, location of the stone, stone consistency, operator skills, and availability of equipment. Endoscopic approach has limited treatment efficacy when PD stones greater than 10 mm diameter, impacted stones, PD strictures present.14–17 Since the last 25 years, ESWL has been used sporadically, to treat CCP. It is used to fragment the pancreatic calculi, that is followed by either spontaneous passage of the PD calculi or repeat endoscopic procedure to achieve ductal clearance. Good outcomes (ductal clearance, pain control, and quality of life) have been noted from the past experiences.5,18 The number of patients requiring surgery after the ESWL treatment drastically went down comparatively. Together with endoscopic procedures, ESWL could be a better noninvasive alternative for managing CCP.15,19,20 There have been multiple recent retrospective and prospective small to medium-sized studies done to evaluate the efficacy of ESWL in CCP. Currently, ESWL, although well known to improve pain and quality of life in CCP, is not widely used due to the scarce data available. This is a meta-analysis of all the studies that look at the performance of ESWL in CCP. Studies from 1966 till April 2015 were included. This study aims to pool the results of all the studies and look at the efficacy of ESWL in CCP, specifically its role in providing pain relief, ductal clearance, and improvement in quality of life.
METHODS Study Selection Criteria Inclusion Criteria Studies using ESWL in the management of CCP were selected. Patients should have had main PD (MPD) stones greater than 5 mm size (diagnosed either by fluoroscopy, ultrasound, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography [ERCP], magnetic resonance cholangiopancreatography). www.pancreasjournal.com
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Patients should have failed conservative management for pain control. In addition, with the abovementioned criteria, Tanden et al6,18 included only those patients whose MPD stones were not amenable to ERCP extraction.
Exclusion Criteria Tanden et al6,18 excluded patients with isolated stones in the pancreas tail; multiple stones in pancreatic head, body and tail; multiple strictures in pancreatic head, body and tail; pancreatic head mass; pancreatic pseudocyst; pregnant; and pancreatic ascites.
Data Collection and Extraction Articles were searched in Medline, PubMed, Ovid journals, EMABSE, Cumulative Index for Nursing & Allied Health Literature, ACP journal club, DARE, International Pharmaceutical Abstracts, old Medline, Medline nonindexed citations, OVID Healthstar, and Cochrane Central Register of Controlled Trials. The search was performed for the years 1966 to April 2015. Abstracts were manually searched in the major gastroenterology journals for the past 3 years. Study authors for the abstracts included in this analysis were contacted when the required data for the outcome measures could not be determined from the publications. The search terms used were ESWL, chronic pancreatitis, CCP. Two authors (H.M. and S.P.) independently searched and extracted the data into an abstraction form. Any differences were resolved by mutual agreement. The agreement between reviewers for the collected data was quantified using the Cohen κ.21
Measurement of Variables In majority of the studies included in this meta-analysis, pain assessment was done using visual analogue scale of 1 to 10, 0 being no pain and 10 being the worst pain. Score greater than 7 correlates to severe pain, score of 4 to 6 correlates to moderate pain, score of 1 to 3 correlated to mild pain, and score of 0 is no pain. We could not quantify the decrease in narcotic usage due to the nature of data available from individual studies. Only a qualitative assessment could be done based on the decreased narcotic usage reported by patients. Quality of life was assessed using a scale of 1 to 10, 10 being the best quality of life as reported by the patient and 1 being the worst quality of life. Although it is a subjective assessment, it had to be used due to several limitations that include illiterate patients, social circumstances of patients, and so on. Pain assessment and quality of life assessment was done during follow-up either by direct interview or phone call. Ductal clearance was assessed based on the findings on one of the imaging studies (fluoroscopy/ultrasonography/ ERCP/magnetic resonance cholangiopancreatography/endoscopic ultrasound). Ductal clearance was said to be complete if greater than 90% of the MPD stones were cleared; partial if 50% to 90% of the MPD stones were cleared; and unsuccessful if less than 50% of the MPD stones were cleared. Exocrine function was assessed in individual studies using various markers (N-benzoyl-L-tyrosyl-paminobenzoic acid test, [14C]triolein breath test, fecal chymotrypsin concentration, fecal elastase concentration, and so on), steatorrhea as reported by patients and weight gain. In this analysis, we assessed exocrine function with weight changes because it was more commonly evaluated in individual studies. Endocrine function was assessed by the quantity of diabetic medication as reported by the patients before and after ESWL therapy. Some studies also reported the total number of diabetics before and after ESWL therapy. HbA1c levels, 75-hour glucose tolerance tests, were measured all across the board; however, values before and after ESWL therapy were not mentioned. So, this could not be
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translated into meaningful results. The median time of follow-up in the studies included in this meta-analysis was 2 years. However, the follow-up time in the studies ranged from 2 months to longer than 5 years. Subgroup analysis could not be performed based on follow-up period due to extremely variable follow-up periods in each study.
Quality of Studies Clinical trials designed with a control and treatment arms can be assessed for quality of the study. A number of criteria have been used to assess this quality of a study (eg, randomization, selection bias of the arms in the study, concealment of allocation, and blinding of outcome).22,23 There is no consensus on how to assess studies designed without a control arm. Hence, these criteria do not apply to studies without a control arm.23
Statistical Methods This meta-analysis was performed by calculating pooled proportions. First the individual study proportion of pain control, ductal clearance, quality of life, and so on, was transformed into a quantity using Freeman-Tukey variant of the arcsine square root transformed proportion. The pooled proportion is calculated as the back-transform of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed effects model and DerSimonian-Laird weights for the random effects model.24,25 Forrest plots were drawn to show the point estimates in each study in relation to the summary pooled estimate. The width of the point estimates in the Forrest plots indicates the assigned weight to that study. The heterogeneity among studies was tested using Cochran Q test based on inverse variance weights.26 If P value is greater than 0.10, it rejects the null hypothesis that the studies are heterogeneous. The effect of publication and selection bias on the summary estimates was tested by both Harbord-Egger bias indicator27 and Begg-Mazumdar bias indicator.28 Also, funnel plots were constructed to evaluate potential publication bias.29,30 Microsoft Excel 2013 software was used to perform statistics for this meta-analysis.
RESULTS Initial search identified 1471 reference articles, in which 184 articles were selected and reviewed. Data was extracted from 27 studies6,13–15,18–20,31–50 (N = 3189) of ESWL in the management of CCP, which met the inclusion criterion. All the studies are published as full text articles. Figure 1 shows the flow diagram of search results. All the pooled estimates given are estimates calculated by the fixed effect model. Fixed effect model was preferred to random effects model for better accuracy based on the nature of individual study characteristics and heterogeneity. None of the studies included in this analysis were randomized controlled trials. So there were no control groups for comparison. Almost every study included in this meta-analysis had a mix of patients who underwent only ESWL and ESWL + endoscopic procedures. Subgroup analysis for patients with only ESWL or ESWL + endoscopic procedures was not done in the individual studies. So we do not have sufficient data to perform subgroup analysis for patients that underwent only ESWL. The total number of patients included in this meta-analysis is 3189, with a predominant male population (N = 2201). In 25 of the studies, the most common etiology of chronic pancreatitis was alcohol, except 2 studies from India where idiopathic pancreatitis was the most common etiology. Table 1 shows the baseline characteristics of the studies. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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(95% CI, 31.40–35.50), and severe pain at follow up was 10.45% (95% CI, 8.45–12.64). Figure 2 shows the individual study proportions and the pooled estimate for patients with absence of pain at follow-up. The value of P for test of heterogeneity was greater than 0.10. Publication bias calculated using HarbordEgger bias indicator gave a value of 0.86 (95% CI, −1.88 to 3.6; P = 0.56), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.12 (P = 0.42), signifying no publication bias. The funnel plots in Figure 3 shows no publication bias for ESWL in CCP studies included in this analysis. The agreement between reviewers for the collected data gave a Cohen's κ value of 1.0. Patients that did not get any pain relief with ESWL therapy were further referred for surgical ductal decompression, surgical resection, or celiac plexus nerve blocks.
Quality of Life Quality of life was improved in 88.21% (95% CI, 85.43– 90.73) and no change in 9.68% (95% CI, 7.38–12.24) of the pooled percentage of patients. Bias calculated using Harbord-Egger bias indicator gave a value of −5.31 (95% CI, −25.82 to 15.19, P = 0.46), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.66 (P = 0.08), signifying no publication bias. The agreement between reviewers for the collected data gave a Cohen's κ value of 1.0.
FIGURE 1. Flow diagram: search results.
Pain at Follow-Up The pooled proportion of patients with absence of pain at follow-up was 52.7% (95% confidence interval [95% CI], 50.85–54.56), mild to moderate pain at follow-up was 33.43%
Ductal Clearance The pooled proportion of patients with complete ductal clearance at follow-up was 70.69% (95% CI, 68.97 to 72.38), and
TABLE 1. Basic Characteristics of the Included Studies No.
Study
Country
Type of Study
Year
No. Patients
Male
Female
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Tandan et al18 Seven et al47 Milovic et al40 Merrill et al39 Tandan et al6 Lawrence et al19 Parsi et al42 Conigliaro et al32 Choi et al31 Tadenuma et al48 Inui et al35 Kozarek et al37 Karasawa et al15 Brand et al13 Adamek et al14 Costamagna et al33 Matthews et al38 Ohara et al41 Johanns et al36 Schreiber et al46 Wolf et al20 Van der hul et al50 Schneider et al45 Delhaye et al34 Sauerbruch et al44 Den toom et al49 Sauerbruch et al43
India USA UK USA India USA USA Italy Korea Japan Japan USA Japan Germany Germany Italy USA Japan Germany Austria USA Netherlands Germany Belgium Germany Netherlands Germany
Retrospective Retrospective Prospective Retrospective Prospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective
2013 2012 2011 2011 2010 2010 2010 2006 2005 2005 2004 2002 2002 2000 1999 1997 1997 1996 1996 1996 1995 1994 1994 1992 1992 1991 1989
636 120 32 30 1006 25 10 82 58 70 555 40 24 48 80 35 19 32 35 10 12 17 50 123 24 8 8
414 52 24 20 663 17 3 40 48 43 465 21 19 35 62 31 6 28 17 8 8 10 39 100 20 3 5
222 68 8 10 343 8 7 42 10 27 90 19 5 13 18 4 13 4 18 2 4 7 11 23 4 5 3
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FIGURE 2. Individual study proportions and the pooled estimate for patients with absence of pain at follow-up (fixed effects).
partial ductal clearance was 22.38% (95% CI, 20.51–24.30). Recurrence of calculi was noted in 18.84% (95% CI, 15.83–20.40) of the pooled proportion. In Figure 4, the individual study proportions and the pooled estimate for patient with complete ductal
clearance at follow-up are shown. The value of P for test of heterogeneity was greater than 0.10. Publication bias calculated using Harbord-Egger bias indicator gave a value of −2.58 (95% CI = −3.78 to −1.37, p = 0.0006), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.18 (P = 0.22), signifying no publication bias. The funnel plot in Figure 5 represents publication bias for complete ductal clearance. The agreement between reviewers for the collected data gave a Cohen's κ value of 1.0.
Miscellaneous Outcomes
FIGURE 3. Funnel plot showing no publication bias (for absence of pain at follow-up).
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Narcotic use was decreased in 79.7% (95% CI, 77.40–81.96) of the pooled proportion of patients. Publication bias calculated using Harbord-Egger bias indicator gave a value of −8.33 (92.5% CI, −19.33 to 2.66; P = 0.12), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.33 (P = 0.33), signifying low power. Patient's weight was constant or increased in 81.45% (95% CI, 78.64–84.11) of the pooled proportion, and weight decrease was noted in only 7.90% (95% CI, 6.06–9.95). Number of patients requiring decreased quantity of antidiabetic medications after ESWL management was 5.15% (95% CI, 3.88–6.58). The number of patients with diabetes before and after ESWL management © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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FIGURE 4. Individual study proportions and the pooled estimate for patients with complete ductal clearance (fixed effects).
was 31.27% (95% CI, 29.04–33.53) and 37.90% (95% CI, 33.56– 42.34), respectively.
Complications The ESWL-associated pancreatitis was noted only in 4.2% (95% CI, 3.42–5.18) with a Harbord bias of 1.14 (92.5% CI, 0.38–1.91) (P = 0), and Kendall's τ b value of 0.27 (P = 0.16) among the pooled proportion of patients. After the management with ESWL, 4.4% (95% CI, 3.62–5.35) of the pooled proportion required surgery for various reasons, mainly from inadequate pain control with ESWL. Pancreatic fluid collection, gastric submucosal hematoma, and sepsis from biliary/pancreatic origin were some other complications that were extremely sporadic and rare, thus could not be analyzed further.
DISCUSSION Chronic pancreatitis is characterized by progressive inflammation, fibrosis, and ultimately loss of parenchymal tissue with permanent structural damage.15,18,39,48,49 The most common cause of chronic pancreatitis in industrialized countries is alcohol, © 2015 Wolters Kluwer Health, Inc. All rights reserved.
although other etiologies include idiopathic and hereditary.5,6 Several studies found approximately 90% of patients with alcoholic chronic calcifying pancreatitis develop pancreatic lithiasis.43,46,49 Consequently, there is associated endocrine and exocrine dysfunction with continuous or recurrent severe abdominal pain mostly likely caused by calculi obstruction of the MPD leading to an increase in intraductal pressure.6,15,34,35,43,44 As more calculi form, the inflammatory process and symptoms of chronic pancreatitis, such as pain, may worsen.20 Decompression of PD by endoscopic stone extraction has been the treatment of choice.18,33,48,50 Surgery has been used, but is unfavorable because of high morbidity and mortality rates.48,50 Endoscopic stone extraction, endoscopic retrograde cholangiopancreatogram (ERCP), and sphincterotomy have also been successful in the past. However, they are restricted by variables, such as size and location of the stone (>5 mm).15,44,49,50 Other limiting factors include strictures, difficulty accessing the sphincter of Oddi and previous gastric surgeries.15,44,49 Fragmentation of PD calculi using ESWL allows for natural passage of calculi and facilitates in endoscopic removal of stones.40 Furthermore, reduction of pain and improvement of exocrine www.pancreasjournal.com
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FIGURE 5. Funnel plot showing no publication bias (for complete ductal clearance).
and endocrine function has been observed after the use of ESWL.18,20 Prior meta-analysis done by Guda et al5 in 2005 showed a mean effect size for pain as 0.62 and mean effect size for duct clearance as 0.74. In the current study, we could further stratify pain relief into complete pain relief at follow-up (52.7%), mild to moderate pain at follow-up (33.43%), and persistence of severe pain at follow-up (10.45%). Effect of ESWL on quality of life improvement was assessed in recent studies.13,18,40,47 All these studies showed an improved quality of life (defined as subjective appreciation of feeling better per patient) with the use of ESWL. This could be from the pain relief, decreased requirement of narcotic pain medications, possibly improved endocrine and exocrine function, and so on. Outcomes regarding quality of life were never pooled together till date. This study showed an improved quality of life in 88.21% of pooled patients with no change in quality of life in only 9.68%. Ductal clearance was defined by surveillance for PD calculi clearance on a repeat ERCP versus abdominal ultrasound or ERCP15,36,46 versus plain abdominal films or ERCP34,41,50 versus only plain abdominal X-ray.49 Compared to the prior meta-analysis, we were able to stratify ductal clearance into complete ductal clearance (70.69%) and partial ductal clearance (22.38%). Recurrent stones were present in only 18.84% of the pooled patients. It is likely that these recurrent stones might be contributing to the severe nonresolving pain at follow-up in few patients. The improved outcomes as mentioned above could be attributed to appropriate use of ESWL in the studies done over last few years.6,18,31,32,35,47,48 Majority of the patients had multiple stones in the PD, with the stone size ranging from 5 mm to 20 mm. Most of the patients had a PD calculi size greater than 10 mm. Number of ESWL sessions each patient had to undergo ranged from 1 to 4. This again depended on clinical response and ductal clearance on follow-up imaging. Follow-up time frame for the patients in all the studies ranged from 0.16 to longer than 5 years, although most of the studies followed up on the patients around the 2-year mark. To improve/augment the PD drainage after ESWL, patients in most of the studies had to undergo additional endoscopic PD drainage procedures that included sphincterotomy and/or PD stent placement.6,13,18,33,36,40,46,47 Improvement of exocrine and endocrine functions of pancreas has been evaluated in prior studies. Improved endocrine function with the use of ESWL in CCP has been assessed by the amount of antidiabetic medications used18,35 or by comparing the number of patients with diabetes before and after the
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ESWL management.13,14,33,41,45 Improvement of exocrine function has been assessed by the monitoring the weight of the patient13,14,18,33,41,45 or steatorrhea before and after ESWL.13,14 The current meta-analysis was not able to derive any significant conclusions regarding the impact of ESWL management on exocrine and endocrine function. The values mentioned in the results section describing the endocrine and exocrine function had low power due to the nonhomogenous data from the studies. There is a need to perform structured randomized studies to evaluate these topics. There is ambiguity regarding the use of ESWL alone versus ESWL combined with endoscopic procedures to manage the patients with CCP. There was only 1 randomized control trial performed by Dumonceau et al51 comparing the percentage of patients with pain relapse in both the groups. It concluded that combining ESWL with systematic endoscopy added to the cost of patient care without improving the pancreatic pain outcome. Further randomized control trials are required in this regard. Pancreatic ESWL has been relatively a safe procedure. Although it had no contribution to mortality,5 it was associated with post ESWL pancreatitis in 4.2% of the pooled patients. This however cannot be attributed to ESWL alone as most of the patients also had endoscopic drainage procedures including manipulation of sphincter of Oddi and PD. The number of patients requiring surgery for CCP has reduced as a result of ESWL therapy.5 Based on the aforementioned results and prior studies, ESWL is a safe and effective way of managing CCP. It should specifically be indicated when the PD calculi size is greater than 5 mm, in the presence of PD strictures, impacted PD calculi, failure of endoscopic methods of PD stone extraction. There are few limitations to this study. Studies were done in different countries with different patient demographic and varying etiologies for chronic pancreatitis. There is a wide range of follow-up periods among various studies. The ESWL equipment varied among the studies. Pain score and quality of life score were not universal. Pain improvement, quality of life improvement, and narcotic usage reduction could not be quantified due to the nature of data available from individual studies. All the studies included in this metaanalysis were observational studies. There was no control arm. Studies with statistically significant positive results tend to be published and cited. Additionally, smaller studies may show larger treatment effects compared to larger studies. This publication and selection bias may affect the summary estimates. The bias can be estimated using Egger bias indicators and the construction of funnel plots, whose shape can be affected by bias. In the present meta-analysis and systematic review, bias calculations both Egger 27 and Begg-Mazumdar 28 bias indicators showed no statistically significant bias. Furthermore, analysis using funnel plots showed no significant publication bias among the studies included in the present analysis.
CONCLUSIONS In summary, ESWL is a safe and efficacious treatment modality in managing CCP patients with MPD stones >5 mm who did not get adequate pain relief with conservative management. This study demonstrated significant pain relief, improved quality of life, and pancreatic ductal clearance with the use of pancreatic ESWL. It can be used alone or in addition to endoscopic therapies to improve the drainage from PD. It has a relatively safe side effect profile. The ESWL might have improved exocrine function of the pancreas manifested by either constant or increased body weight in majority of the patients. Endocrine function was not significantly different before and after the ESWL management in patients with CCP. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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REFERENCES 1. Chaussy C, Brendel W, Schmiedt E. Extracorporeally induced destruction of kidney stones by shock waves. Lancet. 1980;2:1265–1268. 2. Sauerbruch T, Holl J, Sackmann M, et al. Disintegration of a pancreatic duct stone with extracorporeal shock waves in a patient with chronic pancreatitis. Endoscopy. 1987;19:207–208. 3. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med. 1995;332:1482–1490.
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23. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012. 24. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 25. Stuart A, Ord JK. Kendall's Advanced Theory of Statistics (6th edition). London: Edward Arnold; 1994.
4. Bornman PC, Marks IN, Girdwood AW, et al. Pathogenesis of pain in chronic pancreatitis: ongoing enigma. World J Surg. 2003;27: 1175–1182.
26. Deeks JJ. Systematic reviews of evaluations of diagnostic and screening tests. In Egger M, Smith GD, Altman DG (eds). Systematic Reviews in Health Care. Meta-analysis in context. London: BMJ. Books; 2001.
5. Guda NM, Partington S, Freeman ML. Extracorporeal shock wave lithotripsy in the management of chronic calcific pancreatitis: a meta-analysis. JOP. 2005;6:6–12.
27. Harbord RM, Egger M, Sterne JAC. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2005;25:3443–3457.
6. Tandan M, Reddy DN, Santosh D, et al. Extracorporeal shock wave lithotripsy and endotherapy for pancreatic calculi—a large single center experience. Indian J Gastroenterol. 2010;29:143–148.
28. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–1101.
7. Ammann RW, Muench R, Otto R, et al. Evolution and regression of pancreatic calcification in chronic pancreatitis. A prospective long-term study of 107 patients. Gastroenterology. 1988;95:1018–1028. 8. Devière J, Delhaye M, Cremer M. Pancreatic duct stones management. Gastrointest Endosc Clin N Am. 1998;8:163–179. 9. Bockman DE, Buchler M, Malfertheiner P, et al. Analysis of nerves in chronic pancreatitis. Gastroenterology. 1988;94:1459–1469. 10. Bradley EL 3rd. Pancreatic duct pressure in chronic pancreatitis. Am J Surg. 1982;144:313–316. 11. Klöppel G. Pathology of chronic pancreatitis and pancreatic pain. Acta Chir Scand. 1990;156:261–265. 12. Okazaki K, Yamamoto Y, Ito K. Endoscopic measurement of papillary sphincter zone and pancreatic main ductal pressure in patients with chronic pancreatitis. Gastroenterology. 1986;91:409–418. 13. 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 calcific pancreatitis. Am J Gastroenterol. 2000;95:3428–3438. 14. 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;45:402–405. 15. Karasawa Y, Kawa S, Aoki Y, et al. Extracorporeal shock wave lithotripsy of pancreatic duct stones and patient factors related to stone disintegration. J Gastroenterol. 2002;37:369–375. 16. Kozarek RA, Ball TJ, Patterson DJ. Endoscopic approach to pancreatic duct calculi and obstructive pancreatitis. Am J Gastroenterol. 1992;87: 600–603. 17. Sherman S, Lehman GA, Hawes RH, et al. Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc. 1991;37:511–517. 18. Tandan M, Reddy DN, Talukdar R, et al. Long-term clinical outcomes of extracorporeal shockwave lithotripsy in painful chronic calcific pancreatitis. Gastrointest Endosc. 2013;78:726–733.
29. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol. 2001;54:1046–1055. 30. Sterne JA, Egger M, Smith G. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ. 2001;323:101–105. 31. Choi KS, Kim MH, Lee YS, et al. Disintegration of pancreatic duct stones with extracorporeal shockwave lithotripsy. Korean J Gastroenterol. 2005;46:396–403. 32. Conigliaro R, Camellini L, Zuliani CG, et al. Clearance of irretrievable bile duct and pancreatic duct stones by extracorporeal shockwave lithotripsy, using a transportable device: effectiveness and medium-term results. J Clin Gastroenterol. 2006;40:213–219. 33. Costamagna G, Gabbrielli A, Mutignani M, et al. Extracorporeal shock wave lithotripsy of pancreatic stones in chronic pancreatitis: immediate and medium-term results. Gastrointest Endosc. 1997;46:231–236. 34. Delhaye M, Vandermeeren A, Baize M, et al. Extracorporeal shock-wave lithotripsy of pancreatic calculi. Gastroenterology. 1992;102: 610–620. 35. Inui K, Tazuma S, Yamaguchi T, et al. Treatment of pancreatic stones with extracorporeal shock wave lithotripsy: results of a multicenter survey. Pancreas. 2005;30:26–30. 36. Johanns W, Jakobeit C, Greiner L, et al. Ultrasound-guided extracorporeal shock wave lithotripsy of pancreatic ductal stones: six years' experience. Can J Gastroenterol. 1996;10:471–475. 37. 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;56:496–500. 38. Matthews K, Correa RJ, Gibbons RP, et al. Extracorporeal shock wave lithotripsy for obstructing pancreatic duct calculi. J Urol. 1997;158: 522–525. 39. Merrill JT, Mullady DK, Early DS, et al. Timing of endoscopy after extracorporeal shock wave lithotripsy for chronic pancreatitis. Pancreas. 2011;40:1087–1090.
19. Lawrence C, Siddiqi MF, Hamilton JN, et al. Chronic calcific pancreatitis: combination ERCP and extracorporeal shock wave lithotripsy for pancreatic duct stones. South Med J. 2010;103:505–508.
40. Milovic V, Wehrmann T, Dietrich CF, et al. Extracorporeal shock wave lithotripsy with a transportable mini-lithotripter and subsequent endoscopic treatment improves clinical outcome in obstructive calcific chronic pancreatitis. Gastrointest Endosc. 2011;74:1294–1299.
20. Wolf JS Jr, Nakada SY, Aliperti G, et al. Washington University experience with extracorporeal shock-wave lithotripsy of pancreatic duct calculi. Urology. 1995;46:638–642.
41. 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;91:1388–1394.
21. Brennan P, Silman A. Statistical methods for assessing observer variability in clinical measures. BMJ. 1992;304:1491–1494.
42. Parsi MA, Stevens T, Lopez R, et al. Extracorporeal shock wave lithotripsy for prevention of recurrent pancreatitis caused by obstructive pancreatic stones. Pancreas. 2010;39:153–155.
22. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.
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43. Sauerbruch T, Holl J, Sackmann M, et al. Extracorporeal shock wave lithotripsy of pancreatic stones. Gut. 1989;30:1406–1411.
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44. Sauerbruch T, Holl J, Sackmann M, et al. Extracorporeal lithotripsy of pancreatic stones in patients with chronic pancreatitis and pain: a prospective follow up study. Gut. 1992;33:969–972.
48. Tadenuma H, Ishihara T, Yamaguchi T, et al. Long-term results of extracorporeal shockwave lithotripsy and endoscopic therapy for pancreatic stones. Clin Gastroenterol Hepatol. 2005;3:1128–1135.
45. Schneider HT, May A, Benninger J, et al. Piezoelectric shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol. 1994;89: 2042–2048.
49. Toom Den, Nijs HG, van Blankenstein M, et al. Extracorporeal shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol. 1991;86: 1033–1036.
46. Schreiber F, Gurakugi GC, Pristautz H, et al. Sonographically-guided extracorporeal shockwave lithotripsy for pancreatic stones in patients with chronic pancreatitis. J Gastroenterol Hepatol. 1996;11: 247–251.
50. Van der Hul R, Plaisier P, Jeekel J, et al. Extracorporeal shock-wave lithotripsy of pancreatic duct stones: immediate and long-term results. Endoscopy. 1994;26:573–578.
47. Seven G, Schreiner MA, Ross AS, et al. Long-term outcomes associated with pancreatic extracorporeal shock wave lithotripsy for chronic calcific pancreatitis. Gastrointest Endosc. 2012;75:997–1004.
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51. Dumonceau JM, Costamagna G, Tringali A, et al. Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic treatment: a randomised controlled trial. Gut. 2007;56: 545–552.
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Success of Extracorporeal Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management A Meta-Analysis and Systematic Review Harsha Moole, MD,* Amy Jaeger, MD,* Matthew L. Bechtold, MD,† David Forcione, MD,‡ Deepak Taneja, MD,§ and Srinivas R. Puli, MD|| Objectives: This is a meta-analysis and systematic review to assess the overall utility and safety of Extracorporeal shock wave lithotripsy (ESWL) in chronic calcific pancreatitis. Primary outcomes are pain relief, narcotic usage, ductal clearance, quality of life, and pancreatic exocrine and endocrine function. Methods: Studies involving ESWL in chronic calcific pancreatitis with main pancreatic duct stones greater than 5 mm and patients that failed conservative pain management were included. Fixed and random effects models were used to calculate the pooled proportions. Results: Initial search identified 1471 reference articles, in which 184 articles were selected and reviewed. Data were extracted from 27 studies (N = 3189) which met the inclusion criterion. The pooled proportion of patients with absence of pain at follow-up was 52.7% (95% confidence interval [95% CI], 50.85–54.56) and mild to moderate pain at follow-up was 33.43% (95% CI, 31.40–35.50). Quality of life improved in 88.21% (95% CI, 85.43–90.73) and complete ductal clearance was 70.69% (95% CI, 68.97–72.38) in the pooled patients. Conclusions: The ESWL is an effective and safe management option in patients with chronic calcific pancreatitis patients with main pancreatic duct stone size greater than 5 mm who did not get adequate pain relief with conservative management. Key Words: extracorporeal shock wave lithotripsy, chronic pancreatitis, meta-analysis, systematic review (Pancreas 2016;45: 651–658)
E
xtracorporeal shock wave lithotripsy (ESWL) was first described by Chaussy et al1 in 1980, who used it to disintegrate renal calculi. Since then, it has been in use for a wide array of clinical applications. Its use in chronic pancreatitis was first described in 1987 by Sauerbrunch et al.2 Chronic pancreatitis is a progressive inflammatory condition of pancreas associated with parenchymal tissue loss with fibrosis, recurrent episodes of abdominal pain, and exocrine and endocrine dysfunction.3 These patients also develop pancreatic ductal strictures and pancreatic parenchymal and ductal calcifications (calculi) causing retrograde ductal hypertension.4 Alcoholic pancreatitis is the most common etiology for chronic calcific pancreatitis (CCP); however, idiopathic and hereditary etiologies From the *Division of General Internal Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL; †Division of Gastroenterology and Hepatology, University of Missouri-Columbia, Columbia, MO; ‡Interventional Endoscopy Services, Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA; §Division of Pulmonary Medicine, Department of Medicine, Saint Francis Medical Center, Peoria, IL; and ||Division of Gastroenterology and Hepatology, University of Illinois College of Medicine at Peoria, Peoria, IL. Received for publication May 7, 2015; accepted July 20, 2015. Reprints: Harsha Moole, MD, Department of Internal Medicine, University of Illinois College of Medicine Peoria, 530 NE Glen Oak Ave, Peoria, IL 61637 (e‐mail: [email protected]). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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contribute to a significant number of cases.5,6 On long-term follow-up, it was observed that close to 90% of alcoholic CCP patients have pancreatic duct (PD) stones.7 Exact pathology of PD stone formation is unclear.8 Abdominal pain in CCP has multifactorial etiology: impacted stones and strictures causing elevated ductal pressure seem to be the primary contributors, although tissue necrosis, perineural inflammation, pseudocysts, and fibrosis of pancreatic parenchyma can cause pain.9–12 Because of these reasons, the treatment modalities focused on improving the PD drainage by removing the stones/dilating the strictures to attain clinical improvement. Historically, surgical approaches used to treat CCP were associated with increased mortality (up to 5%) due to the invasive nature of the procedures, also, these procedures were associated with increased pain recurrence at follow-up (in up to 50% of the patients).13 Endoscopic approaches, including sphincterotomy, basket stone removal, stricture dilatation, PD stent placement, mechanical lithotripsy, and intraductal lithotripsy, have been tried and tested. Success of these procedures by far depended on the size of the stone, location of the stone, stone consistency, operator skills, and availability of equipment. Endoscopic approach has limited treatment efficacy when PD stones greater than 10 mm diameter, impacted stones, PD strictures present.14–17 Since the last 25 years, ESWL has been used sporadically, to treat CCP. It is used to fragment the pancreatic calculi, that is followed by either spontaneous passage of the PD calculi or repeat endoscopic procedure to achieve ductal clearance. Good outcomes (ductal clearance, pain control, and quality of life) have been noted from the past experiences.5,18 The number of patients requiring surgery after the ESWL treatment drastically went down comparatively. Together with endoscopic procedures, ESWL could be a better noninvasive alternative for managing CCP.15,19,20 There have been multiple recent retrospective and prospective small to medium-sized studies done to evaluate the efficacy of ESWL in CCP. Currently, ESWL, although well known to improve pain and quality of life in CCP, is not widely used due to the scarce data available. This is a meta-analysis of all the studies that look at the performance of ESWL in CCP. Studies from 1966 till April 2015 were included. This study aims to pool the results of all the studies and look at the efficacy of ESWL in CCP, specifically its role in providing pain relief, ductal clearance, and improvement in quality of life.
METHODS Study Selection Criteria Inclusion Criteria Studies using ESWL in the management of CCP were selected. Patients should have had main PD (MPD) stones greater than 5 mm size (diagnosed either by fluoroscopy, ultrasound, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography [ERCP], magnetic resonance cholangiopancreatography). www.pancreasjournal.com
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Patients should have failed conservative management for pain control. In addition, with the abovementioned criteria, Tanden et al6,18 included only those patients whose MPD stones were not amenable to ERCP extraction.
Exclusion Criteria Tanden et al6,18 excluded patients with isolated stones in the pancreas tail; multiple stones in pancreatic head, body and tail; multiple strictures in pancreatic head, body and tail; pancreatic head mass; pancreatic pseudocyst; pregnant; and pancreatic ascites.
Data Collection and Extraction Articles were searched in Medline, PubMed, Ovid journals, EMABSE, Cumulative Index for Nursing & Allied Health Literature, ACP journal club, DARE, International Pharmaceutical Abstracts, old Medline, Medline nonindexed citations, OVID Healthstar, and Cochrane Central Register of Controlled Trials. The search was performed for the years 1966 to April 2015. Abstracts were manually searched in the major gastroenterology journals for the past 3 years. Study authors for the abstracts included in this analysis were contacted when the required data for the outcome measures could not be determined from the publications. The search terms used were ESWL, chronic pancreatitis, CCP. Two authors (H.M. and S.P.) independently searched and extracted the data into an abstraction form. Any differences were resolved by mutual agreement. The agreement between reviewers for the collected data was quantified using the Cohen κ.21
Measurement of Variables In majority of the studies included in this meta-analysis, pain assessment was done using visual analogue scale of 1 to 10, 0 being no pain and 10 being the worst pain. Score greater than 7 correlates to severe pain, score of 4 to 6 correlates to moderate pain, score of 1 to 3 correlated to mild pain, and score of 0 is no pain. We could not quantify the decrease in narcotic usage due to the nature of data available from individual studies. Only a qualitative assessment could be done based on the decreased narcotic usage reported by patients. Quality of life was assessed using a scale of 1 to 10, 10 being the best quality of life as reported by the patient and 1 being the worst quality of life. Although it is a subjective assessment, it had to be used due to several limitations that include illiterate patients, social circumstances of patients, and so on. Pain assessment and quality of life assessment was done during follow-up either by direct interview or phone call. Ductal clearance was assessed based on the findings on one of the imaging studies (fluoroscopy/ultrasonography/ ERCP/magnetic resonance cholangiopancreatography/endoscopic ultrasound). Ductal clearance was said to be complete if greater than 90% of the MPD stones were cleared; partial if 50% to 90% of the MPD stones were cleared; and unsuccessful if less than 50% of the MPD stones were cleared. Exocrine function was assessed in individual studies using various markers (N-benzoyl-L-tyrosyl-paminobenzoic acid test, [14C]triolein breath test, fecal chymotrypsin concentration, fecal elastase concentration, and so on), steatorrhea as reported by patients and weight gain. In this analysis, we assessed exocrine function with weight changes because it was more commonly evaluated in individual studies. Endocrine function was assessed by the quantity of diabetic medication as reported by the patients before and after ESWL therapy. Some studies also reported the total number of diabetics before and after ESWL therapy. HbA1c levels, 75-hour glucose tolerance tests, were measured all across the board; however, values before and after ESWL therapy were not mentioned. So, this could not be
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translated into meaningful results. The median time of follow-up in the studies included in this meta-analysis was 2 years. However, the follow-up time in the studies ranged from 2 months to longer than 5 years. Subgroup analysis could not be performed based on follow-up period due to extremely variable follow-up periods in each study.
Quality of Studies Clinical trials designed with a control and treatment arms can be assessed for quality of the study. A number of criteria have been used to assess this quality of a study (eg, randomization, selection bias of the arms in the study, concealment of allocation, and blinding of outcome).22,23 There is no consensus on how to assess studies designed without a control arm. Hence, these criteria do not apply to studies without a control arm.23
Statistical Methods This meta-analysis was performed by calculating pooled proportions. First the individual study proportion of pain control, ductal clearance, quality of life, and so on, was transformed into a quantity using Freeman-Tukey variant of the arcsine square root transformed proportion. The pooled proportion is calculated as the back-transform of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed effects model and DerSimonian-Laird weights for the random effects model.24,25 Forrest plots were drawn to show the point estimates in each study in relation to the summary pooled estimate. The width of the point estimates in the Forrest plots indicates the assigned weight to that study. The heterogeneity among studies was tested using Cochran Q test based on inverse variance weights.26 If P value is greater than 0.10, it rejects the null hypothesis that the studies are heterogeneous. The effect of publication and selection bias on the summary estimates was tested by both Harbord-Egger bias indicator27 and Begg-Mazumdar bias indicator.28 Also, funnel plots were constructed to evaluate potential publication bias.29,30 Microsoft Excel 2013 software was used to perform statistics for this meta-analysis.
RESULTS Initial search identified 1471 reference articles, in which 184 articles were selected and reviewed. Data was extracted from 27 studies6,13–15,18–20,31–50 (N = 3189) of ESWL in the management of CCP, which met the inclusion criterion. All the studies are published as full text articles. Figure 1 shows the flow diagram of search results. All the pooled estimates given are estimates calculated by the fixed effect model. Fixed effect model was preferred to random effects model for better accuracy based on the nature of individual study characteristics and heterogeneity. None of the studies included in this analysis were randomized controlled trials. So there were no control groups for comparison. Almost every study included in this meta-analysis had a mix of patients who underwent only ESWL and ESWL + endoscopic procedures. Subgroup analysis for patients with only ESWL or ESWL + endoscopic procedures was not done in the individual studies. So we do not have sufficient data to perform subgroup analysis for patients that underwent only ESWL. The total number of patients included in this meta-analysis is 3189, with a predominant male population (N = 2201). In 25 of the studies, the most common etiology of chronic pancreatitis was alcohol, except 2 studies from India where idiopathic pancreatitis was the most common etiology. Table 1 shows the baseline characteristics of the studies. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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(95% CI, 31.40–35.50), and severe pain at follow up was 10.45% (95% CI, 8.45–12.64). Figure 2 shows the individual study proportions and the pooled estimate for patients with absence of pain at follow-up. The value of P for test of heterogeneity was greater than 0.10. Publication bias calculated using HarbordEgger bias indicator gave a value of 0.86 (95% CI, −1.88 to 3.6; P = 0.56), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.12 (P = 0.42), signifying no publication bias. The funnel plots in Figure 3 shows no publication bias for ESWL in CCP studies included in this analysis. The agreement between reviewers for the collected data gave a Cohen's κ value of 1.0. Patients that did not get any pain relief with ESWL therapy were further referred for surgical ductal decompression, surgical resection, or celiac plexus nerve blocks.
Quality of Life Quality of life was improved in 88.21% (95% CI, 85.43– 90.73) and no change in 9.68% (95% CI, 7.38–12.24) of the pooled percentage of patients. Bias calculated using Harbord-Egger bias indicator gave a value of −5.31 (95% CI, −25.82 to 15.19, P = 0.46), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.66 (P = 0.08), signifying no publication bias. The agreement between reviewers for the collected data gave a Cohen's κ value of 1.0.
FIGURE 1. Flow diagram: search results.
Pain at Follow-Up The pooled proportion of patients with absence of pain at follow-up was 52.7% (95% confidence interval [95% CI], 50.85–54.56), mild to moderate pain at follow-up was 33.43%
Ductal Clearance The pooled proportion of patients with complete ductal clearance at follow-up was 70.69% (95% CI, 68.97 to 72.38), and
TABLE 1. Basic Characteristics of the Included Studies No.
Study
Country
Type of Study
Year
No. Patients
Male
Female
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Tandan et al18 Seven et al47 Milovic et al40 Merrill et al39 Tandan et al6 Lawrence et al19 Parsi et al42 Conigliaro et al32 Choi et al31 Tadenuma et al48 Inui et al35 Kozarek et al37 Karasawa et al15 Brand et al13 Adamek et al14 Costamagna et al33 Matthews et al38 Ohara et al41 Johanns et al36 Schreiber et al46 Wolf et al20 Van der hul et al50 Schneider et al45 Delhaye et al34 Sauerbruch et al44 Den toom et al49 Sauerbruch et al43
India USA UK USA India USA USA Italy Korea Japan Japan USA Japan Germany Germany Italy USA Japan Germany Austria USA Netherlands Germany Belgium Germany Netherlands Germany
Retrospective Retrospective Prospective Retrospective Prospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective
2013 2012 2011 2011 2010 2010 2010 2006 2005 2005 2004 2002 2002 2000 1999 1997 1997 1996 1996 1996 1995 1994 1994 1992 1992 1991 1989
636 120 32 30 1006 25 10 82 58 70 555 40 24 48 80 35 19 32 35 10 12 17 50 123 24 8 8
414 52 24 20 663 17 3 40 48 43 465 21 19 35 62 31 6 28 17 8 8 10 39 100 20 3 5
222 68 8 10 343 8 7 42 10 27 90 19 5 13 18 4 13 4 18 2 4 7 11 23 4 5 3
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FIGURE 2. Individual study proportions and the pooled estimate for patients with absence of pain at follow-up (fixed effects).
partial ductal clearance was 22.38% (95% CI, 20.51–24.30). Recurrence of calculi was noted in 18.84% (95% CI, 15.83–20.40) of the pooled proportion. In Figure 4, the individual study proportions and the pooled estimate for patient with complete ductal
clearance at follow-up are shown. The value of P for test of heterogeneity was greater than 0.10. Publication bias calculated using Harbord-Egger bias indicator gave a value of −2.58 (95% CI = −3.78 to −1.37, p = 0.0006), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.18 (P = 0.22), signifying no publication bias. The funnel plot in Figure 5 represents publication bias for complete ductal clearance. The agreement between reviewers for the collected data gave a Cohen's κ value of 1.0.
Miscellaneous Outcomes
FIGURE 3. Funnel plot showing no publication bias (for absence of pain at follow-up).
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Narcotic use was decreased in 79.7% (95% CI, 77.40–81.96) of the pooled proportion of patients. Publication bias calculated using Harbord-Egger bias indicator gave a value of −8.33 (92.5% CI, −19.33 to 2.66; P = 0.12), demonstrating that there was no publication bias. The Begg-Mazumdar indicator gave a Kendall's τ b value of −0.33 (P = 0.33), signifying low power. Patient's weight was constant or increased in 81.45% (95% CI, 78.64–84.11) of the pooled proportion, and weight decrease was noted in only 7.90% (95% CI, 6.06–9.95). Number of patients requiring decreased quantity of antidiabetic medications after ESWL management was 5.15% (95% CI, 3.88–6.58). The number of patients with diabetes before and after ESWL management © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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FIGURE 4. Individual study proportions and the pooled estimate for patients with complete ductal clearance (fixed effects).
was 31.27% (95% CI, 29.04–33.53) and 37.90% (95% CI, 33.56– 42.34), respectively.
Complications The ESWL-associated pancreatitis was noted only in 4.2% (95% CI, 3.42–5.18) with a Harbord bias of 1.14 (92.5% CI, 0.38–1.91) (P = 0), and Kendall's τ b value of 0.27 (P = 0.16) among the pooled proportion of patients. After the management with ESWL, 4.4% (95% CI, 3.62–5.35) of the pooled proportion required surgery for various reasons, mainly from inadequate pain control with ESWL. Pancreatic fluid collection, gastric submucosal hematoma, and sepsis from biliary/pancreatic origin were some other complications that were extremely sporadic and rare, thus could not be analyzed further.
DISCUSSION Chronic pancreatitis is characterized by progressive inflammation, fibrosis, and ultimately loss of parenchymal tissue with permanent structural damage.15,18,39,48,49 The most common cause of chronic pancreatitis in industrialized countries is alcohol, © 2015 Wolters Kluwer Health, Inc. All rights reserved.
although other etiologies include idiopathic and hereditary.5,6 Several studies found approximately 90% of patients with alcoholic chronic calcifying pancreatitis develop pancreatic lithiasis.43,46,49 Consequently, there is associated endocrine and exocrine dysfunction with continuous or recurrent severe abdominal pain mostly likely caused by calculi obstruction of the MPD leading to an increase in intraductal pressure.6,15,34,35,43,44 As more calculi form, the inflammatory process and symptoms of chronic pancreatitis, such as pain, may worsen.20 Decompression of PD by endoscopic stone extraction has been the treatment of choice.18,33,48,50 Surgery has been used, but is unfavorable because of high morbidity and mortality rates.48,50 Endoscopic stone extraction, endoscopic retrograde cholangiopancreatogram (ERCP), and sphincterotomy have also been successful in the past. However, they are restricted by variables, such as size and location of the stone (>5 mm).15,44,49,50 Other limiting factors include strictures, difficulty accessing the sphincter of Oddi and previous gastric surgeries.15,44,49 Fragmentation of PD calculi using ESWL allows for natural passage of calculi and facilitates in endoscopic removal of stones.40 Furthermore, reduction of pain and improvement of exocrine www.pancreasjournal.com
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FIGURE 5. Funnel plot showing no publication bias (for complete ductal clearance).
and endocrine function has been observed after the use of ESWL.18,20 Prior meta-analysis done by Guda et al5 in 2005 showed a mean effect size for pain as 0.62 and mean effect size for duct clearance as 0.74. In the current study, we could further stratify pain relief into complete pain relief at follow-up (52.7%), mild to moderate pain at follow-up (33.43%), and persistence of severe pain at follow-up (10.45%). Effect of ESWL on quality of life improvement was assessed in recent studies.13,18,40,47 All these studies showed an improved quality of life (defined as subjective appreciation of feeling better per patient) with the use of ESWL. This could be from the pain relief, decreased requirement of narcotic pain medications, possibly improved endocrine and exocrine function, and so on. Outcomes regarding quality of life were never pooled together till date. This study showed an improved quality of life in 88.21% of pooled patients with no change in quality of life in only 9.68%. Ductal clearance was defined by surveillance for PD calculi clearance on a repeat ERCP versus abdominal ultrasound or ERCP15,36,46 versus plain abdominal films or ERCP34,41,50 versus only plain abdominal X-ray.49 Compared to the prior meta-analysis, we were able to stratify ductal clearance into complete ductal clearance (70.69%) and partial ductal clearance (22.38%). Recurrent stones were present in only 18.84% of the pooled patients. It is likely that these recurrent stones might be contributing to the severe nonresolving pain at follow-up in few patients. The improved outcomes as mentioned above could be attributed to appropriate use of ESWL in the studies done over last few years.6,18,31,32,35,47,48 Majority of the patients had multiple stones in the PD, with the stone size ranging from 5 mm to 20 mm. Most of the patients had a PD calculi size greater than 10 mm. Number of ESWL sessions each patient had to undergo ranged from 1 to 4. This again depended on clinical response and ductal clearance on follow-up imaging. Follow-up time frame for the patients in all the studies ranged from 0.16 to longer than 5 years, although most of the studies followed up on the patients around the 2-year mark. To improve/augment the PD drainage after ESWL, patients in most of the studies had to undergo additional endoscopic PD drainage procedures that included sphincterotomy and/or PD stent placement.6,13,18,33,36,40,46,47 Improvement of exocrine and endocrine functions of pancreas has been evaluated in prior studies. Improved endocrine function with the use of ESWL in CCP has been assessed by the amount of antidiabetic medications used18,35 or by comparing the number of patients with diabetes before and after the
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ESWL management.13,14,33,41,45 Improvement of exocrine function has been assessed by the monitoring the weight of the patient13,14,18,33,41,45 or steatorrhea before and after ESWL.13,14 The current meta-analysis was not able to derive any significant conclusions regarding the impact of ESWL management on exocrine and endocrine function. The values mentioned in the results section describing the endocrine and exocrine function had low power due to the nonhomogenous data from the studies. There is a need to perform structured randomized studies to evaluate these topics. There is ambiguity regarding the use of ESWL alone versus ESWL combined with endoscopic procedures to manage the patients with CCP. There was only 1 randomized control trial performed by Dumonceau et al51 comparing the percentage of patients with pain relapse in both the groups. It concluded that combining ESWL with systematic endoscopy added to the cost of patient care without improving the pancreatic pain outcome. Further randomized control trials are required in this regard. Pancreatic ESWL has been relatively a safe procedure. Although it had no contribution to mortality,5 it was associated with post ESWL pancreatitis in 4.2% of the pooled patients. This however cannot be attributed to ESWL alone as most of the patients also had endoscopic drainage procedures including manipulation of sphincter of Oddi and PD. The number of patients requiring surgery for CCP has reduced as a result of ESWL therapy.5 Based on the aforementioned results and prior studies, ESWL is a safe and effective way of managing CCP. It should specifically be indicated when the PD calculi size is greater than 5 mm, in the presence of PD strictures, impacted PD calculi, failure of endoscopic methods of PD stone extraction. There are few limitations to this study. Studies were done in different countries with different patient demographic and varying etiologies for chronic pancreatitis. There is a wide range of follow-up periods among various studies. The ESWL equipment varied among the studies. Pain score and quality of life score were not universal. Pain improvement, quality of life improvement, and narcotic usage reduction could not be quantified due to the nature of data available from individual studies. All the studies included in this metaanalysis were observational studies. There was no control arm. Studies with statistically significant positive results tend to be published and cited. Additionally, smaller studies may show larger treatment effects compared to larger studies. This publication and selection bias may affect the summary estimates. The bias can be estimated using Egger bias indicators and the construction of funnel plots, whose shape can be affected by bias. In the present meta-analysis and systematic review, bias calculations both Egger 27 and Begg-Mazumdar 28 bias indicators showed no statistically significant bias. Furthermore, analysis using funnel plots showed no significant publication bias among the studies included in the present analysis.
CONCLUSIONS In summary, ESWL is a safe and efficacious treatment modality in managing CCP patients with MPD stones >5 mm who did not get adequate pain relief with conservative management. This study demonstrated significant pain relief, improved quality of life, and pancreatic ductal clearance with the use of pancreatic ESWL. It can be used alone or in addition to endoscopic therapies to improve the drainage from PD. It has a relatively safe side effect profile. The ESWL might have improved exocrine function of the pancreas manifested by either constant or increased body weight in majority of the patients. Endocrine function was not significantly different before and after the ESWL management in patients with CCP. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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REFERENCES 1. Chaussy C, Brendel W, Schmiedt E. Extracorporeally induced destruction of kidney stones by shock waves. Lancet. 1980;2:1265–1268. 2. Sauerbruch T, Holl J, Sackmann M, et al. Disintegration of a pancreatic duct stone with extracorporeal shock waves in a patient with chronic pancreatitis. Endoscopy. 1987;19:207–208. 3. Steer ML, Waxman I, Freedman S. Chronic pancreatitis. N Engl J Med. 1995;332:1482–1490.
ESWL in Chronic Calcific Pancreatitis
23. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–2012. 24. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. 25. Stuart A, Ord JK. Kendall's Advanced Theory of Statistics (6th edition). London: Edward Arnold; 1994.
4. Bornman PC, Marks IN, Girdwood AW, et al. Pathogenesis of pain in chronic pancreatitis: ongoing enigma. World J Surg. 2003;27: 1175–1182.
26. Deeks JJ. Systematic reviews of evaluations of diagnostic and screening tests. In Egger M, Smith GD, Altman DG (eds). Systematic Reviews in Health Care. Meta-analysis in context. London: BMJ. Books; 2001.
5. Guda NM, Partington S, Freeman ML. Extracorporeal shock wave lithotripsy in the management of chronic calcific pancreatitis: a meta-analysis. JOP. 2005;6:6–12.
27. Harbord RM, Egger M, Sterne JAC. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2005;25:3443–3457.
6. Tandan M, Reddy DN, Santosh D, et al. Extracorporeal shock wave lithotripsy and endotherapy for pancreatic calculi—a large single center experience. Indian J Gastroenterol. 2010;29:143–148.
28. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–1101.
7. Ammann RW, Muench R, Otto R, et al. Evolution and regression of pancreatic calcification in chronic pancreatitis. A prospective long-term study of 107 patients. Gastroenterology. 1988;95:1018–1028. 8. Devière J, Delhaye M, Cremer M. Pancreatic duct stones management. Gastrointest Endosc Clin N Am. 1998;8:163–179. 9. Bockman DE, Buchler M, Malfertheiner P, et al. Analysis of nerves in chronic pancreatitis. Gastroenterology. 1988;94:1459–1469. 10. Bradley EL 3rd. Pancreatic duct pressure in chronic pancreatitis. Am J Surg. 1982;144:313–316. 11. Klöppel G. Pathology of chronic pancreatitis and pancreatic pain. Acta Chir Scand. 1990;156:261–265. 12. Okazaki K, Yamamoto Y, Ito K. Endoscopic measurement of papillary sphincter zone and pancreatic main ductal pressure in patients with chronic pancreatitis. Gastroenterology. 1986;91:409–418. 13. 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 calcific pancreatitis. Am J Gastroenterol. 2000;95:3428–3438. 14. 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;45:402–405. 15. Karasawa Y, Kawa S, Aoki Y, et al. Extracorporeal shock wave lithotripsy of pancreatic duct stones and patient factors related to stone disintegration. J Gastroenterol. 2002;37:369–375. 16. Kozarek RA, Ball TJ, Patterson DJ. Endoscopic approach to pancreatic duct calculi and obstructive pancreatitis. Am J Gastroenterol. 1992;87: 600–603. 17. Sherman S, Lehman GA, Hawes RH, et al. Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc. 1991;37:511–517. 18. Tandan M, Reddy DN, Talukdar R, et al. Long-term clinical outcomes of extracorporeal shockwave lithotripsy in painful chronic calcific pancreatitis. Gastrointest Endosc. 2013;78:726–733.
29. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol. 2001;54:1046–1055. 30. Sterne JA, Egger M, Smith G. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ. 2001;323:101–105. 31. Choi KS, Kim MH, Lee YS, et al. Disintegration of pancreatic duct stones with extracorporeal shockwave lithotripsy. Korean J Gastroenterol. 2005;46:396–403. 32. Conigliaro R, Camellini L, Zuliani CG, et al. Clearance of irretrievable bile duct and pancreatic duct stones by extracorporeal shockwave lithotripsy, using a transportable device: effectiveness and medium-term results. J Clin Gastroenterol. 2006;40:213–219. 33. Costamagna G, Gabbrielli A, Mutignani M, et al. Extracorporeal shock wave lithotripsy of pancreatic stones in chronic pancreatitis: immediate and medium-term results. Gastrointest Endosc. 1997;46:231–236. 34. Delhaye M, Vandermeeren A, Baize M, et al. Extracorporeal shock-wave lithotripsy of pancreatic calculi. Gastroenterology. 1992;102: 610–620. 35. Inui K, Tazuma S, Yamaguchi T, et al. Treatment of pancreatic stones with extracorporeal shock wave lithotripsy: results of a multicenter survey. Pancreas. 2005;30:26–30. 36. Johanns W, Jakobeit C, Greiner L, et al. Ultrasound-guided extracorporeal shock wave lithotripsy of pancreatic ductal stones: six years' experience. Can J Gastroenterol. 1996;10:471–475. 37. 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;56:496–500. 38. Matthews K, Correa RJ, Gibbons RP, et al. Extracorporeal shock wave lithotripsy for obstructing pancreatic duct calculi. J Urol. 1997;158: 522–525. 39. Merrill JT, Mullady DK, Early DS, et al. Timing of endoscopy after extracorporeal shock wave lithotripsy for chronic pancreatitis. Pancreas. 2011;40:1087–1090.
19. Lawrence C, Siddiqi MF, Hamilton JN, et al. Chronic calcific pancreatitis: combination ERCP and extracorporeal shock wave lithotripsy for pancreatic duct stones. South Med J. 2010;103:505–508.
40. Milovic V, Wehrmann T, Dietrich CF, et al. Extracorporeal shock wave lithotripsy with a transportable mini-lithotripter and subsequent endoscopic treatment improves clinical outcome in obstructive calcific chronic pancreatitis. Gastrointest Endosc. 2011;74:1294–1299.
20. Wolf JS Jr, Nakada SY, Aliperti G, et al. Washington University experience with extracorporeal shock-wave lithotripsy of pancreatic duct calculi. Urology. 1995;46:638–642.
41. 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;91:1388–1394.
21. Brennan P, Silman A. Statistical methods for assessing observer variability in clinical measures. BMJ. 1992;304:1491–1494.
42. Parsi MA, Stevens T, Lopez R, et al. Extracorporeal shock wave lithotripsy for prevention of recurrent pancreatitis caused by obstructive pancreatic stones. Pancreas. 2010;39:153–155.
22. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
43. Sauerbruch T, Holl J, Sackmann M, et al. Extracorporeal shock wave lithotripsy of pancreatic stones. Gut. 1989;30:1406–1411.
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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Moole et al
44. Sauerbruch T, Holl J, Sackmann M, et al. Extracorporeal lithotripsy of pancreatic stones in patients with chronic pancreatitis and pain: a prospective follow up study. Gut. 1992;33:969–972.
48. Tadenuma H, Ishihara T, Yamaguchi T, et al. Long-term results of extracorporeal shockwave lithotripsy and endoscopic therapy for pancreatic stones. Clin Gastroenterol Hepatol. 2005;3:1128–1135.
45. Schneider HT, May A, Benninger J, et al. Piezoelectric shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol. 1994;89: 2042–2048.
49. Toom Den, Nijs HG, van Blankenstein M, et al. Extracorporeal shock wave lithotripsy of pancreatic duct stones. Am J Gastroenterol. 1991;86: 1033–1036.
46. Schreiber F, Gurakugi GC, Pristautz H, et al. Sonographically-guided extracorporeal shockwave lithotripsy for pancreatic stones in patients with chronic pancreatitis. J Gastroenterol Hepatol. 1996;11: 247–251.
50. Van der Hul R, Plaisier P, Jeekel J, et al. Extracorporeal shock-wave lithotripsy of pancreatic duct stones: immediate and long-term results. Endoscopy. 1994;26:573–578.
47. Seven G, Schreiner MA, Ross AS, et al. Long-term outcomes associated with pancreatic extracorporeal shock wave lithotripsy for chronic calcific pancreatitis. Gastrointest Endosc. 2012;75:997–1004.
658
www.pancreasjournal.com
51. Dumonceau JM, Costamagna G, Tringali A, et al. Treatment for painful calcified chronic pancreatitis: extracorporeal shock wave lithotripsy versus endoscopic treatment: a randomised controlled trial. Gut. 2007;56: 545–552.
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Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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