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Clinical Trials of the Surgical Management of Urolithiasis: Current Status and Future Needs

2008; Elsevier BV; Volume: 16; Issue: 1 Linguagem: Inglês

10.1053/j.ackd.2008.10.011

1548-5609

Francis X. Keeley, Dean G. Assimos,

Intestinal and Peritoneal Adhesions

We reviewed the literature on the surgical treatment of urolithiasis. All prospective, randomized trials on the surgical treatment of stone disease were reviewed. Percutaneous nephrolithotomy (PNL) is superior to shockwave lithotripsy (SWL) or open surgery in the treatment of staghorn calculi. For ureteral stones, ureteroscopy appears to result in a higher stone-free rate and lower need for retreatment compared with SWL but has a higher complication rate and increased hospital stay. For lower pole renal calculi, PNL results in a higher stone-free rate and lower need for retreatment compared with SWL but has a higher complication rate and increased hospital stay. Most areas of surgical stone treatment have been addressed by a randomized controlled trial; however, most trials were of poor quality. Trials tend to focus only on radiologic outcomes. No study to date has been able to show a measurable quality of life benefit to patients, possibly because no condition-specific quality of life instruments have been developed. In addition, economic impact, both direct and indirect, has been rarely characterized. The surgical treatment of kidney stones is poorly researched. Future trials should be performed with adequate funding and patient-focused outcomes. We reviewed the literature on the surgical treatment of urolithiasis. All prospective, randomized trials on the surgical treatment of stone disease were reviewed. Percutaneous nephrolithotomy (PNL) is superior to shockwave lithotripsy (SWL) or open surgery in the treatment of staghorn calculi. For ureteral stones, ureteroscopy appears to result in a higher stone-free rate and lower need for retreatment compared with SWL but has a higher complication rate and increased hospital stay. For lower pole renal calculi, PNL results in a higher stone-free rate and lower need for retreatment compared with SWL but has a higher complication rate and increased hospital stay. Most areas of surgical stone treatment have been addressed by a randomized controlled trial; however, most trials were of poor quality. Trials tend to focus only on radiologic outcomes. No study to date has been able to show a measurable quality of life benefit to patients, possibly because no condition-specific quality of life instruments have been developed. In addition, economic impact, both direct and indirect, has been rarely characterized. The surgical treatment of kidney stones is poorly researched. Future trials should be performed with adequate funding and patient-focused outcomes. The surgical management of patients with kidney stones has undergone tremendous changes since the advent of shockwave lithotripsy (SWL), ureteroscopy (URS), and percutaneous nephrolithotomy (PNL). The rapid rate of change has brought tremendous benefits to patients in the form of less invasive options for kidney stone treatment, and, yet, it has also hindered the rigorous assessment of these techniques and technologies. Although surgical trials are difficult, especially in a rapidly advancing field, management of common urinary stone conditions remains controversial in large part because of the lack of good evidence. Thirty years on from the inception of minimally invasive stone treatment, most surgical treatment options have reached a degree of maturity that would allow for valid comparative trials, yet the literature on the subject is sparse. This review sets out the evidence for the selection of treatment for the following conditions: (1) staghorn calculi; (2) renal calculi, including lower pole stones and SWL; and (3) ureteral calculi, including the choice of a ureteral stent. Proposals regarding the need for future trials will be made on the basis of the evidence available. Meretyk et al1Meretyk S. Gofrit O.N. Gafni O. et al.Complete staghorn calculi: random prospective comparison between extracorporeal shock wave lithotripsy monotherapy and combined with percutaneous nephrostolithotomy.J Urol. 1997; 157: 780-786Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar reported on a single-institution randomized controlled trial (RCT) for the treatment of staghorn calculi. A total of 50 patients were enrolled; 27 underwent SWL and 23 underwent PNL. They found that SWL monotherapy was inferior to the combination of PNL with or without adjunctive SWL. SWL monotherapy had a lower stone-free rate (22% v 74%) and a higher incidence of sepsis (37% v 9%). Al-Kohlany et al2Al-Kohlany K.M. Shokeir A.A. Mosbah A. et al.Treatment of complete staghorn stones: A prospective randomized comparison of open surgery versus percutaneous nephrolithotomy.J Urol. 2005; 173: 469-473Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar subsequently performed an RCT comparing open stone surgery with PNL in 79 patients with 88 staghorn calculi. They found that the stone-free rate was not significantly different (82% v 74%), but PNL was associated with significantly less intraoperative and postoperative complications, shorter hospitalization and procedural time, and earlier return to work. Thus, PNL with or without SWL can be considered the standard of care for the majority of patients harboring staghorn calculi. Do asymptomatic patients with renal calculi benefit from intervention in the form of SWL? Keeley et al3Keeley Jr., F.X. Tilling K. Elves A. et al.Preliminary results of a randomized controlled trial of prophylactic shock wave lithotripsy for small asymptomatic renal calyceal stones.BJU Int. 2001; 87: 1-8Crossref PubMed Scopus (90) Google Scholar reported a trial of 228 patients randomized to SWL versus observation for renal calculi 5 to 15 mm in size and showed no benefit to treatment in terms of quality of life or stone-free rate. However, there was a benefit in terms of a reduced need for surgical intervention in the treated group after a mean follow-up of 2.2 years. Thus, SWL for the treatment of asymptomatic stones has some clinical benefits, but it has not been shown to result in improved stone-free rates. Further trials would be helpful to determine which, if any, asymptomatic patients benefit from SWL. Renal calculi located in the lower pole calyces have been shown to have worse stone-free outcomes after SWL in retrospective case reports and, therefore, have been the subject of several studies by the Lower Pole Study Group. Albala et al4Albala D.M. Assimos D.G. Clayman R.V. et al.Lower pole I: A prospective randomized trial of extracorporeal shock wave lithotripsy and percutaneous nephrostolithotomy for lower pole nephrolithiasis-initial results.J Urol. 2001; 166: 2072-2080Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar compared PNL with SWL for the treatment of patients with lower pole stones in 160 patients at 18 centers. A total of 128 patients completed the study, which clearly showed a higher stone-free rate with PNL. The benefit of PNL was magnified for stones greater than 10 mm in size. There were no differences in quality of life parameters using the Standard Form-36 questionnaire at 1 and 3 months. Although the complication rate was higher for PNL than SWL, the degree of these complications varied. Thus, the clinical significance of this difference was not fully explored in this study. Pearle et al5Pearle M.S. Lingeman J.E. Leveillee R. et al.Prospective randomized trial comparing shock wave lithotripsy and ureteroscopy for lower pole caliceal calculi 1 cm or less.J Urol. 2005; 173: 2005-2009Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar reported a study comparing SWL with URS in patients with lower pole renal calculi <10 mm in size. The sample size calculation required 100 patients for 80% power to detect a 25% difference, but only 52 completed the study, despite recruitment from 19 hospitals over 3.5 years. The study was terminated early because of poor recruitment and lack of a difference between the groups. The stone-free rate for lower pole stones was slightly higher for URS (50%) than SWL (35%) as determined by a computed tomography scan at 3 months, but this did not reach statistical significance. Patients who underwent URS had more complications, required more pain relief, and took longer to return to normal activities. More patients reported that they would choose SWL again than patients who would choose URS. Poor recruitment unfortunately limits the validity of some of the outcomes; nevertheless, the results challenge the assertion made in many single-center case series that URS is a treatment associated with a high success rate and low morbidity. Computed tomography scans were used to determine stone-free status, which might explain the disparity regarding stone-free status with prior studies in which less sensitive imaging was used. In addition, better ureteroscopic equipment is now available that could improve stone-free rates with this approach. The Lower Pole Study Group has also compared URS versus PNL in patients with lower pole stones between 11 and 25 mm in size. The sample size was determined to be 80, but only 36 completed the protocol. Leveillie et al6Leveillie R.J. Lingeman J.E. Pearle M.S. et al.A prospective randomized trial of flexible ureteropyelolithotripsy (URS) and percutaneous nephrostolithotomy (PNL) for medium to large lower pole nephrolithiasis [AUA abstract X].J Urol. 2006; 175 (suppl): 253AAbstract Full Text Full Text PDF Google Scholar found that PNL resulted in a higher stone-free rate (71% v 37%) and a reduced need for secondary procedures but had a higher postoperative complication rate. Patients reported similar quality of life outcomes. When asked if they would undergo the procedure again, 91% of PNL patients said they would compared with 69% of URS patients. Again, despite the poor recruitment in this study, the results are compelling in that they suggested that patients would prefer not to undergo URS, despite what many urologists might think. Taken as a whole, the Lower Pole Group studies clearly show the limitations of prospective randomized studies in the surgical management of stone disease because of poor recruitment. Possible reasons for this include the following: lack of buy-in from investigators and patients, attempts to perform the trial in an inappropriate setting (ie, tertiary care), and lack of funding. These trials were largely unfunded, relying on the enthusiasm of participating surgeons to complete the studies. Surgical trials require surgeons and patients to forego making a treatment decision, yet patients typically are referred to surgeons on the assumption that a definitive decision will be made. This difficulty is made worse in tertiary care centers where patients are more likely to have undergone unsuccessful treatment elsewhere and to have fixed views on what treatment they will be offered. Patients and urologists prefer SWL over other treatment options, as evidenced by the fact that it remains by far the most common form of treatment for kidney stones. Yet, concerns have been raised about its efficacy, especially with the advent of second- and third-generation machines believed by many to be less effective than the original lithotriptor, the Dornier HM3 (Dornier Medizintecknik GMBH, Munich, West Germany). The comparison of results with lithotriptors has been hindered by the simple fact that few centers have more than 1 machine. Graber et al7Graber S.F. Danuser H. Hochreiter W.W. et al.A prospective randomized trial comparing 2 lithotriptors for stone disintegration and induced renal trauma.J Urol. 2003; 169: 54-57Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar reported on an RCT that compared outcomes with the Dornier HM-3 and Siemens Litho Star lithotriptors (Siemens Medical Solutions Urology, New York, NY). The success, complication, and retreatment rates were superior with the Dornier HM-3. Unfortunately, the HM-3 has been out of production for over 20 years, rendering these results irrelevant for many urologists. More comparative studies like this would be extremely helpful because the literature is full of single-center reports stating that they have the best results. Animal and laboratory studies have suggested that a slow treatment rate in SWL may be beneficial in terms of fragmentation and protection of the kidney from damage. Semins et al8Semins M.J. Trock B.J. Matlaga B.R. The effect of shock wave rate on the outcome of shock wave lithotripsy: A meta-analysis.J Urol. 2008; 179: 194-197Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar recently published a meta-analysis of studies of SWL rate that found that a slow rate of 60 shocks per minute was superior to a faster rate of 120 shocks per minute. The study results were difficult to analyze, however, because different lithotriptors were used as well as different techniques to assess stone size and outcome. There are a number of other variables that affect outcomes, including the machine, intensity and size of the focal zone, decay of the generator, and localization accuracy. Finally, success can also be affected by parameters such as operator competence; stone composition, size, and location; anesthetic technique; and patient anatomic factors. An increasing body mass index in the population also may have a role in the apparent dropping success rate of SWL. Large cooperative trials are needed to determine the precise influence each of these factors should be given in treatment decisions. The use of stents significantly affects patients’ perceptions of stone procedures. A meta-analysis of 9 RCTS comparing stenting with nonstenting with URS showed that the latter group had fewer lower urinary tract symptoms and a somewhat greater chance of readmission, chiefly for renal colic. Stone-free and complication rates were similar to the stented cohort.9Nabi G. Cook J. N'Dow J. et al.Outcomes of stenting after uncomplicated ureteroscopy: Systematic review and meta-analysis.BMJ. 2007; 334: 572Crossref PubMed Scopus (143) Google Scholar Joshi et al10Joshi H.B. Stainthorpe A. MacDonagh R.P. et al.Indwelling ureteral stents: Evaluation of symptoms, quality of life and utility.J Urol. 2003; 169: 1065-1069Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar reported a survey of patients receiving stents, which found that 78% had bothersome lower urinary tract symptoms such as storage symptoms (eg, frequency, urgency, and nocturia), incontinence, and hematuria; more than 80% reported pain; 32% had sexual dysfunction; and 58% reported reduced work capacity.10Joshi H.B. Stainthorpe A. MacDonagh R.P. et al.Indwelling ureteral stents: Evaluation of symptoms, quality of life and utility.J Urol. 2003; 169: 1065-1069Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar Significantly, Joshi's Ureteric Stent Symptom Questionnaire is the only condition-specific questionnaire in the field of urolithiasis. RCTs of stent comfort found no difference between soft or firm stents.11Joshi H.B. Chitale S.V. Nagarajan M. et al.A prospective randomized single-blind comparison of ureteral stents composed of firm and soft polymer.J Urol. 2005; 174: 2303-2306Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Djaladat et al12Djaladat H. Tajik P. Payandemehr P. Alehashemi S. Ureteral catheterization in uncomplicated ureterolithotripsy: A randomized, controlled trial.Eur Urol. 2007; 52: 836-841Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar reported a randomized trial comparing the use of a ureteral catheter overnight to no drainage and found that the patients with a catheter had less pain, fewer episodes of colic, and fewer readmissions. Studies comparing use of a stent versus catheter versus no intervention are needed. Deliveliotis et al13Deliveliotis C. Chrisofos M. Gougousis E. et al.Is there a role for alpha1-blockers in treating double-J stent-related symptoms?.Urology. 2006; 67: 35-39Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar recently reported that the use of α-blockers reduces stent symptoms, suggesting that medical therapy may ultimately help solve a clinical problem that manufacturers and urologists have been trying to address with engineering alone. Nabi et al14Nabi G. Downey P. Keeley F. et al.Extra-corporeal shock wave lithotripsy (ESWL) versus ureteroscopic management for ureteric calculi.Cochrane Database Syst. 2007; Rev 1 (CD006029)Google Scholar recently conducted a Cochrane review involving a meta-analysis of trials of SWL versus URS for ureteral stones. They found that URS appears to result in a higher stone-free rate and lower need for retreatment but had a higher complication rate and increased hospital stays. The authors state that the studies had very heterogeneous results; hence, the analysis had very wide confidence intervals. Furthermore, the studies in the review involved outdated ureteroscopic techniques and a variety of lithotriptors, making the findings of little value to urologists using a combination of small-caliber, semirigid, and flexible ureteroscopes with a holmium laser. The authors concluded that we need better studies on the subject. The RCTs outlined in this article represent a great combined effort of many urologists and their patients to address fairly basic issues in the field of the surgical management of urinary stone disease. Nonetheless, very few of them accomplished their goal of determining which treatment is best in terms of patient quality of life, objective outcomes such as stone-free rates, and cost. A number of factors have made these trials difficult, including the fact that patients and their stones come in a variety of shapes and sizes, surgical techniques are operator dependent, and outcome measures have not been defined well. The American Urological Association and the European Association of Urology recently convened an expert panel to make guidelines for the management of ureteral stones based on the literature.15Preminger G.M. Tiselius H.G. Assimos D.G. et al.2007 guideline for the management of ureteral calculi.J Urol. 2007; 178: 2418-2434Abstract Full Text Full Text PDF PubMed Scopus (647) Google Scholar They reviewed 244 trials involving over 24,000 patients, only 732 of which were enrolled in RCTs. Not surprisingly, there was a significant degree of heterogeneity in the 244 trials as well as some degree of publication bias. They cautiously recommended that URS appears to have superior stone-free outcomes for distal ureteral stones as well as proximal ureteral stones larger than 10 mm. The most striking part of the guidelines was the fact that they went to great lengths to outline the issues that still need to be addressed in the field. They made the following recommendations: more RCTs of techniques such as SWL versus URS using contemporary techniques; better reporting of stone-free rates and consistent use of nomenclature; stratification of data by patient and stone factors; complete reporting of all treatments, including stents; and development of more accurate methods to predict outcome. Issues that remain unresolved include the following: (1) improving outcomes for SWL, (2) a comparison of SWL versus URS for ureteral stones, (3) a comparison of SWL versus URS versus PNL (and possibly observation) for renal stones, (4) adjuvant medical therapy such as alpha-blockers and calcium-channel blockers to enhance SWL and URS, (5) ways to improve stent tolerance, and (6) medical therapy to prevent postoperative stone activity. Standardized methods of randomization and reporting outcomes are needed to determine significant differences in treatment approaches. Importantly, condition-specific quality of life instruments need to be developed so that we can objectively ascertain the effects that our treatments have on our patients. Following on from the recommendations of the American Urological Association and the European Association of Urology Guidelines Panel, we believe that future studies should be performed in a way that assesses patient quality of life as well as cost and objective clinical outcomes. To date, the urologic community has been very good at developing innovative treatments. We now need to evaluate those treatments more rigorously.