1028 | 1Department of Urology, Koru Hospital, Ankara, Turkey 2Department of Urology, Uni- versity of Gazi, Ankara, Turkey Mustafa Kiraç,1 Mehmet Sinan Atkin,2 Hasan Biri,2 Nuri Deniz1 Ureteroscopy: The First-Line Treatment for Distally Located Ureteral Stones Smaller Than 10 mm Corresponding Author: Mustafa Kirac, MD. Umit mah. Yeni Çağın Si- tesi, A Blok No:38, Yenimahalle Ankara-Turkey. Tel: +90 533 357 2617 Fax: +90 312 287 9898 E mail: mkirac@gmail.com Received July 2012 Accepted November 2012 Purpose: To compare the efficacy of different treatment strategies for distal ureteral stones smaller than 10 mm. Material and Methods: A total 127 patient were included in the study. Based on the treatment modality, patients were divided into three groups. Patients in group 1 only received conven- tional treatment including daily hydration of 2500 mL, ciprofloxacin, diclofenac sodium and a spasmolytic agent; group 2 patients received conventional treatment (daily hydration of 2500 mL, ciprofloxacin, diclofenac sodium and a spasmolytic agent) and tamsulosin 0.4 mg orally daily for 4 weeks; and group 3 patients underwent ureteroscopy. Patients were further subdi- vided into 2 categories based on maximum stone diameter: category A (less than 5 mm) and category B (5.0-9.9 mm). Following treatment, all groups were compared in terms of stone-free rate and time to expulsion. Results: Following treatment, the stone-free rates for groups 1, 2 and 3 were 48.7%, 59.5% and 95.6%, respectively (P < .0001). The mean expulsion times for groups 1, 2 and 3 were 15.3 ± 5.33, 15.1 ± 5.5 and 1.95 ± 2.2 days, respectively (P < .001). Compared to the other treat- ments, the stone-free rate and mean expulsion time in the ureteroscopy group were significantly increased and decreased, respectively. Conclusion: There are several treatment options for distal ureteral stones. Based on our data, we conclude that ureterorenoscopy should be the standard of care for distal ureteral stones smaller than 10 mm. Key words: drug therapy; lithotripsy; treatment options; ureteroscopy; ureteral calculi. ENDOUROLOGY AND STONE DISEASE Endourology and Stone Disease 1029Vol. 10 | No. 4 | Autumn 2013 |U R O LO G Y J O U R N A L INTRODUCTION Ureteral stones account for roughly 20% of all uri-nary calculi, and 70% of these stones are located in the distal third of the ureter. Management of ureteral stones includes observation, medical expulsive treatment, extracorporeal shock wave lithotripsy (SWL), percutaneous antegrade ureteroscopy, retrograde ureteros- copy (especially for distal ureteral stones), and open/lapa- roscopic ureterolithotomy.(1) Although current therapeutic options for ureteral stones include both active intervention and conservative watch and wait approaches, the endoscop- ic treatment of ureteral stones has a high success rate and reliably results in immediate stone removal.(2,3) Further- more, developments in ureteroscopic instrumentation has increased operational success while decreasing severe com- plications.(4,5) Currently, ureteroscopy is often used as a first choice treatment option for distal ureteral stones and as an alternative method to SWL or medical treatment modalities. In the present study, we evaluated the efficacy, feasibility and success rate of endoscopy for the treatment of distal ureteral stones smaller than 10 mm. We compared this treat- ment modality to observation and tamsulosin therapy. MATERIAL AND METHODS The study was approved by the local ethic committee. This study was conducted randomized and prospectively. Patients A total 127 patients with distal ureteral stones that were less than 10 mm were included in the study from February 2009 to July 2011. All of the patients had been admitted to and were managed by the Gazi University and Koru hos- pitals’ department of urology due to distal ureteral stones. All patients were diagnosed with distal ureteral stones with smaller than 10 mm based on plain abdominal X-rays and urinary tract ultrasonography as well as with helical com- puted tomography when necessary. A case history was obtained from all patients; additionally, they underwent a physical examination and a series of measurements, includ- ing a complete blood cell count, blood electrolyte analysis, routine urinalysis, and serum urea and creatinine analyses. Patients who were pregnant or had severe hydronephrosis, a solitary kidney, a urinary tract infection, renal failure, stones greater than 10 mm, bilateral ureteral stones, multiple ure- teral stones or previous urinary tract surgery were excluded from the study. All the patients′ plain abdominal X-rays and urinary ultrasonography results were reviewed and con- firmed by two experienced radiologists, and the stone diam- eters were measured using X-rays, computed tomography and ultrasonography. All patients signed a written informed consent, and we discussed with them in detail the potential side effects and complications prior to treatment. Grouping Patients were divided into three groups based on treatment (see below). They were further subdivided into 2 categories based on maximum stone diameter: category A (less than 5 mm) and category B (5.0-9.9 mm). Group-1 (Observation)-Thirty-nine patients were included in this group. Treatment included daily hydration of 2500 mL and ciprofloxacin (500 mg orally, twice a day) for the first 7 days. During the 4-week treatment period, diclofenac sodium (50 mg orally, twice a day) and a spasmolytic agent (hyoscine butylbromide, 10 mg orally, three times a day) were given. Group-2 (Tamsulosin)-Forty-two patients were included in this group and were given tamsulosin 0.4 mg daily orally for 4 weeks. Additionally, these patients received conven- tional treatment with daily hydration of 2500 mL and cip- rofloxacin (500 mg orally, twice a day) for the first 7 days. Diclofenac sodium (50 mg orally, twice a day) and spasmo- lytic (hyoscine butylbromide, 10 mg orally, three times a day) were also given to the patients in this group. Group-3 (Ureteroscopy)-Forty-six patients were included in this group. Ureteroscopy was performed under general anesthesia using a 9.5 Fr (Karl Storz GmbH & Co KG, Tuttlingen, Germany) semi-rigid ureteroscope and a 0.035 mm safety guide wire. Patients were covered with antibiot- ics prior to instrumentation. All stones were located in the distal ureter and fragmented with a Swiss lithoclast (2.4 Fr long probe; 0.8 mm thick). Stone fragmentation was con- tinued until all fragments were < 2 mm in diameter. In the event that fragments were larger than 2 mm, extraction was performed. Fragments < 2 mm were left for spontaneous Ureteroscopy in Ureteral Stones | Kiraç et al 1030 | passage. Ureteral stenting was left to the discretion of the treating surgeon. However, in the event of proximal stone migration with ureteral extravasation, a stent was placed. Post-operative treatment of this patient population included daily hydration of 2500 mL, ciprofloxacin (500 mg orally, twice a day) and an analgesic agent for the first 7 days. Group 1 and 2 patients were followed weekly for 4 weeks, or until alternative treatment (ureteroscopy) was under- taken. Follow-up visits included plain abdominal X-rays, urinary tract ultrasonography, urinalysis, serum urea cre- atinine and computed tomography if needed. During each visit, stone-free condition, analgesic dose, side effects and complications were recorded. Stone-free condition was de- fined as the absence of stones on plain abdominal X-rays and computed tomography. Following ureteroscopy, group 3 patients were followed with routine biochemical analysis, blood counts and urinal- ysis. Preoperative aerobic urine cultures were routinely per- formed. In the event of a urinary tract infection, the patient was treated, and urine cultures were repeated to confirm sterility. The stone-free rate was determined by plain ab- dominal radiography and computed tomography on postop- erative days 1 and 7. If inserted, the double-J ureteral stent was removed during postoperative week 3. Statistical analysis All groups were compared in terms of stone-free rate and time to expulsion. All data were recorded with SPSS (sta- tistical program for social science) Statistical analyses were performed using Pearson chi-square test, t test and Fisher′s exact test using the statistical package for the social science (SPSS Inc, Chicago, Illinois, USA) version 11.0. The Efficiency Quotient Rate (EQ) was calculated using the following formula: EQ = percentage of stone-free pa- tients/100% + percentage of re-treatment patients rate + ancillary procedures rate.(6) P < .05 was considered as sta- tistically significant. RESULTS Of the 127 patients included the study, 71 were male and 56 were female. The mean patient age was 30.27 ± 6.7 (range, 19-44). Four patients in group 1 (2 included category A and 2 included category B) and five patients in group 2 (1 included category A and 4 included category B) withdrew from the study due to severe renal colic, infection or fever. These patients underwent immediate ureteroscopy. In the group 3, ureteroscopy was not successful in two category A patients. In one patient, the stone was inadvertently pushed up the ureter into the upper urinary system, and in the sec- ond patient, the stone was impacted in the ureteral wall. In postoperatively, re-ureterorenoscopy were applied to two patients (in category B) for residual fragment. Ancillary procedures was not need required any patient. Re-treatment rate was 4.34 and ancillary procedures rate 0.0 for group 3. There were no minor and major complications in group 1 and 2 during treatment. In the ureteroscopy group, there were no intraoperative and major postoperative complica- tions; however there were two postoperative minor com- plications. Of these patients, one (included category A) had appeared acute pyelonephritis in postoperative second days. The patient treated with antibiotic including cephalosporin. In the other patient (included category B), the ureteral stent was spontaneously fallen in postoperative five days. Ad- ditionally, no statistical difference was found for patients’ age, sex distribution or stone size between groups 1, 2 and 3 (Table 1). The stone-free rates for groups 1, 2 and 3 were 48.7%, 59.5% and 95.6%, respectively. The Efficiency Quotient rate for group 3 was 0.91. Across treatment groups, uret- Endourology and Stone Disease Table 1. Patients’ characteristics in the three treatment groups and in the two stone-diameter categories. Characteristics Patients Treatment groups (n = 127) P 1 2 3 Patient, n 127 39 42 46 Age, years 30.27 ± 6.7 29.3 ± 7.1 30.7 ± 6.4 30.6 ± 6.4 .38 Sex, n (%) Male 71(55.9) 23 (59.0) 25 (59.5) 23 (50.0) .60 Female 56 (44.1) 16 (41.0) 17 (40.5) 23 (50.0) .61 Stone location, n (%) Left 61(48.1) 21 (53.8) 18 (42.9) 22 (47.8) .78 Right 66 (51.9) 18 (46.2) 24 (57.1) 24 (52.2) .80 Stone diameter, mm 6.79 ± 2.8 6.98 ± 2.1 6.46 ± 2.1 6.92 ± 2.0 .85 1031Vol. 10 | No. 4 | Autumn 2013 |U R O LO G Y J O U R N A L eroscopy was significantly more effective in terms of the stone-free rate (P < .0001) (Table 2). In both the patients with stones smaller than 5 mm and in those with stones larger than 5 mm, surgical treatment was also significantly more effective in terms of the stone-free rate (P = .011 and P < .001 for category A and category B, respectively). In groups 1 and 2 (groups treated non-surgically), there was no significant difference in terms of the stone-free rate (P = .29); furthermore, There was no significant difference be- tween category A and B patients in either group 1 or 2. The mean expulsion times for groups 1, 2 and 3 were 15.3 ± 5.33, 15.1 ± 5.5 and 1.95 ± 2.2 days, respectively. Com- pared to groups 1 and 2, the expulsion time for the uret- eroscopy group (group 3) was statistically different. Ure- teroscopy was also significantly more effective than other treatment modalities (P < .001). In group 3, no difference was observed between category A and B patients (P = .69). DISCUSSION Due to recent technological advances, there are many op- tions for the treatment of ureteral stones. The factors that determine suitable treatment choices include stone location, number of stones, renal function, surgical experience, ad- ditional patient health factors, technological qualification, cost and the patient’s decision.(1,7) In our study, we com- pared three different options for the treatment of distal ure- teral stones smaller than 10 mm. Observation remains an alternative to treatment. To increase the likelihood of stone passage, patients are encouraged to increase fluid intake, and these patients are followed with regular visits to assess for spontaneous passage. Location and stone size should always be considered before decid- ing on observation. Small stones that are distally located are more suited to spontaneous passage. Analgesics over- use, debility, frequent doctor visits and emergent urinary diversion may be required in such cases.(8) In clinical trials, stones smaller than 4 mm usually pass spontaneously. Spon- taneous passage rate falls significantly for stones larger than 5 mm.(1,9-11) Morse and colleagues found that distal ureteral stones pass spontaneous 71% of the time, whereas Hübner and colleagues reported an expulsion rate of distal ureteral stones of 45%.(12) In our study, the stone expulsion rate in the observational group was 48.7%. This rate was higher in individuals with stones smaller than 5 mm (52.9%), but this rate was not significantly higher than that for stones larger than 5 mm. Therefore, our results are compatible with those reported in the literature. Both observation and treatment of distal ureteral stones have advantages and disadvantages. For observation, the disadvantages are persistent renal colic and frequent phy- sician visits. Furthermore, urinary diversion or urgent in- tervention is sometimes required. Therefore, observation as the first choice remains controversial. Another treatment for distal stones is medical expulsive therapy (MET). The presence of a ureteral stone often caus- es ureteral spasm, edema, pain and infection. The purpose of MET is to relax the smooth muscle, relieve pain and decrease edema without impeding peristalsis. Drugs used for MET include non-steroidal anti-inflammatory drugs (NSAIDs), antimuscarinics, steroids, calcium channel blockers and alpha-blockers. Of these drugs, alpha-blockers are the most effective and the most widely used. Blockage Table 2. The comparison of patient’s stone-free rates and expulsion times. Condition Group 1 Group 2 Group 3 P Category A Category B Total Category A Category B Total Category A Category B Total Stone-free rate, n (%) 52.9 (9/17) 45.5 (10/22) 48.7 (19/39) 60.8 (14/23) 57.8 (11/19) 59.5 (25/42) 95.0 (19/20) 96.1 (25/26) 95.6 (44/46) < .0001 Expulsion time, day 12.9 ± 5.4 16.0 ± 3.8 15.3 ± 5.3 13.5 ± 3.2 16.7 ± 7.0 15.1 ± 5.5 1.65 ± 2.7 1.97 ± 2.4 1.95 ± 2.2 < .001 Category A: stone size < 5 mm, Category B: stone size between 5.0-9.9 mm. P values are for total stone-free rates. Ureteroscopy in Ureteral Stones | Kiraç et al 1032 | of alpha-receptors, which are located throughout the ureter but are concentrated distally, causes propulsive contractions without blocking physiologic peristalsis.(13) Various studies have shown that alpha-blockers accelerate the passage of the distal ureteral stones.(14-16) In a meta-analysis on the treatment of ureteral stones with alpha-blockers, it was shown that the use of alpha-blockers increases the rate of spontaneous passage to as high as 44 %.10 Additionally, in a study by Küpeli and colleagues, it was shown that the addition of tamsulosin increased the rate of distal stone clearance.(15) In a study by Erturhan and col- leagues, the stone-free rate in individuals with distal ure- teral stones was 73.3% following treatment with tamsulo- sin alone.16 On the other hand, Hermanns and colleagues showed that tamsulosin treatment does not improve stone expulsion rates in patients with distal ureteral stones ≤ 7 mm.(17) In our study, the stone-free rate was 59.5% in the tamsulosin group (group 2). In patients with stones smaller than 5 mm, the stone-free rate was 60.8%, and in individuals with stones larger than 5 mm, it was 57.8%. Ureterorenos- copy was performed in 41.5% of these patients due to the failure of medical treatment. In contrast to the literature, we found no significant difference between the tamsulosin and observational groups. However, tamsulosin does accelerate the expulsion of distal ureteral stones. Thus, if the stone is likely to pass, tamsulosin accelerates this process. As mentioned above, the addition of tamsulosin to the med- ical treatment of distal ureteral stones has been shown to increase expulsion rates. However, there are two parame- ters that remain controversial: the duration of treatment and problems such as uncontrollable pain, the development of hydronephrosis, and surgical intervention. Although tamsu- losin increases the expulsion of distal ureteral stones, we think that the use of alpha-blockers should not be the stand- ard of care due to the controversial treatment duration and the high need of surgical intervention. Because of improvements in instrumentation coupled with ureteroscopy’s quick learning curve, ureteroscopy is the best treatment for ureteral stones. Although extra SWL was historically the first choice treatment for ureteral stones, the 2010 European Association of Urology (EAU) urolithiasis guidelines now list ureteroscopy as the best choice.(18,19) Additionally, in the guidelines published by Preminger and colleagues, URS is the treatment of choice for mid and dis- tal ureteral stones smaller than 10 mm.(1) The ureteroscopy is the treatment with the highest stone-free rate after a single procedure for distal ureteral stones.(1,18) Thus, patients with ureteral stones also prefer URS over other treatments due to immediate cessation of pain and disability. In fact, Perchel and colleagues reported patient satisfaction in 100% of ure- teroscopy cases.(20) Differing energy sources coupled with ureteroscopy have produced successful results. Ultrasonic, electrohydrolic, la- ser and pneumatic lithotripters are widely used methods of lithotripsy. The effectiveness of ureteroscopy is well known in the treatment of distal ureteral stones when pneumatic lithotripters are used.(1,18,21) In our study, we also used a pneumatic lithotripter that is a widely used and compara- tively inexpensive. In a study by Ceylan and colleagues, they reported a 95.0% success rate for 209 distal ureteral stones (average size of 8.7 mm) treated with URS.(22) Tuğcu and colleagues reported a success rate of 96.7% in their group of patients with distal ureteral stones (average size of 9 mm).(23) In our study, the average stone size was 6.9 mm, and our success rate for ureteroscopy was 95.6%. The stone-free rate was 95.3% for cases where the stone was smaller than 5 mm and 96.1% in cases where the stone was larger than 5 mm. This result shows that ureteroscopy is more effective than observation and alpha-blockers for the treatment of distal ureteral stones smaller than 10 mm. Stone size and localization affect ureteroscopy success.(1,24) If the location of the stones is near the distal proportion of the ureter, ureteroscopy success is more likely.(1,18,24,25) Thus, distally located stones smaller than 10 mm are more suitable for ureteroscopy. The ureteroscopy also has a low- er complication rate, morbidity and mortality compared to other treatments. In addition, it is much more effective. Factors included male sex, proximal ureteral stone, large stone size, surgical inexperience and symptoms for more than three months may increase the complication rate.(26,27) In our study, there were no major or minor complications in patients treated with URS. Thus, we think that it is unneces- sary to treat patients with alpha-blockers for distal ureteral stones of any size, unless the patient cannot tolerate ureter- Endourology and Stone Disease 1033Vol. 10 | No. 4 | Autumn 2013 |U R O LO G Y J O U R N A L 10. Parsons JK, Hergan LA, Sakamato K, Lakin C. Efficacy of alpha-blockers for the treatment of ureteral stones. J Urol. 2007;177:983-7. 11. Segura JW, Preminger GM, Assimos DG, et al. Ureteral stones clinical guidelines panel summary report on the manage- ment of ureteral calculi. The American Urological Associa- tion. J Urol. 1997;158:1915-21. 12. Morse RM, Resnick MI. Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol. 1991;145:263-5. 13. Itoh Y, Kojima Y, Yasui T, Tozawa K, Sasaki S, Kohri K. Examina- tion of alpha 1 adrenoceptor subtypes in the human ureter. Int J Urol. 2007;14:749-3. 14. Singh A, Alter HJ, Littlepage A. A systematic review of medi- cal therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007;50:552-63. 15. Küpeli B, Irkilata L, Gürocak S, et al. Does tamsulosin en- hance lower ureteral stone ̀ clearance with or without shock wave lithotripsy? Urology. 2004 ;64:1111-5. 16. Erturhan S, Erbagci A, Yagci Fr, Celik M, Solakhan M, Sarica K. Comparative evaluation of efficacy of use of tamsulosin and/or tolterodine for medical treatment of distal ureteral stones. Urology. 2007;69:633-6. 17. Hermanns T, Sauermann P, Rufibach K, Frauenfelder T, Sulser T, Strebel RT. Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a ran- domised, double-blind, placebo-controlled trial. Eur Urol. 2009;56:407-12. 18. Tiselius HG, Ackermann D, Alken P, Buck C, Conort P, Gallucci M. Working Party on Lithiasis, European Association of Urol- ogy. Guidelines on urolithiasis. Eur Urol. 2001;40:362-1. 19. Türk C, Knoll T, Petrik A et al. Guidelines on Urolithiasis. Euro- pean Association of Urology 2010. Available at http://www. uroweb.org/guidelines/online-guidelines 20. Peschel R, Janetschek G, Bartsch G. Extracorporeal shock wave lithotripsy versus ureteroscopy for distal ureteral cal- culi: a prospective randomized study. J Urol. 1999;162:1909- 12. 21. Pearle MS, Nadler R, Bercowsky E, et al. Prospective rand- omized trial comparing shock wave lithotripsy and uret- eroscopy for management of distal ureteral calculi. J Urol. 2001;166:1255-60. 22. Ceylan K, Sünbül O, Sahin A, Güneş M. Ureteroscopic treat- ment of ureteral lithiasis with pneumatic litho-tripsy: analysis of 287 procedures in a public hospital. Urol Res. 2005;33:422-5. REFERENCES 1. Preminger GM, Tiselius HG, Assimos DG, et al. Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610- 31. 2. Strohmaier WL, Schubert G, Rosenkranz T, Weigl A. Com- parison of extracorporeal shock wave lithotripsy and uret- eroscopy in the treatment of ureteral calculi: a prospective study. Eur Urol. 1999;36:376-9. 3. Osorio L, Lima E, Soares J, et al. Emergency ureteroscop- ic management of ureteral stones: why not? Urology. 2007;69:27-31. 4. Geavlete P, Georgescu D, Nita G, Mirciulescu V, Cauni V. Com- plications of 2735 retrograde semirigid ureteroscopy proce- dures: a single-center experience. J Endourol. 2006;20:179- 85. 5. Chow GK, Patterson DE, Blute ML, Segura JW. Ureteroscopy: effect of technology and technique on clinical practice. J Urol. 2003;170:99-102. 6. Denstedt JD, Clayman RV, Preminger GM. Efficiency quo- tient as a means of comparing lithotripters. J Endourol. 1990;4:100-3. 7. Bensalah K, Pearle M, Lotan Y. Cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones. Eur Urol. 2008;53:411-8. 8. Hollingsworth JM, Rogers MA, Kaufman SR, et al. Medical therapy to facilitate urinary stone passage: a meta-analysis. Lancet. 2006;368:1171-9. 9. Hübner WA, Irby P, Stoller ML. Natural history and current concepts for the treatment of small ureteral calculi. Eur Urol. 1993;24:172-6. oscopy. CONCLUSION We concluded that ureteroscopy was shown to be the most effective in our study. The advantages of ureteroscopy are its low complication rate, short expulsion time, and high stone-free rate after a single application and high patient satisfaction. Therefore, we believe that ureteroscopy should be the standard of care for distal ureteral stones smaller than 10 mm. CONFLICT OF INTERSET None declared. Ureteroscopy in Ureteral Stones | Kiraç et al 1034 | 23. Tuğcu V, Gürbüz G, Aras B, Gürkan L, Otunctemur A, Tasci AI. Primary ureteroscopy for distal ureteral stones compared with ureteroscopy after failed extracorporeal lithotripsy. J Endourol. 2006;20:1025-9. 24. Tunc L, Kupeli B, Senocak C et al. Pneumatic lithotripsy for large ureteral stones: is it the first line treatment? Int Urol Nephrol. 2007;39:759-64. 25. Ather MH, Nazim SM, Sulaiman MN. Efficacy of semirig- id ureteroscopy with pneumatic lithotripsy for ureteral stone surface area of greater than 30 mm2. J Endourol. 2009;23:619-22. 26. Fuganti PE, Pires S, Branco R, Porto J. Predictive factors for intraoperative complications in semirigid ureteroscopy: analysis of 1235 ballistic ureterolithotripsies. Urology. 2008;72:770-4. 27. Abdelrahim AF, Abdelmaguid A, Abuzeid H, Amin M, Mousa el-S, Abdelrahim Fr. Rigid ureteroscopy for ureteral stones: factors associated with intraoperative adverse events. J En- dourol. 2008;22:277-80. Endourology and Stone Disease