Current Outcome of Patients With Ureteral Stents for the Management of Malignant Ureteral Obstruction

Current Outcome of Patients With Ureteral Stents for the Management of Malignant Ureteral Obstruction Kouji Izumi,* Atsushi Mizokami, Yuji Maeda, Eitetsu Koh and Mikio Namiki From the Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan Abbreviations and Acronyms GIT gastrointestinal tract MUO malignant ureteral obstruction OS overall survival PCN percutaneous nephrostomy RUS retrograde ureteral stent placement SCr serum creatinine SFFS stent failure-free survival UU ureteral unit Submitted for publication June 7, 2010. * Correspondence: Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan (telephone: 81-76-265-2393; FAX: 81-76- 222-6726; e-mail: azuizu2003@yahoo.co.jp). See Editorial on page 387. Purpose: We analyzed the prognostic factors associated with overall survival and predictive factors of stent failure in patients treated with an indwelling retrograde ureteral stent for malignant ureteral obstruction. Materials and Methods: Among 186 Japanese patients treated with an indwelling retrograde ureteral stent for ureteral obstruction from January 2005 to March 2010, 61 with malignant ureteral obstruction and 95 ureteral units were analyzed retrospectively. Results: Median survival was estimated at 228 days. Unfavorable prognostic factors of overall survival were no treatment after indwelling retrograde ureteral stent placement (p 0.023) and a serum creatinine before indwelling retrograde ureteral stent placement of 1.2 mg/dl or greater (p 0.016). Overall survival differed significantly among cancer groups (p 0.001) as did stent failure-free survival (p 0.011). Overall survival differed significantly among 3 risk groups divided according to the score calculated with regard to prognostic factors (p 0.001). Conclusions: Gynecologic cancer was a significant favorable predictor of stent failure-free survival. Patients treated with an indwelling retrograde ureteral stent for malignant ureteral obstruction were divided into 3 groups, which showed significant differences in overall survival. This risk classification may help urologists predict survival time. Key Words: stents, ureteral obstruction, neoplasm metastasis THE appearance of ureteral obstruction caused by metastasis or invasion of malignancy is generally regarded as a sign of poor prognosis. The cause of malignant MUO may be invasion of the ureter by cervical, bladder, prostate or colorectal cancer, extrinsic compression by a retroperitoneal primary lesion, metastatic neoplasia from distant primary lesion or peritonitis carcinomatosa of GIT primary lesion. 1 RUS does not usually lead to major complications, is less invasive than PCN and is better tolerated, suggesting that it may be more advantageous than PCN especially in view of the limited life expectancy of patients with advanced malignancies. 2,3 However, stent failure is a problem encountered frequently by urologists. Furthermore, the frequency of the primary site of malignancy differs considerably among countries. These differences in primary site may impact clinical outcomes such as survival time. Accordingly median survival of patients with MUO was reported over a wide range from 3.7 to 15.3 months. 2,4 In addition, the recent development of chemotherapeutic agents or emergence of molecular targeting therapies improved the OS 556 www.jurology.com 0022-5347/11/1852-0556/0 Vol. 185, 556-561, February 2011 THE JOURNAL OF UROLOGY Printed in U.S.A. 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI:10.1016/j.juro.2010.09.102

URETERAL STENT FOR MALIGNANT URETERAL OBSTRUCTION 557 of patients with cancer. However, there have been only a few reports of data from such patients in recent years. In this study we analyzed the prognostic factors in recent cases of RUS for MUO and predictive factors of stent failure. To aid urologists in predicting patient survival we defined risk classification for patient prognosis. MATERIALS AND METHODS Patients This retrospective analysis followed the Helsinki Declaration. Among 186 Japanese patients who underwent RUS under x-ray guidance for ureteral obstruction at Kanazawa University Hospital between January 2005 and March 2010, 61 patients with 95 UUs for MUO with hydronephrosis were extracted. The date of the initial RUS attempt was used as the start of observation. OS was measured from the start of observation to death from any cause. SFFS was measured from the start of observation to stent failure. We defined stent failure as UUs that required an alternative form of urinary diversion. The obstruction level was defined as the upper, middle or lower ureter as determined by the location above, over or below the sacroiliac joint. In cases in which the obstruction levels were different between bilateral ureters, the more severely obstructed side was selected. Multi-length ureteral stents of 4.8 or 6Fr (Contour ) were used. The interval between stent changes was initially planned at 3 months. RUS related major complications such as severe bleeding which needs transfusion, stent migration and uncontrollable sepsis were assessed. Statistical Analysis Statistical analyses were performed using commercially available software (PRISM and SPSS version 17.0). The crude probability of survival was estimated using the Kaplan-Meier method. Univariate analysis of differences among patient groups was performed with the log rank test. Multivariate analysis to identify independent prognostic factors was performed with Cox proportional hazards regression and the stepwise backward procedure, with statistical significance defined as p 0.05. RESULTS Table 1. Patient characteristics Median pt age (range) 64 (27 89) No. gender (%): M 19 (31) F 42 (69) No. side (%): Bilat 25 (41) Lt 16 (26) Rt 20 (33) No. gynecologic Ca group (%): 21 (34) Cervical 13 (21) Endometrial 1 (2) Ovarian 7 (11) No. upper gastrointestinal Ca group (%): 13 (21) Gastric 12 (20) Esophageal 1 (2) No. lower gastrointestinal Ca group (%): 10 (16) Rectal 6 (10) Colon 4 (7) No. urological Ca group (%): 10 (16) Retroperitoneal tumor 3 (5) Prostate 2 (3) Bladder 2 (3) Ureteral 2 (3) Adrenal 1 (2) No. other Ca group (%): 7 (11) Lung 2 (3) Pancreas 2 (3) Breast 1 (2) Liver 1 (2) Malignant melanoma 1 (2) Median (range) SCr (mg/dl): 1.11 (0.52 9.9) No. 1.2 or greater (%) 24 (39) No. less than 1.2 (%) 29 (48) No. unknown (%) 8 (13) No. obstruction level (%): Upper middle ureter 34 (56) Lower ureter 22 (36) Unknown 5 (8) No. no treatment after retrograde stenting (%) 22 (36) No. treatment after retrograde stenting (%): 39 (64) Chemotherapy 26 (43) Radiation 3 (5) Chemoradiation 5 (8) Immunotherapy 1 (2) Hormonal therapy 1 (2) Surgery 3 (5) Patient Population Patient characteristics are shown in table 1. In a total of 61 patients with 95 UUs in which RUS was attempted, the stent failed to indwell in 13 patients (21.3%) and 17 UUs (17.9%). The numbers of patients with bilateral and unilateral RUS failure were 4 (8 UUs) and 9 (9 UUs), respectively. The reasons for RUS failure were severe ureteral stricture (9 UUs), undetectable orifice (3 UUs), severe pain (2 UUs), kink of the ureter, deviation of the orifice and urethral stricture (each 1 UU). For prompt rescue of initial RUS failure 2 patients underwent PCN on the same day. RUS at 7 days and 6 months, and PCN at 8 months after the date of initial RUS failure were performed in 1 patient each. The data of SCr before RUS in 8 patients and 12 UUs, and of obstruction level in 5 patients and 5 UUs were not available, and were omitted from analysis. Nadir SCr after successful RUS of 1.2 mg/dl or greater and less than 1.2 mg/dl were available in 8 and 38 patients, respectively. A total of 78 initially successful UUs were analyzed statistically and the characteristics of these 78 UUs are shown in table 2. Nadir SCr after successful RUS of 1.2 mg/dl or greater and less than 1.2 mg/dl were available in 12 and 54 UUs, respectively. There were no RUS related major complications.

558 URETERAL STENT FOR MALIGNANT URETERAL OBSTRUCTION Table 2. Characteristics of ureteral units No. gender (%): M 24 (31) F 54 (69) No. side (%): L 38 (49) R 40 (51) No. gynecologic Ca group (%): 28 (36) Cervical 20 (26) Endometrial 1 (1) Ovarian 7 (9) No. upper gastrointestinal Ca group (%): 20 (26) Gastric 19 (24) Esophageal 1 (1) No. lower gastrointestinal Ca group (%): 9 (12) Rectal 4 (5) Colon 5 (6) No. urological Ca group (%): 13 (17) Retroperitoneal tumor 4 (5) Prostate 4 (5) Bladder 2 (3) Ureteral 2 (3) Adrenal 1 (1) No. other Ca group (%): 8 (10) Lung 2 (3) Pancreas 1 (1) Breast 2 (3) Liver 2 (2) Malignant melanoma 1 (2) Median (range) SCr (mg/dl): 1.10 (0.52 9.17) No. 1.2 or greater (%) 30 (38) No. less than 1.2 (%) 36 (46) No. unknown (%) 12 (15) No. obstruction level (%): Upper middle ureter 50 (64) Lower ureter 23 (29) Unknown 5 (6) No. no treatment after retrograde stenting (%) 33 (42) No. treatment after retrograde stenting (%): 45 (58) Chemotherapy 30 (43) Radiation 4 (5) Chemoradiation 5 (6) Immunotherapy 1 (1) Hormonal therapy 2 (3) Surgery 3 (4) No. Fr stent diameter (%): 4.8 39 (50) 6 36 (46) Unknown 3 (4) Prognostic Factors for OS Median survival was estimated at 228 days. The effects of each prognostic factor on OS were examined with univariate analysis. Unfavorable prognostic factors for OS were male gender (p 0.031, HR 2.336, 95% CI 1.079 5.054), no treatment after RUS (p 0.023, HR 2.333 95% CI 1.124 4.841) and SCr before RUS of 1.2 mg/dl or greater (p 0.016, HR 2.426, 95% CI 1.178 4.997). OS also differed significantly among cancer groups (p 0.001), and median OS of gynecologic cancer, urological cancer, lower GIT cancer, upper GIT cancer and cancer of other primary sites was 510, 403, 252, 148 and 53 days, respectively. Age 64 years old or older (p 0.202, HR 1.536, 95% CI 0.795 2.968), nadir SCr after successful RUS of 1.2 mg/dl or greater (p 0.087, HR 3.208, 95% CI 0.843 12.21) and initial failure of RUS (p 0.504, HR 1.290, 95% CI 0.611 2.721) were not significant factors for OS. Attempted RUS into bilateral ureters (p 0.079, HR 1.817, 95% CI 0.934 3.536), and upper and middle ureteral obstruction (p 0.076, HR 1.815, 95% CI 0.940 3.504) were marginally significant predictors of unfavorable prognosis. On multivariate analysis SCr before RUS of 1.2 mg/dl or greater (p 0.011, HR 2.501, 95% CI 1.231 5.082) and no treatment after RUS (p 0.028, HR 2.222, 95% CI 1.087 4.544) remained significant predictors of unfavorable prognosis. Type of cancer remained a marginally significant prognostic factor (p 0.050, HR 1.303, 95% CI 1.000 1.698) (table 3). Predictors of SFFS Median stent placement period for 78 UUs was 89.5 days and 17 UUs (21.8%) had stent failure in the followup period. The numbers of UUs undergoing PCN and metallic ureteral stent placement for stent failure were 11 and 5, respectively. In addition, PCN and metallic ureteral stent placement were performed in 1 UU for a persistently increasing SCr despite unilateral urinary diversion. The frequency of stent change was not clear in 9 of 78 UUs because they were followed elsewhere. The stents were not changed before stent failure or death in 41 of the remaining 69 UUs. The largest number of stent changes in a single patient was 16 in 1,484 days in a patient with cervical cancer. The average interval between stent changes was 139.6 days. The effects of each prognostic factor on SFFS were examined by univariate analysis. Male gender was an unfavorable Table 3. Multivariate analysis of variables and median survival time No. Pts Median Days Survival HR (95% CI) p Value Gender: 0.987 (0.453 2.147) 0.973 M 19 103 F 42 374 Ca group: 1.303 (1.000 1.698) 0.050 Gynecologic 21 510 Upper gastrointestinal 13 148 Lower gastrointestinal 10 252 Urological 10 403 Other 7 53 SCr (mg/dl): 2.501 (1.231 5.082) 0.011 1.2 or Greater 24 103 Less than 1.2 29 390 Treatment after stenting: 2.222 (1.087 4.544) 0.028 No 22 103 Yes 39 374

URETERAL STENT FOR MALIGNANT URETERAL OBSTRUCTION 559 predictor of SFFS (p 0.015, HR 5.454, 95% CI 1.383 21.51). SFFS also differed significantly among cancer groups (p 0.011), and median SFFS of urological cancer, lower GIT cancer, upper GIT cancer and cancer of other primary sites was 588, 255, 512 and 62 days, respectively. Median SFFS of gynecologic cancer was not reached. Age 64 years old or older (p 0.801, HR 1.139, 95% CI 0.413 3.141), SCr before RUS of 1.2 mg/dl or greater (p 0.597, HR 1.419, 95% CI 0.386 5.214), nadir SCr after successful RUS of 1.2 mg/dl or greater (p 0.124, HR 6.773, 95% CI 0.591 77.58), upper and middle ureteral obstruction (p 0.105, HR 2.485, 95% CI 0.827 7.466), stent diameter of 4.8Fr (p 0.060, HR 2.606, 95% CI 0.959 7.080), no treatment after RUS (p 0.145, HR 2.100, 95% CI 0.775 5.695) and left side (p 0.457, HR 1.453, 95% CI 0.542 3.892) were not significant factors for SFFS. On multivariate analysis type of cancer remained a significant predictor of SFFS (p 0.011, HR 1.626, 95% CI 1.118 2.365) (table 4). Gynecologic cancer was an especially significant favorable predictor of SFFS (fig. 1). Figure 1. Kaplan-Meier analysis of SFFS in cases of gynecologic and other cancers (p 0.011). Gynecologic cancer was especially significant favorable predictor of SFFS. Risk Classification for OS A total of 53 patients were divided into 3 risk groups according to the scores calculated with regard to 4 prognostic factors. As SCr before RUS of 1.2 mg/dl or greater and no treatment after RUS were significant predictors of unfavorable prognosis, patients who had these factors were given a score of 2 points. Type of cancer was also a significant predictor of prognosis, and cancer groups were divided in 3 categories of gynecologic cancer (category A), urological and lower GIT cancer (category B), and upper GIT cancer and other cancer (category C). Patients in categories B and C were given scores of 1 and 2 points, respectively. The patients in whom RUS was attempted into the bilateral ureters were given a score of 1 point because this was a marginally significant predictor of unfavorable prognosis. However, obstruction level was excluded from prognostic factors because primary cancer site was thought to be strongly connected with obstruction level. Therefore, all patients were given a score from 0 to 7 in accordance with 4 prognostic factors. Patients with scores of 0 to 2 were assigned to the good prognosis group, those with scores of 3 or 4 were assigned to the intermediate prognosis group and those with scores of 5 to 7 were assigned to the poor prognosis group. According to this risk classification the numbers of patients in good, intermediate and poor prognosis groups were 20, 20 and 13, respectively, and OS differed significantly among these 3 groups (p 0.001, fig. 2). Median survival times of good, intermediate and poor prognosis groups were 403, 252 and 51 days, respectively. DISCUSSION Experience with ureteral stents was first reported in 1978 and stents were subsequently used for patients with malignancies that were causing external compression of the ureter. 1,5 Although benign, intrinsic ureteral obstruction such as stone Table 4. Multivariate analysis of variables and median SFFS time No. Pts Median (Days) SFFS HR (95% CI) p Value Gender: 1.821 (0.606 5.472) 0.286 M 24 103 F 54 374 Ca group: 1.626 (1.118 2.365) 0.011 Gynecologic 28 Undefined Upper gastrointestinal 20 525 Lower gastrointestinal 9 255 Urological 13 588 Other 8 62 Figure 2. Kaplan-Meier analysis of OS in each risk group. OS differed significantly among 3 groups (p 0.001).

560 URETERAL STENT FOR MALIGNANT URETERAL OBSTRUCTION disease, ureteral stricture or ureteropelvic junction obstruction is usually successfully managed in the long term by RUS, the incidence of stent failure is significantly higher in cases of MUO. 1 In the present study the success rate of initial RUS was 79%, which was consistent with the rates of 72% to 92% in previous reports of MUO. 2,6 However, the rate of late stent failure was reported with a wide range from 16% to 53%. 4,7 10 In a study of 103 advanced malignancies 51% of patients required secondary PCN 4 and in a cohort of 39 UUs with MUO 43% of UUs were reobstructed. 7 In addition, in 15-year experience of the management of extrinsic ureteral obstruction, 44% of patients with MUO had stent failure. 8 In contrast, in 2 studies published in 2007 only 16% of patients with nonurological MUO and 21.6% of those with MUO, including urological malignancy, had stent failure. 9,10 In the present study 21.8% of UUs had stent failure and this result was equivalent to those of recent studies. Although the differences in rate of stent failure among previous studies were explained as the result of improvements in stent design and biocompatibility, 8,9 these studies could not be directly compared with each other because of obvious differences in patient background, sample size and etiology of malignancy. Accordingly different factors were considered predictors of SFFS or OS. Factors reported as predictors of stent failure were baseline SCr, no treatment after RUS, gross tumor invasion noted at cystoscopy, degree of hydronephrosis and male gender. 8,9,11,12 Type of cancer was a significant predictor of SFFS in the present study and gynecologic cancer was an especially good predictor of better SFFS. To our knowledge this is the first report that type of cancer is a significant predictor of SFFS. However, the results should be interpreted carefully because the patient backgrounds differed considerably among studies. The OS of patients with MUO was also examined previously and median survival times were reported over a wide range. Median survival in the present study was 228 days (7.6 months), and SCr before RUS of 1.2 mg/dl or greater, no treatment after RUS and cancer group (especially nongynecologic cancer) were significant or marginally significant factors for OS. The shortest median survival time previously reported was 3.7 months in a study in which 57% of patients had urological cancer. 4 In contrast, a median survival of 15.3 months was reported in another study of 28 patients with MUO. However, more than half of the patients in the study had gynecologic cancer. 2 Most previous studies included only a few patients with gastric cancer. Although the estimated rate of gastric cancer is only 1.4% of newly diagnosed cancers in the United States, 13 it has a highly malignant nature and is the second leading cause of cancer death in the world. 14 A study including gastric cancer (33% of patients) indicated median survival was 8.6 months, 9 which was equivalent to the present study. This previous study concluded that patients with a low performance status, upper ureteral obstruction, no chemotherapy after RUS and GIT cancer had a short survival time. 9 Wong et al proposed risk factors for inferior OS in patients with intervention for MUO including presence of metastasis, prior therapy, diagnosis of MUO in previously established malignancy and high SCr. 15 Although patients with 3 or 4 of these risk factors were associated with poor survival, only 25 of 102 underwent RUS. The present study may be reasonable for examination of OS because it had a well balanced patient background with regard to type of cancer. In our risk classification patients who underwent RUS for MUO were divided into 3 groups which differed significantly in OS. This classification may be applied universally and help urologists predict survival time. The present study had a number of limitations. Small sample size may have prevented determination of precise statistical significance. Several factors previously reported as significant factors for OS or SFFS were not considered prognostic variables because they were not clear in some patients. All patients were Japanese so the distribution of cancer may differ in patients from other ethnic backgrounds. Hematological malignancies such as lymphoma were not included in the present study. In addition, SCr before RUS was relatively low, and median survival may be lengthened by lead time bias. Finally, our risk classification should be confirmed by prospective validation study before it can be used routinely in clinical settings. CONCLUSIONS Gynecologic cancer was a favorable predictor of SFFS. SCr before RUS of 1.2 mg/dl or greater and no treatment after RUS were significant predictors of unfavorable prognosis, and type of cancer was a marginally significant predictor of OS. The risk classification calculated using these 3 predictive factors and attempted RUS into bilateral ureters could concisely assign patients into 3 groups with significantly different OS. This risk classification may help urologists predict survival.

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