european urology 51 (2007) 1639 1644 available at www.sciencedirect.com journal homepage: www.europeanurology.com Laparoscopy Long-Term Oncologic Outcome after Laparoscopic Radical Nephroureterectomy for Upper Tract Transitional Cell Carcinoma Michael Muntener *, Matthew E. Nielsen, Frederico R. Romero, Edward M. Schaeffer, Mohamad E. Allaf, Fabio Augusto R. Brito, Christian P. Pavlovich, Louis R. Kavoussi 1, Thomas W. Jarrett 2 The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA Article info Article history: Accepted January 9, 2007 Published online ahead of print on January 16, 2007 Keywords: Carcinoma Transitional cell Kidney Laparoscopy Nephrectomy Ureter Abstract Objective: To assess the long-term oncologic efficacy of laparoscopic radical nephroureterectomy (RNU). Methods: Between August 1993 and May 2001, 39 patients underwent laparoscopic RNU for upper tract transitional cell carcinoma (TCC) at our institution. The medical records of these patients were retrospectively reviewed. Results: Clinical outcomes were available in all 39 patients with an actual follow-up ranging from 60 to 148 mo (median: 74). During this time 27 patients (69%) developed at least one TCC recurrence. Eighteen patients had urothelial recurrences, and 9 patients had nonurothelial recurrences. Of these latter patients, 2 patients (5%) had local recurrences. No patient developed a port site metastasis. Eleven patients ultimately had disease progression and died from TCC 7 59 mo (median: 31) after the operation. On statistical analysis, tumor stage was the only factor significantly associated with death from the disease, and tumor location (ureter) was the only factor significantly associated with disease recurrence. Conclusions: The long-term overall and disease-specific survival rates after laparoscopic RNU for upper tract TCC are well within the range of results reported after open surgery. Thus, the results of the present study support the continued development of laparoscopic techniques in the management of this aggressive disease. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. James Buchanan Brady Urological Institute, The Johns Hopkins Hospital, 600 N. Wolfe Street, Marburg 1, Baltimore, MD 21287-2101, USA. Tel. +1 410 955 5494; Fax: +1 410 955 0833. E-mail address: muntener@jhmi.edu (M. Muntener). 1 Author s current address: The Department of Urology, North Shore-LIJ Health System, Long Island, NY, USA. 2 Author s current address: Department of Urology, The George Washington University Medical Center, Washington, DC, USA. 0302-2838/$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.01.038
1640 european urology 51 (2007) 1639 1644 1. Introduction Table 1 Perioperative information (n = 39) Transitional cell carcinoma (TCC) of the upper urinary tract is an aggressive disease with a propensity for recurrence, multifocality, and progression to advanced stage. These factors, coupled with the relative limitations of upper tract surveillance, have supported the development of radical nephroureterectomy (RNU) as the standard of care, especially for lesions of high grade or stage. Open RNU is a highly effective cancer treatment [1]; however, there is significant morbidity associated with the incision(s) necessary to gain adequate exposure. Laparoscopic RNU was first described in 1991 by Clayman et al [2], and since has become an alternative standard of care at many centers of excellence [3 5]. Results from a number of studies have shown significant advantages of laparoscopic RNU compared with open RNU in terms of blood loss, postoperative pain, and recovery time [4,6,7]. Equivalent short- and intermediate-term tumor control has also been demonstrated for the two approaches [4,6,8]. A principal limitation to the wider adoption of laparoscopic RNU, however, is the paucity of data on long-term oncologic efficacy. Thus, urologists worldwide are still less likely to choose a laparoscopic approach in the case of upper tract TCC than in cases involving other solid renal tumors [9]. The aim of this study was to assess the long-term outcome after laparoscopic RNU for upper tract TCC at our institution. 2. Patients and methods After institutional review board approval was obtained, the medical records of all 39 patients who underwent laparoscopic RNU for upper tract TCC at our institution between August 1993 and May 2001 were retrospectively reviewed. Demographic, perioperative, pathologic, and clinical follow-up information was collected from the charts. Preoperative evidence of invasive tumor or high-grade tumor and tumor size of 2 cm or greater were considered indications for RNU. No patient received neoadjuvant chemotherapy. All patients were operated by one of two surgeons (L.R.K., T.W.J.). Our technique of laparoscopic RNU as well as the preoperative workup have been reported in an earlier publication [3]. The nephrectomy and dissection of the proximal ureter were performed via a transperitoneal approach in all cases. No formal lymphadenectomy was performed. Either an open approach or a laparoscopic stapler resection was used to treat the distal ureter in the vast majority of the cases (Table 1). All pathology specimens were processed and evaluated by dedicated genitourinary pathologists. Tumor stage was determined according to the 1992 TNM classification [10]; tumor grade was determined according to the 1998 World Health Organization/International Median operating time (range) 312 min (191 715) Median estimated blood loss (range) 300 ml (50 2000) Intraoperative complications (%) 35 no (90) 4 yes (10) Open conversion (%) 35 no (90) 4 yes (10) Postoperative complications (%) 31 no (79) 3 major, including 1 mortality (8) 5 minor (13) Median length of hospital stay (range) 4 d (2 46) Morcellation of the specimen (%) 4 cases (10) Lapbag used to extract specimen (%) (Information unavailable in 2 cases) Management of the distal ureter (%) (Information unavailable in 2 cases) * See Results for details. Society of Urological Pathology consensus conference definitions [11]. Follow-up was not standardized over the entire study period but typically consisted of cystoscopy, urine cytology, and axial imaging (computed tomography or magnetic resonance imaging) every 3 12 mo and when clinically indicated. In patients not followed at our institution, information was collected from treating physicians or the patients themselves. Follow-up time was calculated from the date of surgery to the date of the most recent documented examination or patient contact. Overall disease recurrence was defined as the development of local recurrence, distant metastasis, or urothelial recurrence of TCC. When patients died, the cause of death was determined by the treating physicians, by chart review corroborated by death certificates, or by death certificates alone. Patients who died of causes other than TCC were censored at the date of last follow-up for TCC-specific survival analyses. The Kaplan-Meier method was used to calculate survival functions, and differences were assessed with the log-rank statistic. The following variables were evaluated for association with the survival outcomes of disease recurrence and disease-specific mortality: patient age (older vs. younger than the mean age), sex (male vs. female), history of bladder TCC (yes vs. no), tumor stage (Tis, Ta, or T1 vs. T2 T4), tumor grade (low vs. high), tumor site (ureteral involvement vs. no ureteral involvement), tumor multifocality (yes vs. no), presence of carcinoma in situ (yes vs. no), resection of the distal ureter (laparoscopic vs. open), and use of a specimen retrieval bag (yes vs. no). Statistical significance in this study was set as p < 0.05. Statistical analysis was performed with the use of commercially available software. 3. Results 21 no (54) 16 yes (41) Laparoscopic stapler resection 13 (33) Open resection 19 (49) Other * 5 (13) Perioperative information (Table 1) and demographic data (Table 2) were available in all 39 cases. The management of the distal ureter was transvesical or extravesical open excision with a bladder
european urology 51 (2007) 1639 1644 1641 Table 2 Patients characteristics (n = 39) Median age (range) 67 yr (34 87) Sex (%) Male 25 (64) Female 14 (36) Median BMI (range) 26.7 (19.4 37.2) Tumor side (%) Right 18 (46) Left 21 (54) Tumor site (%) Pelvicalyceal 22 (56) Ureter 10 (26) Proximal 0 (0) Mid 3 (8) Distal 7 (18) Pelvicalyceal and ureter 7 (18) Proximal ureter 3 (8) Mid ureter 2 (5) Distal ureter 2 (5) History of bladder TCC (%) No 24 (62) Yes 15 (38) BMI = body mass index; TCC = transitional cell carcinoma. cuff in 19 cases. In 13 cases, the distal ureter was resected by using the previously described laparoscopic stapling technique [3], in 3 cases the resection was cystoscopically assisted, and in 2 cases a part of the distal ureter was left in situ. These latter two cases involved older patients with extensive adhesions attributable to prior surgery in the retroperitoneum and the pelvis. No information on the management of the distal ureter was available in 2 cases. Intraoperative complications occurred in 4 patients including two bowel injuries, one iliac vein injury, and one splenic laceration. Two of these complications were associated with the open resection of the distal ureter. One patient died 46 d postoperatively from sepsis and gastrointestinal bleeding. The two other major postoperative complications included one vesicovaginal fistula at the open bladder cuff resection site and one trocar site hernia. Five patients had minor postoperative complications, which included two trocar site hematomas, one idiopathic transient coagulopathy, one prolonged ileus, and one pneumonia. Pathologic information is summarized in Table 3. In 4 cases of low-grade disease verified on preoperative biopsy, the specimen was morcellated in a nonpermeable laparoscopic retrieval bag (Cook Urological Inc, Spencer, IN, USA) prior to extraction, accounting for the incomplete pathologic stage data in those cases. One patient with N1 disease and one patient with T4 disease received adjuvant chemotherapy. Table 3 Final pathology information (n = 39) Median tumor size (range) 3.1 cm (0.8 7.5) Tumor stage (%) Tis 3 (8) Ta 12 (30) T1 7 (18) T2 7 (18) T3 7 (18) T4 1 (3) Unavailable 2 (5) Tumor grade (%) Low grade 8 (20) High grade 31 (80) Lymph nodes (%) Nx or N0 38 (97) N+ 1 (3) Venous/lymphatic invasion (%) Not present 27 (70) Present 6 (15) Unavailable 6 (15) CIS present (%) No 22 (56) Yes 14 (36) Unavailable 3 (8) Multifocal disease (%) No 14 (36) Yes 23 (59) Unavailable 2 (5) Surgical margins (%) Negative for tumor 31 (80) Positive for tumor 4 (10) Unavailable 4 (10) Positive margin type (n = 4) Bladder cuff margin 3 (2 CIS) Soft tissue and vascular margin 1 CIS = carcinoma in situ. Follow-up information was available for all 39 patients with a minimum actual follow-up of 60 mo (median: 74; range: 60 148). During this time 27 patients (69%) developed at least one TCC recurrence. Eighteen patients had a urothelial recurrence, which included 2 patients with recurrences in the contralateral upper tract, and 9 patients had nonurothelial recurrences. Two of the latter patients (5%) had a local recurrence of the disease (one in the retroperitoneum and one in the pelvis); the remaining seven patients developed lymph node metastases or distant metastases. No port site metastases were seen. The 2 patients in whom the distal ureter was not excised did not develop a recurrence in the ureteral stump during follow-up. The median time to detection of the first recurrence was 9 mo (range: 4 54) for the patients with urothelial recurrences and 7 mo (range: 1 31) for patients with nonurothelial recurrences. On statistical analysis, tumor site was the only variable significantly associated
1642 european urology 51 (2007) 1639 1644 survival than patients with higher stage tumors (T2 T4), (hazard ratio: 0.25; 95%CI, 0.08 0.88; p = 0.03). At the time of study completion 23 patients (59%) were alive after a median follow-up of 74 mo (range: 60 148), and all were without evidence of disease. The actuarial 5-yr overall and cancerspecific survival rates were 59% and 68%, respectively. The Kaplan-Meier curves for overall and disease-specific survival are shown in Fig. 2. 4. Discussion Fig. 1 Kaplan-Meier curves for overall, urothelial, and nonurothelial recurrence-free survival. with overall disease recurrence. Patients with ureteral tumors were more likely to develop a recurrence than patients with pelvicalyceal tumors, (hazard ratio: 0.46; 95% confidence interval [95%CI], 0.18 0.93; p = 0.03). None of the analyzed parameters was significantly associated with nonurothelial recurrence-free survival. Kaplan-Meier curves for overall, urothelial, and nonurothelial recurrencefree survival are shown in Fig. 1. Eleven patients ultimately died from progressive TCC 7 to 59 mo (median: 31) after the operation. For these 11 patients the median time from recurrence to death was 13 mo (range: 0 46). One patient who had a local recurrence died with evidence of disease, but not from the disease, 24 mo after surgery; in another patient the cause of death was unknown. Three patients died without evidence of disease. On statistical analysis tumor stage was the only factor significantly associated with disease-specific mortality. Patients with lower-stage disease (Tis, Ta, and T1) had a significantly greater disease-specific Fig. 2 Kaplan-Meier curves for overall and disease-specific survival. Laparoscopic RNU was developed in an effort to reduce the morbidity of the surgical management of upper tract TCC. Indeed, the benefits of laparoscopic RNU with regard to perioperative morbidity, cosmesis, and convalescence have been well established [4,6,7]. The value of these advantages is obviously predicated on the assumption that the laparoscopic technique, adhering to time-honored principles of surgical oncology, can offer comparable cancer control. Up to this point, however, limited data regarding the long-term oncologic efficacy of laparoscopic RNU have limited the more widespread adoption of this approach. This valid concern has resulted in urologists in general being less eager to pursue a laparoscopic technique for aggressive upper tract TCC than has been the case for other renal tumors [9]. Against this background, we present encouraging long-term oncologic outcomes on 39 patients who underwent laparoscopic RNU for upper tract TCC at our institution. This series represents our initial experience and, therefore, includes a period of time in the learning curve, which to a certain extent makes our results more generalizable to the urologic community at large. Five-year disease-specific survival of 68% compares favorably with the benchmarks from mature series of open RNU, for which the corresponding 5-yr figures range from 50% to 74% [1,12 14]. With more than 80% of our patients having the indications of high-grade and/or invasive (T2) disease, the composition of our series is reasonably comparable to open series in terms of upper tract TCC case mix [1,14]. One notable exception is the multicenter study of open RNU reported by Ozsahin et al [15] in which the proportion of high-stage tumors was greater (76%) and the 5- and 10-yr overall survival rates were correspondingly lower (29% and 19%, respectively). These authors found only tumor stage, tumor site, and residual tumor after surgery were independently associated with survival. Our experience is consistent with these findings in which only tumor
european urology 51 (2007) 1639 1644 1643 stage and tumor site (ureter worse than renal pelvis) were significantly associated with cancer-specific survival and recurrence-free survival, respectively. We did not find a significant association of tumor grade with clinical outcomes, as has been previously shown [16], most likely because of the small number of low-grade tumors in our cohort. Though ours is the largest single-center series of laparoscopic RNU with long-term follow-up (minimum actual follow-up: 5 yr), the cohort size represents a relative limitation of this study. The retrospective nature of the study also carries inherent limitations; however, we provide complete long-term follow-up information on a series of consecutive patients. Since our minimum actual follow-up of 60 mo is roughly twice as long as the median survival time of the patients who died from TCC and more than six times as long as the median time to recurrence, we believe that our results correctly reflect the oncologic outcomes after laparoscopic RNU for upper tract TCC. High-grade TCC is an aggressive disease with a propensity not only for metachronous recurrence in the urothelium, but also for local implantation. Therefore the risk of tumor seeding and port site metastasis is a specific concern related to the laparoscopic treatment of these tumors [17]. We report a 5% incidence of local recurrence. In light of the high number of patients with adverse tumor characteristics, these results again compare well with the data reported in series of open RNU for upper tract TCC. In a recent review of 18 studies, Rassweiler et al [14] found incidences of local recurrence of 0 15% after both open and laparoscopic RNU. Furthermore, in the multicenter study reported by Ozsahin et al [15], the local recurrence rate after open RNU was 22%. In the present study no incidence of port site metastasis occurred. However, it should be noted that we saw one case of port site metastasis in our experience subsequent to the series reported herein. The specific and somewhat exceptional circumstances of that case, including an obvious violation of the tumor boundaries, have been previously reported [18]. That case represents less than 1% of our overall experience with laparoscopic RNU, and it is one of a total of seven cases of port site metastasis after laparoscopic RNU reported to date [14,19]. Furthermore, incisional scar metastasis is a well-recognized problem in open oncologic surgery with reported incidences of 0.4% for renal cell carcinoma and 1.5% for colon cancer [20]. Portsitemetastasis is hence considered a rare event that is a function of tumor biology rather than of surgical approach [14,20,21]. Our study demonstrates long-term cancer control for laparoscopic RNU well in the range of the results of open RNU. Therefore we believe that a laparoscopic approach does not in itself compromise the oncologic efficacy of RNU. In the face of the welldescribed advantages of laparoscopic surgery in the areas of morbidity and perioperative outcomes, these findings support the further development of laparoscopic RNU as a reasonable and effective alternative to the standard of care for high-grade or high-stage upper tract TCC. 5. Conclusions Laparoscopic RNU is a highly effective treatment for aggressive TCC of the upper urinary tract, and its long-term overall and disease-specific survival rates compare favorably with the respective rates reported after open surgery. Concerns about long-term tumor control, therefore, should not limit the further expansion and refinement of laparoscopic techniques in the management of upper tract TCC. If our results are corroborated in other large series, laparoscopic RNU should become the new standard of care for the surgical treatment of upper tract TCC. Conflicts of interest None of the authors has any commercial association to disclose that might pose a conflict of interest in connection with this work. References [1] Hall MC, Womack S, Sagalowsky AI, et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology 1998;52:594 601. [2] Clayman RV, Kavoussi LR, Figenshau RS, et al. Laparoscopic nephroureterectomy: initial clinical case report. J Laparoendosc Surg 1991;1:343 9. [3] Jarrett TW, Chan DY, Cadeddu JA, et al. Laparoscopic nephroureterectomy for the treatment of transitional cell carcinoma of the upper urinary tract. Urology 2001;57: 448 53. [4] Shalhav AL, Dunn MD, Portis AJ, et al. Laparoscopic nephroureterectomy for upper tract transitional cell cancer: the Washington University experience. J Urol 2000;163:1100 4. [5] Yoshino Y, Ono Y, Hattori R, et al. Retroperitoneoscopic nephroureterectomy for transitional cell carcinoma of the renal pelvis and ureter: Nagoya experience. Urology 2003;61:533 8.
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