Laparoscopic versus Open Nephroureterectomy: Perioperative and Oncologic Outcomes from a Randomised Prospective Study

EUROPEAN UROLOGY 56 (2009) 520–526

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Urothelial Cancer

Laparoscopic versus Open Nephroureterectomy: Perioperative and Oncologic Outcomes from a Randomised Prospective Study Giuseppe Simone *, Rocco Papalia, Salvatore Guaglianone, Mariaconsiglia Ferriero, Costantino Leonardo, Ester Forastiere, Michele Gallucci ‘‘Regina Elena’’ National Cancer Institute, Department of Urology, Rome, Italy

Article info

Abstract

Article history: Accepted June 9, 2009 Published online ahead of print on June 21, 2009

Background: Laparoscopic nephroureterectomy (LNU) is increasingly being used instead of open nephroureterectomy (ONU) for the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT), but the evidence of equal oncologic effectiveness is still lacking. Objective: To present perioperative and oncologic results from a prospective randomised study comparing ONU and LNU. Design, setting, and participants: Eighty patients with nonmetastatic UUT UC and without previous history of UC were enrolled. Of those, 40 patients (group A) randomly received ONU and 40 patients (group B) randomly received LNU. Interventions: ONU was performed through a flank incision with a lower quadrant incision to allow excision of a bladder cuff. Transperitoneal LNU was performed with a four-trocar technique, and bladder cuff was detached with a 10-mm LigaSure device. Measurements: Perioperative data were compared with the student t test. Bladder tumour–free survival (BTFS), metastasis-free survival (MFS), and cancer-specific survival (CSS) curves for both groups were compared with the log-rank test before and after stratifying patients for pT category and tumour grade. Results and limitations: Operative times were comparable, while mean blood loss and mean time to discharge were significantly lower in group B (both p values <0.001). At a median follow-up of 44 mo, BTFS, CSS, and MFS were not significantly different between the two groups (log rank test; BTFS: p = 0.86; CSS: p = 0.2; MFS: p = 0.124). When matched for pT3 and high-grade tumours, CSS and MFS were significantly different between the two groups in favour of ONU ( p = 0.039 and p = 0.004, respectively, for pT3 tumours; p = 0.078 and p = 0.014, respectively, for high-grade tumours). The limitations of our study include the small sample size, the single-centre experience, the personal choice of laparoscopic technique, and not performing lymphadenectomies. Perioperative data and preliminary oncologic results were presented at 22nd Congress of the European Association of Urology, Berlin, Germany. Conclusions: In patients with organ-confined UUT UCs, LNU has the advantages of minimal invasiveness and oncologic outcomes comparable to those of ONU, while its effectiveness in patients with advanced stage diseases remains to be proven. # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Keywords: Laparoscopic nephroureterectomy Open nephroureterectomy Urothelial carcinomas of the upper urinary tract

* Corresponding author. Istituto Nazionale Tumori ‘‘Regina Elena’’, Dipartimento di Urologia Oncologica, Via Elio, Chianesi 53, 00144, Roma, Italy. Tel. +39 0652665005; Fax: +39 0652666983. E-mail address: [email protected] (G. Simone). 0302-2838/$ – see back matter # 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eururo.2009.06.013

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EUROPEAN UROLOGY 56 (2009) 520–526

1.

Introduction

Urothelial carcinomas (UCs) of the upper urinary tract (UUT) are rare, accounting for about 5% of all urothelial tumours. The propensity for recurrence, multifocality, and progression, especially in cases with high-grade and highstage tumours, has supported nephroureterectomy as the standard of care [1–3]. Conservative treatments, such as segmental ureterectomy [4] and endoscopic management [5], showed encouraging results in patients with low-grade tumours, but there is not a consensus on the role of endoscopic management of UUT UCs. Laparoscopic nephroureterectomy (LNU) was first described in 1991 by Clayman et al. [2] and has since become an alternative standard of care at many centres of excellence [3,6]. We have found that LNU reduces operative blood loss and duration of hospitalisation [7]. Prospective studies comparing long-term outcomes of LNU and open nephroureterectomy (ONU) are lacking, mainly due to the low incidence of UUT UC. This study compares perioperative data and oncologic outcome of laparoscopic and conventional open procedures. To the best of our knowledge, this paper is the first report of oncologic results from a prospective study comparing LNU and ONU.

Table 1 – Preoperative data of patients p value*

ONU

LNU

No. of patients Mean age, yr (range) Male Female Right side Left side

40 61.3 (52–70) 26 14 19 21

40 59.6 (48–71) 24 16 22 18

Preoperative stage cT1N0M0 cT2N0M0 cT3N0M0

11 20 9

9 24 7

0.6

13 18 9

16 14 10

0.65

24 7 11 1

25 11 9 2

Tumor location Pelvis Ureter Pelvis and ureter Presenting symptoms Gross haematuria Microscopic haematuria Flank pain Incidental diagnosis

0.65 0.6 0.5

–

ONU = open nephroureterectomy; LNU = laparoscopic nephroureterectomy. x2 test.

*

LNU was performed with a four-trocar technique. Once nephrectomy was carried out, the ureter was dissected progressively up to its distal tract. Caudal ureteral dissection continued until the detrusor

2.

Patients and methods

2.1.

Study design

From January 2003 to January 2006, 80 patients underwent nephroureterectomy for UC primarily occurring in the UUT. Forty patients (group A) were randomly assigned to receive ONU and 40 patients (group B) were randomly assigned to receive LNU. Exclusion criteria included previous history of urothelial cancer, presence of nodal involvement, distant metastasis and coexistent bladder tumour at diagnosis. After formal study approval by our institutional review board, all patients gave a written informed consent to participate. Treatment was assigned on a 1:1 ratio. Randomisation was performed using a stratified permuted randomisation algorithm. The stratification factors included clinical stage and age. End points of the study were perioperative outcomes (intraoperative blood loss, operative times, and time to discharge) and oncologic outcomes (bladder tumour–free survival [BTFS], metastasis-free survival [MFS], and cancer-specific survival [CSS]). The primary end point by which the sample size was determined was mean time to hospital

muscle fibres at the ureterovesical junction were identified. A 1-cm area of bladder adventitia around the ureterovesical junction was cleared. The ureter was retracted upwards and laterally, tenting up the bladder wall. The intramural tract of the distal ureter was excised using a 10-mm LigaSure Atlas (Valleylab, Tyco Healthcare UK Ltd, Gosport, UK) and was detached from the bladder wall. A 6-cm lower-quadrant incision was used to remove the specimen in an Endocatch bag (Endocatch Gold, Tyco Healthcare UK Ltd, Gosport, UK). Two drains were placed through the 5-mm ports. This technique has been recently described by Tsivian et al. [8]. Lymph node dissection was not performed in any case. All surgical procedures were performed by a single, experienced surgeon (MG).

2.4.

Discharge criteria

Drains were removed when drainage was lower than 50 ml/d. Patients were discharged once they had an absence of fever and anaemia and an absence of leucocytosis (white blood count <11.0  109  L

1

), with

clear evidence of absence of nausea or vomiting and with recovered bowel function and when tolerating satisfactory oral intake.

discharge. Assuming a difference in mean time to discharge between the two groups of about 0.70 of the standard deviation, 80 patients were

2.5.

Follow-up

enrolled to detect this difference with a power of 90% at a significance level of 5% (two-tailed student t test).

Mean follow-up was 41 mo (range: 30–66). Bladder and contralateral UUT recurrences were recorded as urothelial recurrences, while

2.2.

Diagnosis and preoperative staging

nonurothelial recurrences were recorded as metastases. The sites and the timing of recurrences were reported and analysed.

Presenting symptoms and tumour localisation are summarised in

The follow-up regimen included abdominal ultrasound and cysto-

Table 1. Preoperative evaluation included blood work, urine cytology,

scopy at 3-mo intervals for the first 2 yr, at 6-mo intervals for the

computed tomography (CT), and bone scan.

subsequent 2 yr, and annually thereafter. Chest x-rays and CT scans were alternately performed at 6-mo intervals for the first 5 yr and, subsequently,

2.3.

Surgical technique

were alternately performed yearly. Urine cytology was performed at 6-mo intervals.

ONU was performed according to standard criteria through a flank

No patients received adjuvant treatments, although gemcitabine–

incision combined with a lower quadrant incision. A formal bladder cuff

cisplatin systemic chemotherapy was administered when metastases

was performed through a completely extravesical approach.

developed.

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Fig. 1 – Comparison with the log-rank test of cancer-specific survival (CSS) and metastasis-free survival (MFS) of patients treated either with laparoscopic nephroureterectomy (LNU) or with open nephroureterectomy (ONU); (A) between-group comparison of CSS curves ( p = 0.2); (B) between-group comparison of MFS curves ( p = 0.124); (C) between-group comparison of CSS curves of patients with pT3 tumours ( p = 0.039); (D) between-group comparison of MFS curves of patients with pT3 tumours ( p = 0.004); (E) between-group comparison of CSS curves of patients with high-grade tumours ( p = 0.014); (F) between-group comparison of MFS curves of patients with high-grade tumours ( p = 0.078).

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EUROPEAN UROLOGY 56 (2009) 520–526

Table 2 – Perioperative data

Mean operative time, min (range) Mean blood loss, ml (range) Mean time to discharge, d (range)

Group A (ONU)

Group B (LNU)

p value*

78 (35–150) 430 (250–760) 3.65 (3–5)

82 (50–140) 104 (50–260) 2.3 (2–3)

0.72 <0.001 <0.001

ONU = open nephroureterectomy; LNU = laparoscopic nephroureterectomy. Student t test.

*

2.6.

Statistical analysis

Perioperative data of the two groups were compared with the student t test. Differences were considered significant when the p value was <0.05. The prognostic roles of pT category, tumour grade, and surgical approach were tested univariately with the log-rank test, and the significance threshold was settled at 0.05. Comparisons of BTFS, MFS, and CSS curves were performed between groups with the log rank-test. Subsequent comparisons of curves were performed after stratifying patients for pT category and tumour grade to establish the oncologic safety of LNU in the treatment of organ-confined and advanced disease. Statistical analysis was performed with the Statistical Package for the Social Sciences v.15.0 (SPSS Inc, Chicago, IL, USA).

3.

Results

The two treatment groups were homogeneous in terms of preoperative characteristics and clinical stages, as shown in Table 1. Perioperative data are given in Table 2 and were presented in a previous report [7]. Operative times were comparable, while mean blood loss and mean time to discharge were significantly lower in group B (both p values <0.001). No blood transfusion was administered to any patient, and no complications occurred postoperatively in any patient.

Table 3 – Pathologic results and sites of metastases Pathologic Stage Ta/T1 T2 T3 Tumour Grade G1 G2 Low grade High grade G3 Sites of metastases RP nodes Bone Lung Liver Port site

ONU

LNU

p value*

12 15 13

20 8 12

0.8**

5 22 10 12 13

6 22 11 11 12

2 3 1 – –

2 4 2 2 1

0.6***

–

ONU = open nephroureterectomy; LNU = laparoscopic nephroureterectomy; RP = retroperitoneal. x2 test. ** pT 2 versus pT3. *** Low-grade versus high-grade tumours. *

Pathologic results are summarised in Table 3. At a median follow-up of 44 mo (range: 6–70), 12 cancer-related deaths occurred (4 in group A and 8 in group B). The 5-yr CSS rate of group B (79.8%) was lower than that of group A (89.9%), although this difference was not statistically significant (log-rank test, p = 0.2) (Fig. 1A). Metastases occurred in 17 patients (6 in group A and 11 in group B; 1 was a 12-mm port-site metastasis). As observed for CSS, 5-yr MFS of group B (72.5%) was lower than that of group A (77.4%), although this difference was not statistically significant (log rank test, p = 0.124) (Fig. 1B). The BTFS rates of the two groups were similar: Subsequent bladder tumour occurred in 9 patients from group A and in 10 patients from group B (log rank test, p = 0.86). When matched for pT category, CSS and MFS of pT3 tumours were significantly different between the two groups in favour of ONU (log rank test, p = 0.039 and p = 0.004, respectively). When matched for tumour grade, MFS and CSS of the two groups were similar in cases with low-grade tumours: Neither metastasis nor cancer-related death was observed, while the outcomes of patients with high-grade UC were significantly impaired by LNU (log rank test, p = 0.078 for CSS (Fig. 1E) and p = 0.014 for MFS (Fig. 1F), respectively). 4.

Discussion

The minimal invasiveness of LNU in terms of reduced blood loss and faster patient recovery make this procedure increasingly popular in the urologic community. In addition to our prospective experience, the advantages of laparoscopic procedures in terms of perioperative data and patient recovery have been documented. The current trial clearly establishes the benefits of LNU in terms of perioperative data. Since the first report of LNU by Clayman et al. [2], a major concern has been the oncologic safety of this procedure. Over the past 18 yr, three major issues have emerged as debating points: (1) the role and appropriate template for lymph node dissection, (2) the incidence of port-site metastases after LNU and the supposed role of pneumoperitoneum in tumour-cell seeding, and (3) the management of distal ureter during LNU. With regard to the incidence of port-site metastases, an increased risk of tumour-cell spillage due to elevated pressure and lack of tactile control has been presumed. But a recent review by Zigeuner and Pummer showed that only 11 port-site metastases have been reported in literature [9]. In a series of 100 cases with three port-site metastases, Schattemann et al. addressed the importance of extracting

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the specimen into a secured endobag [10]. Although the specimen was removed into an endobag in our series and although no signs of urinary tract violation were detected, a case of port-site metastasis occurred. In these cases, it is difficult to find a link between high intra-abdominal pressure and tumour-cell spillage. It must be considered that, certainly, some cases have not been published and may never be; therefore, the incidence rate of port-site metastases is difficult to establish. Schatteman et al. [10] estimated the incidence rate to be about 1.2%, but in 2004, Rassweiler et al. [11] estimated it to be about 1.6%; thus, the incidence rate of port-site metastases after LNU can be estimated at approximately 1–2%. The risk of port-site metastases should not be the main reason to reserve LNU for patients with low-stage disease. In 2004, Rassweiler et al. [11] suggested that LNU be considered in cases of cT2 tumours or lower and of cN0 tumours. Many recent reports of LNU have been published and all support the feasibility of using LNU to treat UUT UCs. Recently, Terakawa et al. published data on 240 consecutive patients, 120 treated with LNU and 120 with ONU [12]. They found that the outcomes of patients with high-grade UUT UC who had undergone LNU were poorer than those of patients treated with ONU. Although the laparoscopic approach had not an independent prognostic impact on the outcomes of patients in the series by Terakawa et al., the authors concluded that the role of LNU in patients with high-grade UUT UC needed to be investigated further. Although not provided by prospective studies, recent evidence shows that an extended lymphadenectomy could lead to improved oncologic outcome [13,14]. Kondo et al. reported interesting data concerning the appropriate template and possible therapeutic role of an extended lymph node dissection [15]. The appropriate template for lymph node dissection remains to be established according to tumour site as well as to ‘‘how extended’’ the dissection should be. Abe et al. failed to find a significant correlation between the increasing number of removed nodes and CSS probability [16]. Although many authors addressed the importance of lymphadenectomy in cases with preoperative or intraoperative evidence of nodal involvement, the indication for lymphadenectomy in patients without evidence of nodal involvement is not substantiated to date. In a previous report, we highlighted how, in patients with organ-confined disease and without evidence of clinical node involvement, the outcomes for those with pN0 and with pNx tumours seemed comparable at 5-yr follow-up [17]. Moreover, Zigeuner and Pummer concluded in a recent review of literature that if lymph node dissection is intended in locally advanced disease, the open approach should be preferred and considered the gold standard [9]. Further prospective studies will address the indications for lymphadenectomy in UUT-UC; the template according to tumour location, the feasibility during LNU and, finally, the oncologic safety of lymphadenectomy in cases with nodal involvement due to the supposed risk of tumour-cell spillage from high intra-abdominal pressure. The standard management of distal ureter during LNU is open. A variety of options have been reported, including the

pluck technique with transurethral resection [18] or incision [19] of the ureteral orifice, the endoscopic use of a GIA stapler [20] and the use of a 10-mm LigaSure device [8], which was used in this series. Several laparoscopic management techniques of distal ureter have been described, and it is well established that the goal would be avoiding urinary leakage from the urinary tract and performing a complete bladder-cuff excision. In a retrospective, international, multicentre study by El Fettouh et al., several approaches were used, depending on the centre [21]. In that study of 116 patients, no differences regarding recurrence were noted. Again, no prospective comparative data are available; thus, all alternative approaches to the open one need to be validated. The most important issue is the oncologic feasibility of LNU: the contrasting data available in literature make it difficult to evaluate. In a recent review, Zigeuner and Pummer reported 5-yr disease-specific survival rates from several published series of LNU [9]. Surprisingly, rates ranged from 56% to 92%. Appropriate patient selection could lead to different oncologic results; however, when considering that patients with cN+ tumours were usually excluded from laparoscopic procedure, it is reasonable to think that all series had a mix of cases and, thus, to expect similar oncologic outcomes. In the current study, we highlight the feasibility and oncologic safety of LNU for patients with organ-confined disease (pT <3). We found that the occurrence of subsequent metastases and the CSS of patients treated with LNU were comparable to those of patients treated with ONU. Interestingly, when evaluating the outcomes of the two groups of patients without adjusting for pT category and tumour grade, differences in survival were not statistically significant. This result was probably due to the small cohort of patients. We are aware of the possible differences between preoperative clinical staging and final pathologic examination; although preoperative biopsy can provide useful information about the tumour grade, it can reduce clinical understaging, even if not completely. Langner et al. found a remarkable difference between pT3 tumours with microscopic parenchymal invasion and pT3 tumours with macroscopic parenchymal or peripelvic fat invasion, with 5-yr MFS rates of 92% versus 8%, respectively [22]. We agree with Langner et al. about heterogeneity of T3 tumours and, as we addressed in a recent report, the importance of other prognosticators, such as tumour diameter, that could be helpful in determining the best approach for each patient [17]. With regard to tumour grade, we found that the two-tier World Health Organisation/International Society of Urologic Pathology classification was able to stratify the outcome unequivocally. No patients with low-grade disease experienced metastatic occurrence in this series; similarly, in a recent series of 162 ONU, we reported a 5-yr MFS for patients with low-grade UUT UC of 100% [17]. Thus, we confirm the equivalent oncologic efficacy of LNU performed in patients with low-grade tumours. After adjusting curves for pT3 category and high-grade tumours, the between-group comparison demonstrated

EUROPEAN UROLOGY 56 (2009) 520–526

lower MFS and CSS probabilities in patients treated with LNU. Terakawa et al. [12] recently found that the outcomes of patients treated with LNU were significantly poorer than those of patients treated with ONU, addressing the necessity for further investigations to determine the optimal indications for LNU in patients with high-grade disease. In contrast, Waldert et al. recently published results of his series comparing LNU and ONU and concluded that surgical approach did not affect the oncologic outcomes [23]. In our series, the outcomes of patients with organconfined (pT <3) high-grade tumours were not different between the two groups. The limitations of our study are the small sample size, the single-centre experience, the personal choice of laparoscopic technique (totally laparoscopic procedure using the 10-mm LigaSure device to manage distal ureter), and the exclusion of all patients with preoperative evidence of lymph node involvement. Although excluding patients with cN+ tumours can be considered a bias to evaluate the oncologic appropriateness of LNU, it allowed us to compare outcomes of patients without metastatic diseases at diagnosis and to perform ONU with an extended retroperitoneal lymph node dissection in all patients with node involvement at clinical staging. The sample size was defined based on mean time to discharge, so our findings provided strong evidence of superiority of LNU over ONU in terms of perioperative data. The oncologic outcomes have to be considered preliminary because the sample size was not determined to detect differences in oncologic outcomes between the two groups. Only further studies with larger cohorts of patients and with long follow-up will be able to provide conclusive data.

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Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.

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5.

Conclusions

53:720–31. [10] Schatteman P, Chatzopoulos C, Assenmacher C, et al. Laparoscopic

LNU proved to be superior to ONU in terms of perioperative outcome, thanks to the advantages of minimal invasiveness and oncologic outcomes that were comparable to ONU in patients with organ-confined disease. Long-term follow-up of larger prospective series comparing LNU and ONU is needed to prove the oncologic effectiveness of LNU in patients with advanced-stage tumours.

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Author contributions: Giuseppe Simone had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Administrative, technical, or material support: None.

of the extent of regional lymphadenectomy on the survival of

Supervision: Gallucci, Forastiere.

patients with urothelial carcinoma of the upper urinary tract.

Other (specify): None.

J Urol 2007;178:1212–7.

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