Original Paper
Urologia
Received: April 2, 2014 Accepted after revision: May 24, 2014 Published online: September 19, 2014
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
Internationalis
Matched-Pair Analysis of Open versus Laparoscopic Nephroureterectomy for Upper Urinary Tract Urothelial Cell Carcinoma James P. Blackmur a Grant D. Stewart b, d Eric A. Egong c Mark L. Cutress b, d David A. Tolley b Anthony C.P. Riddick d, e S. Alan McNeill b, d
a
Department of Surgery, Victoria Hospital, Kirkcaldy, b Department of Urology, Western General Hospital, c College of Medicine and Veterinary Medicine, University of Edinburgh, and d Edinburgh Urological Cancer Group, Edinburgh, and e Department of Urology, Addenbrookes Hospital, Cambridge, UK
Abstract Objective: Laparoscopic nephroureterectomy (LNU) offers a superior morbidity profile compared with open nephroureterectomy (ONU) in treating upper urinary tract urothelial cell carcinoma. Evidence of oncological equivalence between LNU and ONU is limited. We compare operative and oncological outcomes for LNU and ONU using matched-pair analysis. Methods: Of 159 patients who underwent a nephroureterectomy at a single institution between April 1992 and April 2010, 13 pairs of ONU and LNU patients were matched for gender, age, tumour location, tumour grade and stage. Operative details, post-operative characteristics and recurrences were collated and survival rates analysed using the Kaplan-Meier method. Results: There was no significant difference in mean operation time between LNU (191 min) and ONU (194 min, p = 0.92). There was no significant difference in the 5-year survival rate between LNU and ONU (overall survival 59.1% vs. 73.5%, p = 0.18; progression-free survival 24.0% vs. 56.0%, p = 0.14; cancer-specific survival 60.9% vs. 73.5%, p = 0.56; bladder cancer recurrence-free survival 8.7% vs. 0.0%, p = 0.09). Conclusion: Amidst limited RCT and com-
© 2014 S. Karger AG, Basel 0042–1138/14/0942–0156$39.50/0 E-Mail [email protected] www.karger.com/uin
parative studies, this study presents further evidence of oncological equivalence between LNU and ONU. There was a trend towards poorer outcomes following LNU though, which merits further study. © 2014 S. Karger AG, Basel
Introduction
Upper urinary tract urothelial cell carcinomas (UUTUCC) are rare, accounting for only 5% of cases of UCC [1] and with an annual incidence of 1–2 cases per 100,000 per year [2]. UUT-UCC is a biologically aggressive disease with a high potential for recurrence and death [3]. Up to 60% of UUT-UCCs are invasive at diagnosis compared with only 15–25% of bladder tumours [4]. Aggressive extirpative treatment is therefore required [5]. Nephrectomy in combination with ureterectomy and complete excision of the ureteral orifice from the bladder wall is considered the standard curative surgical treatment [6]. Although open nephroureterectomy (ONU) has been regarded as the gold standard, it is associated with signifi-
James P. Blackmur and Grant D. Stewart contributed equally to this work.
Mr Grant Stewart Clinical Senior Lecturer, Department of Urology Western General Hospital, Crewe Road South Edinburgh, EH4 2XU (UK) E-Mail grant.stewart @ ed.ac.uk
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Key Words Ureter · Transitional cell carcinoma · Laparoscopy · Matched-pair analysis · Nephroureterectomy
cant morbidity. Laparoscopic nephroureterectomy (LNU) has increasingly been used as a minimally invasive alternative [1]. Given the rarity of UUT-UCC, there are few studies comparing the efficacy and safety of LNU versus ONU. A Cochrane review concluded that there were no adequately controlled trials to compare LNU with ONU [7]. Even meta-analyses have been on a relatively small scale: one compared outcomes from 131 patients undergoing LNU with 681 undergoing ONU [8]. One small randomised trial (80 patients) demonstrated that LNU was associated with less blood loss and shorter length of hospital stay than ONU [9]. The conclusion of many studies is that there is no significant difference in oncological outcomes: overall survival (OS), progression-free survival (PFS) or cancer-specific survival (CSS) [7, 10, 11]. Interestingly, while the study by Simone et al. [9] was powered to examine differences in length of hospital stay, they found trends towards worse 5-year CSS with LNU than ONU (79.8 vs. 89.9%, p = 0.2) and 5-year metastases-free survival (72.5 vs. 77.4%, p = 0.12). CSS was significantly lower in LNU than in ONU with higher-grade tumours (p = 0.04 for pT3 tumours). Many observational studies have been criticised for a negative selection bias in the group undergoing ONU [6]. LNU has tended to be undertaken in patients with more favourable pathological stages and a more favourable primary tumour locus (more likely to be tumour of renal pelvis than ureter) [11, 12]. Advanced tumour stage and grade are established strong negative prognostic factors on multivariate analysis [13] and the more favourable selection bias in LNU patients has precluded any definitive statements on oncological equivalency between the two treatments to date. In such a rare condition, a large-scale RCT would require multiple centres and international collaboration to attain sufficient statistical power. It would then be difficult to standardise factors such as surgical technique, post-operative care and oncological management. In the absence of such a trial, a matched-pair analysis is useful. Matched-pair analysis controls for confounding factors and therefore allows more accurate comparison of survival rates. A matched-pair analysis can achieve acceptable statistical power with smaller numbers of patients. The approach was recently used to compare short-term outcomes in 22 pairs undergoing robotic nephroureterectomy or LNU for UUT-UCC [14]. It has also been used to compare lithotripsy and ureteroscopy for upper tract ureteric calculi [15] and to compare outcomes after chemo-
therapy in small numbers of patients with lymphoma [16], squamous cell carcinoma [17, 18], primary glioblastoma [19] and macular degeneration [20]. It is therefore a valid approach with which to compare outcomes in rare conditions. A total of 120 cases of LNU over a period of 18 years have been undertaken in our centre. Given the volume of work, the department was able to develop and maintain a standardised protocol for post-operative care and followup. To minimise the confounding impact of outside variables and selection bias, we undertook matched-pair analysis of operative and oncological parameters for patients who underwent LNU or ONU for UUT-UCC. To our knowledge this is the first study of its kind to be undertaken.
Laparoscopic versus Open Nephroureterectomy
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
Methods
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All patients who underwent LNU and ONU for UUT-UCC at our institution between April 1992 and April 2010 were included in this study. Surgery was undertaken by 9 different consultant urologists. LNU was performed via a transperitoneal approach, as previously described [10, 21]. Patients undergoing both ONU and LNU had preliminary mobilisation of their kidney and proximal ureter before extra- or trans-vesical mobilisation of the lower ureter and bladder cuff. Neither LNU nor ONU included formal lymphadenectomy, unless there were suspicious lymph nodes observed on pre-operative staging scans or intraoperatively. Strict criteria were used to match LNU and ONU patients. Five parameters were employed in sequence: (1) gender; (2) age (divided into 5-year cohorts: 56–60, 61–65, 66–70, 71–75 and 76–80 years); (3) tumour locus (upper ureter, lower ureter, renal pelvis and renal calyx); (4) tumour stage, and (5) tumour grade. These variables where selected for matching as they are established prognostic factors for OS, CSS and PFS [12, 22–24]. When more than one match was identified, random numbers were assigned in order to rank potential matches. Standard post-operation follow-up involved a review at 3 months, then at 6-monthly intervals for 2 years, and subsequently once yearly. The follow-up protocol was standardised across the study period, consisting of history and examination, urinary cytology, cystoscopy, radiographic imaging of the UUT, and chest radiography, CT or MRI when indicated. Data were collected retrospectively from hospital medical records. Data collected included the following: pre-operative grade and stage, operative characteristics (estimated blood loss, operation time) and length of post-operative stay. Post-operative complications were assessed using the Clavien-Dindo classification [25]. Data were also collected regarding follow-up, disease recurrence and cause of death. If cause of death was not available in the medical notes, this was obtained from death certificates from the General Registry Office of Scotland. The primary end points of this study were oncological outcomes (OS, CSS and PFS). To achieve a power of 0.8, with a moderate effect size of 0.6 and an α-error probability of 0.05, we re-
Table 1. Descriptive characteristics of the 13 matched pairs of pa-
Table 2. Operative and post-operative outcomes
tients identified LNU (n = 13)
Gender, n Male 7 (26.9%) Female 6 (23.1%) Age, years Mean 68.0 Range 58.2–77.0 Tumour location, n Renal pelvis/calyces 5 Upper ureter 1 Mid ureter 0 Lower ureter 7 Stage, n pTa 10 pT2 1 pT3 2 Grade, n I 1 II 9 III 3 Length of follow-up, months Median 25.8 Range 2.8–166.0
ONU (n = 13)
7 (26.9%) matched 6 (23.1%) 67.5 57.1–77.3
0.92
5 1 0 7
matched
10 1 2
matched
1 9 3
matched
57.0 14.0–187.0
0.13
quired 12 pairs. By comparison, the same t test comparison of two independent means would require a total sample size of 90 patients. Statistical analysis was carried out using IBM SPSS, version 20.0. Significance was indicated by p < 0.05. Independent samples t test was used to compare age, operation time and blood loss. OS, PFS, CSS and bladder cancer recurrence-free survival rates were estimated using the Kaplan-Meier method and p values were generated through the log-rank test.
Results
A total of 13 matched pairs (n = 26 patients) were identified from a pool of LNU (n = 120) and ONU (n = 39) patients, according to the strict matching criteria outlined above. Descriptive characteristics of the matched patients are included in table 1. There was no significant difference in mean age between the two groups. There was a distribution of tumour loci, with 5 pairs in the renal pelvis or calyces, 1 in the upper ureter and 7 in the lower ureter. There was no matched pair identified for mid-ureteric tumours. While the majority of patients had pTa disease (77%), 1 patient pair had pT2 and 2 had pT3 disease. 158
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
Variable
LNU
ONU
Operation time, min Mean Range
191 135–220
194 125–390
p value
p value
Length of post-operative stay, days 7 Median 7.5 Mean Range 3–10 Post-operative complications, n No complication 10 Grade I 1 Grade II 2 Grade IIIa 0 Grade IIIb 0 Grade IVa 0 Grade IVb 0 Grade V (death) 0
10 12.3 5–29
0.02
9 1 1 1 0 1 0 0
0.35
Mean follow-up was not significantly different between the two groups (LNU 25.8 months, ONU 57.0 months, p = 0.13). In the LNU group, 3 patients had pTa bladder recurrence, 1 had pT2 recurrence requiring cystectomy, 2 had retroperitoneal nodal recurrence and 2 had distant recurrence (hepatic, skeletal, cerebral and retroperitoneal nodes). In the ONU group, 4 patients had pTa bladder recurrence and 1 had pulmonary recurrence. Operative and post-operative outcomes are outlined in table 2. The length of post-operative stay was significantly shorter in the LNU group (median: 7 vs. 10 days, p = 0.02). There was no significant difference in operation times between the groups (mean: 191 min LNU vs. 194 min ONU, p = 0.92). Blood loss was only clearly recorded in 1 of the LNU patients and hence comparison was not possible. In the ONU group, estimated median blood loss was 468 ml (range 150–1,100 ml). Post-operative complications occurred in 3 patients in the LNU group and 4 in the ONU group. Grade I postoperative complications developed in 1 patient following LNU (prolonged post-operative ileus) and in 1 patient in the ONU group (acute shortness of breath which settled with analgesia and bronchodilator therapy). Following LNU, 2 patients developed grade II complications: a postoperative wound infection in 1 case and a chest infection in the other. Both of these were treated with antibiotics; 1 patient in the ONU group developed an intra-abdominal Blackmur/Stewart/Egong/Cutress/Tolley/ Riddick/McNeill
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Variable
Table 3. Estimated OS, PFS, CSS, and bladder cancer recurrence-free survival for LNU and ONU
Factor
Operative approach
Mean survival, months
Median survival, months
Estimated 5-year survival
p value
OS
LNU ONU
97.9 136.6
69.0 109.0
59.1% 73.5%
0.18
PFS
LNU ONU
42.0 125.6
34.0 100.0
24.0% 56.0%
0.14
CSS
LNU ONU
109.4 145.2
not reached 141.0
60.9% 73.5%
0.56
Bladder cancer
LNU ONU
58.7 131.3
34.0 167.0
8.7% 0.0%
0.09
collection requiring antibiotics (grade II complication). No patients in the LNU group developed grade III, IV or V complications. In the ONU group, 1 patient developed a grade IIIa complication (acute respiratory distress syndrome requiring a tracheostomy under local anaesthetic, but not intensive therapy unit support) and 1 developed a grade IVa complication (pneumonia requiring intensive therapy unit admission for ventilatory support). Oncological results are summarised in table 3 and figure 1.
Given the small number of patients presenting with UUT-UCC, retrospective observational studies have been the main evidence base for advocating the merits of one treatment over another. Previous studies have been criticised for preferential allocation of LNU to patients with favourable tumour characteristics [7]. Our data demonstrate that in patients matched according to tumour characteristics and demographics there was no significant difference in oncological outcomes between LNU and ONU. There were consistent trends, however, for better outcomes with ONU. This study also demonstrates there was a significantly shorter length of post-operative stay associated with LNU, as has been shown in previous studies [3, 8, 9]. There was no significant difference in operation time between the two patient groups. The major strength of this matched-pair analysis is its head-to-head comparison between LNU and ONU, com-
paring the outcome of similar patients with almost identical tumours. Surgery was conducted by 9 consultant surgeons and all patients underwent uniform surgical approaches (as previously described [10, 21]) with standardised post-operative care and follow-up. As demonstrated by the large percentage of cases undertaken laparoscopically (75% of the total pool), this was the standard approach in our centre. While our study did not control for patient co-morbid status, this has recently been demonstrated not to significantly affect outcome [26]. The limitations of our study are the small sample size, the lack of prospective randomisation and the single-centre experience. While the number of patients matched was relatively small, post hoc power analysis demonstrates a range from 0.72 for OS to 0.99 for PFS. This suggests that there was a 72% chance of detecting a difference in OS between groups if one existed and a 99% chance for PFS. The majority of patients in this study had early-stage disease. There is, therefore, a question as to how far the oncological trends can be generalised. Of the total patient pool only 39 underwent ONU. The strict matching criteria could have been relaxed to increase the number of pairs identified, but this would have defeated the purpose of the study. We considered broadening the study to include other centres; however, other larger studies have presented significant logistical challenges [12], especially in standardising surgical approach and follow-up. Our results support other studies which have demonstrated comparable oncological outcomes for LNU and ONU [8, 10, 11]. While our results were not statistically
Laparoscopic versus Open Nephroureterectomy
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
Discussion
159
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Survival calculated by Kaplan-Meier method.
Color version available online
Operation
1.0
1.0
LNU-censored ONU-censored
0.6
0.4
0.2
0 50
100 150 Time (months)
200
250
0.2
0
50
100 150 Time (months)
200
250
1.0 Cumulative bladder recurrence free survival
Cumulative cancer specific survival
0.4
b
1.0
0.8
0.6
0.4
0.2
0
c
0.6
0 0
a
0.8
0
50
100 150 Time (months)
200
250
d
0.8
0.6
0.4
0.2
0 0
50
100 150 Time (months)
200
Fig. 1. Comparison with log-rank test of oncological outcomes for LNU vs. ONU. a Between-group comparison of OS curves (p = 0.18). b Between-group comparison of PFS curves (p = 0.14).
c Between-group comparison of CSS curves (p = 0.56). d Between-
significant, there was a consistent trend towards worse oncological outcomes in the LNU group. It is not clear whether this trend was because of the small number of patients meeting the strict matching criteria or because of true increased risk of recurrence following LNU. Post hoc analysis does, however, suggest that the study was adequately powered to detect differences in survival. While many previous studies have demonstrated no significant difference in oncological outcomes, Kume et al. [27] found a significantly higher bladder cancer recurrence
rate in laparoscopic cases (69% vs. 36%, p = 0.04). Simone et al. [9] demonstrated that in higher-grade tumours, CSS was significantly lower in LNU (p = 0.04 for pT3 tumours). Fairey et al. [28] recently reported a trend toward worse 5-year recurrence-free survival with LNU (43% vs. 33%, p = 0.06). The reasons for these findings are unclear. Proposed explanations include surgical expertise, whether and to what extent regional lymph node dissection is undertaken and baseline clinico-pathological status [28]. The trend for oncological outcomes found in our study,
160
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
group comparison of bladder cancer recurrence-free survival curves (p = 0.09).
Blackmur/Stewart/Egong/Cutress/Tolley/ Riddick/McNeill
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Cumulative overall survival
ONU 0.8
Cumulative progression free survival
LNU
therefore, further reinforce the call that large-scale work is urgently required. Bladder recurrence-free survival was analysed separately in our study due to the high frequency of recurrence in patients with UUT-UCC; 2 patients had a documented bladder cancer prior to being diagnosed with UUT-UCC (both in the LNU group) – 1 had a bladder recurrence and subsequently died and the other patient had bladder recurrence 48 months after LNU but was still alive at the end of the study period. While the recurrence results in our study were not statistically significant, we hypothesise that the difference in median time to bladder recurrence in our cohort (34 months for LNU vs. 167 months for ONU) could point towards more aggressive cancers in the LNU group. This may then explain the trend towards worse oncological outcomes across the other parameters. Many other studies have found shorter mean time to discharge in both groups than in our cohort [3, 8, 9]. Without knowing the full details of patient co-morbidities and post-operative care involved in previous studies it is difficult to state what the reasons for lengthier stays in our unit may be. The ONU group was an earlier cohort, being undertaken in 1992–1997 versus in 1993–2010 for LNU. The length of post-operative stay following nephrectomy has reduced over time [29] and hence our results may reflect the bias in case selection. It is noticeable that the mean operating time for LNU in our study (191 min) is shorter than in other case series (mean: 275 min from meta-analysis [6]). Ours is a tertiary referral unit with a large volume of laparoscopic work undertaken. Greater experience with LNU may therefore lead to a shorter mean length of operation. Unfortunately, an estimate of blood loss was only available for 1 LNU patient. 3 LNU patients had documented post-operative complications compared with 4
ONU patients. These numbers were too small for meaningful comparison, although it is reassuring to note that most complications were judged as minor. While not statistically significant, the grade IIIa and IVa complications observed with ONU would seem to be clinically significant. Other studies have found minor complications in 0–40% with LNU and 0–45% with ONU. Major complications were found in 0–19% with LNU and 0–29% with ONU [8]. Our results support these previous studies. The study presented here supports the body of literature demonstrating oncological equivalence between LNU and ONU, while being free of the criticisms of other studies regarding preferential allocation of patients to LNU. This supports clinicians who continue to offer LNU as a viable alternative to ONU. While our results showed no significant difference between oncological outcomes, they do suggest a trend towards worse outcomes in LNU patients. This highlights the need for continued study to determine equivalence with greater certainty. The mean operating time for LNU was shorter in this study that in most previous studies, supporting the notion of undertaking such work in tertiary referral centres. In future studies it would be useful to increase the pool of patients for potential matching. This would probably require international, multi-centre collaboration. While this would increase the likelihood of matches being identified, it would provide logistical challenges. Clearly, a large-scale RCT would provide the most robust evidence; however, this would be hampered by difficulties in patient recruitment, along with difficulties in standardising operative approaches and post-operative care.
Disclosure Statement The authors have no conflicts of interest to declare.
References
Laparoscopic versus Open Nephroureterectomy
ease-specific survival associated with surgical technique? Eur Urol 2010;58:645–651. 4 Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. 5 Stewart GD, Bariol SV, Grigor KM, et al: A comparison of the pathology of transitional cell carcinoma of the bladder and upper urinary tract. BJU Int 2005;95:791–793. 6 Kuczyk MAS W, Stenzl A, Nagele U: Critical considerations regarding laparoscopic nephroureterectomy for the treatment of upper urinary tract carcinoma. Eur Urol Suppl 2007;6: 555–559.
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
7 Rai BP, Shelley M, Coles B, et al: Surgical management for upper urinary tract transitional cell carcinoma. Cochrane Database Syst Rev 2011;4:CD007349. 8 Rassweiler JJ, Schulze M, Marrero R, et al: Laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: is it better than open surgery? Eur Urol 2004;46:690–697. 9 Simone G, Papalia R, Guaglianone S, et al: Laparoscopic versus open nephroureterectomy: perioperative and oncologic outcomes from a randomised prospective study. Eur Urol 2009;56:520–526.
161
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1 Oosterlinck W, Solsona E, van der Meijden AP, et al: EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma. Eur Urol 2004; 46: 147– 154. 2 Roupret M, Babjuk M, Comperat E, et al: European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol 2013; 63: 1059–1071. 3 Favaretto RL, Shariat SF, Chade DC, et al: Comparison between laparoscopic and open radical nephroureterectomy in a contemporary group of patients: are recurrence and dis-
162
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
16 Kim YS, Ji JH, Ko YH, et al: Matched-pair analysis comparing the outcomes of T cell/ histiocyte-rich large B cell lymphoma and diffuse large B cell lymphoma in patients treated with rituximab-CHOP. Acta Haematol 2013; 131:156–161. 17 Rades D, Kronemann S, Meyners T, et al: Acute toxicity of three versus two courses of cisplatin for radiochemotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN): a matched pair analysis. Oral Oncol 2010;46:549–552. 18 Morris LG, Patel SG, Shah JP, et al: Squamous cell carcinoma of the oral tongue in the pediatric age group: a matched-pair analysis of survival. Arch Otolaryngol Head Neck Surg 2010;136:697–701. 19 Gutenberg A, Bock HC, Reifenberger G, et al: Toxicity and survival in primary glioblastoma patients treated with concomitant plus adjuvant temozolomide versus adjuvant temozolomide: results of a single-institution, retrospective, matched-pair analysis. Acta Neurochir (Wien) 2013;155:429–435. 20 Guthoff R, Meigen T, Hennemann K, et al: Comparison of bevacizumab and triamcinolone for treatment of macular edema secondary to branch retinal vein occlusion in a pairmatched analysis. Ophthalmologica 2010; 224:319–324. 21 Stewart GD, Phipps S, Little B, et al: Description and validation of a modular training system for laparoscopic nephrectomy. J Endourol 2012;26:1512–1517. 22 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.
23 Lehmann J, Suttmann H, Kovac I, et al: Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. Eur Urol 2007;51:1281–1288. 24 Mallin K, David KA, Carroll PR, et al: Transitional cell carcinoma of the bladder: racial and gender disparities in survival (1993–2002), stage and grade (1993–2007). J Urol 2011;185: 1631–1636. 25 Dindo D, Demartines N, Clavien PA: Classification of surgical complications: a new proposal with evaluation in a cohort of 6,336 patients and results of a survey. Ann Surg 2004; 240:205–213. 26 Fairey AS, Jacobsen NE, Estey E, et al: Comorbidity status does not independently predict survival outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. Eur Urol 2013;64:518–519. 27 Kume H, Teramoto S, Tomita K, et al: Bladder recurrence of upper urinary tract cancer after laparoscopic surgery. J Surg Oncol 2006; 93: 318–322. 28 Fairey AS, Kassouf W, Estey E, et al: Comparison of oncological outcomes for open and laparoscopic radical nephroureterectomy: results from the Canadian Upper Tract Collaboration. BJU Int 2013;112:791–797. 29 Length of Stay Post-Nephrectomy Data, 1993–2011. Healthcare Cost and Utilization Project (HCUP). US Department of Health and Human Services. http://hcupnet.ahrq. gov/HCUPnet.jsp (accessed 2014).
Blackmur/Stewart/Egong/Cutress/Tolley/ Riddick/McNeill
Downloaded by: University of Exeter 149.126.76.97 - 8/14/2015 7:34:14 AM
10 Stewart GD, Humphries KJ, Cutress ML, et al: Long-term comparative outcomes of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial-cell carcinoma after a median follow-up of 13 years. J Endourol 2011;25:1329–1335. 11 Ni S, Tao W, Chen Q, et al: Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies. Eur Urol 2012;61:1142–1153. 12 Capitanio U, Shariat SF, Isbarn H, et al: Comparison of oncologic outcomes for open and laparoscopic nephroureterectomy: a multiinstitutional analysis of 1,249 cases. Eur Urol 2009;56:1–9. 13 Manabe D, Saika T, Ebara S, et al: Comparative study of oncologic outcome of laparoscopic nephroureterectomy and standard nephroureterectomy for upper urinary tract transitional cell carcinoma. Urology 2007;69: 457–461. 14 Ambani SN, Weizer AZ, Wolf JS Jr, et al: Matched comparison of robotic vs laparoscopic nephroureterectomy: an initial experience. Urology 2014;83:345–349. 15 Stewart GD, Bariol SV, Moussa SA, et al: Matched pair analysis of ureteroscopy vs. shock wave lithotripsy for the treatment of upper ureteric calculi. Int J Clin Pract 2007; 61:784–788.
Urologia
Received: April 2, 2014 Accepted after revision: May 24, 2014 Published online: September 19, 2014
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
Internationalis
Matched-Pair Analysis of Open versus Laparoscopic Nephroureterectomy for Upper Urinary Tract Urothelial Cell Carcinoma James P. Blackmur a Grant D. Stewart b, d Eric A. Egong c Mark L. Cutress b, d David A. Tolley b Anthony C.P. Riddick d, e S. Alan McNeill b, d
a
Department of Surgery, Victoria Hospital, Kirkcaldy, b Department of Urology, Western General Hospital, c College of Medicine and Veterinary Medicine, University of Edinburgh, and d Edinburgh Urological Cancer Group, Edinburgh, and e Department of Urology, Addenbrookes Hospital, Cambridge, UK
Abstract Objective: Laparoscopic nephroureterectomy (LNU) offers a superior morbidity profile compared with open nephroureterectomy (ONU) in treating upper urinary tract urothelial cell carcinoma. Evidence of oncological equivalence between LNU and ONU is limited. We compare operative and oncological outcomes for LNU and ONU using matched-pair analysis. Methods: Of 159 patients who underwent a nephroureterectomy at a single institution between April 1992 and April 2010, 13 pairs of ONU and LNU patients were matched for gender, age, tumour location, tumour grade and stage. Operative details, post-operative characteristics and recurrences were collated and survival rates analysed using the Kaplan-Meier method. Results: There was no significant difference in mean operation time between LNU (191 min) and ONU (194 min, p = 0.92). There was no significant difference in the 5-year survival rate between LNU and ONU (overall survival 59.1% vs. 73.5%, p = 0.18; progression-free survival 24.0% vs. 56.0%, p = 0.14; cancer-specific survival 60.9% vs. 73.5%, p = 0.56; bladder cancer recurrence-free survival 8.7% vs. 0.0%, p = 0.09). Conclusion: Amidst limited RCT and com-
© 2014 S. Karger AG, Basel 0042–1138/14/0942–0156$39.50/0 E-Mail [email protected] www.karger.com/uin
parative studies, this study presents further evidence of oncological equivalence between LNU and ONU. There was a trend towards poorer outcomes following LNU though, which merits further study. © 2014 S. Karger AG, Basel
Introduction
Upper urinary tract urothelial cell carcinomas (UUTUCC) are rare, accounting for only 5% of cases of UCC [1] and with an annual incidence of 1–2 cases per 100,000 per year [2]. UUT-UCC is a biologically aggressive disease with a high potential for recurrence and death [3]. Up to 60% of UUT-UCCs are invasive at diagnosis compared with only 15–25% of bladder tumours [4]. Aggressive extirpative treatment is therefore required [5]. Nephrectomy in combination with ureterectomy and complete excision of the ureteral orifice from the bladder wall is considered the standard curative surgical treatment [6]. Although open nephroureterectomy (ONU) has been regarded as the gold standard, it is associated with signifi-
James P. Blackmur and Grant D. Stewart contributed equally to this work.
Mr Grant Stewart Clinical Senior Lecturer, Department of Urology Western General Hospital, Crewe Road South Edinburgh, EH4 2XU (UK) E-Mail grant.stewart @ ed.ac.uk
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Key Words Ureter · Transitional cell carcinoma · Laparoscopy · Matched-pair analysis · Nephroureterectomy
cant morbidity. Laparoscopic nephroureterectomy (LNU) has increasingly been used as a minimally invasive alternative [1]. Given the rarity of UUT-UCC, there are few studies comparing the efficacy and safety of LNU versus ONU. A Cochrane review concluded that there were no adequately controlled trials to compare LNU with ONU [7]. Even meta-analyses have been on a relatively small scale: one compared outcomes from 131 patients undergoing LNU with 681 undergoing ONU [8]. One small randomised trial (80 patients) demonstrated that LNU was associated with less blood loss and shorter length of hospital stay than ONU [9]. The conclusion of many studies is that there is no significant difference in oncological outcomes: overall survival (OS), progression-free survival (PFS) or cancer-specific survival (CSS) [7, 10, 11]. Interestingly, while the study by Simone et al. [9] was powered to examine differences in length of hospital stay, they found trends towards worse 5-year CSS with LNU than ONU (79.8 vs. 89.9%, p = 0.2) and 5-year metastases-free survival (72.5 vs. 77.4%, p = 0.12). CSS was significantly lower in LNU than in ONU with higher-grade tumours (p = 0.04 for pT3 tumours). Many observational studies have been criticised for a negative selection bias in the group undergoing ONU [6]. LNU has tended to be undertaken in patients with more favourable pathological stages and a more favourable primary tumour locus (more likely to be tumour of renal pelvis than ureter) [11, 12]. Advanced tumour stage and grade are established strong negative prognostic factors on multivariate analysis [13] and the more favourable selection bias in LNU patients has precluded any definitive statements on oncological equivalency between the two treatments to date. In such a rare condition, a large-scale RCT would require multiple centres and international collaboration to attain sufficient statistical power. It would then be difficult to standardise factors such as surgical technique, post-operative care and oncological management. In the absence of such a trial, a matched-pair analysis is useful. Matched-pair analysis controls for confounding factors and therefore allows more accurate comparison of survival rates. A matched-pair analysis can achieve acceptable statistical power with smaller numbers of patients. The approach was recently used to compare short-term outcomes in 22 pairs undergoing robotic nephroureterectomy or LNU for UUT-UCC [14]. It has also been used to compare lithotripsy and ureteroscopy for upper tract ureteric calculi [15] and to compare outcomes after chemo-
therapy in small numbers of patients with lymphoma [16], squamous cell carcinoma [17, 18], primary glioblastoma [19] and macular degeneration [20]. It is therefore a valid approach with which to compare outcomes in rare conditions. A total of 120 cases of LNU over a period of 18 years have been undertaken in our centre. Given the volume of work, the department was able to develop and maintain a standardised protocol for post-operative care and followup. To minimise the confounding impact of outside variables and selection bias, we undertook matched-pair analysis of operative and oncological parameters for patients who underwent LNU or ONU for UUT-UCC. To our knowledge this is the first study of its kind to be undertaken.
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Methods
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All patients who underwent LNU and ONU for UUT-UCC at our institution between April 1992 and April 2010 were included in this study. Surgery was undertaken by 9 different consultant urologists. LNU was performed via a transperitoneal approach, as previously described [10, 21]. Patients undergoing both ONU and LNU had preliminary mobilisation of their kidney and proximal ureter before extra- or trans-vesical mobilisation of the lower ureter and bladder cuff. Neither LNU nor ONU included formal lymphadenectomy, unless there were suspicious lymph nodes observed on pre-operative staging scans or intraoperatively. Strict criteria were used to match LNU and ONU patients. Five parameters were employed in sequence: (1) gender; (2) age (divided into 5-year cohorts: 56–60, 61–65, 66–70, 71–75 and 76–80 years); (3) tumour locus (upper ureter, lower ureter, renal pelvis and renal calyx); (4) tumour stage, and (5) tumour grade. These variables where selected for matching as they are established prognostic factors for OS, CSS and PFS [12, 22–24]. When more than one match was identified, random numbers were assigned in order to rank potential matches. Standard post-operation follow-up involved a review at 3 months, then at 6-monthly intervals for 2 years, and subsequently once yearly. The follow-up protocol was standardised across the study period, consisting of history and examination, urinary cytology, cystoscopy, radiographic imaging of the UUT, and chest radiography, CT or MRI when indicated. Data were collected retrospectively from hospital medical records. Data collected included the following: pre-operative grade and stage, operative characteristics (estimated blood loss, operation time) and length of post-operative stay. Post-operative complications were assessed using the Clavien-Dindo classification [25]. Data were also collected regarding follow-up, disease recurrence and cause of death. If cause of death was not available in the medical notes, this was obtained from death certificates from the General Registry Office of Scotland. The primary end points of this study were oncological outcomes (OS, CSS and PFS). To achieve a power of 0.8, with a moderate effect size of 0.6 and an α-error probability of 0.05, we re-
Table 1. Descriptive characteristics of the 13 matched pairs of pa-
Table 2. Operative and post-operative outcomes
tients identified LNU (n = 13)
Gender, n Male 7 (26.9%) Female 6 (23.1%) Age, years Mean 68.0 Range 58.2–77.0 Tumour location, n Renal pelvis/calyces 5 Upper ureter 1 Mid ureter 0 Lower ureter 7 Stage, n pTa 10 pT2 1 pT3 2 Grade, n I 1 II 9 III 3 Length of follow-up, months Median 25.8 Range 2.8–166.0
ONU (n = 13)
7 (26.9%) matched 6 (23.1%) 67.5 57.1–77.3
0.92
5 1 0 7
matched
10 1 2
matched
1 9 3
matched
57.0 14.0–187.0
0.13
quired 12 pairs. By comparison, the same t test comparison of two independent means would require a total sample size of 90 patients. Statistical analysis was carried out using IBM SPSS, version 20.0. Significance was indicated by p < 0.05. Independent samples t test was used to compare age, operation time and blood loss. OS, PFS, CSS and bladder cancer recurrence-free survival rates were estimated using the Kaplan-Meier method and p values were generated through the log-rank test.
Results
A total of 13 matched pairs (n = 26 patients) were identified from a pool of LNU (n = 120) and ONU (n = 39) patients, according to the strict matching criteria outlined above. Descriptive characteristics of the matched patients are included in table 1. There was no significant difference in mean age between the two groups. There was a distribution of tumour loci, with 5 pairs in the renal pelvis or calyces, 1 in the upper ureter and 7 in the lower ureter. There was no matched pair identified for mid-ureteric tumours. While the majority of patients had pTa disease (77%), 1 patient pair had pT2 and 2 had pT3 disease. 158
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
Variable
LNU
ONU
Operation time, min Mean Range
191 135–220
194 125–390
p value
p value
Length of post-operative stay, days 7 Median 7.5 Mean Range 3–10 Post-operative complications, n No complication 10 Grade I 1 Grade II 2 Grade IIIa 0 Grade IIIb 0 Grade IVa 0 Grade IVb 0 Grade V (death) 0
10 12.3 5–29
0.02
9 1 1 1 0 1 0 0
0.35
Mean follow-up was not significantly different between the two groups (LNU 25.8 months, ONU 57.0 months, p = 0.13). In the LNU group, 3 patients had pTa bladder recurrence, 1 had pT2 recurrence requiring cystectomy, 2 had retroperitoneal nodal recurrence and 2 had distant recurrence (hepatic, skeletal, cerebral and retroperitoneal nodes). In the ONU group, 4 patients had pTa bladder recurrence and 1 had pulmonary recurrence. Operative and post-operative outcomes are outlined in table 2. The length of post-operative stay was significantly shorter in the LNU group (median: 7 vs. 10 days, p = 0.02). There was no significant difference in operation times between the groups (mean: 191 min LNU vs. 194 min ONU, p = 0.92). Blood loss was only clearly recorded in 1 of the LNU patients and hence comparison was not possible. In the ONU group, estimated median blood loss was 468 ml (range 150–1,100 ml). Post-operative complications occurred in 3 patients in the LNU group and 4 in the ONU group. Grade I postoperative complications developed in 1 patient following LNU (prolonged post-operative ileus) and in 1 patient in the ONU group (acute shortness of breath which settled with analgesia and bronchodilator therapy). Following LNU, 2 patients developed grade II complications: a postoperative wound infection in 1 case and a chest infection in the other. Both of these were treated with antibiotics; 1 patient in the ONU group developed an intra-abdominal Blackmur/Stewart/Egong/Cutress/Tolley/ Riddick/McNeill
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Variable
Table 3. Estimated OS, PFS, CSS, and bladder cancer recurrence-free survival for LNU and ONU
Factor
Operative approach
Mean survival, months
Median survival, months
Estimated 5-year survival
p value
OS
LNU ONU
97.9 136.6
69.0 109.0
59.1% 73.5%
0.18
PFS
LNU ONU
42.0 125.6
34.0 100.0
24.0% 56.0%
0.14
CSS
LNU ONU
109.4 145.2
not reached 141.0
60.9% 73.5%
0.56
Bladder cancer
LNU ONU
58.7 131.3
34.0 167.0
8.7% 0.0%
0.09
collection requiring antibiotics (grade II complication). No patients in the LNU group developed grade III, IV or V complications. In the ONU group, 1 patient developed a grade IIIa complication (acute respiratory distress syndrome requiring a tracheostomy under local anaesthetic, but not intensive therapy unit support) and 1 developed a grade IVa complication (pneumonia requiring intensive therapy unit admission for ventilatory support). Oncological results are summarised in table 3 and figure 1.
Given the small number of patients presenting with UUT-UCC, retrospective observational studies have been the main evidence base for advocating the merits of one treatment over another. Previous studies have been criticised for preferential allocation of LNU to patients with favourable tumour characteristics [7]. Our data demonstrate that in patients matched according to tumour characteristics and demographics there was no significant difference in oncological outcomes between LNU and ONU. There were consistent trends, however, for better outcomes with ONU. This study also demonstrates there was a significantly shorter length of post-operative stay associated with LNU, as has been shown in previous studies [3, 8, 9]. There was no significant difference in operation time between the two patient groups. The major strength of this matched-pair analysis is its head-to-head comparison between LNU and ONU, com-
paring the outcome of similar patients with almost identical tumours. Surgery was conducted by 9 consultant surgeons and all patients underwent uniform surgical approaches (as previously described [10, 21]) with standardised post-operative care and follow-up. As demonstrated by the large percentage of cases undertaken laparoscopically (75% of the total pool), this was the standard approach in our centre. While our study did not control for patient co-morbid status, this has recently been demonstrated not to significantly affect outcome [26]. The limitations of our study are the small sample size, the lack of prospective randomisation and the single-centre experience. While the number of patients matched was relatively small, post hoc power analysis demonstrates a range from 0.72 for OS to 0.99 for PFS. This suggests that there was a 72% chance of detecting a difference in OS between groups if one existed and a 99% chance for PFS. The majority of patients in this study had early-stage disease. There is, therefore, a question as to how far the oncological trends can be generalised. Of the total patient pool only 39 underwent ONU. The strict matching criteria could have been relaxed to increase the number of pairs identified, but this would have defeated the purpose of the study. We considered broadening the study to include other centres; however, other larger studies have presented significant logistical challenges [12], especially in standardising surgical approach and follow-up. Our results support other studies which have demonstrated comparable oncological outcomes for LNU and ONU [8, 10, 11]. While our results were not statistically
Laparoscopic versus Open Nephroureterectomy
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
Discussion
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Survival calculated by Kaplan-Meier method.
Color version available online
Operation
1.0
1.0
LNU-censored ONU-censored
0.6
0.4
0.2
0 50
100 150 Time (months)
200
250
0.2
0
50
100 150 Time (months)
200
250
1.0 Cumulative bladder recurrence free survival
Cumulative cancer specific survival
0.4
b
1.0
0.8
0.6
0.4
0.2
0
c
0.6
0 0
a
0.8
0
50
100 150 Time (months)
200
250
d
0.8
0.6
0.4
0.2
0 0
50
100 150 Time (months)
200
Fig. 1. Comparison with log-rank test of oncological outcomes for LNU vs. ONU. a Between-group comparison of OS curves (p = 0.18). b Between-group comparison of PFS curves (p = 0.14).
c Between-group comparison of CSS curves (p = 0.56). d Between-
significant, there was a consistent trend towards worse oncological outcomes in the LNU group. It is not clear whether this trend was because of the small number of patients meeting the strict matching criteria or because of true increased risk of recurrence following LNU. Post hoc analysis does, however, suggest that the study was adequately powered to detect differences in survival. While many previous studies have demonstrated no significant difference in oncological outcomes, Kume et al. [27] found a significantly higher bladder cancer recurrence
rate in laparoscopic cases (69% vs. 36%, p = 0.04). Simone et al. [9] demonstrated that in higher-grade tumours, CSS was significantly lower in LNU (p = 0.04 for pT3 tumours). Fairey et al. [28] recently reported a trend toward worse 5-year recurrence-free survival with LNU (43% vs. 33%, p = 0.06). The reasons for these findings are unclear. Proposed explanations include surgical expertise, whether and to what extent regional lymph node dissection is undertaken and baseline clinico-pathological status [28]. The trend for oncological outcomes found in our study,
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group comparison of bladder cancer recurrence-free survival curves (p = 0.09).
Blackmur/Stewart/Egong/Cutress/Tolley/ Riddick/McNeill
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Cumulative overall survival
ONU 0.8
Cumulative progression free survival
LNU
therefore, further reinforce the call that large-scale work is urgently required. Bladder recurrence-free survival was analysed separately in our study due to the high frequency of recurrence in patients with UUT-UCC; 2 patients had a documented bladder cancer prior to being diagnosed with UUT-UCC (both in the LNU group) – 1 had a bladder recurrence and subsequently died and the other patient had bladder recurrence 48 months after LNU but was still alive at the end of the study period. While the recurrence results in our study were not statistically significant, we hypothesise that the difference in median time to bladder recurrence in our cohort (34 months for LNU vs. 167 months for ONU) could point towards more aggressive cancers in the LNU group. This may then explain the trend towards worse oncological outcomes across the other parameters. Many other studies have found shorter mean time to discharge in both groups than in our cohort [3, 8, 9]. Without knowing the full details of patient co-morbidities and post-operative care involved in previous studies it is difficult to state what the reasons for lengthier stays in our unit may be. The ONU group was an earlier cohort, being undertaken in 1992–1997 versus in 1993–2010 for LNU. The length of post-operative stay following nephrectomy has reduced over time [29] and hence our results may reflect the bias in case selection. It is noticeable that the mean operating time for LNU in our study (191 min) is shorter than in other case series (mean: 275 min from meta-analysis [6]). Ours is a tertiary referral unit with a large volume of laparoscopic work undertaken. Greater experience with LNU may therefore lead to a shorter mean length of operation. Unfortunately, an estimate of blood loss was only available for 1 LNU patient. 3 LNU patients had documented post-operative complications compared with 4
ONU patients. These numbers were too small for meaningful comparison, although it is reassuring to note that most complications were judged as minor. While not statistically significant, the grade IIIa and IVa complications observed with ONU would seem to be clinically significant. Other studies have found minor complications in 0–40% with LNU and 0–45% with ONU. Major complications were found in 0–19% with LNU and 0–29% with ONU [8]. Our results support these previous studies. The study presented here supports the body of literature demonstrating oncological equivalence between LNU and ONU, while being free of the criticisms of other studies regarding preferential allocation of patients to LNU. This supports clinicians who continue to offer LNU as a viable alternative to ONU. While our results showed no significant difference between oncological outcomes, they do suggest a trend towards worse outcomes in LNU patients. This highlights the need for continued study to determine equivalence with greater certainty. The mean operating time for LNU was shorter in this study that in most previous studies, supporting the notion of undertaking such work in tertiary referral centres. In future studies it would be useful to increase the pool of patients for potential matching. This would probably require international, multi-centre collaboration. While this would increase the likelihood of matches being identified, it would provide logistical challenges. Clearly, a large-scale RCT would provide the most robust evidence; however, this would be hampered by difficulties in patient recruitment, along with difficulties in standardising operative approaches and post-operative care.
Disclosure Statement The authors have no conflicts of interest to declare.
References
Laparoscopic versus Open Nephroureterectomy
ease-specific survival associated with surgical technique? Eur Urol 2010;58:645–651. 4 Siegel R, Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. 5 Stewart GD, Bariol SV, Grigor KM, et al: A comparison of the pathology of transitional cell carcinoma of the bladder and upper urinary tract. BJU Int 2005;95:791–793. 6 Kuczyk MAS W, Stenzl A, Nagele U: Critical considerations regarding laparoscopic nephroureterectomy for the treatment of upper urinary tract carcinoma. Eur Urol Suppl 2007;6: 555–559.
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
7 Rai BP, Shelley M, Coles B, et al: Surgical management for upper urinary tract transitional cell carcinoma. Cochrane Database Syst Rev 2011;4:CD007349. 8 Rassweiler JJ, Schulze M, Marrero R, et al: Laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma: is it better than open surgery? Eur Urol 2004;46:690–697. 9 Simone G, Papalia R, Guaglianone S, et al: Laparoscopic versus open nephroureterectomy: perioperative and oncologic outcomes from a randomised prospective study. Eur Urol 2009;56:520–526.
161
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1 Oosterlinck W, Solsona E, van der Meijden AP, et al: EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma. Eur Urol 2004; 46: 147– 154. 2 Roupret M, Babjuk M, Comperat E, et al: European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol 2013; 63: 1059–1071. 3 Favaretto RL, Shariat SF, Chade DC, et al: Comparison between laparoscopic and open radical nephroureterectomy in a contemporary group of patients: are recurrence and dis-
162
Urol Int 2015;94:156–162 DOI: 10.1159/000364833
16 Kim YS, Ji JH, Ko YH, et al: Matched-pair analysis comparing the outcomes of T cell/ histiocyte-rich large B cell lymphoma and diffuse large B cell lymphoma in patients treated with rituximab-CHOP. Acta Haematol 2013; 131:156–161. 17 Rades D, Kronemann S, Meyners T, et al: Acute toxicity of three versus two courses of cisplatin for radiochemotherapy of locally advanced squamous cell carcinoma of the head and neck (SCCHN): a matched pair analysis. Oral Oncol 2010;46:549–552. 18 Morris LG, Patel SG, Shah JP, et al: Squamous cell carcinoma of the oral tongue in the pediatric age group: a matched-pair analysis of survival. Arch Otolaryngol Head Neck Surg 2010;136:697–701. 19 Gutenberg A, Bock HC, Reifenberger G, et al: Toxicity and survival in primary glioblastoma patients treated with concomitant plus adjuvant temozolomide versus adjuvant temozolomide: results of a single-institution, retrospective, matched-pair analysis. Acta Neurochir (Wien) 2013;155:429–435. 20 Guthoff R, Meigen T, Hennemann K, et al: Comparison of bevacizumab and triamcinolone for treatment of macular edema secondary to branch retinal vein occlusion in a pairmatched analysis. Ophthalmologica 2010; 224:319–324. 21 Stewart GD, Phipps S, Little B, et al: Description and validation of a modular training system for laparoscopic nephrectomy. J Endourol 2012;26:1512–1517. 22 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.
23 Lehmann J, Suttmann H, Kovac I, et al: Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. Eur Urol 2007;51:1281–1288. 24 Mallin K, David KA, Carroll PR, et al: Transitional cell carcinoma of the bladder: racial and gender disparities in survival (1993–2002), stage and grade (1993–2007). J Urol 2011;185: 1631–1636. 25 Dindo D, Demartines N, Clavien PA: Classification of surgical complications: a new proposal with evaluation in a cohort of 6,336 patients and results of a survey. Ann Surg 2004; 240:205–213. 26 Fairey AS, Jacobsen NE, Estey E, et al: Comorbidity status does not independently predict survival outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. Eur Urol 2013;64:518–519. 27 Kume H, Teramoto S, Tomita K, et al: Bladder recurrence of upper urinary tract cancer after laparoscopic surgery. J Surg Oncol 2006; 93: 318–322. 28 Fairey AS, Kassouf W, Estey E, et al: Comparison of oncological outcomes for open and laparoscopic radical nephroureterectomy: results from the Canadian Upper Tract Collaboration. BJU Int 2013;112:791–797. 29 Length of Stay Post-Nephrectomy Data, 1993–2011. Healthcare Cost and Utilization Project (HCUP). US Department of Health and Human Services. http://hcupnet.ahrq. gov/HCUPnet.jsp (accessed 2014).
Blackmur/Stewart/Egong/Cutress/Tolley/ Riddick/McNeill
Downloaded by: University of Exeter 149.126.76.97 - 8/14/2015 7:34:14 AM
10 Stewart GD, Humphries KJ, Cutress ML, et al: Long-term comparative outcomes of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial-cell carcinoma after a median follow-up of 13 years. J Endourol 2011;25:1329–1335. 11 Ni S, Tao W, Chen Q, et al: Laparoscopic versus open nephroureterectomy for the treatment of upper urinary tract urothelial carcinoma: a systematic review and cumulative analysis of comparative studies. Eur Urol 2012;61:1142–1153. 12 Capitanio U, Shariat SF, Isbarn H, et al: Comparison of oncologic outcomes for open and laparoscopic nephroureterectomy: a multiinstitutional analysis of 1,249 cases. Eur Urol 2009;56:1–9. 13 Manabe D, Saika T, Ebara S, et al: Comparative study of oncologic outcome of laparoscopic nephroureterectomy and standard nephroureterectomy for upper urinary tract transitional cell carcinoma. Urology 2007;69: 457–461. 14 Ambani SN, Weizer AZ, Wolf JS Jr, et al: Matched comparison of robotic vs laparoscopic nephroureterectomy: an initial experience. Urology 2014;83:345–349. 15 Stewart GD, Bariol SV, Moussa SA, et al: Matched pair analysis of ureteroscopy vs. shock wave lithotripsy for the treatment of upper ureteric calculi. Int J Clin Pract 2007; 61:784–788.
