- Email: [email protected]
Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Bladder Cancer
Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience Syed Johar Raza a, Ali Al-Daghmin a, Sharon Zhuo a, Zayn Mehboob a, Katy Wang b, Gregory Wilding b, Eric Kauffman a,c, Khurshid A. Guru a,* a
Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA;
c
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
b
Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, USA;
Article info
Abstract
Article history: Received 6 January 2014 Published online ahead of print on April 16, 2014
Background: Long-term oncologic outcomes following robot-assisted radical cystectomy (RARC) remain scarce. Objective: To report long-term oncologic outcomes following RARC at a single institution. Design, settings, and participants: Retrospective review of 99 patients who underwent RARC for urothelial carcinoma of bladder between 2005 and 2009. Intervention: RARC was performed. Outcome measurements and statistical analysis: Primary outcomes included recurrencefree survival (RFS), cancer-specific survival (CSS), and overall survival (OS), measured by the Kaplan-Meier method. The association between primary outcomes and perioperative and pathologic factors was assessed using a multivariable Cox proportional hazards model. Results and limitations: Fifty-one (52%) patients had stage pT3 or higher disease. Eight (8%) patients had positive margins and 30 (30%) had positive lymph nodes (LNs), with a median of 21 LNs removed. Median follow-up for patients alive was 74 mo. The 5-yr RFS, CSS, and OS rates were 52.5%, 67.8%, and 42.4%, respectively. Tumor stage, LN stage, and margin status were each significantly associated with RFS, CSS, and OS. On multivariable analysis, tumor and LN stage were independent predictors of RFS, CSS, and OS, while positive margin status and Charlson comorbidity index predicted worse OS and CSS. Adjuvant chemotherapy predicted RFS only. Retrospective design and lack of open comparison are main limitations of this study. Conclusions: Long-term oncologic outcomes following RARC demonstrate RFS and CSS estimates similar to those reported in literature for open radical cystectomy. Randomized controlled trials can better define outcomes of any alternative technique. Patient summary: Survival data 5 yr after RARC for bladder cancer demonstrate that survival outcomes are dependent on the same oncologic parameters as previously reported for open surgery. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Robot-assisted Radical Cystectomy Long term Oncologic Outcomes Outcomes
* Corresponding author. Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Tel. +1 716 845 7612; Fax: +1 716 845 3300. E-mail address: [email protected] (K.A. Guru).
http://dx.doi.org/10.1016/j.eururo.2014.03.015 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
1.
Introduction
Incidence of bladder cancer varies across the globe, with highest rates observed in western countries [1]. In 2013, 72 570 new cases of bladder cancer were diagnosed in the United States, of these, >15 000 patients are expected to die of bladder cancer [2]. Open radical cystectomy (ORC) with pelvic lymph node dissection (PLND) achieves a 60% survival rate after 10 yr, and remains the gold standard
Table 1 – Demographic, perioperative, and postoperative details of the patients Demographic details Age, yr Sex, no. (%) BMI, kg/m2 ASA score, no. (%) CCI, no. (%)
N = 99
Total
Median (IQR) Mean (SD) Male Median (IQR) Mean (SD) 2 >3
71 (61–77) 68.9 (10.9) 78 (78.8) 28.2 (25.2–31.6) 28.8 (5.1) 57 (57.6) 70 (70.7)
CIS T1 T2 T3 T4 NA
63 18 23 46 3 6 3 6
Preoperative details Previous surgery, no. (%) Clinical stage, no. (%)
Neoadjuvant chemotherapy, no. (%)
(63.6) (18.2) (23.2) (46.5) (3) (6.1) (1) (6.1)
Lymph node dissection time, min Overall time, min Estimated blood loss, ml Diversion type, no. (%)
2.
Patients and methods
2.1.
Patient population
A retrospective review was performed of an institutional review boardapproved database (I 79606) including all patients undergoing RARC with
Operative details Cystectomy time, min
treatment for muscle-invasive and high-risk non–muscleinvasive bladder cancer [3,4]. Despite its known oncologic benefit, ORC with PLND is associated with significant morbidity [5], which has ignited efforts to investigate a minimally invasive alternative. Robot-assisted radical cystectomy (RARC) has emerged as an alternative approach to ORC, based on its possible reduction in blood loss, transfusion rate, postoperative analgesia, and quicker recovery of bowel function [6,7]. Only two randomized studies have compared perioperative outcomes between RARC and ORC with limited cohort sizes and follow-up intervals, highlighting the need for more high quality randomized studies [8,9]. Attempts have been made to establish the effectiveness of RARC as a comparable alternative to ORC, including several reports on early and intermediate oncologic outcomes [10,11]. However, data on long-term oncologic outcomes remain scarce and limited by small cohort sizes and nonconsecutive-patient-selection bias [12,13]. The purpose of the present study is to report long-term oncologic outcomes of 99 consecutive bladder urothelial carcinoma patients undergoing RARC with curative intent at a single institution.
curative intent (n = 345) at a National Comprehensive Cancer Network Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Conduit Neobladder Pouch
149.5 (119–200) 165.5 (59.2) 52 (40–76) 60 (27.3) 372 (305–437) 379.5 (123.9) 400 (250–700) 543.4 (423.2) 92 (92.9) 6 (6.1) 1 (1)
(NCCN)-designated cancer center (Roswell Park Cancer Institute [RPCI], Buffalo, NY, USA) between 2005 and 2013. The technique for RARC has previously been reported [14]. All diversions were performed with an extracorporeal approach (intracorporeal diversions were incorporated
Table 2 – Follow-up details of the patients Follow-up details, mo Follow-up, overall
Postoperative details Pathologic T stage, no. (%)
Lymph nodes removed, no. Lymph node status, no. (%)
Lymphovascular invasion, no. (%) Bladder soft tissue margins, no. (%) Adjuvant chemotherapy, no. (%)
pT0 CIS pT2a pT2b pT3a pT3b pT4a pT4b Median (IQR) Mean (SD) pN0 pNx pN1 pN2 pN3 Positive
9 (9.1) 23 (23.2) 10 (10.1) 6 (6.1) 22 (22.2) 12 (12.1) 15 (15.1) 2 (2.1) 21 (13–27) 20.7 (11) 63 (63.6) 6 (6.1) 12 (12.1) 14 (14.1) 4 (4) 25 (25.3) 8 (8.1) 28 (28.9)
Follow-up, alive without recurrence Local recurrence, no. (%) Metastatic recurrence, no. (%) Recurrence, no. (%) Status at last follow-up, no. (%)
Time to recurrence Time to cancer-specific death Time to death
ASA = American Society of Anesthesiology; BMI = body mass index; CCI = Charlson comorbidity index; IQR = interquartile range; NA = not applicable; SD = standard deviation.
Median (IQR) Mean (SD) Median (IQR)
30.9 (12.7–70.8) 43 (32.4) 73.9 (66.4–89.5)
Mean (SD) Only Only
77.9 (12.8) 9 (9.09) 18 (18.2)
Combined Alive without recurrence
14 (14.2) 35 (35.7)
Alive with recurrence Non–cancer-related death Cancer-related death Death due to unknown causes Median (IQR) Mean (SD) Median (IQR)
5 26 26 6
Mean (SD) Median (IQR) Mean (SD)
20.8 (15.6) 15.3 (6.5–28.8) 19.5 (16.6)
(5.1) (26.5) (26.5) (6.1)
8.6 (4.5–18.3) 11.9 (10.8) 18.1 (8.7–29.3)
IQR = interquartile range, SD = standard deviation.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
in May 2009). A total of 119 patients were identified who had undergone
3
true pelvis (bifurcation of aorta as the cephalic boundary) and metastatic
RARC >5 yr prior to their most recent follow-up date. Of these, patients
disease was defined as evidence of disease outside the true pelvis. The
with nonurothelial carcinoma (n = 9) and palliative RARC (n = 6) were
cause of death was recorded from the electronic medical records or death
excluded. Additionally, five (5.1%) patients who were lost to follow-up
certificate obtained from the primary care physician, and an institutional
were also excluded from the final analysis. No ORC has been performed at
tumor registry database. The last contact recorded by the RPCI clinic or
the institution since 2005. Final analysis was performed on the remaining
tumor registry, or the date of death, was considered as the date of last
99 patients with at least 60 mo of follow-up data.
follow-up.
2.2.
2.3.
Outcome parameters
Statistical analysis
Primary outcome measures included recurrence-free survival (RFS),
Descriptive statistics were obtained for demographic variables. Primary
cancer-specific survival (CSS), and overall survival (OS). Univariable and
outcome measures included RFS, CSS, and OS, which were compared by
multivariable analyses were performed to evaluate the influence of
standard Kaplan-Meier methodology using a log-rank test. Patients who
perioperative factors (ie, age, American Society of Anesthesiologists
were still alive without experiencing an event at their last follow-up
score, body mass index, Charlson comorbidity index [CCI], and operative
date were considered censored from survival estimates. Patients who
time) on primary outcomes, along with pathologic features including
were still alive or expired without experiencing an event at their last
tumor stage (pT), LN stage (pN), surgical margin, and lymphovascular
follow-up date or death date were considered censored in an event-free
invasion (LVI). Survival outcomes were stratified by pT, pN, margin status,
interval estimate. The association among RFS, CSS, OS, and risk factors of
and LVI. Tumor grade and pathologic staging were determined based on
interest were assessed using a Cox proportional hazards model, with
the 2002 American Joint Committee on Cancer TNM staging system and
p < 0.05 as the nominal significance level. Factors that were significant
the 2004 World Health Organization/International Society of Urologic
on univariable analysis were admitted to the multivariable model. SAS
Pathologists classification of papillary urothelial neoplasms, respectively.
v.9.3 (SAS Institute, Cary, NC, USA) was used for statistical analysis.
Surgical margin included radial bladder and apical/urethral margins. Patients were followed according to the NCCN guidelines. The OS was defined as time to death due to any cause. CSS was defined as death due to
3.
Results
bladder cancer, while RFS was defined as time from date of cystectomy to local and/or metastatic recurrence, based on histologic or radiologic evidence. Local recurrence was defined as evidence of disease within the
Demographic and perioperative details of the 99 RARC patients are presented in Table 1. Table 2 highlights oncologic
Fig. 1 – Kaplan-Meir survival curves for (A) recurrence-free survival, (B) cancer-specific survival, and (C) overall survival.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 4
EUROPEAN UROLOGY XXX (2014) XXX–XXX
and survival outcomes. The median duration of follow-up was 73.9 mo (interquartile range: 66.4–89.5) for patients alive without recurrence. Forty (40.8%) patients were alive at the time of analysis, and 26 (26.5%) died of bladder cancer. Local recurrence occurred in 9 (9.1%) patients, and 18 (18.2%) patients developed distant recurrence only. The 5-yr RFS, CSS, and OS rates were 52.5%, 67.8%, and 42.4%, respectively (Fig. 1). When substratified according to pT stage, pN stage, and margin status, significant differences in the RFS, CSS, and OS were observed; however, no significant differences were noted when stratified according to LVI (Figs. 2–4). Multivariable analysis identified higher pT stage and pN stage as independent predictors of worse RFS, CSS, and OS, while positive surgical margins and CCI (continuous variable) predicted CSS and OS only. Adjuvant chemotherapy predicted the RFS only (Table 3). 4.
Discussion
Despite the increase in performance of RARC in the past decade [15], long-term oncologic outcomes are still unknown. ORC remains the gold standard treatment for muscleinvasive or recurrent or high-risk non–muscle-invasive
bladder cancer due to the thorough characterization of long-term oncologic outcomes [4]. Few RARC studies have included 5-yr oncologic outcomes data and are limited by small numbers of patients with 5-yr outcomes [10]. The current study presents long-term oncologic outcomes of bladder cancer patients treated with RARC by a single surgeon at an NCCN-designated cancer center. Median follow-up was 30.9 mo, and 40 patients (41%) were alive >60 mo who had a median follow-up of 73.9 mo. RFS, CSS, and OS rates were 52%, 68%, and 42%, respectively. In comparison, Stein et al. reported 5-yr RFS and OS rates of 68% and 66%, respectively, although the median age was 66 yr compared to 71 yr in our study, and comorbidity status was not reported [3]. In the same study, 63% of patients had pT3a or lower disease with 23% positive LNs; 25% of recurrences involved the pelvis. Our study demonstrates lower OS compared to the Stein et al. study; this may be attributable to the more advanced age of our cohort and to common comorbidity. Consistent with this explanation, CCI was demonstrated in our cohort to be an independent contributor for OS and CSS, without affecting RFS. The association between survival and advanced age or increased comorbidity is well established. Ploussard et al. [16] found a continuous increase in hazard risk of survival for patients
Table 3 – Univariable and multivariable Cox regression analysis for factors affecting the recurrence-free survival, cancer-specific survival, and overall survival Univariable analysis Variable Recurrence-free survival Age ASA score CCI pT stage Surgical margins pN stage
Adjuvant chemotherapy Cancer-specific survival Age ASA score CCI pT Stage Surgical margins pN stage
Adjuvant chemotherapy Overall survival Age ASA score CCI pT stage Surgical margins pN stage
Adjuvant chemotherapy
Multivariable analysis
HR
Lower CI
Upper CI
p value
1.005 0.71 1.11 4.28 7.76 0.30 3.28 4.19 1.36 5.52
0.97 0.37 0.94 1.91 3.23 0.09 1.30 1.83 0.18 0.09
1.04 1.37 1.32 9.59 18.64 1.04 8.26 9.63 10.29 0.36
0.766 0.306 <0.001 <0.001
1.04 0.62 1.25 5.57 7.20 0.07 2.54 6.10 8.09 3.08
0.99 0.28 1.02 2.07 2.47 0.02 0.72 2.42 1.71 0.15
1.08 1.34 1.56 14.99 21.03 0.22 8.99 15.38 38.36 0.72
0.11 0.22 <0.001 0.0005
1.04 0.59 1.26 4.46 5.11 0.16 3.80 4.76 6.42 2.05
1.01 0.35 1.09 2.33 2.47 0.07 1.83 2.40 2.16 0.28
1.07 1.02 1.44 8.54 10.55 0.36 7.92 9.45 19.05 0.85
0.01 0.06 <0.0001 <0.0001
0.057 0.003
<0.0001
<0.001 0.0005
0.006
<0.0001 <0.0001
0.01
Reference
10-yr increments 2 vs >2 (Continuous) pT3 vs (pT2) pT4 vs (pT2) Positive vs negative pN1 vs pN0 pN2 vs pN0 pN3 vs pN0 No vs yes
HR
Lower CI
Upper CI
p value
Dropped 1.08 2.07 4.99 1.67 1.99 3.79 0.88 1.67
0.89 0.79 1.79 0.16 0.69 1.47 0.11 0.13
1.31 5.39 13.94 2.18 5.74 9.76 7.39 0.61
0.403 0.135 0.002 0.435 0.197 0.006 0.909 0.001
10-yr increments 2 vs >2 (Continuous variable) pT3 vs (pT2) pT4 vs (pT2) Positive vs negative pN1 vs pN0 pN2 vs pN0 pN3 vs pN0 No vs yes
Dropped 1.29 2.67 2.67 6.17 1.61 7.16 7.36 1.93
1.04 0.84 0.69 0.05 0.34 2.36 1.23 0.20
1.61 8.50 10.19 0.54 7.59 21.73 43.95 1.31
0.021 0.096 0.151 0.002 0.546 0.0005 0.028 0.165
10-yr increments 2 vs >2 (Continuous variable) pT3 vs (pT2) pT4 vs (pT2) Positive vs. negative pN1 vs pN0 pN2 vs pN0 pN3 vs pN0 No vs yes
1.01 1.05 1.21 2.76 3.24 2.78 3.29 5.12 3.55 1.16
0.97 0.56 0.99 1.29 1.37 0.14 1.39 2.34 1.05 0.46
1.05 1.97 1.47 5.87 7.64 0.89 7.76 11.21 12.04 1.61
0.462 0.876 0.052 0.009 0.007 0.028 0.006 <0.0001 0.042 0.636
ASA = American Society of Anesthesiologists; CCI = Charlson comorbidity index; CI = confidence interval; HR = hazard ratio.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
5
Fig. 2 – Substratified Kaplan-Meir survival curves according to (A) pT stage, (B) pN stage, (C) margins, and (D) lymphovascular invasion (LVI) for recurrence-free survival.
aged >65 yr. While evaluating the association of various comorbidity parameters, Boorjian et al. reported that morbidity scores were independent predictors of 5-yr allcause mortality [17]. Additionally Mayr et al. reported that all comorbidity indices were associated with cancerindependent mortality, and high-risk profile (dichotomized age and comorbidity indices) had a 6.9-fold risk of mortality [18]. The recurrence rate of 41% in our study is higher than prior reports on ORC [3], and can be attributed to the higher T stage, positive margin, and LN metastasis observed in our cohort. Ghoneim et al., in their series of 2720 ORCs, reported a 56% disease-free survival (DFS) rate at 5 yr in transitional cell carcinoma patients [4]. They highlighted that LN positivity was associated with worse RFS, irrespective of tumor histology, and recommended retrieval of 20 LNs to achieve adequate oncologic control. Hautmann et al. also reported lower RFS, DFS, and OS in their cohort of 1100 ORC patients at 5 yr (69.5%, 71.2%, and 57.9%, respectively), although they did not report margin positivity [19]. All patients in our current series were recommended RARC and none underwent ORC during
the time interval of this study, supporting the absence of selection bias. Consistent with no selection bias, pathologic outcomes of patients in this series were notably higher risk than that of previous reports (including a 51% rate of extravesical disease and 30% of LN positivity), potentially representing referral patterns at a tertiary cancer center. Benchmark standards for ORC reported by Herr and colleagues drive current operative standards for cystectomy [20]. Although intended originally for comparison among ORC surgeons, they may also be applied for critical examination of minimally invasive approaches, including RARC. Others have previously evaluated RARC oncologic outcomes with these standards; however, these studies are limited by small numbers of patients and/or lack of longterm follow-up [13,21]. Our operative outcomes with RARC meet the standards proposed by Herr et al., including our 8.1% positive margin rate (<10% recommended) and 87% rate of extended LN dissection with a median 21 LNs removed (>10–14 recommended) [20]. However Xylinas et al. reported a 5% soft tissue surgical margin in a review of 4335 patients from 11 institutions [22].
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 6
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Fig. 3 – Substratified Kaplan-Meir survival curves according to (A) pT stage, (B) pN stage, (C) margins, and (D) lymphovascular invasion (LVI) for cancerspecific survival.
Currently, no study exists that can lay out the standards for RARC, similar to those reported by Herr et al. for opencystectomy cases. Such a study would require long-term oncologic outcomes derived from a large cohort of RARC performed by multiple surgeons at different institutions. Khan et al. have reported RFS, CSS, and OS rates of 50%, 75%, and 64%, respectively, with a 63-mo median follow-up interval, for patients with organ-confined disease [13]. In comparison, although we observed a lower OS and CSS, the RFS rate was better in a higher-risk cohort. Snow-Lisy et al. reported long-term outcomes following minimally invasive radical cystectomy [23]. The series reported a CSS of 69% and OS of 39% in 17 RARC patients over a median follow-up of 5.6 yr [23]. Tyritzis et al. reported better RFS, CSS, and OS rates (80.7%, 88.9%, and 88.9%, respectively) in their cohort of 70 RARC patients, but the median follow-up interval was only 30 mo and the majority of patients had pathologically organ-confined disease (85%) [11]. Nepple et al. compared the early oncologic outcomes between ORC and RARC, with 36 patients in the RARC group [24]. In contrast to other
RARC studies, nearly half of all RARC patients (47%) had non–organ-confined disease, but only short-term outcomes were reported, including RFS, CSS, and OS of 67%, 75%, and 68%, respectively, at 2 yr [24]. Similar to the findings of this study, Kauffman et al. reported poor survival outcomes for patients with non–organ-confined LN-positive disease undergoing RARC [21]. In our study, eight patients had positive surgical margins, five had pT4 disease, and no patient with pathologically organ-confined disease had a positive margin. Additionally, the multivariable analysis did not demonstrate margin status to be associated with RFS. In a multi-institutional series of >4000 ORC patients, soft tissue surgical margin (6.3%) was found to be an independent predictor of recurrence and cancer-specific death in the advanceddisease subgroup [25]. ORC studies have established tumor stage, LN stage, margin status, and LVI as independent predictors of oncologic outcomes after surgery [26,27]. We observed similar results in the current study, although we did not find
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
7
Fig. 4 – Substratified Kaplan-Meir survival curves according to (A) pT stage, (B) pN stage, (C) margins, and (D) lymphovascular invasion (LVI) for overall survival.
LVI to be an independent predictor of survival outcomes. Similarly, Kauffman et al. reported that T stage and LN status (density) were independent predictors of survival outcomes after RARC, while the LVI did not exhibit any influence [21]. Local recurrence has a major impact on determining the efficacy of RARC (local control). The local recurrence rate in our series is relatively higher than the other RARC series. Our high local recurrence rate largely reflects the significant oncologic risk of the high rate of LN positivity, which, at 30%, is notably higher than commonly reported (approximately 20–24%) [3,4]. The predictors for local recurrence after ORC, as identified by Herr et al., includes non–organ-confined disease, <10 LN yield, no or limited PNLD, and positive surgical margins [20]. Their study supports the finding that final pathologic stage influences the local recurrence rate, which may not have been clearly evident in the contemporary selective RARC series. Improvements in outcomes following radical cystectomy have been suggested with timely cystectomy, meticulous surgical technique for cancer control, adequate LN yield, and aggressive use of neoadjuvant chemotherapy [28]. In our series, only 6% of
patients received neoadjuvant chemotherapy, a shortcoming of our study. Adjuvant chemotherapy (28%) was associated with better RFS on multivariable analysis, as earlier reported [28]. Lack of multidisciplinary approach, patient age, renal function, and comorbid status of the patients (age >75 yr: 35%; creatinine clearance <60 ml/ min: 64%; and CCI 3: 71%) were the probable reasons for limited use of neoadjuvant chemotherapy. However, with a multidisciplinary approach toward management of invasive bladder cancer restricting physician bias, the utilization rates have significantly improved (10.8–55%) within 24 mo [29]. Similarly, advanced age, poor creatinine clearance, and comorbid status contributed to our lower numbers of neobladder, along with perceived risks of outcomes associated with this type of diversion, which can be a limitation of this study. This study has several limitations. Foremost, it uses a retrospective design and lacks a comparative arm of ORC cases. In addition, because survival information was retrieved from the tumor registry and death certificates, the cause of death may not have been captured accurately.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 8
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Additionally, although the series represents the largest current report on 5-yr oncologic outcomes, the number of patients still remains limited. Finally, this series needs to be carefully interpreted, as it represents a single surgeon experience. Nevertheless, despite these limitations, this study provides informative data supporting minimally invasive cystectomy as an alternative to the open approach. As seen in larger ORC series, multi-institutional oncologic outcome analyses will help better understand and explain the long-term oncologic efficacy of RARC.
[5] Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009;55:164–76. [6] Wang GJ, Barocas DA, Raman JD, Scherr DS. Robotic vs open radical cystectomy: prospective comparison of perioperative outcomes and pathological measures of early oncological efficacy. BJU Int 2008;101:89–93. [7] Guru KA, Wilding GE, Piacente P, et al. Robot-assisted radical cystectomy versus open radical cystectomy: assessment of postoperative pain. Can J Urol 2007;14:3753–6. [8] Nix J, Smith A, Kurpad R, Nielsen ME, Wallen EM, Pruthi RS. Prospective randomized controlled trial of robotic versus open
5.
Conclusions
This single-institution, consecutive series reports long-term oncologic outcomes that are affected by their pathologic tumor and nodal stage after RARC. Randomized controlled trials can better define the outcomes of an alternative operative technique.
radical cystectomy for bladder cancer: perioperative and pathologic results. Eur Urol 2010;57:196–201. [9] Parekh DJ, Messer J, Fitzgerald J, Ercole B, Svatek R. Perioperative outcomes and oncologic efficacy from a pilot prospective randomized clinical trial of open versus robotic assisted radical cystectomy. J Urol 2013;189:474–9. [10] Xylinas E, Green DA, Otto B, et al. Robotic-assisted radical cystectomy with extracorporeal urinary diversion for urothelial carcinoma of the bladder: analysis of complications and oncologic outcomes in
Author contributions: Khurshid A. Guru 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.
175 patients with a median follow-up of 3 years. Urology 2013;82: 1323–9. [11] Tyritzis SI, Hosseini A, Collins J, et al. Oncologic, functional, and complications outcomes of robot-assisted radical cystectomy with
Study concept and design: Guru. Acquisition of data: Raza, Zhuo, Mehboob, Al-Daghmin. Analysis and interpretation of data: Raza, Zhuo, Al-Daghmin, Kauffman.
totally intracorporeal neobladder diversion. Eur Urol 2013;64: 734–41. [12] Keren Paz GE, Laudone VP, Bochner BH. Does minimally invasive
Drafting of the manuscript: Raza, Al-Daghmin, Kauffman.
surgery for radical cystectomy provide similar long-term cancer
Critical revision of the manuscript for important intellectual content:
control as open radical surgery? Curr Opin Urol 2013;23:449–55.
Kauffman, Guru. Statistical analysis: Wang, Wilding. Obtaining funding: None. Administrative, technical, or material support: Raza. Supervision: Guru. Other (specify): None. Financial disclosures: Khurshid A. Guru certifies 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: K. Guru is a board member of Simulated Surgical Systems. Funding/Support and role of the sponsor: Roswell Park Alliance Foundation assisted with the design and conduct of this study.
[13] Khan MS, Elhage O, Challacombe B, et al. Long-term outcomes of robot-assisted radical cystectomy for bladder cancer. Eur Urol 2013;64:219–24. [14] Poch MA, Raza J, Nyquist J, Guru KA. Tips and tricks to robotassisted radical cystectomy and intracorporeal diversion. Curr Opin Urol 2013;23:65–71. [15] Leow JJ, Reese SW, Jiang W, et al. Propensity-matched comparison of morbidity and costs of open and robot-assisted radical cystectomies: a contemporary population-based analysis in the United States. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.01.029 [16] Ploussard G, Shariat SF, Dragomir A, et al. Conditional survival after radical cystectomy for bladder cancer: evidence for a patient changing risk profile over time. Eur Urol. In press. http://dx.doi. org/10.1016/j.eururo.2013.09.050 [17] Boorjian SA, Kim SP, Tollefson MK, et al. Comparative performance of comorbidity indices for estimating perioperative and 5-year all cause mortality following radical cystectomy for bladder cancer. J Urol 2013;190:55–60.
References
[18] Mayr R, May M, Martini T, et al. Comorbidity and performance indices as predictors of cancer-independent mortality but not of
[1] Chavan S, Bray F, Lortet-Tieulent J, Goodman M, Jemal A. International variations in bladder cancer incidence and mortality. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2013.10.001
cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder. Eur Urol 2012;62:662–70. [19] Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical
[2] Howlader N, Krapcho M, Garshell J, et al. SEER cancer statistics
cystectomy for urothelial carcinoma of the bladder without neoad-
review (CSR) 1975-2010. National Cancer Institute Web site. http://
juvant or adjuvant therapy: long-term results in 1100 patients. Eur
seer.cancer.gov/csr/1975_2010/. Updated June 14, 2013.
Urol 2012;61:1039–47.
[3] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the
[20] Herr H, Lee C, Chang S, Lerner S. Standardization of radical cystectomy
treatment of invasive bladder cancer: long-term results in 1,054
and pelvic lymph node dissection for bladder cancer: a collaborative
patients. J Clin Oncol 2001;19:666–75. [4] Ghoneim MA, Abdel-Latif M, el-Mekresh M, et al. Radical cystec-
group report. J Urol 2004;171:1823–8, discussion 1827–8. [21] Kauffman EC, Ng CK, Lee MM, et al. Early oncological outcomes for
tomy for carcinoma of the bladder: 2,720 consecutive cases 5 years
bladder urothelial carcinoma patients treated with robotic-assisted
later. J Urol 2008;180:121–7.
radical cystectomy. BJU Int 2011;107:628–35.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
9
[22] Xylinas E, Rink M, Novara G, et al. Predictors of survival in patients
[26] Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of radical
with soft tissue surgical margin involvement at radical cystectomy.
cystectomy for transitional cell carcinoma of the bladder: a con-
Ann Surg Oncol 2013;20:1027–34. [23] Snow-Lisy DC, Campbell SC, Gill IS, et al. Robotic and laparoscopic radical cystectomy for bladder cancer: long-term oncologic outcomes. Eur Urol 2014;65:193–200. [24] Nepple KG, Strope SA, Grubb III RL, Kibel AS. Early oncologic outcomes of robotic vs. open radical cystectomy for urothelial cancer. Urol Oncol 2013;31:894–8.
temporary series from the Bladder Cancer Research Consortium. J Urol 2006;176:2414–22. [27] Zehnder P, Studer UE, Skinner EC, et al. Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades. BJU Int 2013;112:E51–8. [28] Montie JE. Improving outcomes after radical cystectomy. J Urol 2008;180:12–3.
[25] Novara G, Svatek RS, Karakiewicz PI, et al. Soft tissue surgical margin
[29] Rehman S, Crane A, Din R, et al. Understanding avoidance, refusal,
status is a powerful predictor of outcomes after radical cystectomy: a
and abandonment of chemotherapy before and after cystectomy for
multicenter study of more than 4,400 patients. J Urol 2010;183:
bladder cancer. Urology 2013;82:1370–5.
2165–70.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Bladder Cancer
Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience Syed Johar Raza a, Ali Al-Daghmin a, Sharon Zhuo a, Zayn Mehboob a, Katy Wang b, Gregory Wilding b, Eric Kauffman a,c, Khurshid A. Guru a,* a
Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA;
c
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
b
Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, USA;
Article info
Abstract
Article history: Received 6 January 2014 Published online ahead of print on April 16, 2014
Background: Long-term oncologic outcomes following robot-assisted radical cystectomy (RARC) remain scarce. Objective: To report long-term oncologic outcomes following RARC at a single institution. Design, settings, and participants: Retrospective review of 99 patients who underwent RARC for urothelial carcinoma of bladder between 2005 and 2009. Intervention: RARC was performed. Outcome measurements and statistical analysis: Primary outcomes included recurrencefree survival (RFS), cancer-specific survival (CSS), and overall survival (OS), measured by the Kaplan-Meier method. The association between primary outcomes and perioperative and pathologic factors was assessed using a multivariable Cox proportional hazards model. Results and limitations: Fifty-one (52%) patients had stage pT3 or higher disease. Eight (8%) patients had positive margins and 30 (30%) had positive lymph nodes (LNs), with a median of 21 LNs removed. Median follow-up for patients alive was 74 mo. The 5-yr RFS, CSS, and OS rates were 52.5%, 67.8%, and 42.4%, respectively. Tumor stage, LN stage, and margin status were each significantly associated with RFS, CSS, and OS. On multivariable analysis, tumor and LN stage were independent predictors of RFS, CSS, and OS, while positive margin status and Charlson comorbidity index predicted worse OS and CSS. Adjuvant chemotherapy predicted RFS only. Retrospective design and lack of open comparison are main limitations of this study. Conclusions: Long-term oncologic outcomes following RARC demonstrate RFS and CSS estimates similar to those reported in literature for open radical cystectomy. Randomized controlled trials can better define outcomes of any alternative technique. Patient summary: Survival data 5 yr after RARC for bladder cancer demonstrate that survival outcomes are dependent on the same oncologic parameters as previously reported for open surgery. # 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Robot-assisted Radical Cystectomy Long term Oncologic Outcomes Outcomes
* Corresponding author. Department of Urology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Tel. +1 716 845 7612; Fax: +1 716 845 3300. E-mail address: [email protected] (K.A. Guru).
http://dx.doi.org/10.1016/j.eururo.2014.03.015 0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 2
EUROPEAN UROLOGY XXX (2014) XXX–XXX
1.
Introduction
Incidence of bladder cancer varies across the globe, with highest rates observed in western countries [1]. In 2013, 72 570 new cases of bladder cancer were diagnosed in the United States, of these, >15 000 patients are expected to die of bladder cancer [2]. Open radical cystectomy (ORC) with pelvic lymph node dissection (PLND) achieves a 60% survival rate after 10 yr, and remains the gold standard
Table 1 – Demographic, perioperative, and postoperative details of the patients Demographic details Age, yr Sex, no. (%) BMI, kg/m2 ASA score, no. (%) CCI, no. (%)
N = 99
Total
Median (IQR) Mean (SD) Male Median (IQR) Mean (SD) 2 >3
71 (61–77) 68.9 (10.9) 78 (78.8) 28.2 (25.2–31.6) 28.8 (5.1) 57 (57.6) 70 (70.7)
CIS T1 T2 T3 T4 NA
63 18 23 46 3 6 3 6
Preoperative details Previous surgery, no. (%) Clinical stage, no. (%)
Neoadjuvant chemotherapy, no. (%)
(63.6) (18.2) (23.2) (46.5) (3) (6.1) (1) (6.1)
Lymph node dissection time, min Overall time, min Estimated blood loss, ml Diversion type, no. (%)
2.
Patients and methods
2.1.
Patient population
A retrospective review was performed of an institutional review boardapproved database (I 79606) including all patients undergoing RARC with
Operative details Cystectomy time, min
treatment for muscle-invasive and high-risk non–muscleinvasive bladder cancer [3,4]. Despite its known oncologic benefit, ORC with PLND is associated with significant morbidity [5], which has ignited efforts to investigate a minimally invasive alternative. Robot-assisted radical cystectomy (RARC) has emerged as an alternative approach to ORC, based on its possible reduction in blood loss, transfusion rate, postoperative analgesia, and quicker recovery of bowel function [6,7]. Only two randomized studies have compared perioperative outcomes between RARC and ORC with limited cohort sizes and follow-up intervals, highlighting the need for more high quality randomized studies [8,9]. Attempts have been made to establish the effectiveness of RARC as a comparable alternative to ORC, including several reports on early and intermediate oncologic outcomes [10,11]. However, data on long-term oncologic outcomes remain scarce and limited by small cohort sizes and nonconsecutive-patient-selection bias [12,13]. The purpose of the present study is to report long-term oncologic outcomes of 99 consecutive bladder urothelial carcinoma patients undergoing RARC with curative intent at a single institution.
curative intent (n = 345) at a National Comprehensive Cancer Network Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Conduit Neobladder Pouch
149.5 (119–200) 165.5 (59.2) 52 (40–76) 60 (27.3) 372 (305–437) 379.5 (123.9) 400 (250–700) 543.4 (423.2) 92 (92.9) 6 (6.1) 1 (1)
(NCCN)-designated cancer center (Roswell Park Cancer Institute [RPCI], Buffalo, NY, USA) between 2005 and 2013. The technique for RARC has previously been reported [14]. All diversions were performed with an extracorporeal approach (intracorporeal diversions were incorporated
Table 2 – Follow-up details of the patients Follow-up details, mo Follow-up, overall
Postoperative details Pathologic T stage, no. (%)
Lymph nodes removed, no. Lymph node status, no. (%)
Lymphovascular invasion, no. (%) Bladder soft tissue margins, no. (%) Adjuvant chemotherapy, no. (%)
pT0 CIS pT2a pT2b pT3a pT3b pT4a pT4b Median (IQR) Mean (SD) pN0 pNx pN1 pN2 pN3 Positive
9 (9.1) 23 (23.2) 10 (10.1) 6 (6.1) 22 (22.2) 12 (12.1) 15 (15.1) 2 (2.1) 21 (13–27) 20.7 (11) 63 (63.6) 6 (6.1) 12 (12.1) 14 (14.1) 4 (4) 25 (25.3) 8 (8.1) 28 (28.9)
Follow-up, alive without recurrence Local recurrence, no. (%) Metastatic recurrence, no. (%) Recurrence, no. (%) Status at last follow-up, no. (%)
Time to recurrence Time to cancer-specific death Time to death
ASA = American Society of Anesthesiology; BMI = body mass index; CCI = Charlson comorbidity index; IQR = interquartile range; NA = not applicable; SD = standard deviation.
Median (IQR) Mean (SD) Median (IQR)
30.9 (12.7–70.8) 43 (32.4) 73.9 (66.4–89.5)
Mean (SD) Only Only
77.9 (12.8) 9 (9.09) 18 (18.2)
Combined Alive without recurrence
14 (14.2) 35 (35.7)
Alive with recurrence Non–cancer-related death Cancer-related death Death due to unknown causes Median (IQR) Mean (SD) Median (IQR)
5 26 26 6
Mean (SD) Median (IQR) Mean (SD)
20.8 (15.6) 15.3 (6.5–28.8) 19.5 (16.6)
(5.1) (26.5) (26.5) (6.1)
8.6 (4.5–18.3) 11.9 (10.8) 18.1 (8.7–29.3)
IQR = interquartile range, SD = standard deviation.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
in May 2009). A total of 119 patients were identified who had undergone
3
true pelvis (bifurcation of aorta as the cephalic boundary) and metastatic
RARC >5 yr prior to their most recent follow-up date. Of these, patients
disease was defined as evidence of disease outside the true pelvis. The
with nonurothelial carcinoma (n = 9) and palliative RARC (n = 6) were
cause of death was recorded from the electronic medical records or death
excluded. Additionally, five (5.1%) patients who were lost to follow-up
certificate obtained from the primary care physician, and an institutional
were also excluded from the final analysis. No ORC has been performed at
tumor registry database. The last contact recorded by the RPCI clinic or
the institution since 2005. Final analysis was performed on the remaining
tumor registry, or the date of death, was considered as the date of last
99 patients with at least 60 mo of follow-up data.
follow-up.
2.2.
2.3.
Outcome parameters
Statistical analysis
Primary outcome measures included recurrence-free survival (RFS),
Descriptive statistics were obtained for demographic variables. Primary
cancer-specific survival (CSS), and overall survival (OS). Univariable and
outcome measures included RFS, CSS, and OS, which were compared by
multivariable analyses were performed to evaluate the influence of
standard Kaplan-Meier methodology using a log-rank test. Patients who
perioperative factors (ie, age, American Society of Anesthesiologists
were still alive without experiencing an event at their last follow-up
score, body mass index, Charlson comorbidity index [CCI], and operative
date were considered censored from survival estimates. Patients who
time) on primary outcomes, along with pathologic features including
were still alive or expired without experiencing an event at their last
tumor stage (pT), LN stage (pN), surgical margin, and lymphovascular
follow-up date or death date were considered censored in an event-free
invasion (LVI). Survival outcomes were stratified by pT, pN, margin status,
interval estimate. The association among RFS, CSS, OS, and risk factors of
and LVI. Tumor grade and pathologic staging were determined based on
interest were assessed using a Cox proportional hazards model, with
the 2002 American Joint Committee on Cancer TNM staging system and
p < 0.05 as the nominal significance level. Factors that were significant
the 2004 World Health Organization/International Society of Urologic
on univariable analysis were admitted to the multivariable model. SAS
Pathologists classification of papillary urothelial neoplasms, respectively.
v.9.3 (SAS Institute, Cary, NC, USA) was used for statistical analysis.
Surgical margin included radial bladder and apical/urethral margins. Patients were followed according to the NCCN guidelines. The OS was defined as time to death due to any cause. CSS was defined as death due to
3.
Results
bladder cancer, while RFS was defined as time from date of cystectomy to local and/or metastatic recurrence, based on histologic or radiologic evidence. Local recurrence was defined as evidence of disease within the
Demographic and perioperative details of the 99 RARC patients are presented in Table 1. Table 2 highlights oncologic
Fig. 1 – Kaplan-Meir survival curves for (A) recurrence-free survival, (B) cancer-specific survival, and (C) overall survival.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 4
EUROPEAN UROLOGY XXX (2014) XXX–XXX
and survival outcomes. The median duration of follow-up was 73.9 mo (interquartile range: 66.4–89.5) for patients alive without recurrence. Forty (40.8%) patients were alive at the time of analysis, and 26 (26.5%) died of bladder cancer. Local recurrence occurred in 9 (9.1%) patients, and 18 (18.2%) patients developed distant recurrence only. The 5-yr RFS, CSS, and OS rates were 52.5%, 67.8%, and 42.4%, respectively (Fig. 1). When substratified according to pT stage, pN stage, and margin status, significant differences in the RFS, CSS, and OS were observed; however, no significant differences were noted when stratified according to LVI (Figs. 2–4). Multivariable analysis identified higher pT stage and pN stage as independent predictors of worse RFS, CSS, and OS, while positive surgical margins and CCI (continuous variable) predicted CSS and OS only. Adjuvant chemotherapy predicted the RFS only (Table 3). 4.
Discussion
Despite the increase in performance of RARC in the past decade [15], long-term oncologic outcomes are still unknown. ORC remains the gold standard treatment for muscleinvasive or recurrent or high-risk non–muscle-invasive
bladder cancer due to the thorough characterization of long-term oncologic outcomes [4]. Few RARC studies have included 5-yr oncologic outcomes data and are limited by small numbers of patients with 5-yr outcomes [10]. The current study presents long-term oncologic outcomes of bladder cancer patients treated with RARC by a single surgeon at an NCCN-designated cancer center. Median follow-up was 30.9 mo, and 40 patients (41%) were alive >60 mo who had a median follow-up of 73.9 mo. RFS, CSS, and OS rates were 52%, 68%, and 42%, respectively. In comparison, Stein et al. reported 5-yr RFS and OS rates of 68% and 66%, respectively, although the median age was 66 yr compared to 71 yr in our study, and comorbidity status was not reported [3]. In the same study, 63% of patients had pT3a or lower disease with 23% positive LNs; 25% of recurrences involved the pelvis. Our study demonstrates lower OS compared to the Stein et al. study; this may be attributable to the more advanced age of our cohort and to common comorbidity. Consistent with this explanation, CCI was demonstrated in our cohort to be an independent contributor for OS and CSS, without affecting RFS. The association between survival and advanced age or increased comorbidity is well established. Ploussard et al. [16] found a continuous increase in hazard risk of survival for patients
Table 3 – Univariable and multivariable Cox regression analysis for factors affecting the recurrence-free survival, cancer-specific survival, and overall survival Univariable analysis Variable Recurrence-free survival Age ASA score CCI pT stage Surgical margins pN stage
Adjuvant chemotherapy Cancer-specific survival Age ASA score CCI pT Stage Surgical margins pN stage
Adjuvant chemotherapy Overall survival Age ASA score CCI pT stage Surgical margins pN stage
Adjuvant chemotherapy
Multivariable analysis
HR
Lower CI
Upper CI
p value
1.005 0.71 1.11 4.28 7.76 0.30 3.28 4.19 1.36 5.52
0.97 0.37 0.94 1.91 3.23 0.09 1.30 1.83 0.18 0.09
1.04 1.37 1.32 9.59 18.64 1.04 8.26 9.63 10.29 0.36
0.766 0.306 <0.001 <0.001
1.04 0.62 1.25 5.57 7.20 0.07 2.54 6.10 8.09 3.08
0.99 0.28 1.02 2.07 2.47 0.02 0.72 2.42 1.71 0.15
1.08 1.34 1.56 14.99 21.03 0.22 8.99 15.38 38.36 0.72
0.11 0.22 <0.001 0.0005
1.04 0.59 1.26 4.46 5.11 0.16 3.80 4.76 6.42 2.05
1.01 0.35 1.09 2.33 2.47 0.07 1.83 2.40 2.16 0.28
1.07 1.02 1.44 8.54 10.55 0.36 7.92 9.45 19.05 0.85
0.01 0.06 <0.0001 <0.0001
0.057 0.003
<0.0001
<0.001 0.0005
0.006
<0.0001 <0.0001
0.01
Reference
10-yr increments 2 vs >2 (Continuous) pT3 vs (pT2) pT4 vs (pT2) Positive vs negative pN1 vs pN0 pN2 vs pN0 pN3 vs pN0 No vs yes
HR
Lower CI
Upper CI
p value
Dropped 1.08 2.07 4.99 1.67 1.99 3.79 0.88 1.67
0.89 0.79 1.79 0.16 0.69 1.47 0.11 0.13
1.31 5.39 13.94 2.18 5.74 9.76 7.39 0.61
0.403 0.135 0.002 0.435 0.197 0.006 0.909 0.001
10-yr increments 2 vs >2 (Continuous variable) pT3 vs (pT2) pT4 vs (pT2) Positive vs negative pN1 vs pN0 pN2 vs pN0 pN3 vs pN0 No vs yes
Dropped 1.29 2.67 2.67 6.17 1.61 7.16 7.36 1.93
1.04 0.84 0.69 0.05 0.34 2.36 1.23 0.20
1.61 8.50 10.19 0.54 7.59 21.73 43.95 1.31
0.021 0.096 0.151 0.002 0.546 0.0005 0.028 0.165
10-yr increments 2 vs >2 (Continuous variable) pT3 vs (pT2) pT4 vs (pT2) Positive vs. negative pN1 vs pN0 pN2 vs pN0 pN3 vs pN0 No vs yes
1.01 1.05 1.21 2.76 3.24 2.78 3.29 5.12 3.55 1.16
0.97 0.56 0.99 1.29 1.37 0.14 1.39 2.34 1.05 0.46
1.05 1.97 1.47 5.87 7.64 0.89 7.76 11.21 12.04 1.61
0.462 0.876 0.052 0.009 0.007 0.028 0.006 <0.0001 0.042 0.636
ASA = American Society of Anesthesiologists; CCI = Charlson comorbidity index; CI = confidence interval; HR = hazard ratio.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
5
Fig. 2 – Substratified Kaplan-Meir survival curves according to (A) pT stage, (B) pN stage, (C) margins, and (D) lymphovascular invasion (LVI) for recurrence-free survival.
aged >65 yr. While evaluating the association of various comorbidity parameters, Boorjian et al. reported that morbidity scores were independent predictors of 5-yr allcause mortality [17]. Additionally Mayr et al. reported that all comorbidity indices were associated with cancerindependent mortality, and high-risk profile (dichotomized age and comorbidity indices) had a 6.9-fold risk of mortality [18]. The recurrence rate of 41% in our study is higher than prior reports on ORC [3], and can be attributed to the higher T stage, positive margin, and LN metastasis observed in our cohort. Ghoneim et al., in their series of 2720 ORCs, reported a 56% disease-free survival (DFS) rate at 5 yr in transitional cell carcinoma patients [4]. They highlighted that LN positivity was associated with worse RFS, irrespective of tumor histology, and recommended retrieval of 20 LNs to achieve adequate oncologic control. Hautmann et al. also reported lower RFS, DFS, and OS in their cohort of 1100 ORC patients at 5 yr (69.5%, 71.2%, and 57.9%, respectively), although they did not report margin positivity [19]. All patients in our current series were recommended RARC and none underwent ORC during
the time interval of this study, supporting the absence of selection bias. Consistent with no selection bias, pathologic outcomes of patients in this series were notably higher risk than that of previous reports (including a 51% rate of extravesical disease and 30% of LN positivity), potentially representing referral patterns at a tertiary cancer center. Benchmark standards for ORC reported by Herr and colleagues drive current operative standards for cystectomy [20]. Although intended originally for comparison among ORC surgeons, they may also be applied for critical examination of minimally invasive approaches, including RARC. Others have previously evaluated RARC oncologic outcomes with these standards; however, these studies are limited by small numbers of patients and/or lack of longterm follow-up [13,21]. Our operative outcomes with RARC meet the standards proposed by Herr et al., including our 8.1% positive margin rate (<10% recommended) and 87% rate of extended LN dissection with a median 21 LNs removed (>10–14 recommended) [20]. However Xylinas et al. reported a 5% soft tissue surgical margin in a review of 4335 patients from 11 institutions [22].
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 6
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Fig. 3 – Substratified Kaplan-Meir survival curves according to (A) pT stage, (B) pN stage, (C) margins, and (D) lymphovascular invasion (LVI) for cancerspecific survival.
Currently, no study exists that can lay out the standards for RARC, similar to those reported by Herr et al. for opencystectomy cases. Such a study would require long-term oncologic outcomes derived from a large cohort of RARC performed by multiple surgeons at different institutions. Khan et al. have reported RFS, CSS, and OS rates of 50%, 75%, and 64%, respectively, with a 63-mo median follow-up interval, for patients with organ-confined disease [13]. In comparison, although we observed a lower OS and CSS, the RFS rate was better in a higher-risk cohort. Snow-Lisy et al. reported long-term outcomes following minimally invasive radical cystectomy [23]. The series reported a CSS of 69% and OS of 39% in 17 RARC patients over a median follow-up of 5.6 yr [23]. Tyritzis et al. reported better RFS, CSS, and OS rates (80.7%, 88.9%, and 88.9%, respectively) in their cohort of 70 RARC patients, but the median follow-up interval was only 30 mo and the majority of patients had pathologically organ-confined disease (85%) [11]. Nepple et al. compared the early oncologic outcomes between ORC and RARC, with 36 patients in the RARC group [24]. In contrast to other
RARC studies, nearly half of all RARC patients (47%) had non–organ-confined disease, but only short-term outcomes were reported, including RFS, CSS, and OS of 67%, 75%, and 68%, respectively, at 2 yr [24]. Similar to the findings of this study, Kauffman et al. reported poor survival outcomes for patients with non–organ-confined LN-positive disease undergoing RARC [21]. In our study, eight patients had positive surgical margins, five had pT4 disease, and no patient with pathologically organ-confined disease had a positive margin. Additionally, the multivariable analysis did not demonstrate margin status to be associated with RFS. In a multi-institutional series of >4000 ORC patients, soft tissue surgical margin (6.3%) was found to be an independent predictor of recurrence and cancer-specific death in the advanceddisease subgroup [25]. ORC studies have established tumor stage, LN stage, margin status, and LVI as independent predictors of oncologic outcomes after surgery [26,27]. We observed similar results in the current study, although we did not find
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
7
Fig. 4 – Substratified Kaplan-Meir survival curves according to (A) pT stage, (B) pN stage, (C) margins, and (D) lymphovascular invasion (LVI) for overall survival.
LVI to be an independent predictor of survival outcomes. Similarly, Kauffman et al. reported that T stage and LN status (density) were independent predictors of survival outcomes after RARC, while the LVI did not exhibit any influence [21]. Local recurrence has a major impact on determining the efficacy of RARC (local control). The local recurrence rate in our series is relatively higher than the other RARC series. Our high local recurrence rate largely reflects the significant oncologic risk of the high rate of LN positivity, which, at 30%, is notably higher than commonly reported (approximately 20–24%) [3,4]. The predictors for local recurrence after ORC, as identified by Herr et al., includes non–organ-confined disease, <10 LN yield, no or limited PNLD, and positive surgical margins [20]. Their study supports the finding that final pathologic stage influences the local recurrence rate, which may not have been clearly evident in the contemporary selective RARC series. Improvements in outcomes following radical cystectomy have been suggested with timely cystectomy, meticulous surgical technique for cancer control, adequate LN yield, and aggressive use of neoadjuvant chemotherapy [28]. In our series, only 6% of
patients received neoadjuvant chemotherapy, a shortcoming of our study. Adjuvant chemotherapy (28%) was associated with better RFS on multivariable analysis, as earlier reported [28]. Lack of multidisciplinary approach, patient age, renal function, and comorbid status of the patients (age >75 yr: 35%; creatinine clearance <60 ml/ min: 64%; and CCI 3: 71%) were the probable reasons for limited use of neoadjuvant chemotherapy. However, with a multidisciplinary approach toward management of invasive bladder cancer restricting physician bias, the utilization rates have significantly improved (10.8–55%) within 24 mo [29]. Similarly, advanced age, poor creatinine clearance, and comorbid status contributed to our lower numbers of neobladder, along with perceived risks of outcomes associated with this type of diversion, which can be a limitation of this study. This study has several limitations. Foremost, it uses a retrospective design and lacks a comparative arm of ORC cases. In addition, because survival information was retrieved from the tumor registry and death certificates, the cause of death may not have been captured accurately.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 8
EUROPEAN UROLOGY XXX (2014) XXX–XXX
Additionally, although the series represents the largest current report on 5-yr oncologic outcomes, the number of patients still remains limited. Finally, this series needs to be carefully interpreted, as it represents a single surgeon experience. Nevertheless, despite these limitations, this study provides informative data supporting minimally invasive cystectomy as an alternative to the open approach. As seen in larger ORC series, multi-institutional oncologic outcome analyses will help better understand and explain the long-term oncologic efficacy of RARC.
[5] Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009;55:164–76. [6] Wang GJ, Barocas DA, Raman JD, Scherr DS. Robotic vs open radical cystectomy: prospective comparison of perioperative outcomes and pathological measures of early oncological efficacy. BJU Int 2008;101:89–93. [7] Guru KA, Wilding GE, Piacente P, et al. Robot-assisted radical cystectomy versus open radical cystectomy: assessment of postoperative pain. Can J Urol 2007;14:3753–6. [8] Nix J, Smith A, Kurpad R, Nielsen ME, Wallen EM, Pruthi RS. Prospective randomized controlled trial of robotic versus open
5.
Conclusions
This single-institution, consecutive series reports long-term oncologic outcomes that are affected by their pathologic tumor and nodal stage after RARC. Randomized controlled trials can better define the outcomes of an alternative operative technique.
radical cystectomy for bladder cancer: perioperative and pathologic results. Eur Urol 2010;57:196–201. [9] Parekh DJ, Messer J, Fitzgerald J, Ercole B, Svatek R. Perioperative outcomes and oncologic efficacy from a pilot prospective randomized clinical trial of open versus robotic assisted radical cystectomy. J Urol 2013;189:474–9. [10] Xylinas E, Green DA, Otto B, et al. Robotic-assisted radical cystectomy with extracorporeal urinary diversion for urothelial carcinoma of the bladder: analysis of complications and oncologic outcomes in
Author contributions: Khurshid A. Guru 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.
175 patients with a median follow-up of 3 years. Urology 2013;82: 1323–9. [11] Tyritzis SI, Hosseini A, Collins J, et al. Oncologic, functional, and complications outcomes of robot-assisted radical cystectomy with
Study concept and design: Guru. Acquisition of data: Raza, Zhuo, Mehboob, Al-Daghmin. Analysis and interpretation of data: Raza, Zhuo, Al-Daghmin, Kauffman.
totally intracorporeal neobladder diversion. Eur Urol 2013;64: 734–41. [12] Keren Paz GE, Laudone VP, Bochner BH. Does minimally invasive
Drafting of the manuscript: Raza, Al-Daghmin, Kauffman.
surgery for radical cystectomy provide similar long-term cancer
Critical revision of the manuscript for important intellectual content:
control as open radical surgery? Curr Opin Urol 2013;23:449–55.
Kauffman, Guru. Statistical analysis: Wang, Wilding. Obtaining funding: None. Administrative, technical, or material support: Raza. Supervision: Guru. Other (specify): None. Financial disclosures: Khurshid A. Guru certifies 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: K. Guru is a board member of Simulated Surgical Systems. Funding/Support and role of the sponsor: Roswell Park Alliance Foundation assisted with the design and conduct of this study.
[13] Khan MS, Elhage O, Challacombe B, et al. Long-term outcomes of robot-assisted radical cystectomy for bladder cancer. Eur Urol 2013;64:219–24. [14] Poch MA, Raza J, Nyquist J, Guru KA. Tips and tricks to robotassisted radical cystectomy and intracorporeal diversion. Curr Opin Urol 2013;23:65–71. [15] Leow JJ, Reese SW, Jiang W, et al. Propensity-matched comparison of morbidity and costs of open and robot-assisted radical cystectomies: a contemporary population-based analysis in the United States. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.01.029 [16] Ploussard G, Shariat SF, Dragomir A, et al. Conditional survival after radical cystectomy for bladder cancer: evidence for a patient changing risk profile over time. Eur Urol. In press. http://dx.doi. org/10.1016/j.eururo.2013.09.050 [17] Boorjian SA, Kim SP, Tollefson MK, et al. Comparative performance of comorbidity indices for estimating perioperative and 5-year all cause mortality following radical cystectomy for bladder cancer. J Urol 2013;190:55–60.
References
[18] Mayr R, May M, Martini T, et al. Comorbidity and performance indices as predictors of cancer-independent mortality but not of
[1] Chavan S, Bray F, Lortet-Tieulent J, Goodman M, Jemal A. International variations in bladder cancer incidence and mortality. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2013.10.001
cancer-specific mortality after radical cystectomy for urothelial carcinoma of the bladder. Eur Urol 2012;62:662–70. [19] Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical
[2] Howlader N, Krapcho M, Garshell J, et al. SEER cancer statistics
cystectomy for urothelial carcinoma of the bladder without neoad-
review (CSR) 1975-2010. National Cancer Institute Web site. http://
juvant or adjuvant therapy: long-term results in 1100 patients. Eur
seer.cancer.gov/csr/1975_2010/. Updated June 14, 2013.
Urol 2012;61:1039–47.
[3] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the
[20] Herr H, Lee C, Chang S, Lerner S. Standardization of radical cystectomy
treatment of invasive bladder cancer: long-term results in 1,054
and pelvic lymph node dissection for bladder cancer: a collaborative
patients. J Clin Oncol 2001;19:666–75. [4] Ghoneim MA, Abdel-Latif M, el-Mekresh M, et al. Radical cystec-
group report. J Urol 2004;171:1823–8, discussion 1827–8. [21] Kauffman EC, Ng CK, Lee MM, et al. Early oncological outcomes for
tomy for carcinoma of the bladder: 2,720 consecutive cases 5 years
bladder urothelial carcinoma patients treated with robotic-assisted
later. J Urol 2008;180:121–7.
radical cystectomy. BJU Int 2011;107:628–35.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015
EURURO-5590; No. of Pages 9 EUROPEAN UROLOGY XXX (2014) XXX–XXX
9
[22] Xylinas E, Rink M, Novara G, et al. Predictors of survival in patients
[26] Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of radical
with soft tissue surgical margin involvement at radical cystectomy.
cystectomy for transitional cell carcinoma of the bladder: a con-
Ann Surg Oncol 2013;20:1027–34. [23] Snow-Lisy DC, Campbell SC, Gill IS, et al. Robotic and laparoscopic radical cystectomy for bladder cancer: long-term oncologic outcomes. Eur Urol 2014;65:193–200. [24] Nepple KG, Strope SA, Grubb III RL, Kibel AS. Early oncologic outcomes of robotic vs. open radical cystectomy for urothelial cancer. Urol Oncol 2013;31:894–8.
temporary series from the Bladder Cancer Research Consortium. J Urol 2006;176:2414–22. [27] Zehnder P, Studer UE, Skinner EC, et al. Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades. BJU Int 2013;112:E51–8. [28] Montie JE. Improving outcomes after radical cystectomy. J Urol 2008;180:12–3.
[25] Novara G, Svatek RS, Karakiewicz PI, et al. Soft tissue surgical margin
[29] Rehman S, Crane A, Din R, et al. Understanding avoidance, refusal,
status is a powerful predictor of outcomes after radical cystectomy: a
and abandonment of chemotherapy before and after cystectomy for
multicenter study of more than 4,400 patients. J Urol 2010;183:
bladder cancer. Urology 2013;82:1370–5.
2165–70.
Please cite this article in press as: Raza SJ, et al. Oncologic Outcomes Following Robot-assisted Radical Cystectomy with Minimum 5-year Follow-up: The Roswell Park Cancer Institute Experience. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.03.015