- Email: [email protected]
Quantifying the Overall Survival Benefit With Early Radical Cystectomy for Patients With Histologically Confirmed T1 Non–muscle-invasive Bladder Cancer
Original Study
Quantifying the Overall Survival Benefit With Early Radical Cystectomy for Patients With Histologically Confirmed T1 Nonemuscleinvasive Bladder Cancer Karl H. Tully,1,2 Florian Roghmann,2 Joachim Noldus,2 Xi Chen,1 Lorine Häuser,1,2 Adam S. Kibel,1 Guru P. Sonpavde,3 Matthew Mossanen,1 Quoc-Dien Trinh1 Abstract In patients diagnosed with high-grade nonemuscle-invasive bladder cancer (NMIBC), the value and timing of radical cystectomy are under debate. Using the National Cancer Database, we examined the overall survival of 4900 individuals diagnosed with high-grade NMIBC. Early radical cystectomy was associated with an overall survival benefit. Given the current scarcity of intravesical agents, early radical cystectomy plays an important role in the treatment of patients diagnosed with high-grade NMIBC. Introduction: The objective of this study was to examine the overall survival (OS) in patients diagnosed with highgrade T1 nonemuscle-invasive bladder cancer treated with early radical cystectomy versus local treatment of the primary tumor, defined as endoscopic management with or without intravesical chemotherapy or immunotherapy. Patients and Methods: We identified 4900 patients with histologically confirmed, clinically non-metastatic high-grade T1 bladder cancer undergoing surgical intervention using the National Cancer Database for the period 2010 to 2015. Multivariable logistic regression was used to examine predictors for the receipt of early radical cystectomy (defined as radical cystectomy within 90 days of diagnosis). We then employed multivariable Cox proportional hazards regression models and Kaplan-Meier curves to evaluate the OS according to surgical treatment (early radical cystectomy vs. local treatment). Results: A minority (23.7%) of patients underwent early radical cystectomy. Independent predictors of undergoing early radical cystectomy included lower age, White race, and lower comorbidity status. The median OS was 74.0 months for patients diagnosed with high-grade T1 bladder cancer. The 1- and 5-year survival rates of patients undergoing early radical cystectomy were 94.8% and 71.0%, whereas they were 85.2% and 52.4%, for patients undergoing initial local treatment, respectively (P < .001). Compared with patients undergoing local treatment, patients undergoing early radical cystectomy had a lower risk of all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91; P ¼ .002). Conclusion: In this cohort of patients presenting with high-grade T1 nonemuscle-invasive bladder cancer, we found that early radical cystectomy was associated with an OS benefit compared with initial local treatment. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2020 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, NMIBC, Pelvic lymph node dissection, Radical Cystectomy, Transurethral resection
Introduction Nonemuscle-invasive bladder cancer (NMIBC) comprises the majority of newly diagnosed cases of bladder cancer each year.1 1 Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 2 Department of Urology and Neurourology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany 3 Lank Center for Genitourinary Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA
1558-7673/$ - see frontmatter ª 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2020.03.013
Roughly 10% of these patients are diagnosed as high-grade with T1 NMIBC.2 High-grade T1 NMIBC is, in theory, limited to the bladder wall and does not invade past the lamina propria. However, Submitted: Nov 6, 2019; Revised: Mar 20, 2020; Accepted: Mar 22, 2020 Address for correspondence: Quoc-Dien Trinh, MD, Division of Urological Surgery, Brigham and Women’s Hospital, 45 Francis St, ASB IIe3, Boston, MA 02115 E-mail contact: [email protected]
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Radical Cystectomy for T1-NMIBC Figure 1 Study Flow Diagram Displaying the Assembling of the Study Cohort of Patients Diagnosed With T1 Bladder Cancer Reported to the National Cancer Database Between January 2010 and December 2015
Abbreviations: BCG ¼ bacillus calmette-guerin; NMIBC ¼ nonemuscle-invasive bladder cancer.
2
-
high-grade T1 is associated with a high risk of recurrence and progression to muscle-invasive bladder cancer (MIBC).3-5 According to the current National Comprehensive Cancer Network and other professional guidelines, the standard first-line treatment for these patients consists of transurethral resection of the bladder tumor, followed by repeated resection 2 to 6 weeks later and consequent intravesical immunotherapy using live attenuated Bacillus Calmette-Guérin vaccine (BCG) for up to 3 years.4,5 Based on risk stratification, early radical cystectomy may be considered in select patients diagnosed with high-risk or highest-risk NMIBC.4 In practice, radical cystectomy for high-grade NMIBC is mostly performed in patients with symptomatic tumors, variant histology, high-volume tumors, or patients with contraindications to BCG, such as immunosuppression. There is an ongoing controversy regarding the use of early radical cystectomy in patients diagnosed with T1 NMIBC; arguments
Clinical Genitourinary Cancer Month 2020
against early radical cystectomy include potential over-treatment, morbidity and mortality associated with this complex surgery, and its impact on the patients’ quality of life.4,6 The benefits of radical cystectomy for T1 NMIBC, on the other hand, are a more precise staging of the primary tumor, the ability to perform a pelvic lymph node dissection (PLND), and superior cancer control.7-10 Indeed, over 17% of patients with T1 NMIBC are found to have nodal metastases at radical cystectomy.7 Furthermore, the supply of BCG has been subject to repeated production bottlenecks, resulting in a quasi-continuous shortage of BCG over the greater part of the past decade.11,12 Given the potentially deleterious effect of this shortage on the oncologic outcome of patients diagnosed with NMIBC, it is possible that the use of early radical cystectomy for T1 bladder cancer will increase over time. Contemporary data on patients undergoing radical cystectomy for high-grade T1 bladder cancer are scarce and are often limited to
Karl H. Tully et al Table 1 Baseline Characteristics of Patients Diagnosed With High-grade T1 Bladder Cancer Overall N [ 4627, N (%)
Patients Undergoing Radical Cystectomy N [ 890 (19.2%), N (%)
Patients Undergoing Transurethral Resection N [ 3737 (80.8%), N (%)
P Value <.001
Age, y <60
613 (13.3)
195 (21.9)
60-69
1170 (25.3)
303 (34.0)
867 (23.2)
70-79
1398 (30.2)
300 (33.7)
1098 (29.4)
80
1446 (31.3)
92 (10.3)
1354 (36.2)
3635 (78.6)
714 (80.2)
2921 (78.2)
992 (21.4)
176 (19.8)
816 (21.8)
White
4162 (90.0)
806 (90.6)
3356 (89.8)
Black
313 (6.8)
58 (6.5)
255 (6.8)
Other
114 (2.5)
19 (2.1)
95 (2.5)
38 (0.8)
7 (0.8)
31 (0.8)
418 (11.2)
Gender Male Female
.178
Race
Unknown
.886
CCI 0
3233 (69.9)
625 (70.2)
2608 (69.8)
1
990 (21.4)
203 (22.8)
787 (21.1)
2
294 (6.4)
43 (4.8)
251 (6.7)
3
110 (2.4)
19 (2.1)
91 (2.4)
.148
Insurance status Private
1249 (27.0)
310 (34.8)
939 (25.1)
Government
3227 (69.7)
543 (61.0)
2684 (71.8)
Uninsured
91 (2.0)
21 (2.4)
71 (1.9)
Unknown
59 (1.3)
16 (1.8)
43 (1.2)
48,000
2923 (63.2)
549 (61.7)
2374 (63.5)
<48,000
1704 (36.8)
341 (38.3)
1363 (36.5)
High
2847 (61.5)
570 (64.0)
2277 (60.9)
Low
1780 (38.5)
320 (36.0)
1460 (39.1)
<.001
Annual income, $
Education
.306 .086
Facility type Academic
2091 (45.2)
622 (69.9)
1469 (39.3)
Non-academic
2519 (54.4)
261 (29.3)
2258 (60.4)
17 (0.4)
7 (0.8)
10 (0.3)
Unknown
<.001
Facility location Metro
3866 (83.6)
712 (80.0)
3154 (84.4)
Urban
564 (12.2)
129 (14.5)
435 (11.6)
Rural
52 (1.1)
11 (1.2)
41 (1.1)
145 (3.1)
38 (4.3)
107 (2.9)
East
2094 (45.3)
385 (43.3)
1709 (45.7)
Central
1795 (38.8)
405 (45.5)
1390 (37.1)
721 (15.6)
93 (10.5)
628 (16.8)
17 (0.4)
7 (0.8)
10 (0.3)
3
1103 (23.8)
258 (29.0)
845 (22.6)
>3
1276 (27.6)
315 (35.4)
962 (25.7)
Unknown
2248 (48.6)
317 (35.6)
1931 (51.7)
Unknown
.011
Region
West Unknown
<.001
Tumor size, cm <.001
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Radical Cystectomy for T1-NMIBC Table 1 Continued Overall N [ 4627, N (%)
Patients Undergoing Radical Cystectomy N [ 890 (19.2%), N (%)
Patients Undergoing Transurethral Resection N [ 3737 (80.8%), N (%)
P Value
No
4490 (97.0)
890 (100)
3600 (96.3)
<.001
Yes
138 (3.0)
BCG therapy 0 (0.0)
138 (3.7)
Abbreviations: BCG ¼ bacillus calmette-guérin; CCI ¼ Charlson comorbidity index.
historical or small cohorts.8,9,13 Thus, our main study objectives were to examine the survival benefit of patients with high-grade T1 NMIBC without clinical evidence of metastatic disease undergoing early radical cystectomy compared with that of patients initially managed with local treatment and to examine characteristics of patients undergoing early radical cystectomy. Secondarily, to examine the added value of lymph node staging, we assessed the impact of pelvic lymph node dissection at radical cystectomy on the overall survival (OS) of patients diagnosed with T1 NMIBC. We hypothesize that patients undergoing early radical cystectomy experience better OS compared with patients undergoing initial local treatment.
Patients and Methods Data Source The National Cancer Database (NCDB) for the period of 2004 to 2016 was used. The NCDB, a joint program of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society, is a national cancer registry that compiles data for more than 1500 CoC-accredited cancer programs in the United States (US).14 The database contains over 30 million records from cancer registries across the country, and is an essential cancer surveillance source of standardized data regarding patients, hospitals, and therapies.15
Baseline characteristics for each patient included age at diagnosis, year of diagnosis, gender, race (White, Black, etc), annual median income (defined as high [ $48,000], low [< $48,000], or unknown), and education (defined as high [< 13%], low [ 13%], according to the percentage of residents within the home country without high school degree, or unknown). The modified Charlson comorbidity index (CCI) provided by the NCDB was used to account for underlying disease and was classified as 0, 1, 2, or 3.16 We used the TNM classification system to categorize lymph node status as N0 and Nþ ( N1). Facility-level covariates included facility region, county, and facility type. Facility region was defined as East, Central, or West. County type was defined as metro, urban, rural, or unknown. Follow-up was measured as the time from surgery until death or the date on which the patient was last contacted.
Statistical Analysis
The primary endpoint of our study was OS, defined as the time from surgical treatment (initial local treatment or early radical cystectomy) to death from any cause. For the secondary survival analysis, we compared OS for patients undergoing radical cystectomy with PLND versus patients who underwent radical cystectomy alone.
We calculated frequencies and percentages for categorical variables, as well as medians and interquartile ranges for continuous variables. Ensuing, we examined differences between patients managed by initial local treatment and patients undergoing early radical cystectomy using the c2 test and Mann-Whitney test for categorical and continuous variables, respectively. Multivariable logistic regression analysis using the covariates mentioned above was employed to assess predictors for undergoing early radical cystectomy. We employed survival curves for all subcohorts according to the Kaplan-Meier estimator with the logrank test.17 We censored survival data of patients alive at last follow-up or the end of the study period.17,18 We then employed multivariable Cox proportional hazards regression models to quantify the risk of all-cause mortality in patients initially managed by local treatment versus radical cystectomy, adjusting for all covariates mentioned above. Finally, we performed exploratory survival analyses to examine differences in OS of patients diagnosed with highgrade T1 bladder cancer who underwent radical cystectomy with PLND versus patients who underwent radical cystectomy without PLND.
We included patients with clinical T1 NMIBC and a primary confirmed histology of urothelial high-grade T1 NMIBC (International Classification of Diseases, Tenth Revision, Clinical Modification code C67) between 2010 and 2015 who underwent treatment. Early radical cystectomy was defined as radical cystectomy for NMIBC within 90 days after diagnosis without prior intravesical therapy using BCG. All other patients underwent initial local treatment during the study period. Initial local treatment was defined as endoscopic management with or without intravesical chemotherapy or immunotherapy. We excluded all patients undergoing partial cystectomy (n ¼ 368). Patients with a clinical diagnosis of bladder cancer T2a, clinically lymph node-
-
Covariates
Outcome Measures
Patient Selection
4
positive or metastatic disease (n ¼ 5702), patients with nonurothelial bladder cancer (n ¼ 153), and patients with prior neoadjuvant chemotherapy or prior radiation of the primary tumor (n ¼ 4698) were excluded as well. We also excluded patients with missing data on the surgical procedure (n ¼ 3410) or BCG therapy (n ¼ 80) and patients with missing follow-up data (n ¼ 309) (Figure 1).
Clinical Genitourinary Cancer Month 2020
Karl H. Tully et al Table 2 Predictors for Undergoing Radical Cystectomy for High-grade T1 Bladder Cancer
Age
Odds Ratio
95% Confidence Interval
P Value
0.94
0.93-0.95
<.001
1 [REF]
e
e
Open
596 (67.0)
0.98
0.80-1.20
.806
Robotic
203 (22.8)
Gender Male Female
Table 3 Treatment-specific Characteristic of Patients Undergoing Radical Cystectomy for High-Grade T1 Bladder Cancer Characteristic
N (%)
Median time to treatment, d (IQR)
56 (35-85)
Surgical approach
Race
Laparoscopic
White
1 [REF]
e
e
Black
0.70
0.50-0.97
.030
Other
0.99
0.57-1.71
.964
Unknown
0.58
0.24-1.39
.221
CCI 0
1 [REF]
e
e
1
1.27
1.05-1.55
.014
2
0.81
0.56-1.16
.252
3
1.03
0.60-1.76
.921
Insurance status
5 (0.6)
Laparoscopic converted to open
6 (0.7)
PLND performed Yes
816 (91.7)
No
69 (7.8)
Unknown
5 (0.6)
Median number of lymph nodes removed, n (IQR)
13 (7-22)
Result of PLND Positive
27 (3.4)
Negative
789 (96.7)
1 [REF]
e
Government
1.31
1.07-1.61
.010
Uninsured
0.58
0.34-1.01
.052
R0
Unknown
1.27
0.67-2.44
.466
Rþ
44 (4.9)
Unknown
23 (2.6)
Private
e
80 (9.0)
Robotic converted to open
Annual income High
1 [REF]
e
Low
1.19
0.97-1.45
High
1 [REF]
e
Low
0.73
0.60-0.89
1 (1-3)
Surgical margin 823 (92.5)
e
Unplanned 30-day readmission
81 (9.1)
.095
30-day mortality
20 (2.3)
Education e .002
Facility type 1 [REF]
e
e
Non-academic
0.26
0.22-0.31
<.001
Unknown
0.26
0.09-0.73
.010
Academic
Median number of positive lymph nodes, n (IQR)
Facility location e
90-day mortality
29 (3.3)
Adjuvant chemotherapy within 90 days
22 (2.5)
Abbreviations: IQR ¼ interquartile range; PLND ¼ pelvic lymph node dissection.
board waiver was obtained from the Brigham and Women’s Hospital.
Metro
1 [REF]
e
Urban
1.31
1.02-1.67
.031
Results
Rural
1.17
0.56-2.44
.678
Unknown
1.53
0.99-2.34
.051
Baseline Characteristics and Predictors for the Receipt of Radical Cystectomy
Region 1 [REF]
e
e
Central
1.38
1.16-1.65
<.001
West
0.74
0.57-0.97
.027
1 [REF]
e
East
Tumor size, cm 3
e
>3
1.04
0.84-1.27
.729
Unknown
0.51
0.42-0.62
<.001
The model was adjusted for treatment modality, age, gender, race, comorbidity status, year of diagnosis, insurance status, annual income, level of education, hospital type, hospital location, region, use of adjuvant chemotherapy, tumor size, and variant histology. Abbreviations: CCI ¼ Charlson comorbidity index; REF ¼ reference.
All P-values were 2-sided, and statistical significance was assumed at P < .05. Statistical analysis was performed using Stata (Version Stata/SE 15.1, Stata Corp LLC). An institutional review
Overall, 4627 patients met inclusion criteria. The majority (80.8%) of patients underwent initial local treatment, whereas 19.2% of patients underwent early radical cystectomy. Compared with patients who underwent initial local treatment, patients who underwent radical cystectomy were significantly younger (median age at diagnosis, 68 years [interquartile range (IQR), 6175 years] versus 75 years [IQR, 66-83 years]; P < .001). Further differences in baseline characteristics are shown in Table 1. On multivariable logistic regression analysis, Black race and treatment at a non-academic facility were independent predictors for undergoing initial local treatment for high-grade T1 bladder cancer rather than early radical cystectomy. Increasing age was associated with lower odds of undergoing radical cystectomy (odds ratio, 0.94; 95% confidence interval [CI], 0.93-0.95; P < .001). Results of the multivariable logistic regression analysis are shown in Table 2.
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Radical Cystectomy for T1-NMIBC Figure 2 Kaplan-Meier Curves Examining the Overall Survival in Patients Diagnosed With High-grade T1 Nonemuscle-invasive Bladder Cancer Undergoing Radical Cystectomy versus Patients Undergoing Transurethral Resection of Bladder Tumor as Final Treatment
compared with patients who underwent radical cystectomy without PLND (P < .001) (Figure 3). The 1- and 5-year survival rates were 94.9% and 72.9% in patients who had undergone PLND at radical cystectomy. For patients who had undergone radical cystectomy without PLND, the 1-year survival rate was 91.1% and the 5-year survival rate was 46.9%. This result persisted in multivariable Cox regression analysis adjusting for the covariates mentioned above (HR, 0.55; 95% CI, 0.37-0.83; P ¼ .005).
Discussion
Surgical Characteristics: Radical Cystectomy Overall, 890 patients underwent early radical cystectomy for high-grade T1 bladder cancer. The median time from diagnosis to cystectomy was 47 days (IQR, 28-65 days). PLND was performed in 91.7% of all patients undergoing early radical cystectomy. Of these, 27 (3.3%) of 816 individuals were found to have metastases to the lymph nodes at radical cystectomy. Further data regarding early cystectomy in high-grade T1 bladder cancer are shown in Table 3.
Survival Analysis: Radical Cystectomy Versus Transurethral Resection The overall median follow-up was 48.7 months for patients alive at last follow-up. For the overall cohort of patients diagnosed with high-grade T1 bladder cancer, 1- and 5-year overall survival rates were 87.0% and 56.0%, respectively. The 1-year OS rate was 94.6% and 85.2% for the early radical cystectomy and local treatment cohorts, respectively (P < .001). The 5-year OS rate was 71.1% in patients undergoing early radical cystectomy and 52.4% in patients undergoing initial local treatment (P < .001). The median OS was 72.4 months for patients diagnosed with high-grade T1 bladder cancer and 64.0 months for patients undergoing initial local treatment for high-grad T1 bladder cancer. The median OS was not reached in the early radical cystectomy cohort (Figure 2). In multivariable Cox regression analysis, individuals undergoing early radical cystectomy had a significantly lower risk of mortality compared with patients undergoing initial local treatment (hazard ratio [HR], 0.78; 95% CI, 0.67-0.91; P ¼ .002). Further results of the multivariable Cox regression analysis are shown in Table 4.
Survival Analysis of Patients Undergoing PLND for Highgrade T1 Bladder Cancer at Radical Cystectomy
6
-
Unadjusted Kaplan-Meier analysis showed a significant survival benefit for patients undergoing PLND at radical cystectomy
Clinical Genitourinary Cancer Month 2020
High-grade T1 NMIBC has previously been described as an “unpredictable beast.”19 Although transurethral resection on intravesical therapy using BCG may provide sufficient cancer control in some patients, other patients do not respond to this course of treatment at all, leading to an unnecessary extension of the interval between diagnosis and potentially curative early radical cystectomy.8 That said, given the morbidity associated with this complex procedure, the majority of patients tend to undergo bladder-sparing therapies first. In this study, we examined the OS of patients diagnosed with high-grade T1 NMIBC undergoing radical cystectomy versus initial local treatment. Early radical cystectomy was associated with a significant OS benefit compared with initial local treatment. Furthermore, we found that patients undergoing PLND at the time of early cystectomy had improved OS compared with patients who did not undergo PLND. Patients diagnosed with high-grade T1 bladder cancer face a poorer than usually thought of prognosis. In this large national cohort, 1- and 5-year survival rates were 87.0% and 56.0%, respectively. Earlier clinical studies examining T1 bladder cancer found 5-year survival rates ranging from 54% to 83%.7,8,20 Studies have shown that patients with T1 disease at transurethral resection can harbor anything from T0 to T4 disease at radical cystectomy; specifically, upstaging of T1 disease at radical cystectomy is described in 30% to 50% of cases. Other factors may also explain the grim prognosis. For example, the benefits of intravesical immunotherapy are well-established. When patients are managed with transurethral resection alone, a significantly higher proportion of individuals will progress to muscle-invasive disease within a short timeframe.21 Unfortunately, BCG has been subject to a shortage in the US for the better part of the past decade, which may thus influence survival rates of patients diagnosed with NMIBC in the long run.11,12 However, despite the undoubted benefit of BCG with regard to recurrence, progression, and survival in patients diagnosed with high-grade NMIBC, it has to be kept in mind that, in a large number of cases, BCG does not have the desired effect.22,23 In approximately 8.5% of patients with high-grade NMIBC, progression or metastatic disease will happen. Moreover, it has been shown that patients diagnosed with progression to MIBC after BCG face an even poorer prognosis than those initially diagnosed with muscle-invasive disease.24 With all things considered, our study found a 22% survival benefit in the adjusted analysis in favor of early radical cystectomy. The absolute gain in life was of significant magnitude: the median survival was 64.0 months for the initial local treatment group, whereas it was not reached in the early cystectomy group.
Karl H. Tully et al Table 4 Multivariable Cox Proportional Hazards Regression Examining the Risk of All-cause Mortality in Patients Diagnosed With T1 High-grade Bladder Cancer
Table 4 Continued Hazard Ratio
Hazard Ratio
95% Confidence Interval
P Value
Treatment Local treatment Radical cystectomy Age
1 [REF]
e
0.78
0.67-0.91
.002
e
1.07
1.06-1.07
<.001
1 [REF]
e
e
1.07
0.95-1.20
95% Confidence Interval
P Value
>3
1.17
1.01-1.34
.031
Unknown
1.27
1.12-1.43
<.001
The model was adjusted for treatment modality, age, gender, race, comorbidity status, year of diagnosis, insurance status, annual income, level of education, hospital type, hospital location, region, use of adjuvant chemotherapy, tumor size, and variant histology. Abbreviations: CCI ¼ Charlson omorbidity ndex; REF ¼ reference.
Gender Male Female
.250
Race White
1 [REF]
e
Black
1.15
0.94-1.39
e .173
Other
0.63
0.43-0.92
.017
Unknown
0.86
0.45-1.66
.650
0
1 [REF]
e
e
1
1.24
1.11-1.40
<.001
2
2.03
1.72-2.39
<.001
3
1.94
1.49-2.51
<.001
1 [REF]
e
e
Government
1.06
0.92-1.22
.421
Uninsured
1.84
1.23-2.74
.003
Unknown
1.41
0.88-2.25
.153
CCI
Insurance status Private
Annual income High
1 [REF]
e
Low
1.05
0.93-1.18
e .466
Education High
1 [REF]
e
Low
1.09
0.98-1.23
e .125
Facility type 1 [REF]
e
Non-academic
1.01
0.91-1.12
.877
Unknown
3.72
0.91-15.2
.067
Academic
e
Facility location Metro
1 [REF]
e
Urban
0.94
0.81-1.10
.451
e
Rural
0.78
0.48-1.27
.324
Unknown
0.90
0.66-1.22
.481
Region 1 [REF]
e
Central
1.08
0.97-1.20
.189
West
1.01
0.87-1.17
.895
1 [REF]
e
East
e
Tumor size, cm 3
e
Given these data, it may appear surprising that not more patients choose to undergo early radical cystectomy. Our data do show that patients diagnosed with T1 bladder cancer are generally of elderly age and with multi-morbidity.25,26 In this study population, the median age was 73 years (IQR, 65-82 years), and 8.7% of patients presented with a CCI of 2 or greater. In general, radical cystectomy is associated with morbidity rates of up to 56.1% and mortality rates of up to 9%.27-29 Given these factors, it is understandable that many patients will want to avoid major surgery and opt for conservative management. Our results support this hypothesis: increasing age was associated with increasingly lower odds of undergoing radical cystectomy (Table 2). However, the balance of benefits versus harms likely would reasonably indicate that younger patients have a lot to gain from early radical cystectomy. Despite such considerations, the utilization of early radical cystectomy remains low regardless of age category. In the future, we need to improve our ability to triage responders from non-responders to intravesical immunotherapy/chemotherapy, possibly with the use of molecular characterization using next-generation sequencing.30,31 Another interesting finding of our study pertains to the benefits of PLND at radical cystectomy for T1 bladder cancer. There is little controversy about the use of PLND at radical cystectomy for MIBC, as recommended by most society guidelines. Potential benefits include more accurate staging to guide adjuvant therapy and potentially therapeutic resection of metastatic disease.5,32 However, PLND is associated with a variety of complications, including lymphoceles, thromboembolic events, and neurovascular injuries.33,34 Gupta et al describe that up to 17.5% of patients diagnosed with clinical high-grade T1 NMIBC harbor occult metastases to the lymph nodes.7 The authors found that nearly onehalf of all patients with clinical high-grade T1 NMIBC were upstaged to muscle-invasive disease ( T2a), which is associated with a significantly higher risk of metastatic disease.35 In our cohort of histologically confirmed T1 NMIBC, lymph node-positive disease was found in 3.3% of patients, underscoring the aggressive nature of this disease. As such, we found significant survival benefit for patients undergoing PLND at radical cystectomy in our cohort. Specifically, there was a significant difference in long-term survival between the 2 subgroups. In patients who had undergone PLND, the 5-year survival rate was 72.9%, whereas only 46.9% of patients who had undergone radical cystectomy without PLND survived at
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Radical Cystectomy for T1-NMIBC Figure 3 Kaplan-Meier Curves Examining the Overall Survival in Patients Diagnosed With High-Grade T1 Non emuscle-invasive Bladder Cancer Undergoing PLND During Radical Cystectomy versus Radical Cystectomy Without PLND
have improved OS compared with patients who did not undergo PLND during radical cystectomy.
Clinical Practice Points Given the ongoing shortage of intravesical BCG in the US,
alternative treatment options for high-grade NMIBC need to be discussed in greater detail in order to provide patients with the most reasonable and save therapy possible. Although radical cystectomy can provide the most effective approach from an oncologic point of view, there is ongoing debate about the use of early radical cystectomy in patients diagnosed with high-grade NMIBC. Given that many patients and physicians prefer transurethral/intravesical treatment, current large-scale data examining this question is missing. In this study, we could show that radical cystectomy can provide a survival benefit. Furthermore, PLND at the time of radical cystectomy was associated with a favorable outcome. Regarding these results and the current scarcity of effective intravesical agents, early radical cystectomy plays an important role in the treatment of patients diagnosed with high-grade NMIBC. Abbreviation: PLND ¼ pelvic lymph node dissection.
Disclosure least 5 years. Our study corroborates the findings of Larcher et al, who found that PLND at the time of radical cystectomy provides a survival benefit for patients diagnosed with MIBC. Given the lack of randomized data for nonemuscle-invasive disease, our study provides the best evidence for the role of PLND in the context of radical cystectomy for T1 disease e as is the case with invasive disease, PLND should be performed at radical cystectomy. Our study is subject to several limitations. First, the NCDB does not provide information on the cause of death; thus, cancer-specific survival could not be examined in this cohort. Second, the NCDB is a hospital-based registry with information on patients treated at CoC-accredited hospitals only; our results may not be representative of patients treated outside these facilities. Third, data regarding the quality of prior transurethral resections, as well as more granular histologic data, are missing. For example, information on lymphovascular invasion, presence of detrusor muscle in the specimen, completeness of the initial resection, and the presence of carcinoma in situ are crucial data that may influence further management, as well as the outcome of patients diagnosed with high-grade T1 NMIBC. Fourth, patients undergoing initial local treatment may have undergone radical cystectomy after the study period. As previously described by Denzinger et al, these patients would be likely to experience worse outcomes in the case of recurrence or progression.8 Finally, our study shares the limitations associated with all observational, nonrandomized, retrospective studies, including unmeasured confounders for which we are not able to account.
Conclusion In this cohort of patients diagnosed with high-grade T1 NMIBC, we found that early radical cystectomy was associated with an OS benefit compared with initial local treatment. Additionally, patients undergoing PLND at the time of radical cystectomy were found to
8
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Clinical Genitourinary Cancer Month 2020
Quoc-Dien Trinh reports personal fees from Astellas, Bayer, Janssen, Insightec, and Intuitive Surgical. Adam S. Kibel reports consulting fees from Sanofi, Dendreon, Tokai, and Profound. Guru Sonpavde reports research support to institution from Astrazeneca, Bayer, Amgen, Boehringer-Ingelheim, Janssen, Merck, Sanofi, and Pfizer; is part of the advisory board for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, Astrazeneca, Merck, Genentech, EMD Serono, and Astellas/Agensys, as well as part of the steering committee for Astrazeneca, BMS, Astellas, Debiopharm, and Bavarian Nordic; and is an author for Uptodate and a speaker for Onclive, Research to Practice, and Physician Education Resource (PER). The remaining authors have stated that they have no conflicts of interest.
CRediT authorship contribution statement Karl H. Tully: Conceptualization, Formal analysis, Writing original draft. Florian Roghmann: Methodology. Joachim Noldus: Writing - review & editing. Xi Chen: Validation. Lorine Häuser: Writing - review & editing. Adam S. Kibel: Writing - review & editing. Guru P. Sonpavde: Writing - review & editing. Matthew Mossanen: Writing - original draft. Quoc-Dien Trinh: Supervision, Writing - review & editing.
References 1. Compérat E, Larre S, Rouprêt M, et al. Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old. Virchows Arch 2015; 466:589-94. 2. Soloway MS, Sofer M, Vaidya A. Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol 2002; 167:1573-83. 3. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006; 49:466-75, discussion: 475-7.
Karl H. Tully et al 4. Babjuk M, Böhle A, Burger M, et al. EAU guidelines on non-muscleinvasive urothelial carcinoma of the bladder: update 2016. Eur Urol 2017; 71:447-61. 5. Flaig TW, Spiess PE, Agarwal N, et al. NCCN guidelines insights: bladder cancer, version 5.2018. J Natl Compr Canc Netw 2018; 16:1041-53. 6. Roghmann F, Ravi P, Hanske J, et al. Perioperative outcomes after radical cystectomy at NCI-designated centres: are they any better? Can Urol Assoc J 2015; 9: 207-12. 7. Gupta A, Lotan Y, Bastian PJ, et al, Bladder Cancer Research Consortium. Outcomes of patients with clinical T1 grade 3 urothelial cell bladder carcinoma treated with radical cystectomy. Urology 2008; 71:302-7. 8. Denzinger S, Fritsche HM, Otto W, Blana A, Wieland WF, Burger M. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008; 53:146-52. 9. Fritsche HM, Burger M, Svatek RS, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol 2010; 57:300-9. 10. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001; 19:666-75. 11. Mostafid AH, Palou Redorta J, Sylvester R, Witjes JA. Therapeutic options in high-risk non-muscle-invasive bladder cancer during the current worldwide shortage of bacille Calmette-Guerin. Eur Urol 2015; 67:359-60. 12. Veeratterapillay R, Heer R, Johnson MI, Persad R, Bach C. High-risk non-muscleinvasive bladder cancer-therapy options during intravesical BCG shortage. Curr Urol Rep 2016; 17:68. 13. Gontero P, Sylvester R, Pisano F, et al. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients. Eur Urol 2015; 67:74-82. 14. Cole AP, Friedlander DF, Trinh QD. Secondary data sources for health services research in urologic oncology. Urol Oncol 2018; 36:165-73. 15. Lerro CC, Robbins AS, Phillips JL, Stewart AK. Comparison of cases captured in the national cancer data base with those in population-based central cancer registries. Ann Surg Oncol 2013; 20:1759-65. 16. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992; 45: 613-9. 17. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19:3635-48. 18. Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27:6199-206. 19. Brodie A, McCauley N, Cresswell J, Vasdev N. T1G3 bladder cancer, bacillus Calmette-Guerin and radical cystectomy: continued debate. Transl Androl Urol 2018; 7(Suppl 6):S692-5. 20. Thalmann GN, Markwalder R, Shahin O, Burkhard FC, Hochreiter WW, Studer UE. Primary T1G3 bladder cancer: organ preserving approach or immediate cystectomy? J Urol 2004; 172:70-5.
21. Jakse G, Loidl W, Seeber G, Hofstädter F. Stage T1, grade 3 transitional cell carcinoma of the bladder: an unfavorable tumor? J Urol 1987; 137:39-43. 22. Sylvester RJ, Brausi MA, Kirkels WJ, et al, EORTC Genito-Urinary Tract Cancer Group. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57:766-73. 23. Sylvester RJ, van der Meijden A, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a metaanalysis of the published results of randomized clinical trials. J Urol 2002; 168: 1964-70. 24. Schrier BP, Hollander MP, van Rhijn BW, Kiemeney LA, Witjes JA. Prognosis of muscle-invasive bladder cancer: difference between primary and progressive tumours and implications for therapy. Eur Urol 2004; 45:292-6. 25. Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66(6 Suppl 1):4-34. 26. Piccirillo JF, Vlahiotis A, Barrett LB, Flood KL, Spitznagel EL, Steyerberg EW. The changing prevalence of comorbidity across the age spectrum. Crit Rev Oncol Hematol 2008; 67:124-32. 27. Roghmann F, Gockel M, Schmidt J, et al. [Complications after ileal conduit: Urinary diversion-associated complications after radical cystectomy]. Urologe A 2015; 54:533-41. 28. Aziz A, May M, Burger M, et al, PROMETRICS 2011 research group. Prediction of 90-day mortality after radical cystectomy for bladder cancer in a prospective European multicenter cohort. Eur Urol 2014; 66: 156-63. 29. 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; 55:164-74. 30. Pang KH, Esperto F, Noon AP. EAU Young Academic Urologists-Urothelial Cancer Working party. Opportunities of next-generation sequencing in nonmuscle invasive bladder cancer outcome prediction. Transl Androl Urol 2017; 6: 1043-8. 31. Garczyk S, Ortiz-Bruchle N, Schneider U, et al. Next-generation sequencing reveals potential predictive biomarkers and targets of therapy for urothelial carcinoma in situ of the urinary bladder. Am J Pathol 2020; 190:323-32. 32. Witjes JA, Compérat E, Cowan NC, et al, European Association of Urology. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 2014; 65:778-92. 33. Lein M, Stibane I, Mansour R, et al. Complications, urinary continence, and oncologic outcome of 1000 laparoscopic transperitoneal radical prostatectomiesexperience at the Charite Hospital Berlin, Campus Mitte. Eur Urol 2006; 50: 1278-82, discussion: 1283-4. 34. Briganti A, Chun FK, Salonia A, et al. Complications and other surgical outcomes associated with extended pelvic lymphadenectomy in men with localized prostate cancer. Eur Urol 2006; 50:1006-13. 35. Wu SX, Huang J, Liu ZW, et al. A genomic-clinicopathologic nomogram for the preoperative prediction of lymph node metastasis in bladder cancer. EBioMedicine 2018; 31:54-65.
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Quantifying the Overall Survival Benefit With Early Radical Cystectomy for Patients With Histologically Confirmed T1 Nonemuscleinvasive Bladder Cancer Karl H. Tully,1,2 Florian Roghmann,2 Joachim Noldus,2 Xi Chen,1 Lorine Häuser,1,2 Adam S. Kibel,1 Guru P. Sonpavde,3 Matthew Mossanen,1 Quoc-Dien Trinh1 Abstract In patients diagnosed with high-grade nonemuscle-invasive bladder cancer (NMIBC), the value and timing of radical cystectomy are under debate. Using the National Cancer Database, we examined the overall survival of 4900 individuals diagnosed with high-grade NMIBC. Early radical cystectomy was associated with an overall survival benefit. Given the current scarcity of intravesical agents, early radical cystectomy plays an important role in the treatment of patients diagnosed with high-grade NMIBC. Introduction: The objective of this study was to examine the overall survival (OS) in patients diagnosed with highgrade T1 nonemuscle-invasive bladder cancer treated with early radical cystectomy versus local treatment of the primary tumor, defined as endoscopic management with or without intravesical chemotherapy or immunotherapy. Patients and Methods: We identified 4900 patients with histologically confirmed, clinically non-metastatic high-grade T1 bladder cancer undergoing surgical intervention using the National Cancer Database for the period 2010 to 2015. Multivariable logistic regression was used to examine predictors for the receipt of early radical cystectomy (defined as radical cystectomy within 90 days of diagnosis). We then employed multivariable Cox proportional hazards regression models and Kaplan-Meier curves to evaluate the OS according to surgical treatment (early radical cystectomy vs. local treatment). Results: A minority (23.7%) of patients underwent early radical cystectomy. Independent predictors of undergoing early radical cystectomy included lower age, White race, and lower comorbidity status. The median OS was 74.0 months for patients diagnosed with high-grade T1 bladder cancer. The 1- and 5-year survival rates of patients undergoing early radical cystectomy were 94.8% and 71.0%, whereas they were 85.2% and 52.4%, for patients undergoing initial local treatment, respectively (P < .001). Compared with patients undergoing local treatment, patients undergoing early radical cystectomy had a lower risk of all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.67-0.91; P ¼ .002). Conclusion: In this cohort of patients presenting with high-grade T1 nonemuscle-invasive bladder cancer, we found that early radical cystectomy was associated with an OS benefit compared with initial local treatment. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2020 Elsevier Inc. All rights reserved. Keywords: Bladder cancer, NMIBC, Pelvic lymph node dissection, Radical Cystectomy, Transurethral resection
Introduction Nonemuscle-invasive bladder cancer (NMIBC) comprises the majority of newly diagnosed cases of bladder cancer each year.1 1 Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 2 Department of Urology and Neurourology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany 3 Lank Center for Genitourinary Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA
1558-7673/$ - see frontmatter ª 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2020.03.013
Roughly 10% of these patients are diagnosed as high-grade with T1 NMIBC.2 High-grade T1 NMIBC is, in theory, limited to the bladder wall and does not invade past the lamina propria. However, Submitted: Nov 6, 2019; Revised: Mar 20, 2020; Accepted: Mar 22, 2020 Address for correspondence: Quoc-Dien Trinh, MD, Division of Urological Surgery, Brigham and Women’s Hospital, 45 Francis St, ASB IIe3, Boston, MA 02115 E-mail contact: [email protected]
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Radical Cystectomy for T1-NMIBC Figure 1 Study Flow Diagram Displaying the Assembling of the Study Cohort of Patients Diagnosed With T1 Bladder Cancer Reported to the National Cancer Database Between January 2010 and December 2015
Abbreviations: BCG ¼ bacillus calmette-guerin; NMIBC ¼ nonemuscle-invasive bladder cancer.
2
-
high-grade T1 is associated with a high risk of recurrence and progression to muscle-invasive bladder cancer (MIBC).3-5 According to the current National Comprehensive Cancer Network and other professional guidelines, the standard first-line treatment for these patients consists of transurethral resection of the bladder tumor, followed by repeated resection 2 to 6 weeks later and consequent intravesical immunotherapy using live attenuated Bacillus Calmette-Guérin vaccine (BCG) for up to 3 years.4,5 Based on risk stratification, early radical cystectomy may be considered in select patients diagnosed with high-risk or highest-risk NMIBC.4 In practice, radical cystectomy for high-grade NMIBC is mostly performed in patients with symptomatic tumors, variant histology, high-volume tumors, or patients with contraindications to BCG, such as immunosuppression. There is an ongoing controversy regarding the use of early radical cystectomy in patients diagnosed with T1 NMIBC; arguments
Clinical Genitourinary Cancer Month 2020
against early radical cystectomy include potential over-treatment, morbidity and mortality associated with this complex surgery, and its impact on the patients’ quality of life.4,6 The benefits of radical cystectomy for T1 NMIBC, on the other hand, are a more precise staging of the primary tumor, the ability to perform a pelvic lymph node dissection (PLND), and superior cancer control.7-10 Indeed, over 17% of patients with T1 NMIBC are found to have nodal metastases at radical cystectomy.7 Furthermore, the supply of BCG has been subject to repeated production bottlenecks, resulting in a quasi-continuous shortage of BCG over the greater part of the past decade.11,12 Given the potentially deleterious effect of this shortage on the oncologic outcome of patients diagnosed with NMIBC, it is possible that the use of early radical cystectomy for T1 bladder cancer will increase over time. Contemporary data on patients undergoing radical cystectomy for high-grade T1 bladder cancer are scarce and are often limited to
Karl H. Tully et al Table 1 Baseline Characteristics of Patients Diagnosed With High-grade T1 Bladder Cancer Overall N [ 4627, N (%)
Patients Undergoing Radical Cystectomy N [ 890 (19.2%), N (%)
Patients Undergoing Transurethral Resection N [ 3737 (80.8%), N (%)
P Value <.001
Age, y <60
613 (13.3)
195 (21.9)
60-69
1170 (25.3)
303 (34.0)
867 (23.2)
70-79
1398 (30.2)
300 (33.7)
1098 (29.4)
80
1446 (31.3)
92 (10.3)
1354 (36.2)
3635 (78.6)
714 (80.2)
2921 (78.2)
992 (21.4)
176 (19.8)
816 (21.8)
White
4162 (90.0)
806 (90.6)
3356 (89.8)
Black
313 (6.8)
58 (6.5)
255 (6.8)
Other
114 (2.5)
19 (2.1)
95 (2.5)
38 (0.8)
7 (0.8)
31 (0.8)
418 (11.2)
Gender Male Female
.178
Race
Unknown
.886
CCI 0
3233 (69.9)
625 (70.2)
2608 (69.8)
1
990 (21.4)
203 (22.8)
787 (21.1)
2
294 (6.4)
43 (4.8)
251 (6.7)
3
110 (2.4)
19 (2.1)
91 (2.4)
.148
Insurance status Private
1249 (27.0)
310 (34.8)
939 (25.1)
Government
3227 (69.7)
543 (61.0)
2684 (71.8)
Uninsured
91 (2.0)
21 (2.4)
71 (1.9)
Unknown
59 (1.3)
16 (1.8)
43 (1.2)
48,000
2923 (63.2)
549 (61.7)
2374 (63.5)
<48,000
1704 (36.8)
341 (38.3)
1363 (36.5)
High
2847 (61.5)
570 (64.0)
2277 (60.9)
Low
1780 (38.5)
320 (36.0)
1460 (39.1)
<.001
Annual income, $
Education
.306 .086
Facility type Academic
2091 (45.2)
622 (69.9)
1469 (39.3)
Non-academic
2519 (54.4)
261 (29.3)
2258 (60.4)
17 (0.4)
7 (0.8)
10 (0.3)
Unknown
<.001
Facility location Metro
3866 (83.6)
712 (80.0)
3154 (84.4)
Urban
564 (12.2)
129 (14.5)
435 (11.6)
Rural
52 (1.1)
11 (1.2)
41 (1.1)
145 (3.1)
38 (4.3)
107 (2.9)
East
2094 (45.3)
385 (43.3)
1709 (45.7)
Central
1795 (38.8)
405 (45.5)
1390 (37.1)
721 (15.6)
93 (10.5)
628 (16.8)
17 (0.4)
7 (0.8)
10 (0.3)
3
1103 (23.8)
258 (29.0)
845 (22.6)
>3
1276 (27.6)
315 (35.4)
962 (25.7)
Unknown
2248 (48.6)
317 (35.6)
1931 (51.7)
Unknown
.011
Region
West Unknown
<.001
Tumor size, cm <.001
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Radical Cystectomy for T1-NMIBC Table 1 Continued Overall N [ 4627, N (%)
Patients Undergoing Radical Cystectomy N [ 890 (19.2%), N (%)
Patients Undergoing Transurethral Resection N [ 3737 (80.8%), N (%)
P Value
No
4490 (97.0)
890 (100)
3600 (96.3)
<.001
Yes
138 (3.0)
BCG therapy 0 (0.0)
138 (3.7)
Abbreviations: BCG ¼ bacillus calmette-guérin; CCI ¼ Charlson comorbidity index.
historical or small cohorts.8,9,13 Thus, our main study objectives were to examine the survival benefit of patients with high-grade T1 NMIBC without clinical evidence of metastatic disease undergoing early radical cystectomy compared with that of patients initially managed with local treatment and to examine characteristics of patients undergoing early radical cystectomy. Secondarily, to examine the added value of lymph node staging, we assessed the impact of pelvic lymph node dissection at radical cystectomy on the overall survival (OS) of patients diagnosed with T1 NMIBC. We hypothesize that patients undergoing early radical cystectomy experience better OS compared with patients undergoing initial local treatment.
Patients and Methods Data Source The National Cancer Database (NCDB) for the period of 2004 to 2016 was used. The NCDB, a joint program of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society, is a national cancer registry that compiles data for more than 1500 CoC-accredited cancer programs in the United States (US).14 The database contains over 30 million records from cancer registries across the country, and is an essential cancer surveillance source of standardized data regarding patients, hospitals, and therapies.15
Baseline characteristics for each patient included age at diagnosis, year of diagnosis, gender, race (White, Black, etc), annual median income (defined as high [ $48,000], low [< $48,000], or unknown), and education (defined as high [< 13%], low [ 13%], according to the percentage of residents within the home country without high school degree, or unknown). The modified Charlson comorbidity index (CCI) provided by the NCDB was used to account for underlying disease and was classified as 0, 1, 2, or 3.16 We used the TNM classification system to categorize lymph node status as N0 and Nþ ( N1). Facility-level covariates included facility region, county, and facility type. Facility region was defined as East, Central, or West. County type was defined as metro, urban, rural, or unknown. Follow-up was measured as the time from surgery until death or the date on which the patient was last contacted.
Statistical Analysis
The primary endpoint of our study was OS, defined as the time from surgical treatment (initial local treatment or early radical cystectomy) to death from any cause. For the secondary survival analysis, we compared OS for patients undergoing radical cystectomy with PLND versus patients who underwent radical cystectomy alone.
We calculated frequencies and percentages for categorical variables, as well as medians and interquartile ranges for continuous variables. Ensuing, we examined differences between patients managed by initial local treatment and patients undergoing early radical cystectomy using the c2 test and Mann-Whitney test for categorical and continuous variables, respectively. Multivariable logistic regression analysis using the covariates mentioned above was employed to assess predictors for undergoing early radical cystectomy. We employed survival curves for all subcohorts according to the Kaplan-Meier estimator with the logrank test.17 We censored survival data of patients alive at last follow-up or the end of the study period.17,18 We then employed multivariable Cox proportional hazards regression models to quantify the risk of all-cause mortality in patients initially managed by local treatment versus radical cystectomy, adjusting for all covariates mentioned above. Finally, we performed exploratory survival analyses to examine differences in OS of patients diagnosed with highgrade T1 bladder cancer who underwent radical cystectomy with PLND versus patients who underwent radical cystectomy without PLND.
We included patients with clinical T1 NMIBC and a primary confirmed histology of urothelial high-grade T1 NMIBC (International Classification of Diseases, Tenth Revision, Clinical Modification code C67) between 2010 and 2015 who underwent treatment. Early radical cystectomy was defined as radical cystectomy for NMIBC within 90 days after diagnosis without prior intravesical therapy using BCG. All other patients underwent initial local treatment during the study period. Initial local treatment was defined as endoscopic management with or without intravesical chemotherapy or immunotherapy. We excluded all patients undergoing partial cystectomy (n ¼ 368). Patients with a clinical diagnosis of bladder cancer T2a, clinically lymph node-
-
Covariates
Outcome Measures
Patient Selection
4
positive or metastatic disease (n ¼ 5702), patients with nonurothelial bladder cancer (n ¼ 153), and patients with prior neoadjuvant chemotherapy or prior radiation of the primary tumor (n ¼ 4698) were excluded as well. We also excluded patients with missing data on the surgical procedure (n ¼ 3410) or BCG therapy (n ¼ 80) and patients with missing follow-up data (n ¼ 309) (Figure 1).
Clinical Genitourinary Cancer Month 2020
Karl H. Tully et al Table 2 Predictors for Undergoing Radical Cystectomy for High-grade T1 Bladder Cancer
Age
Odds Ratio
95% Confidence Interval
P Value
0.94
0.93-0.95
<.001
1 [REF]
e
e
Open
596 (67.0)
0.98
0.80-1.20
.806
Robotic
203 (22.8)
Gender Male Female
Table 3 Treatment-specific Characteristic of Patients Undergoing Radical Cystectomy for High-Grade T1 Bladder Cancer Characteristic
N (%)
Median time to treatment, d (IQR)
56 (35-85)
Surgical approach
Race
Laparoscopic
White
1 [REF]
e
e
Black
0.70
0.50-0.97
.030
Other
0.99
0.57-1.71
.964
Unknown
0.58
0.24-1.39
.221
CCI 0
1 [REF]
e
e
1
1.27
1.05-1.55
.014
2
0.81
0.56-1.16
.252
3
1.03
0.60-1.76
.921
Insurance status
5 (0.6)
Laparoscopic converted to open
6 (0.7)
PLND performed Yes
816 (91.7)
No
69 (7.8)
Unknown
5 (0.6)
Median number of lymph nodes removed, n (IQR)
13 (7-22)
Result of PLND Positive
27 (3.4)
Negative
789 (96.7)
1 [REF]
e
Government
1.31
1.07-1.61
.010
Uninsured
0.58
0.34-1.01
.052
R0
Unknown
1.27
0.67-2.44
.466
Rþ
44 (4.9)
Unknown
23 (2.6)
Private
e
80 (9.0)
Robotic converted to open
Annual income High
1 [REF]
e
Low
1.19
0.97-1.45
High
1 [REF]
e
Low
0.73
0.60-0.89
1 (1-3)
Surgical margin 823 (92.5)
e
Unplanned 30-day readmission
81 (9.1)
.095
30-day mortality
20 (2.3)
Education e .002
Facility type 1 [REF]
e
e
Non-academic
0.26
0.22-0.31
<.001
Unknown
0.26
0.09-0.73
.010
Academic
Median number of positive lymph nodes, n (IQR)
Facility location e
90-day mortality
29 (3.3)
Adjuvant chemotherapy within 90 days
22 (2.5)
Abbreviations: IQR ¼ interquartile range; PLND ¼ pelvic lymph node dissection.
board waiver was obtained from the Brigham and Women’s Hospital.
Metro
1 [REF]
e
Urban
1.31
1.02-1.67
.031
Results
Rural
1.17
0.56-2.44
.678
Unknown
1.53
0.99-2.34
.051
Baseline Characteristics and Predictors for the Receipt of Radical Cystectomy
Region 1 [REF]
e
e
Central
1.38
1.16-1.65
<.001
West
0.74
0.57-0.97
.027
1 [REF]
e
East
Tumor size, cm 3
e
>3
1.04
0.84-1.27
.729
Unknown
0.51
0.42-0.62
<.001
The model was adjusted for treatment modality, age, gender, race, comorbidity status, year of diagnosis, insurance status, annual income, level of education, hospital type, hospital location, region, use of adjuvant chemotherapy, tumor size, and variant histology. Abbreviations: CCI ¼ Charlson comorbidity index; REF ¼ reference.
All P-values were 2-sided, and statistical significance was assumed at P < .05. Statistical analysis was performed using Stata (Version Stata/SE 15.1, Stata Corp LLC). An institutional review
Overall, 4627 patients met inclusion criteria. The majority (80.8%) of patients underwent initial local treatment, whereas 19.2% of patients underwent early radical cystectomy. Compared with patients who underwent initial local treatment, patients who underwent radical cystectomy were significantly younger (median age at diagnosis, 68 years [interquartile range (IQR), 6175 years] versus 75 years [IQR, 66-83 years]; P < .001). Further differences in baseline characteristics are shown in Table 1. On multivariable logistic regression analysis, Black race and treatment at a non-academic facility were independent predictors for undergoing initial local treatment for high-grade T1 bladder cancer rather than early radical cystectomy. Increasing age was associated with lower odds of undergoing radical cystectomy (odds ratio, 0.94; 95% confidence interval [CI], 0.93-0.95; P < .001). Results of the multivariable logistic regression analysis are shown in Table 2.
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Radical Cystectomy for T1-NMIBC Figure 2 Kaplan-Meier Curves Examining the Overall Survival in Patients Diagnosed With High-grade T1 Nonemuscle-invasive Bladder Cancer Undergoing Radical Cystectomy versus Patients Undergoing Transurethral Resection of Bladder Tumor as Final Treatment
compared with patients who underwent radical cystectomy without PLND (P < .001) (Figure 3). The 1- and 5-year survival rates were 94.9% and 72.9% in patients who had undergone PLND at radical cystectomy. For patients who had undergone radical cystectomy without PLND, the 1-year survival rate was 91.1% and the 5-year survival rate was 46.9%. This result persisted in multivariable Cox regression analysis adjusting for the covariates mentioned above (HR, 0.55; 95% CI, 0.37-0.83; P ¼ .005).
Discussion
Surgical Characteristics: Radical Cystectomy Overall, 890 patients underwent early radical cystectomy for high-grade T1 bladder cancer. The median time from diagnosis to cystectomy was 47 days (IQR, 28-65 days). PLND was performed in 91.7% of all patients undergoing early radical cystectomy. Of these, 27 (3.3%) of 816 individuals were found to have metastases to the lymph nodes at radical cystectomy. Further data regarding early cystectomy in high-grade T1 bladder cancer are shown in Table 3.
Survival Analysis: Radical Cystectomy Versus Transurethral Resection The overall median follow-up was 48.7 months for patients alive at last follow-up. For the overall cohort of patients diagnosed with high-grade T1 bladder cancer, 1- and 5-year overall survival rates were 87.0% and 56.0%, respectively. The 1-year OS rate was 94.6% and 85.2% for the early radical cystectomy and local treatment cohorts, respectively (P < .001). The 5-year OS rate was 71.1% in patients undergoing early radical cystectomy and 52.4% in patients undergoing initial local treatment (P < .001). The median OS was 72.4 months for patients diagnosed with high-grade T1 bladder cancer and 64.0 months for patients undergoing initial local treatment for high-grad T1 bladder cancer. The median OS was not reached in the early radical cystectomy cohort (Figure 2). In multivariable Cox regression analysis, individuals undergoing early radical cystectomy had a significantly lower risk of mortality compared with patients undergoing initial local treatment (hazard ratio [HR], 0.78; 95% CI, 0.67-0.91; P ¼ .002). Further results of the multivariable Cox regression analysis are shown in Table 4.
Survival Analysis of Patients Undergoing PLND for Highgrade T1 Bladder Cancer at Radical Cystectomy
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Unadjusted Kaplan-Meier analysis showed a significant survival benefit for patients undergoing PLND at radical cystectomy
Clinical Genitourinary Cancer Month 2020
High-grade T1 NMIBC has previously been described as an “unpredictable beast.”19 Although transurethral resection on intravesical therapy using BCG may provide sufficient cancer control in some patients, other patients do not respond to this course of treatment at all, leading to an unnecessary extension of the interval between diagnosis and potentially curative early radical cystectomy.8 That said, given the morbidity associated with this complex procedure, the majority of patients tend to undergo bladder-sparing therapies first. In this study, we examined the OS of patients diagnosed with high-grade T1 NMIBC undergoing radical cystectomy versus initial local treatment. Early radical cystectomy was associated with a significant OS benefit compared with initial local treatment. Furthermore, we found that patients undergoing PLND at the time of early cystectomy had improved OS compared with patients who did not undergo PLND. Patients diagnosed with high-grade T1 bladder cancer face a poorer than usually thought of prognosis. In this large national cohort, 1- and 5-year survival rates were 87.0% and 56.0%, respectively. Earlier clinical studies examining T1 bladder cancer found 5-year survival rates ranging from 54% to 83%.7,8,20 Studies have shown that patients with T1 disease at transurethral resection can harbor anything from T0 to T4 disease at radical cystectomy; specifically, upstaging of T1 disease at radical cystectomy is described in 30% to 50% of cases. Other factors may also explain the grim prognosis. For example, the benefits of intravesical immunotherapy are well-established. When patients are managed with transurethral resection alone, a significantly higher proportion of individuals will progress to muscle-invasive disease within a short timeframe.21 Unfortunately, BCG has been subject to a shortage in the US for the better part of the past decade, which may thus influence survival rates of patients diagnosed with NMIBC in the long run.11,12 However, despite the undoubted benefit of BCG with regard to recurrence, progression, and survival in patients diagnosed with high-grade NMIBC, it has to be kept in mind that, in a large number of cases, BCG does not have the desired effect.22,23 In approximately 8.5% of patients with high-grade NMIBC, progression or metastatic disease will happen. Moreover, it has been shown that patients diagnosed with progression to MIBC after BCG face an even poorer prognosis than those initially diagnosed with muscle-invasive disease.24 With all things considered, our study found a 22% survival benefit in the adjusted analysis in favor of early radical cystectomy. The absolute gain in life was of significant magnitude: the median survival was 64.0 months for the initial local treatment group, whereas it was not reached in the early cystectomy group.
Karl H. Tully et al Table 4 Multivariable Cox Proportional Hazards Regression Examining the Risk of All-cause Mortality in Patients Diagnosed With T1 High-grade Bladder Cancer
Table 4 Continued Hazard Ratio
Hazard Ratio
95% Confidence Interval
P Value
Treatment Local treatment Radical cystectomy Age
1 [REF]
e
0.78
0.67-0.91
.002
e
1.07
1.06-1.07
<.001
1 [REF]
e
e
1.07
0.95-1.20
95% Confidence Interval
P Value
>3
1.17
1.01-1.34
.031
Unknown
1.27
1.12-1.43
<.001
The model was adjusted for treatment modality, age, gender, race, comorbidity status, year of diagnosis, insurance status, annual income, level of education, hospital type, hospital location, region, use of adjuvant chemotherapy, tumor size, and variant histology. Abbreviations: CCI ¼ Charlson omorbidity ndex; REF ¼ reference.
Gender Male Female
.250
Race White
1 [REF]
e
Black
1.15
0.94-1.39
e .173
Other
0.63
0.43-0.92
.017
Unknown
0.86
0.45-1.66
.650
0
1 [REF]
e
e
1
1.24
1.11-1.40
<.001
2
2.03
1.72-2.39
<.001
3
1.94
1.49-2.51
<.001
1 [REF]
e
e
Government
1.06
0.92-1.22
.421
Uninsured
1.84
1.23-2.74
.003
Unknown
1.41
0.88-2.25
.153
CCI
Insurance status Private
Annual income High
1 [REF]
e
Low
1.05
0.93-1.18
e .466
Education High
1 [REF]
e
Low
1.09
0.98-1.23
e .125
Facility type 1 [REF]
e
Non-academic
1.01
0.91-1.12
.877
Unknown
3.72
0.91-15.2
.067
Academic
e
Facility location Metro
1 [REF]
e
Urban
0.94
0.81-1.10
.451
e
Rural
0.78
0.48-1.27
.324
Unknown
0.90
0.66-1.22
.481
Region 1 [REF]
e
Central
1.08
0.97-1.20
.189
West
1.01
0.87-1.17
.895
1 [REF]
e
East
e
Tumor size, cm 3
e
Given these data, it may appear surprising that not more patients choose to undergo early radical cystectomy. Our data do show that patients diagnosed with T1 bladder cancer are generally of elderly age and with multi-morbidity.25,26 In this study population, the median age was 73 years (IQR, 65-82 years), and 8.7% of patients presented with a CCI of 2 or greater. In general, radical cystectomy is associated with morbidity rates of up to 56.1% and mortality rates of up to 9%.27-29 Given these factors, it is understandable that many patients will want to avoid major surgery and opt for conservative management. Our results support this hypothesis: increasing age was associated with increasingly lower odds of undergoing radical cystectomy (Table 2). However, the balance of benefits versus harms likely would reasonably indicate that younger patients have a lot to gain from early radical cystectomy. Despite such considerations, the utilization of early radical cystectomy remains low regardless of age category. In the future, we need to improve our ability to triage responders from non-responders to intravesical immunotherapy/chemotherapy, possibly with the use of molecular characterization using next-generation sequencing.30,31 Another interesting finding of our study pertains to the benefits of PLND at radical cystectomy for T1 bladder cancer. There is little controversy about the use of PLND at radical cystectomy for MIBC, as recommended by most society guidelines. Potential benefits include more accurate staging to guide adjuvant therapy and potentially therapeutic resection of metastatic disease.5,32 However, PLND is associated with a variety of complications, including lymphoceles, thromboembolic events, and neurovascular injuries.33,34 Gupta et al describe that up to 17.5% of patients diagnosed with clinical high-grade T1 NMIBC harbor occult metastases to the lymph nodes.7 The authors found that nearly onehalf of all patients with clinical high-grade T1 NMIBC were upstaged to muscle-invasive disease ( T2a), which is associated with a significantly higher risk of metastatic disease.35 In our cohort of histologically confirmed T1 NMIBC, lymph node-positive disease was found in 3.3% of patients, underscoring the aggressive nature of this disease. As such, we found significant survival benefit for patients undergoing PLND at radical cystectomy in our cohort. Specifically, there was a significant difference in long-term survival between the 2 subgroups. In patients who had undergone PLND, the 5-year survival rate was 72.9%, whereas only 46.9% of patients who had undergone radical cystectomy without PLND survived at
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Radical Cystectomy for T1-NMIBC Figure 3 Kaplan-Meier Curves Examining the Overall Survival in Patients Diagnosed With High-Grade T1 Non emuscle-invasive Bladder Cancer Undergoing PLND During Radical Cystectomy versus Radical Cystectomy Without PLND
have improved OS compared with patients who did not undergo PLND during radical cystectomy.
Clinical Practice Points Given the ongoing shortage of intravesical BCG in the US,
alternative treatment options for high-grade NMIBC need to be discussed in greater detail in order to provide patients with the most reasonable and save therapy possible. Although radical cystectomy can provide the most effective approach from an oncologic point of view, there is ongoing debate about the use of early radical cystectomy in patients diagnosed with high-grade NMIBC. Given that many patients and physicians prefer transurethral/intravesical treatment, current large-scale data examining this question is missing. In this study, we could show that radical cystectomy can provide a survival benefit. Furthermore, PLND at the time of radical cystectomy was associated with a favorable outcome. Regarding these results and the current scarcity of effective intravesical agents, early radical cystectomy plays an important role in the treatment of patients diagnosed with high-grade NMIBC. Abbreviation: PLND ¼ pelvic lymph node dissection.
Disclosure least 5 years. Our study corroborates the findings of Larcher et al, who found that PLND at the time of radical cystectomy provides a survival benefit for patients diagnosed with MIBC. Given the lack of randomized data for nonemuscle-invasive disease, our study provides the best evidence for the role of PLND in the context of radical cystectomy for T1 disease e as is the case with invasive disease, PLND should be performed at radical cystectomy. Our study is subject to several limitations. First, the NCDB does not provide information on the cause of death; thus, cancer-specific survival could not be examined in this cohort. Second, the NCDB is a hospital-based registry with information on patients treated at CoC-accredited hospitals only; our results may not be representative of patients treated outside these facilities. Third, data regarding the quality of prior transurethral resections, as well as more granular histologic data, are missing. For example, information on lymphovascular invasion, presence of detrusor muscle in the specimen, completeness of the initial resection, and the presence of carcinoma in situ are crucial data that may influence further management, as well as the outcome of patients diagnosed with high-grade T1 NMIBC. Fourth, patients undergoing initial local treatment may have undergone radical cystectomy after the study period. As previously described by Denzinger et al, these patients would be likely to experience worse outcomes in the case of recurrence or progression.8 Finally, our study shares the limitations associated with all observational, nonrandomized, retrospective studies, including unmeasured confounders for which we are not able to account.
Conclusion In this cohort of patients diagnosed with high-grade T1 NMIBC, we found that early radical cystectomy was associated with an OS benefit compared with initial local treatment. Additionally, patients undergoing PLND at the time of radical cystectomy were found to
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Quoc-Dien Trinh reports personal fees from Astellas, Bayer, Janssen, Insightec, and Intuitive Surgical. Adam S. Kibel reports consulting fees from Sanofi, Dendreon, Tokai, and Profound. Guru Sonpavde reports research support to institution from Astrazeneca, Bayer, Amgen, Boehringer-Ingelheim, Janssen, Merck, Sanofi, and Pfizer; is part of the advisory board for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, Astrazeneca, Merck, Genentech, EMD Serono, and Astellas/Agensys, as well as part of the steering committee for Astrazeneca, BMS, Astellas, Debiopharm, and Bavarian Nordic; and is an author for Uptodate and a speaker for Onclive, Research to Practice, and Physician Education Resource (PER). The remaining authors have stated that they have no conflicts of interest.
CRediT authorship contribution statement Karl H. Tully: Conceptualization, Formal analysis, Writing original draft. Florian Roghmann: Methodology. Joachim Noldus: Writing - review & editing. Xi Chen: Validation. Lorine Häuser: Writing - review & editing. Adam S. Kibel: Writing - review & editing. Guru P. Sonpavde: Writing - review & editing. Matthew Mossanen: Writing - original draft. Quoc-Dien Trinh: Supervision, Writing - review & editing.
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