Timing of adjuvant chemotherapy and overall survival following radical cystectomy

ARTICLE IN PRESS

Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−8

Clinical-Bladder cancer

Timing of adjuvant chemotherapy and overall survival following radical cystectomy Joshua S. Jue, M.D.a,*, Tulay Koru-Sengul, Ph.D., M.H.S.b,c, Feng Miao, M.S.b, Zachary A. Kroeger, M.D., M.S.a, Kevin J. Moore, M.D., M.P.H.b, Mahmoud Alameddine, M.D.a, Sanoj Punnen, M.D., M.S.a,c, Dipen J. Parekh, M.D.a,c, Chad R. Ritch, M.D., M.B.A.a,c, Mark L. Gonzalgo, M.D., Ph.D.a,c a

Department of Urology, University of Miami Miller School of Medicine, Miami, FL Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL c Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL b

Received 23 May 2019; received in revised form 2 October 2019; accepted 4 November 2019

Abstract Background: We investigated the relationship between timing of adjuvant chemotherapy on overall survival following radical cystectomy. Methods: We retrospectively reviewed the National Cancer Data Base for patients with newly diagnosed pT2-T4, N0, M0 urothelial cell carcinoma who received no treatment prior to radical cystectomy. Patients who received no adjuvant chemotherapy or who received adjuvant chemotherapy more than 45 days after radical cystectomy were propensity matched to patients receiving adjuvant chemotherapy within 45 days of radical cystectomy. Selection bias was assessed by comparing the length of stay, readmission rate, and surgical approach between groups. Median survival was calculated using Kaplan-Meier analysis. Adjusted hazard ratios and 95% confidence intervals were calculated from a multivariable Cox regression model to examine factors affecting overall survival. Results: From 2004 to 2014, 284 patients with muscle-invasive bladder cancer met inclusion criteria. Patients receiving chemotherapy within 45 days had the best 5-year overall survival (47.0%, 95%CI: 40.6%−53.2%) compared to those receiving chemotherapy after 45 days (37.5%, 95%CI: 31.4%−43.7%). Chemotherapy after 45 days and no adjuvant chemotherapy were significant predictors of worse overall survival compared to chemotherapy within 45 days (1.27, 1.02−1.59, P = 0.033 and 1.41, 1.12−1.78, P = 0.003). Receiving no adjuvant chemotherapy was not significantly different than chemotherapy after 45 days (1.11, 0.89−1.38, P = 0.348). Significant predictors of poorer overall survival were female sex (1.37, 1.04−1.81, P = 0.028), Medicare (1.37, 1.06−1.76, P = 0.016), pT3 stage (1.79, 1.35−2.38, P < 0.001), and pT4 stage (3.00, 2.20−4.01, P < 0.001). Significantly more patients with length of stay ≤7 days following RC received chemotherapy within 45 days (53.2%) compared to those who received adjuvant chemotherapy after 45 days after RC (44.0%) or no adjuvant chemotherapy (43.0%; P = 0.0369). Conclusions: Initiation of adjuvant chemotherapy within 45 days of radical cystectomy for patients with pT2-4 bladder cancer was associated with an overall survival benefit compared to patients who received adjuvant chemotherapy after 45 days or no adjuvant chemotherapy. Ó 2019 Elsevier Inc. All rights reserved.

Keywords: Adjuvant chemotherapy; Muscle-invasive bladder cancer; Radical cystectomy; Timing of adjuvant chemotherapy; NCDB

1. Introduction The current standard of care for surgical management of muscle-invasive bladder cancer is radical cystectomy Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. *Corresponding author. Tel.: +1-408-206-7933; fax: +1-305-243-6597. E-mail address: [email protected] (J.S. Jue). https://doi.org/10.1016/j.urolonc.2019.11.001 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.

(RC) with pelvic lymph node dissection. Pathologic upstaging and disease recurrence occurs in approximately 42% [1] and 44% [2] of cases, respectively. Both pathologic upstaging and recurrence may be due to micrometastases present at the time of surgery [3], which contributes to poorer overall survival (OS). Neoadjuvant and adjuvant chemotherapy regimens have been introduced to optimize patient outcomes.

ARTICLE IN PRESS 2

J.S. Jue et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−8

Neoadjuvant chemotherapy (NAC) is a level 1 recommendation by the National Comprehensive Cancer Network due to strong evidence from randomized clinical trials and meta-analyses demonstrating improved OS [4−6]. The Advanced Bladder Cancer meta-analysis collaboration reported that platinum-based therapies resulted in a 5% increase in OS and a 9% increase in 5-year disease-free recurrence in T2-T4a, N0 disease before local curative therapy [6]. However, the time to administer and recover from preoperative chemotherapy lengthens the time to surgery, a well-described prognostic factor in muscle-invasive bladder cancer [7]. Adjuvant chemotherapy (AC) avoids the delay of surgery and allows for accurate pathologic staging prior to administration of systemic therapy. The evidence for utilization of AC for pT3-T4 or N+ disease remains a level 2 recommendation by the National Comprehensive Cancer Network. AC is the standard of care for other primary cancers, and delays in initiating AC in breast [8], colon [9], gastric [10], ovarian [11], and pancreatic [12] cancer have been shown to significantly worsen survival. We investigated the impact of initiating AC within 45 days of RC on OS among patients diagnosed with pT2-4, N0, M0 urothelial carcinoma of the bladder. 2. Materials and methods 2.1. Data source Data from the National Cancer Data Base (NCDB) was used to examine OS related to time between RC and AC. The NCDB is a nationwide, facility-based, comprehensive clinical surveillance oncology data set that captures 70% of all newly diagnosed malignancies in the United States. It is a joint project of the American Cancer Society and the American College of Surgeons Commission on Cancer that includes information on patient demographics, insurance status, comorbidity status, disease stage, and disease treatment compiled from patient records and death registries. This study was exempt from institutional review board approval since no personal patient information was examined. 2.2. Study population The NCDB was used to identify all patients who underwent RC from 2004 to 2014 for transitional cell/urothelial bladder carcinoma using (ICD)-O-3 morphology codes 8120 and 8145. The search for patients who had no AC was limited to patients with pathologic stage T2-4, N0 and M0 disease, underwent RC, and had no history of chemotherapy or radiation treatment. Patients with node positive disease were excluded from the no AC group, since these patients would most likely receive adjuvant/systemic treatment as standard of care. The search for patients who received AC was limited to patients who had pathologic stage T2-4, N0 and M0 disease and received single or multiagent

chemotherapy within 90 days of RC. The exclusion of patients who received AC after 90 days from time of RC is commonly used by national database studies to avoid capturing patients who were given chemotherapy at time of recurrence or without intention to treat [13,14]. The 45 day cut-off was chosen as a halfway point to create 2 AC cohorts. One AC cohort received systemic therapy ≤45 days of RC, while the other received systemic therapy 46 to 90 days after RC. Patients with chemotherapy recorded as being administered before or on the same day of RC or who received radiation treatment at any time were excluded. Node positive patients were excluded from the AC groups so that they could be propensity score matched to the no AC group. Patients who were diagnosed at death or autopsy were excluded. 2.3. Predictor and outcome variables The primary outcome variable was OS, defined as the time elapsed from bladder cancer diagnosis to death or last follow-up. The primary predictor variable was time between RC and the initiation of AC, which was compared between 3 treatment arms: ≤45 days, >45 days, or no chemotherapy. Sociodemographic variables included: age at diagnosis, sex, race, Hispanic ethnicity, insurance status, and facility type as assigned by NCDB (academic/research vs. nonacademic/research). Clinical characteristics included in the analysis were comorbidity score, pathological T stage, unplanned readmission within 30 days of discharge, surgical approach, and surgical inpatient stay length. Due to limitations of the NCDB, only surgical approach data from 2010 to 2014 could be included. 2.4. Propensity score matching A (1:1) nearest neighbor propensity score matched analysis was used to balance the 3 treatment arms (≤45 days between AC and RC, >45 days, and no chemotherapy). A multivariable logistic regression model was created to predict the probability of receiving AC >45 days after RC compared to ≤45 days after RC to create propensity scores adjusted with covariates that included age, race, ethnicity, gender, insurance status, facility type, comorbidity presence, and pathological T stage. Patients who received AC >45 days after RC were matched 1:1 to patients treated with AC ≤45 days after RC by propensity scores derived from the multivariable logistic regression model. Unmatched patients were excluded from analysis. Another multivariable logistic regression model was fitted to predict the probability of no chemotherapy with receiving AC ≤45 days after RC to create propensity scores that were adjusted with the same covariates. Patients who did not receive chemotherapy were matched 1:1 to patients treated with AC ≤45 days after RC by propensity scores derived from the second multivariable logistic regression model. Finally, the 2 datasets were merged with the same number of patients in each arm.

ARTICLE IN PRESS J.S. Jue et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−8

3

2.5. Statistical analysis

3.3. Multivariable Cox survival models

Sociodemographic and clinical variables were tabulated by frequency across treatment groups. Chi-square tests, student t tests, or nonparametric Mann-Whitney U tests were used to assess significance across variables. Kaplan-Meier survival analyses were used to calculate median survival and survival rates at 1, 3, and 5 years after diagnosis. Multivariable Cox proportional hazard regression models adjusted for sociodemographic and clinical characteristics were fit to predict OS. Adjusted hazard ratios (aHR) were calculated with 95% confidence intervals (95%CI) and P values to compare OS. OS was estimated to be the time between diagnosis and death. Type-I error rate was set to 5%, where P values <0.05 were considered statistically significant. All statistical analyses were completed using SAS v9.4 (SAS Institute, Cary, NC).

Patients with >45 days between RC and AC had significantly worse OS compared to those with ≤45 days between RC and AC (aHR 1.27, 95%CI 1.02−1.59, P = 0.033). Patients who did not receive chemotherapy also showed worse OS compared to those with ≤45 days between RC and AC (aHR 1.41; 95%CI 1.12−1.78, P = 0.003). There was no significant difference in OS between the groups with >45 days between RC and AC and those who did not receive chemotherapy (aHR 1.11; 95%CI 0.89−1.38, P = 0.348) (Table 3; Fig. 1). Significant predictors of poorer OS were female sex (1.37, 1.04−1.81, P = 0.028), Medicare (1.37, 1.06−1.76, P = 0.016), pT3 stage (1.79, 1.35−2.38, P < 0.001), and pT4 stage (3.00, 2.20−4.01, P < 0.001).

3. Results 3.1. Sociodemographic and clinical characteristics A total of 4,391 patients with bladder cancer met inclusion criteria before matching (Table 1). Before propensity matching, T3 was the most common stage in the AC groups, while T2 was the most common stage in the no chemotherapy group (P < 0.0001). After propensity matching, a total of 852 patients were included in the analysis comprised of 284 patients in each of the 3 treatment groups: ≤45 days between RC and AC, >45 days between RC and AC, and no chemotherapy treatment. The mean age after matching was 62.4 years (§9.7 years). The majority of patients were male (87.8%), white (93.0%), non-Hispanic (93.1%), and had private insurance (51.1%). The majority of patients received care at an academic/ research institution (63.8%), and a minority had an existing comorbidity (24.3%). The most common pathological T stage was T3 (59.2%) followed by T4 (22.7%) and T2 (18.2%) (Table 1).

3.4. Selection bias analysis The potential contribution of intraoperative and postoperative factors related to selection bias was evaluated (Table 4). A significantly greater proportion of patients who had a postoperative stay of ≤7 days following RC (53.2%) were among those who received AC ≤45 days from surgery, compared to those who received AC >45 days after RC (44.0%) or no AC (43.0%; P = 0.0369). The majority of patients in each group did not have an unplanned readmission within 30 days after discharge from their RC, which did not significantly differ between groups (P = 0.112). The surgical approach used for RC (minimally invasive vs. open) was also similar between patients (P = 0.512), with an identical proportion of patients receiving the open technique in each treatment arm (28%).

3.2. Median survival time The overall median survival time for all patients included in the analysis after matching was 2.9 years (95%CI: 2.5−3.4). Individuals with ≤45 days between RC and AC had a median survival time of 4.3 years (95%CI: 2.9−5.7), which was greater than both other treatment groups. Patients who received AC ≤45 days after RC had the highest 1- (85.9%), 3- (55.1%), and 5-year (47.0%) OS rates compared to the other treatment groups (Table 2). Patients receiving chemotherapy within 45 days had the best 5-year OS (47.0%, 95%CI: 40.6%−53.2%) compared to those receiving chemotherapy after 45 days (37.5%, 95%CI: 31.4%−43.7%) and those receiving no chemotherapy (41.2%, 95%CI: 35.0%−47.2%).

Fig. 1. Overall survival between ≤45 days RC + AC, >45 days RC + AC, and no AC. Kaplan-Meier analyses comparing overall survival of patients with ≤45 days between RC and AC, patients with >45 days between RC and AC, and patients who did not receive AC.

4

Table 1 Patient demographic and clinical characteristics. Nonpropensity matched data

Propensity-matched data

Days between RC and AC ≤45 days

All patients N

N

100.0

286

38.9 61.1

% 6.5

No chemo

N

%

N

%

529

12.0

3,576

81.4

261 268 64.1 (9.6) 65 (58; 71) 35; 88

49.3 50.7

1,282 2,294 67.9 (10.5) 69 (61; 76) 28; 90

35.9 64.1

57.0 43.0

16.1 83.9

37 249

12.9 87.1

76 453

14.4 85.6

593 2,983

16.6 83.4

91.9 4.9 2.2 1.1

262 10 8 6

91.6 3.5 2.8 2.1

489 28 7 5

92.4 5.3 1.3 0.9

3,283 175 80 38

2.8 90.8 6.3

4 264 18

1.4 92.3 6.3

20 470 39

3.8 88.8 7.4

101 3,254 221

5.5

17

5.9

35

6.6

56.6 3.5 33.2 1.2

112 9 145 3

39.2 3.1 50.7 1.0

251 21 215 7

47.4 4.0 40.6 1.3

2,123 125 1,097 42

59.4 3.5 30.7 1.2

42.5 57.5

102 184

35.7 64.3

208 321

39.3 60.7

1,558 2,018

43.6 56.4

32.0 68.0

68 218

23.8 76.2

143 386

27.0 73.0

1,196 2,380

45.3 41.2 13.5

55 163 68

19.2 57.0 23.8

82 327 120

15.5 61.8 22.7

1,854 1,318 404

P value

<0.0001

> 45 days

No chemo

N

%

N

%

N

%

N

%

852

100.0

284

33.3

284

33.3

284

33.3

161 123 62.4 (9.4) 63 (55; 69) 34; 85

56.7 43.3

152 132 62.5 (9.4) 63 (56; 69) 37; 84

53.5 46.5

159 125 62.4 (10.3) 63 (55; 70) 28; 86

56.0 44.0

P value

472 380 62.4 (9.7) 63 (55; 69) 28; 86

55.4 44.6

0.1413

104 748

12.2 87.8

37 247

13.0 87.0

31 253

10.9 89.1

36 248

12.7 87.3

0.7121

91.8 4.9 2.2 1.1

0.4541

792 26 18 16

93.0 3.1 2.1 1.9

262 10 6 6

92.3 3.5 2.1 2.1

265 8 6 5

93.3 2.8 2.1 1.8

265 8 6 5

93.3 2.8 2.1 1.8

0.9879

2.8 91.0 6.2

0.1359

12 793 47

1.4 93.1 5.5

4 262 18

1.4 92.3 6.3

4 266 14

1.4 93.7 4.9

4 265 15

1.4 93.3 5.3

0.9998

5.3

<0.0001

49

5.8

17

6.0

17

6.0

15

5.3

0.7526

339 23 435 6

39.8 2.7 51.1 0.7

112 9 143 3

39.4 3.2 50.4 1.1

117 5 142 3

41.2 1.8 50.0 1.1

110 9 150 .

38.7 3.2 52.8 .

0.0095

308 544

36.2 63.8

101 183

35.6 64.4

105 179

37.0 63.0

102 182

35.9 64.1

0.9360

33.4 66.6

0.0001

207 645

24.3 75.7

68 216

23.9 76.1

68 216

23.9 76.1

71 213

25.0 75.0

0.9442

51.8 36.9 11.3

<0.0001

155 504 193

18.2 59.2 22.7

54 162 68

19.0 57.0 23.9

47 174 63

16.5 61.3 22.2

54 168 62

19.0 59.2 21.8

0.8473

<0.0001

0.7274 0.9938

ARTICLE IN PRESS

163 123 62.3 (9.4) 63 (55; 69) 34; 85

189

≤ 45 days

All Patients

J.S. Jue et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−8

All 4,391 Age at diagnosis 17<−64 1,706 64< to high 2,685 Mean (sd) 67.1 (10.5) Median (Q1; Q3) 68 (60; 75) Min; max 28; 90 Sex Female 706 Male 3,685 Race White 4,034 Black 213 Other 95 Unknown 49 Hispanic Yes 125 No 3,988 Unknown 278 Primary payor Medicaid/other 241 government Medicare 2,486 No insurance 155 Private insurance 1,457 Unknown status 52 Academic/research program Yes 1,868 No 2,523 Comorbidity Yes 1,407 No 2,984 Pathological T stage 2 1,991 3 1,808 4 592

%

>45 days

Days between RC and AC

ARTICLE IN PRESS J.S. Jue et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−8

5

Table 2 Median overall survival between treatment groups. Time

≤45 days

>45 days

Non chemo

All

Median survival 1y 3y 5y

4.3 (2.9−5.7) 85.9% (81.3−89.4) 55.1% (48.9−60.8) 47.0% (40.6−53.2)

2.8 (2.1−3.2) 85.6% (80.9−89.3) 46.5% (40.3−52.4) 37.5% (31.4−43.7)

2.2 (1.8−3.4) 74.2% (68.6−78.9) 44.9% (38.8−50.8) 41.2% (35.0−47.2)

2.9 (2.5−3.4) 82.0% (79.2−84.4) 48.9% (45.3−52.3) 41.9% (38.3−45.5)

4. Discussion Randomized clinical trials have investigated the effect of various chemotherapy agents, doses, and durations in the setting of AC following RC. Despite specific inclusion criteria for each trial, few have used a time to initiation of AC (TTAC) that was <90 days as part of eligibility criteria [15]. The median TTAC after RC was 52 days in 1 national database study, so 45 days was chosen as the cutoff in this study since it is the halfway point of the commonly used 90 day inclusion criteria [13,14]. TTAC has been shown to be important as indicated by data from randomized trials and meta-analyses for breast and colon cancer, respectively [8,9]. A 3 to 4 week delay in administration of AC had significant implications on disease-free survival and OS. Although this parameter has significance in other organs, it has not been extensively studied for bladder cancer. Prior studies analyzing the effect of TTAC demonstrated worse

survival when AC was administered more than 12 weeks from RC and when chemotherapy was administered at the time of recurrence [16,17]. With few studies adequately assessing an AC parameter that has been proven to be important for other cancers, this study investigated the impact of administering AC within the first half of a commonly used 90 day timeframe [13]. Factors shown to delay TTAC in colorectal cancer are longer length of stay, unplanned readmission, and open technique during the primary surgery [18]. We evaluated potential bias from these factors and found that unplanned readmission and surgical technique did not significantly differ between the 3 groups (Table 2). However, significantly more patients were discharged within 1 week of RC in the ≤45 day AC group compared to the >45 day AC group and no AC group. Earlier discharge following RC may allow more time for the hospital and patient to prepare for administration of AC, facilitating an earlier TTAC. Increased

Table 3 Cox models predicting overall survival. Prognostic factors

Category

HR (95%CI)

P value

Adjusted HR(95%CI)

P value

> 45 days vs. ≤45 days No Chemo vs. ≤45 days No Chemo vs. >45 days Per year increase White Black Other Unknown No Unknown Yes Male Female Private insurance Medicaid/other government Medicare No insurance Unknown status Yes No No Yes 2 3 4

1.25 (1.01, 1.56) 1.36 (1.09, 1.70) 1.09 (0.88, 1.35) 1.01 (1.00, 1.02) 1.00 1.91 (1.17, 3.10) 0.66 (0.31, 1.40) 0.88 (0.46, 1.71) 1.00 1.12 (0.77, 1.63) 0.64 (0.27, 1.56) 1.00 1.33 (1.02, 1.74) 1.00 1.82 (1.26, 2.64) 1.44 (1.20, 1.74) 0.94 (0.51, 1.72) 0.54 (0.13, 2.18) 1.00 1.17 (0.97, 1.41) 1.00 1.17 (0.95, 1.44) 1.00 1.88 (1.42, 2.50) 3.10 (2.28, 4.22)

0.044 0.006 0.442 0.174 . 0.009 0.280 0.710 . 0.562 0.330 . 0.034 . 0.002 <.001 0.842 0.390 . 0.107 . 0.135 . <.001 <.001

1.27 (1.02, 1.59) 1.41 (1.12, 1.78) 1.11 (0.89, 1.38) 0.99 (0.98, 1.01) 1.00 1.62 (0.95, 2.78) 0.77 (0.37, 1.59) 0.81 (0.38, 1.70) 1.00 1.15 (0.75, 1.78) 0.62 (0.23, 1.65) 1.00 1.37 (1.04, 1.81) 1.00 1.52 (1.01, 2.30) 1.37 (1.06, 1.76) 0.89 (0.50, 1.60) 0.75 (0.22, 2.56) 1.00 1.06 (0.87, 1.29) 1.00 1.15 (0.93, 1.42) 1.00 1.79 (1.35, 2.38) 3.00 (2.20, 4.10)

0.033 0.003 0.348 0.378 . 0.078 0.479 0.570 . 0.512 0.341 . 0.028 . 0.045 0.016 0.699 0.643 . 0.558 . 0.212 . <.001 <.001

Days between AC and RC

Age at diagnosis Race

Hispanic

Sex Primary payor

Academic/research program Comorbidity Pathological T stage

ARTICLE IN PRESS 6

J.S. Jue et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−8

Table 4 Intraoperative and postoperative characteristics. Days between RC and AC ≤45 days

All patients n(%) N All 852 Duration of inpatient stay after radical cystectomy ≤7 days 398 >7 days 370 Unknown 84 Unplanned readmission within 30 days of discharge Yes 62 No 774 Unknown 16 Radical cystectomy surgical approach Minimally invasive 98 Open 241 Unknown 513

>45 days

No chemo

Col%

N

Col%

N

Col%

N

Col%

100.0

284

33.3

284

33.3

284

33.3

46.7 43.4 9.9

151 110 23

53.2 38.7 8.1

125 121 38

44.0 42.6 13.4

122 139 23

43.0 48.9 8.1

0.0369

7.3 90.8 1.9

18 261 5

6.3 91.9 1.8

28 250 6

9.9 88.0 2.1

16 263 5

5.6 92.6 1.8

0.1118

11.5 28.3 60.2

30 81 173

10.6 28.5 60.9

39 80 165

13.7 28.2 58.1

29 80 175

10.2 28.2 61.6

0.5124

length of stay in the >45 day AC group and no AC group may be indicative of poorer baseline health, greater frailty, intraoperative/postoperative complications, or quality of surgery that may have delayed or prohibited AC. Unfortunately, the aforementioned possibilities for delayed or forgone AC may prevent up to 30% of patients who undergo RC from receiving AC [19]. NAC has been promoted as the preferred therapy due to its benefit in clinical trials and independence from RC recovery. Nevertheless, patients were matched by factors that could potentially affect health status or quality of surgery, such as age, insurance, academic/research program, comorbidity, and pathological stage. While sex may be a surprising predictor of survival in pT2-T4 bladder cancer, females have been found to be significantly more likely to be upstaged [20] and progress to nonorgan confined disease after RC [21]. This may be due a later presentation of bladder cancer among females, who may be less likely to be referred to a urologist for hematuria [22]. Additionally, significant social and biological differences surrounding AC have been observed between sexes. Female sex has been shown to be a significant predictor of AC omission and discontinuation in colorectal cancer [23]. This finding may be due to higher rates of symptoms such as nausea, vomiting, and myelosuppression [24,25]. Another interesting finding was that Medicare was a significant predictor of overall worse survival. Age has been shown to negatively correlate with the use of AC, despite similar benefits with aggressive therapies in older adults [26]. Age was included within our multivariate analysis and was not an independent predictor of mortality. Even after accounting for age in multivariable analysis, Medicare has been shown to be significantly associated with increased TTAC in breast cancer [27] and worse OS in colorectal cancer patients receiving AC [28]. These studies did not

P value

postulate reasons why Medicare may impact TTAC and OS after controlling for other confounding variables. Without Medicaid or age as predictors of survival in our results, perhaps aspects intrinsic to Medicare insurance policies, referral patterns, and treatment facilities may be responsible for poorer OS. Our results highlight the potential significance of timing in the administration of AC after RC. By incorporating age, race, sex, insurance, academic/research program, comorbidity, and stage into multivariable analyses, we attempted to account for potential confounders of OS. Pathological stage T2 was the most common stage before propensity matching due to the large number of nonchemotherapy patients captured, but stages T3 and T4 became more represented in the final propensity matched cohorts and more accurately reflect disease stages treated with AC. Although performance status and renal impairment may be unobserved confounders in administration of AC, these factors appear to be addressed by our propensity matching and multivariable analysis [13]. In addition to the retrospective nature of our study, other limitations include the potential heterogeneity of chemotherapy regimens, absence of central pathology review, and inability to control for standardization of RC technique. Another limitation is the large number of patients with unknown surgical approach, although this number was not significantly different among the cohorts. Lastly, despite our attempt to control for confounders of survival, the possibility of selection bias still remains. Excluding node positive patients from this study does not restrict the applicability of these results, as the purpose of this study was to compare patients who received no AC or who received AC more than 45 days after RC to patients receiving AC within 45 days of RC. Inclusion of node positive patients would prevent an accurate comparison with patients who did not receive AC. Perhaps the survival benefit from AC will be more similar to that observed with NAC, if AC is administered within 45 days of RC.

ARTICLE IN PRESS J.S. Jue et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−8

5. Conclusions In this nationwide observational study, initiation of AC ≤45 days following RC was associated with significantly better OS compared to administration of AC >45 days following RC, or no AC. Conflict of interest The authors do not have any financial disclaimers to or conflicts of interest to disclose. Acknowledgments We would like to acknowledge the American College of Surgeons for creating the National Cancer Data Base to facilitate the study of urologic oncology. References [1] Xylinas E, Rink M, Robinson BD, et al. Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. Eur J Cancer 2013;49 (8):1889–97. https://doi.org/10.1016/j.ejca.2013.02.001. [2] Yafi FA, Aprikian AG, Fradet Y, et al. Surveillance guidelines based on recurrence patterns after radical cystectomy for bladder cancer: the Canadian Bladder Cancer Network experience. BJU Int 2012;110 (9):1317–23. https://doi.org/10.1111/j.1464-410X.2012.11133.x. [3] Kurahashi T, Hara I, Oka N, et al. Detection of micrometastases in pelvic lymph nodes in patients undergoing radical cystectomy for locally invasive bladder cancer by real-time reverse transcriptasePCR for cytokeratin 19 and uroplakin II. Clin Cancer Res 2005;11 (10):3773–7. https://doi.org/10.1158/1078-0432.CCR-04-2297. [4] International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011;29(16):2171–7. https://doi.org/10.1200/ JCO.2010.32.3139. [5] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859–66. https:// doi.org/10.1056/NEJMoa022148. [6] Advanced Bladder Cancer (ABC) Meta-analysis Collaboration CL. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48 (2):202–5. https://doi.org/10.1016/j.eururo.2005.04.006: discussion 205-6. [7] Sanchez-Ortiz RF, Huang WC, Mick R, et al. An interval longer than 12 weeks between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder carcinoma. J Urol 2003;169 (1):110–5. https://doi.org/10.1097/01.ju.0000039620.76907.0d: discussion 115. [8] Colleoni M, Bonetti M, Coates AS, et al. Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. The International Breast Cancer Study Group. J Clin Oncol 2000;18 (3):584–90. https://doi.org/10.1200/JCO.2000.18.3.584.

7

[9] Biagi JJ, Raphael MJ, Mackillop WJ, et al. Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 2011;305 (22):2335–42. https://doi.org/10.1001/jama.2011.749. [10] Kaito A, Kinoshita T, Shitara K, et al. Timing of initiation of adjuvant chemotherapy for gastric cancer: a case-matched comparison study of laparoscopic vs. open surgery. Eur J Surg Oncol 2017;43 (4):801–7. https://doi.org/10.1016/j.ejso.2017.01.008. [11] Tewari KS, Java JJ, Eskander RN, et al. Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study. Ann Oncol Off J Eur Soc Med Oncol 2016;27(1):114–21. https://doi.org/10.1093/annonc/ mdv500. [12] Murakami Y, Uemura K, Sudo T, et al. Early initiation of adjuvant chemotherapy improves survival of patients with pancreatic carcinoma after surgical resection. Cancer Chemother Pharmacol 2013;71 (2):419–29. https://doi.org/10.1007/s00280-012-2029-1. [13] Galsky MD, Stensland KD, Moshier E, et al. Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J Clin Oncol 2016;34(8):825–32. https://doi.org/10.1200/JCO.2015.64.1076. [14] Chen F V, Koru-Sengul T, Miao F, et al. Propensity-matched analysis of stage-specific efficacy of adjuvant chemotherapy for bladder cancer. Urol Oncol Semin Orig Investig August 2019. https://doi.org/ 10.1016/j.urolonc.2019.06.022. [15] Leow JJ, Martin-Doyle W, Rajagopal PS, et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 2014;66(1):42–54. https://doi.org/10.1016/j.eururo.2013.08.033. [16] Booth CM, Siemens DR, Peng Y, et al. Delivery of perioperative chemotherapy for bladder cancer in routine clinical practice. Ann Oncol Off J Eur Soc Med Oncol 2014;25(9):1783–8. https://doi.org/ 10.1093/annonc/mdu204. [17] Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol 2015;16(1):76–86. https://doi.org/10.1016/S1470-2045(14) 71160-X. [18] Malietzis G, Mughal A, Currie AC, et al. Factors implicated for delay of adjuvant chemotherapy in colorectal cancer: a meta-analysis of observational studies. Ann Surg Oncol 2015;22(12):3793–802. https://doi.org/10.1245/s10434-015-4479-2. [19] Donat SM, Shabsigh A, Savage C, et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol 2009;55(1):177–85. https://doi.org/ 10.1016/j.eururo.2008.07.018. [20] Gray PJ, Lin CC, Jemal A, et al. Clinical-pathologic stage discrepancy in bladder cancer patients treated with radical cystectomy: results from the national cancer data base. Int J Radiat Oncol Biol Phys 2014;88 (5):1048–56. https://doi.org/10.1016/j.ijrobp.2014.01.001. [21] Turker P, Bostrom PJ, Wroclawski ML, et al. Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome. BJU Int 2012;110(6):804–11. https://doi.org/10.1111/j.1464-410X.2012.10939.x. [22] Johnson EK, Daignault S, Zhang Y, et al. Patterns of hematuria referral to urologists: does a gender disparity exist? Urology 2008;72 (3):498–502. https://doi.org/10.1016/j.urology.2008.01.086. [23] van der Geest LGM, Portielje JEA, Wouters MWJM, et al. Complicated postoperative recovery increases omission, delay and discontinuation of adjuvant chemotherapy in patients with Stage III colon cancer. Color Dis 2013;15(10):e582–91. https://doi.org/10.1111/ codi.12288. [24] Sloan JA, Goldberg RM, Sargent DJ, et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal

ARTICLE IN PRESS 8

J.S. Jue et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−8

cancer. J Clin Oncol 2002;20(6):1491–8. https://doi.org/10.1200/ JCO.2002.20.6.1491. [25] Zalcberg J, Kerr D, Seymour L, et al. Haematological and non-haematological toxicity after 5-fluorouracil and leucovorin in patients with advanced colorectal cancer is significantly associated with gender, increasing age and cycle number. Tomudex International Study Group. Eur J Cancer 1998;34(12):1871–5 http://www.ncbi.nlm.nih. gov/pubmed/10023308. Accessed April 27, 2017. [26] Reardon ZD, Patel SG, Zaid HB, et al. Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-

invasive bladder cancer: a sign of changing tides. Eur Urol 2015;67 (1):165–70. https://doi.org/10.1016/j.eururo.2014.01.009. [27] Vandergrift JL, Niland JC, Theriault RL, et al. Time to adjuvant chemotherapy for breast cancer in National Comprehensive Cancer Network institutions. J Natl Cancer Inst 2013;105(2):104–12. https://doi. org/10.1093/jnci/djs506. [28] Parikh AA, Robinson J, Zaydfudim VM, et al. The effect of health insurance status on the treatment and outcomes of patients with colorectal cancer. J Surg Oncol 2014;110(3):227–32. https://doi.org/ 10.1002/jso.23627.