- Email: [email protected]
Brachytherapy boost for prostate cancer: Trends in care and survival outcomes
Brachytherapy
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Brachytherapy boost for prostate cancer: Trends in care and survival outcomes S.M. Glaser1, M.J. Dohopolski2, G.K. Balasubramani3, R.M. Benoit4, R.P. Smith1, S. Beriwal1,* 1 Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 3 Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 4 Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA
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ABSTRACT
PURPOSE: Androgen suppression combined with elective nodal and dose-escalated radiation therapy recently demonstrated an improved biochemical failureefree survival in men who received external beam radiation therapy (EBRT) plus a brachytherapy boost (BB) compared with doseescalated external beam radiotherapy (DE-EBRT). We sought to analyze the factors predictive for use of EBRT þ BB as compared with DE-EBRT and report resulting survival outcomes on a national level using a hospital-based registry. METHODS AND MATERIALS: We identified 113,719 men from the National Cancer Database from 2004 to 2013 with intermediate- or high-risk prostate cancer who were treated with EBRT þ BB or DE-EBRT. We performed univariate and multivariate analyses of all available factors potentially predictive of receipt of treatment selection. Survival was evaluated in a multivariable model with propensity adjustment. RESULTS: For intermediate-risk patients, utilization of BB decreased from 33.1% (n 5 1742) in 2004 to 12.5% (n 5 766) in 2013 and for high-risk patients, utilization dropped from 27.6% (n 5 879) to 10.8% (n 5 479). Numerous factors predictive for use of BB were identified. Cox proportional hazards analysis was performeddadjusting for age, CharlsoneDeyo comorbidity score, T stage, prostatespecific antigen, Gleason score, and sociodemographic factorsdand demonstrated BB use was associated with a hazard ratio of 0.71 (95% confidence interval, 0.67e0.75; p ! 0.0005) and 0.73 (95% confidence interval, 0.68e0.78; p ! 0.0005) for intermediate- and high-risk patients, respectively. CONCLUSIONS: There has been a concerning decline in the utilization of BB for intermediateand high-risk prostate cancer patients despite an association with improved on overall survival. Numerous factors predictive for use of BB have been identified. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
EBRT; Brachytherapy boost; Prostate cancer; NCDB
Received 5 November 2016; received in revised form 12 December 2016; accepted 22 December 2016. Declaration: Data were presented in abstract format at the American Brachytherapy Society Annual Meeting/World Congress, San Francisco, 2016. The data used in the present study were derived from a deidentified National Cancer Data Base file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used or the conclusions drawn from these data by the investigators. The interpretation and reporting of these data are the sole responsibility of the authors. Financial disclosure/conflicts of interest: Acute or potential conflict of interest does not exist. The authors do not have anything to disclose. * Corresponding author. Department of Radiation Oncology, Magee Womens Hospital of UPMC, 300 Halket Street, Pittsburgh, PA 15213. Tel.: þ1-412-641-4600; fax: þ1-412-641-6601. E-mail address: [email protected] (S. Beriwal).
Introduction Prostate cancer is the most common cancer in males with an estimated 181,000 cases and 26,100 deaths in the United States during 2016 (1). Patients with prostate cancer are typically stratified into three risk groups (low, intermediate, and high) based on clinical T stage, Gleason score, and serum prostate-specific antigen (PSA) levels. Treatment selection, which can broadly include radiotherapy, surgery, and androgen deprivation therapy, is largely influenced by risk group stratification, provider preference, and patient preference (2). Treatment options for intermediateand high-risk groups include surgery or various modalities of radiotherapy, at times combined with androgen
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.12.015
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deprivation therapy. There are limited data, however, from randomized controlled trials comparing radical prostatectomy to radiation therapy for men with intermediate- or high-risk disease (3). For intermediate- to high-risk patients, multiple radiation therapy treatment options exist, including external beam radiation therapy (EBRT), EBRT with brachytherapy boost (BB), brachytherapy as monotherapy, and stereotactic body radiation therapy (the latter two typically reserved for loweintermediate-risk patients). Studies evaluating doseescalated EBRT (DE-EBRT) have demonstrated improved progression-free survival compared with lower dose treatment (3e7). The addition of low dose rate (LDR) or high dose rate (HDR) BB to EBRT has allowed for further dose escalation to the primary tumor site as the dosimetric properties of brachytherapy allow for the ultimate form of highly conformal dose escalation (3, 8e11). Moreover, both LDR and HDR boost have shown excellent toxicity profiles (8, 12). Recently, the androgen suppression combined with elective nodal and dose-escalated radiation therapy trial compared DE-EBRT to EBRT with iodine-125 LDR boost and demonstrated an improvement in 5-, 7-, and 9-year relapse-free survival for the EBRT plus BB arm
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compared with the EBRT arm (13). However, because of limited power and limited number of deaths in relatively short followup, they were unable to comment on overall survival (OS). Given these promising findings, we sought to investigate the trends in utilization of BBdincluding both LDR and HDR, factors predictive for utilization, and associated survival outcomes using a national data set.
Methods and materials Data source Deidentified data exempt from the National Cancer Database (NCDB) oversight were queried from 2004 to 2013 for men with nonoperative, nonmetastatic, and intermediate- or high-risk prostate cancer treated with EBRT þ BB (44e54 Gy of EBRT followed by a BB) or DE-EBRT (75.6e81 Gy of EBRT at 1.8e2.0 Gy per fraction). The NCDB is a nationally recognized clinical oncology database sourced by more than 1500 Commission on Cancereaccredited facilities maintained by the American College of Surgeons and the American Cancer Society.
Fig. 1. Consolidated Standards of Reporting Trials diagram for patient selection. NCCN 5 National Comprehensive Cancer Network.
S.M. Glaser et al. / Brachytherapy
It captures more than 70% of newly diagnosed cancer in the United States (14, 15). Patient selection Within the NCDB, 113,719 men with nonoperative, nonmetastatic, and intermediate- to high-risk prostate cancer treated with DE-EBRT or EBRT þ BB were identified from an initial prostate cancer cohort of 1,208,180. Details of the patient selection process are given in Fig. 1. In accordance with the National Comprehensive Cancer Network, intermediate risk was defined as Gleason score of 7, PSA of 10e20 ng/mL but without any high-risk featuredclinical stage $T3a, PSA O20 ng/mL, Gleason score 8e10dor with clinical stage T2b or T2c (15, 16), and high risk was defined as T3a, Gleason score 8e10, or PSA O20 ng/mL (16). Definition of variables BB includes both LDR and HDR as NCDB does not reliably distinguish between the two. Race was defined as white, black, other, or unknown. Insurance was categorized as private, government (including Medicare, Medicaid, and other government), no insurance, or unknown. Charlsone Deyo comorbidity score was recorded as the summation of comorbid conditions and was scored as 0, 1, $2, with a score of 0 representing no comorbid conditions recorded (16e18). The 2013 U.S. Department of Agriculture RuralUrban Continuum was used to define metropolitan, urban, and rural areas. Counties in metropolitan areas were coded metropolitan, counties with an urban population of $2500 but not in a metropolitan area were termed urban, and counties with an urban population of !2500 were termed rural. Distance from residence to facility was calculated using the center of the patient’s zip code to the treating facilities mailing address. Facility location was defined as northeast: CT, MA, ME, NH, NJ, NY, PA, RI, and VT; south: AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV; midwest: IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI; and west: AZ, AK, CA, CO, ID, HI, MT, NM, NV, OR, UT, WA, and WY.
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standard differences of less than !0.10 (21). By this method, the validity of the propensity model was successfully confirmed (22, 23). Parsimonious survival analysis was conducted both including and excluding propensity score. The multivariate portion of survival analysis was obtained from Cox proportional hazards modeling, whereas the univariate component was calculated from log-rank statistics.
Results Baseline characteristics Baseline patient demographics and characteristics are given in Table 1. The median age was 70 years, with an interquartile range of 64e75 years. Most patients were white (79%), lived in a metropolitan area (82%), had government insurance (67%), and had Stage T1 primary (59%). Of the final cohort (n 5 113,719), 68,886 (60.6%) were classified as intermediate-risk category and 44,833 (39.4%) were classified as high-risk category. Of the intermediate-risk patients, 41.3% received hormonal therapy, and 77% of the high-risk patients received hormonal therapy. BB was administered to 19.2% of those with intermediate-risk disease (80.8% received DE-EBRT), whereas 16.4% in the high-risk category received EBRT with BB (83.6% received DE-EBRT). Trends in BB utilization Both a relative and an absolute decline was observed in BB utilization from 2004 to 2013 in both intermediate-risk and high-risk categories compared with DE-EBRT. The use of BB for patients with intermediate-risk disease experienced a statistically significant ( p ! 0.001) decline from 33.1% (n 5 1742) in 2004 to 12.5% (n 5 766) in 2013 (Fig. 2a). Declining utilization was seen in both Gleason scores of 3 þ 4 and 4 þ 3. A similarly statistically significant ( p ! 0.001) trend was noted in high-risk patients treated with BB as usage declined from 27.6% (n 5 879) in 2004 to 10.8% (n 5 479) in 2013 (Fig. 2b). Factors predictive of preferential BB utilization
Statistical analysis IBM SPSS, version 22.0 (IBM, Armonk, NY) was used to analyze the data. Separately for intermediate- and highrisk patients, univariate analysis was performed on all available factors potentially predictive for receipt of each given treatment modality. Multivariable models of utilization were created from factors significant on univariate analysis, and from the multivariable models, propensity scores indicative of the likelihood of treatment utilization were generated to attempt to account for indication bias (19, 20). The distribution of propensity scores was evaluated using the binned quintiles method and the requirement of
Preferential use of EBRT plus BB was associated with earlier year of diagnosis, younger age, CharlsoneDeyo comorbidity score !2, race other than white or black, private insurance, higher residential area median income, treatment at a nonacademic facility, geographical location (south for both intermediate risk and high risk and west for high risk), higher facility volume, higher T stage (except 2C for high risk), PSA #10, Gleason score (7 for intermediate risk and 7e8 for high risk), and primary Gleason pattern of four for both groups on multivariate analysis. In addition, increased residential area graduation rate predicted preferential use of BB for intermediate-risk patients. For high-risk patients,
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Table 1 Baseline characteristics of all patients with intermediate- or high-risk prostate cancer who received DE-EBRT or EBRT plus BB (n 5 113,719)
Baseline characteristics Sociodemographic factors Year of diagnosis 2004e2007 2008e2010 2011e2013 Age (y) Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity score 0 1 $2 Race White Black Other Unknown Insurance status Private Government None Unknown Residential setting Metropolitan Urban Rural Unknown Median income (residential area) !$38,000 $38,000e$47,999 $48,000e$62,999 $$63,000 Unknown Without high school degree (residential area), % !7 7e12.9 13e20.9 $21 Unknown Distance from facility to residence, miles !5 5e9.9 10e24.9 25þ Unknown Facility type Nonacademic Academic/research Unknown Facility location Northeast South Midwest
Number of intermediate-risk patients (%)
Number of high-risk patients (%)
26,019 (37.8) 22,325 (32.4) 20,542 (29.8)
16,054 (35.8) 14,719 (32.8) 14,060 (31.4)
18,729 15,840 17,444 16,873
11,098 9211 10,645 13,879
(27.2) (23.0) (25.3) (24.5)
(24.8) (20.5) (23.7) (31.0)
59,647 (86.6) 7675 (11.1) 1564 (2.3)
38,705 (86.3) 5068 (11.3) 1060 (2.4)
54,702 11,480 1878 826
(79.4) (16.7) (2.7) (1.2)
35,064 7883 1373 513
(78.2) (17.6) (3.1) (1.1)
21,019 45,713 1022 1132
(30.5) (66.4) (1.5) (1.6)
12,390 30,919 809 715
(27.6) (69.0) (1.8) (1.6)
56,542 9361 1153 1830
(82.1) (13.6) (1.7) (2.7)
36,220 6519 870 1224
(80.8) (14.5) (1.9) (2.7)
12,190 15,581 18,195 22,234 686
(17.7) (22.6) (26.4) (32.3) (1.0)
8407 10,470 11,598 13,882 476
(18.8) (23.4) (25.9) (31.0) (1.1)
16,832 22,722 17,281 11,402 649
(24.4) (33.0) (25.1) (16.6) (0.9)
10,625 14,465 11,544 7753 446
(23.7) (32.3) (25.7) (17.3) (1.0)
22,274 16,486 17,772 11,748 606
(32.3) (23.9) (25.8) (17.1) (0.9)
14,593 10,675 11,495 7647 423
(32.5) (23.8) (25.6) (17.1) (0.9)
47,658 (69.2) 21,225 (30.8) 3 (0.0)
31,185 (69.6) 13,645 (30.4) 3 (0.0)
17,957 (26.1) 22,121 (32.1) 16,937 (24.6)
11,197 (25.0) 15,127 (33.7) 11,313 (25.2) (Continued)
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Table 1 (continued )
Baseline characteristics West Unknown Facility volume, cases !100 101e200 201e300 O300 Pathologic factors T stage 1 2A 2B 2C 3 PSA #10 10.1e20 20.1e40 O40 Total Gleason score #6 7 8 9 10 Primary Gleason pattern #3 4 5 Unknown Therapeutic factors Radiotherapy EBRT þ BB DE-EBRT Hormonal therapy No Yes Unknown
Number of intermediate-risk patients (%) 11,868 (17.2) 3 (0.0)
Number of high-risk patients (%) 7193 (16.0) 3 (0.0)
17,258 18,324 13,319 19,985
(25.1) (26.6) (19.3) (29.0)
12,213 12,246 8613 11,761
(27.2) (27.3) (19.2) (26.2)
45,085 9341 6337 8123 d
(65.4) (13.6) (9.2) (11.8)
22,642 4917 4336 6446 6492
(50.5) (11.0) (9.7) (14.4) (14.5)
50,018 (72.6) 18,868 (27.4) d d
19,087 8018 9359 8369
(42.6) (17.9) (20.9) (18.7)
10,711 (15.5) 58,175 (84.5) d d d
4137 9284 19,000 11,347 1065
(9.2) (20.7) (42.4) (25.3) (2.4)
48,441 18,688 6 1751
10,671 28,785 3998 1379
(23.8) (64.2) (8.9) (3.1)
(70.3) (27.1) (0.0) (2.5)
13,218 (19.2) 55,668 (80.8)
7370 (16.4) 37,463 (83.6)
38,463 (55.8) 28,448 (41.3) 1975 (2.9)
9547 (21.3) 34,529 (77.0) 757 (1.7)
DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost; PSA 5 prostate-specific antigen.
additional factors that predicted for BB use were metropolitan residential setting, increased distance from facility to residence, and no receipt of hormonal therapy. These results are depicted in Table 2. Survival outcomes Median followup was 54 months with 33e78 months as the interquartile range. Unadjusted 5-year OS for intermediate-risk patients receiving DE-EBRT vs. EBRT þ BB was 87.3% (95% confidence interval [95% CI] 5 86.9e87.7) vs. 91.6% (95% CI 5 91.0e92.2) and 58.0% (95% CI 5 56.4e59.6) vs. 71.6% (95% CI 5 69.4e73.8) for unadjusted 10-year OS ( p ! 0.0005; Fig. 3a). In a subset analysis of intermediate-risk patients receiving the highest radiotherapy doses (79.2e81 Gy) vs. EBRT þ BB, unadjusted 5-year OS was 89.5% (95%
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intermediate- and high-risk patients are given in Table 3. These findings persisted with incorporation of propensity scores for treatment selection into the Cox model with HRs of 0.73 (95% CI 5 0.68e0.77; p ! 0.0005) and 0.74 (95% CI 5 0.69e0.79; p ! 0.0005) for intermediateand high-risk patients, respectively.
Discussion
Fig. 2. Utilization of brachytherapy boost from 2004 to 2013 for men with (a) intermediate-risk and (b) high-risk prostate cancer. DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost.
CI 5 88.9e90.1) vs. 91.6% (95% CI 5 91.0e92.2) and unadjusted 10-year OS was 62.8% (95% CI 5 58.8e66.8) vs. 71.6% (95% CI 5 69.4e73.8) ( p ! 0.0005). Unadjusted 5year OS for high-risk patients receiving DE-EBRT vs. EBRT plus BB was 82.0% (95% CI 5 81.4e82.6) vs. 88.7% (95% CI 5 87.9e89.5) and 50.4% (95% CI 5 48.6e52.2) vs. 63.0% (60.0e66.0) for unadjusted 10-year OS ( p ! 0.0005; Fig. 3b). In a subset analysis of highrisk patients receiving the highest radiotherapy doses (79.2e81 Gy) vs. EBRT þ BB, unadjusted 5-year OS was 83.5% (95% CI 5 82.5e84.5) vs. 88.7% (95% CI 5 87.9e89.5) and unadjusted 10-year OS was 54.9% (95% CI 5 51.1e58.7) vs. 63.0% (95% CI 5 60.0e66.0) ( p ! 0.0005). For intermediate-risk patients, BB use was associated with a hazard ratio (HR) of 0.71 (95% CI 5 0.67e0.75, p ! 0.0005) on multivariate Cox proportional hazards analysis of factors predictive for survival. Similarly, for highrisk patients, the HR was 0.73 (95% CI 5 0.68e0.78; p ! 0.0005) in favor of EBRT þ BB. In subset analysis of only patients treated with the highest radiotherapy doses (79.2e81 Gy), the benefit was smaller but still present with an HR of 0.78 (95% CI 5 0.72e0.85; p ! 0.0005) and 0.78 (95% CI 5 0.71e0.85; p ! 0.0005) for intermediate risk and high risk, respectively. The complete models for
In this analysis, we have cohesively demonstrated a decline in the utilization of EBRT with BB in patients with intermediate- or high-risk prostate cancer despite our results indicating a small absolute survival advantage in both groups when compared with patients treated with DEEBRT. Intermediate-risk patients treated with EBRT plus BB experienced an absolute difference in 5- and 10-year OS of 4.3% and 13.6% compared with DE-EBRT. Highrisk patients saw a 6.7% absolute improvement in OS at 5 years and 12.6% at 10 years. Moreover, as significant imbalances existed between groups, adjusted multivariate analysis continued to demonstrate an associated OS benefit with use of BB in both groups. Our analysis also confirmed positive prognostic factors for OS, such as younger age, lower PSA, lower Gleason score, and others, which have been discussed extensively in the literature (24, 25). Consistent with other studies of dose escalation, our data suggest improved outcomes with the increased radiation doses permissible through BB (26e29). The importance of dose escalation has been described in the setting of brachytherapy monotherapy as well with increased doses correlated with improved outcomes (30). Furthermore, both retrospective and prospective data suggest that BB may be superior to DE-EBRT (13, 26, 31e33). Although since prior studies have been relatively small or had short followup, it is not surprising that differences in OS with the use of EBRT with BB have not been significant or reported until the recent large retrospective series published by Amini et al. (34, 35). They were able to observe an increase in OS in intermediate- and high-risk prostate cancer patients (n 5 20,279) treated from 2004 to 2006 with EBRT plus BB compared with those treated with DE-EBRT (75.6e 81 Gy). Yet, on subset analysis, they conceded that no significant difference was observed in OS when higher dose DE-EBRT (79.2e81 Gy) was used. In contrast, our analysis demonstrated an OS benefit with the use of BB even when compared with EBRT doses ranging from 79.2 to 81 Gy. We were able to show this persisting survival difference likely because of a broader inclusion criteria resulting in a higher number of patients and better powered analysis. We have also identified several factors associated with preferential use of EBRT with BB: earlier year of diagnosis, younger age, CharlsoneDeyo comorbidity score !2, treatment at a nonacademic facility, and others, all of which can be reviewed in Table 2. The two strongest predictors in our analysis that pointed toward decrease in use of BB were
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Table 2 Comparative utilization of DE-EBRT vs. EBRT plus BB for intermediate-risk and high-risk prostate cancer patients Intermediate risk Sociodemographic factors Year of diagnosisa 2004e2007 2008e2010 2011e2013 Age,a y Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity scorea 0 1 $2 Racea White Black Other Insurance statusa Private Government None Residential setting Metropolitan Urban Rural Median income (residential area)a !$38,000 $38,000e47,999 $48,000e62,999 $$63,000 Without high school degree (residential area),a % !7 7e12.9 13e20.9 $21 Distance from facility to residence, miles !5 5e9.9 10e24.9 25þ Facility typea Nonacademic Academic/research Facility locationa Northeast South Midwest West Facility volume,a cases !100 101e200 201e300 O300 Pathologic factors T stagea 1 2A 2B 2C
DE-EBRT (n 5 55,668)
EBRT þ BB (n 5 13,218)
Odds Ratio (95% CI)
p !0.0005
19,132 (73.5%) 18,676 (83.7%) 17,860 (86.9%)
6887 (26.5) 3649 (16.3) 2682 (13.1)
1 (Reference) 0.54 (0.52e0.57) 0.42 (0.40e0.44)
13,790 12,519 14,434 14,925
4939 3321 3010 1948
1 (Reference) 0.74 (0.70e0.78) 0.58 (0.55e0.61) 0.36 (0.34e0.39)
!0.0005 (73.6%) (79.0%) (82.7%) (88.5%)
(26.4%) (21.0%) (17.3%) (11.5%)
!0.0005 48,187 (80.8%) 6151 (80.1%) 1330 (85.0%)
11,460 (19.2%) 1524 (19.9%) 234 (15.0%)
1 (Reference) 1.04 (0.98e1.11) 0.74 (0.64e0.85)
44,314 (81.0%) 9230 (80.4%) 1472 (78.4%)
10,388 (19.0%) 2250 (19.6%) 406 (21.6%)
1 (Reference) 1.04 (0.99e1.09) 1.18 (1.05e1.32)
15,718 (74.8%) 38,071 (83.3%) 919 (88.9%)
5301 (25.2%) 7642 (16.7%) 103 (10.1%)
1 (Reference) 0.60 (0.57e0.62) 0.33 (0.27e0.41)
45,553 (96.7%) 7715 (95.7%) 939 (96.9%)
10,989 (19.4%) 1646 (17.6%) 214 (18.6%)
1 (Reference) 0.88 (0.84e0.94) 0.94 (0.81e1.10)
0.008
!0.0005
!0.0005
!0.0005 9967 12,643 15,076 17,474
(81.8%) (81.1%) (82.9%) (78.6%)
2233 2938 3119 4760
(18.2%) (18.9%) (17.1%) (21.4%)
1 (Reference) 1.04 (0.98e1.11) 0.93 (0.87e0.98) 1.22 (1.15e1.29) !0.0005
13,432 18,424 14,081 9254
(79.8%) (81.1%) (81.5%) (81.2%)
3400 4298 3200 2148
(20.2%) (18.9%) (18.5%) (18.8%)
1 (Reference) 0.92 (0.86e0.97) 0.90 (0.85e0.95) 0.92 (0.88e0.97) !0.0005
18,235 13,214 14,256 9520
(81.9%) (80.2%) (80.2%) (81.0%)
4039 3272 3516 2228
(18.1%) (19.8%) (19.8%) (19.0%)
1 (Reference) 1.12 (1.06e1.18) 1.11 (1.06e1.17) 1.06 (1.00e1.12)
37,946 (79.6%) 17,720 (83.5%)
9712 (20.4%) 3505 (16.5%)
1 (Reference) 0.77 (0.74e0.81)
14,678 16,917 14,283 9788
(81.7%) (76.5%) (84.3%) (82.5%)
3279 5204 2654 2080
(18.3%) (23.5%) (15.7%) (17.5%)
1 (Reference) 1.38 (1.31e1.45) 0.83 (0.79e0.88) 0.95 (0.90e1.01)
14,264 14,894 10,528 15,982
(82.7%) (81.3%) (79.0%) (80.0%)
2994 3430 2791 4003
(17.3%) (18.7%) (21.0%) (20.0%)
1 (Reference) 1.10 (1.04e1.16) 1.26 (1.19e1.34) 1.19 (1.13e1.26)
36,793 7433 4942 6500
(81.6%) (79.6%) (78.0%) (80.0%)
8292 1908 1395 1623
(18.4%) (20.4%) (22.0%) (20.0%)
1 (Reference) 1.14 (1.08e1.20) 1.25 (1.17e1.34) 1.11 (1.04e1.18)
!0.0005 !0.0005
!0.0005
!0.0005
(Continued)
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Table 2 (continued ) Intermediate risk
DE-EBRT (n 5 55,668)
High risk
DE-EBRT (n 5 37,463)
Sociodemographic factors Year of diagnosisa 2004e2007 2008e2010 2011e2013 Age,a y !65 65e69 70e74 $75 CharlsoneDeyo comorbidity scorea 0 1 $2 Racea White Black Other Insurance statusa Private Government None Residential settinga Metropolitan Urban Rural Median income (residential area)a !$38,000 $38,000e$47,999 $48,000e$62,999 $$63,000 Without high school degree (residential area), % !7% 7e12.9% 13e20.9% $21% Distance from facility to residence,a miles !5 5e9.9 10e24.9 25þ Facility typea Nonacademic Academic/research
EBRT þ BB (n 5 13,218)
Odds Ratio (95% CI)
p !0.0005
PSAa #10 10.1e20 Total Gleason scorea #6 7 Primary Gleason patterna #3 4 5 Therapeutic factors Hormonal therapy No Yes
39,878 (79.7%) 15,790 (83.7%)
10,140 (20.3%) 3078 (16.3%)
1 (Reference) 0.77 (0.73e0.80)
9122 (85.2%) 46,546 (80.0%)
1589 (14.8%) 11,629 (20.0%)
1 (Reference) 1.43 (1.35e1.52)
39,477 (81.5%) 14,800 (79.2%) 6 (100%)
8964 (18.5%) 3888 (20.8%) 0 (0%)
1 (Reference) 1.16 (1.11e1.21) N/A
31,020 (80.6%) 23,090 (81.2%)
7443 (19.4%) 5358 (18.8%)
1 (Reference) 0.97 (0.93e1.01)
!0.0005 !0.0005
0.093
EBRT þ BB (n 5 7370)
Odds Ratio (95% CI)
p !0.0005
12,403 (77.3%) 12,619 (85.7%) 12,441 (88.5%)
3651 (22.7%) 2100 (14.3%) 1619 (11.5%)
1 (Reference) 0.57 (0.53e0.60) 0.44 (0.41e0.47)
8616 7476 8922 12,449
2482 1735 1723 1430
1 (Reference) 0.81 (0.75e0.86) 0.67 (0.63e0.72) 0.40 (0.37e0.43)
!0.0005 (77.6%) (81.2%) (83.8%) (89.7%)
(22.4%) (18.8%) (16.2%) (10.3%)
0.001 32,312 (83.5%) 4222 (83.3%) 929 (87.6%)
6393 (16.5%) 846 (16.7%) 131 (12.4%)
1 (Reference) 1.01 (0.94e1.10) 0.71 (0.59e0.86)
29,406 (83.9%) 6585 (83.5%) 1059 (77.1%)
5658 (16.1%) 1298 (16.5%) 314 (22.9%)
1 (Reference) 1.02 (0.96e1.09) 1.54 (1.35e1.75)
9640 (77.8%) 26,443 (85.5%) 745 (92.1%)
2750 (22.2%) 4476 (14.5%) 64 (7.9%)
1 (Reference) 0.59 (0.56e0.63) 0.30 (0.23e0.39)
30,097 (83.1%) 5597 (85.9%) 735 (84.5%)
6123 (16.9%) 922 (14.1%) 135 (15.5%)
1 (Reference) 0.81 (0.75e0.87) 0.90 (0.75e1.09)
7159 8914 9835 11,178
1248 1556 1763 2704
1 (Reference) 1.00 (0.92e1.09) 1.03 (0.95e1.11) 1.39 (1.29e1.49)
!0.0005
!0.0005
!0.0005
!0.0005 (85.2%) (85.1%) (84.8%) (80.5%)
(14.8%) (14.9%) (15.2%) (19.5%)
!0.0005 8646 12,165 9768 6535
(81.4%) (84.1%) (84.6%) (84.3%)
1979 2300 1776 1218
(18.6%) (15.9%) (15.4%) (15.7%)
1 (Reference) 0.83 (0.77e0.88) 0.79 (0.74e0.85) 0.81 (0.75e0.88) 0.001
12,288 8943 9623 6277
(84.2%) (83.8%) (83.7%) (82.1%)
2305 1732 1872 1370
(15.8%) (16.2%) (16.3%) (17.9%)
1 (Reference) 1.03 (0.96e1.11) 1.04 (0.97e1.11) 1.16 (1.08e1.25)
5521 (17.7%) 1848 (13.5%)
1 (Reference) 0.73 (0.69e0.77)
!0.0005 25,664 (82.3%) 11,797 (86.5%)
(Continued)
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Table 2 (continued ) Intermediate risk Facility locationa Northeast South Midwest West Facility volume,a cases !100 101e200 201e300 O300 Pathologic factors T stagea 1 2A 2B 2C 3 PSAa #10 10.1e20 20.1e40 O40 Total Gleason scorea #6 7 8 9 10 Primary Gleason patterna #3 4 5 Therapeutic factors Hormonal therapya No Yes
DE-EBRT (n 5 55,668)
EBRT þ BB (n 5 13,218)
Odds Ratio (95% CI)
p !0.0005
9712 12,163 9756 5830
(86.7%) (80.4%) (86.2%) (81.1%)
1485 2964 1557 1363
(13.3%) (19.6%) (13.8%) (18.9%)
1 (Reference) 1.59 (1.49e1.71) 1.04 (0.97e1.13) 1.53 (1.41e1.66)
10,480 10,403 7071 9509
(85.8%) (85.0%) (82.1%) (80.9%)
1733 1843 1542 2252
(14.2%) (15.0%) (17.9%) (19.1%)
1 (Reference) 1.07 (1.00e1.15) 1.32 (1.22e1.42) 1.43 (1.34e1.53)
18,984 4034 3551 5509 5385
(83.8%) (82.0%) (81.9%) (85.5%) (82.9%)
3658 883 785 937 1107
(16.2%) (18.0%) (18.1%) (14.5%) (17.1%)
1 (Reference) 1.14 (1.05e1.23) 1.15 (1.05e1.25) 0.88 (0.82e0.95) 1.07 (0.99e1.15)
15,334 6830 7965 7334
(80.3%) (85.2%) (85.1%) (87.6%)
3753 1188 1394 1035
(19.7%) (14.8%) (14.9%) (12.4%)
1 (Reference) 0.71 (0.66e0.76) 0.72 (0.67e0.76) 0.58 (0.54e0.62)
3542 7711 15,634 9652 924
(85.6%) (83.1%) (82.3%) (85.1%) (86.8%)
595 1573 3366 1695 141
(14.4%) (16.9%) (17.7%) (14.9%) (13.2%)
1 (Reference) 1.21 (1.10e1.35) 1.28 (1.17e1.41) 1.05 (0.94e1.16) 0.91 (0.75e1.11)
8967 (84.0%) 23,923 (83.1%) 3421 (85.6%)
1704 (16.0%) 4862 (16.9%) 577 (14.4%)
1 (Reference) 1.07 (1.01e1.14) 0.89 (0.80e0.98)
7716 (80.8%) 29,131 (84.4%)
1831 (19.2%) 5398 (15.6%)
1 (Reference) 0.78 (0.74e0.83)
!0.0005
!0.0005
!0.0005
!0.0005
!0.0005
!0.0005
DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost; 95% CI 5 95% confidence interval; PSA 5 prostate-specific antigen; N/A 5 not available. a Indicates variable was significant on multivariable analysis and used to generate propensity score.
lack of health insurance and increasing age in both risk groups. We imagine that those without health insurance were less inclined to receive the more cost and resource-
intensive multimodality treatment, whereas older patients were less likely to be candidates for brachytherapy because of the requirements of anesthesia as they were more likely
Fig. 3. Unadjusted KaplaneMeier survival analysis for (a) intermediate-risk and (b) high-risk patients. NCCN 5 National Comprehensive Cancer Network; DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost.
S.M. Glaser et al. / Brachytherapy Table 3 Unadjusted multivariable Cox proportional hazard models for overall survival for intermediate-risk and high-risk prostate cancer patients who received DE-EBRT or EBRT plus BB Variable Significant factors (intermediate risk) Year of diagnosis 2004e2007 2008e2010 2011e2013 Age, y Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity score 0 1 $2 Race White Black Other Insurance status Private Government None Median income (residential area) !$38,000 $38,000e47,999 $48,000e62,999 $$63,000 Without high school degree (residential area), % !7 7e12.9 13e20.9 $21 Distance from facility to residence, miles !5 5e9.9 10e24.9 25þ Facility type Nonacademic Academic/research Facility location Northeast South Midwest West Facility volume, cases !100 101e200 201e300 O300
Hazard of death (95% CI)
p
0.052 Reference 1.05 (1.00e1.12) 1.11 (1.00e1.23) !0.0005 Reference 1.11 (1.02e1.21) 1.42 (1.31e1.54) 1.99 (1.84e2.16) !0.0005 Reference 1.47 (1.37e1.57) 2.36 (2.10e2.65) 0.008 Reference 0.99 (0.92e1.06) 0.77 (0.65e0.91) !0.0005 Reference 1.36 (1.28e1.46) 1.01 (0.79e1.28) !0.0005 Reference 0.97 (0.91e1.05) 0.89 (0.82e0.96) 0.83 (0.76e0.91) 0.004
Reference 1.06 (0.99e1.13) 1.08 (1.00e1.17) 1.19 (1.08e1.31) !0.0005
Reference 0.96 (0.90e1.01) 0.93 (0.88e0.99) 0.86 (0.80e0.92) 0.001 Reference 0.92 (0.87e0.97) !0.0005 Reference 1.08 (1.01e1.15) 1.03 (0.96e1.10) 0.80 (0.74e0.87) !0.0005 Reference 0.93 (0.88e0.99) 0.99 (0.93e1.06) 0.87 (0.82e0.93) (Continued)
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Table 3 (continued ) Variable T stage 1 2A 2B 2C PSA #10 10.1e20 Total Gleason score #6 7 Primary Gleason pattern #3 4 5 Radiotherapy DE-EBRT EBRT þ BB Hormonal therapy No Yes 79.2e81 Gy DE-EBRT EBRT þ BB Significant factors (high risk) Year of diagnosis 2004e2007 2008e2010 2011e2013 Age, y Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity score 0 1 $2 Race White Black Other Insurance status Private Government None Median income (residential area) !$38,000 $38,000e47,999 $48,000e62,999 $$63,000 Facility type Nonacademic Academic/research Facility location Northeast South Midwest West
Hazard of death (95% CI)
p !0.0005
Reference 1.03 (0.96e1.10) 1.16 (1.07e1.25) 1.20 (1.13e1.28) !0.0005 Reference 1.28 (1.22e1.35) !0.0005 Reference 1.18 (1.10e1.26) 0.009 Reference 1.08 (1.03e1.14) 0.59 (0.08e4.19) !0.0005 Reference 0.71 (0.67e0.75) 0.006 Reference 0.94 (0.89e0.98) !0.0005 Reference 0.78 (0.72e0.85) 0.011 Reference 1.04 (0.98e1.10) 1.17 (1.05e1.29) !0.0005 Reference 1.11 (1.01e1.21) 1.29 (1.18e1.41) 2.01 (1.85e2.19) !0.0005 Reference 1.40 (1.30e1.51) 2.30 (2.03e2.61) 0.035 Reference 0.96 (0.89e1.03) 0.82 (0.69e0.97) !0.0005 Reference 1.18 (1.10e1.26) 0.81 (0.63e1.05) !0.0005 Reference 0.97 (0.90e1.04) 0.87 (0.81e0.94) 0.80 (0.74e0.87) 0.002 Reference 0.92 (0.87e0.97) !0.0005 Reference 1.11 (1.04e1.19) 1.13 (1.05e1.21) 0.89 (0.82e0.97) (Continued)
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Table 3 (continued ) Variable Facility volume, cases !100 101e200 201e300 O300 T stage 1 2A 2B 2C 3 PSA #10 10.1e20 20.1e40 O40 Total Gleason score #6 7 8 9 10 Primary Gleason pattern #3 4 5 Radiotherapy DE-EBRT EBRT þ BB 79.2e81 Gy DE-EBRT EBRT þ BB
Hazard of death (95% CI)
p 0.001
Reference 0.93 (0.87e0.99) 0.99 (0.93e1.07) 0.88 (0.82e0.94) !0.0005 Reference 0.94 (0.86e1.02) 1.08 (0.99e1.17) 1.17 (1.09e1.25) 1.19 (1.10e1.28) !0.0005 Reference 1.21 (1.13e1.29) 1.36 (1.26e1.46) 1.29 (1.20e1.40) !0.0005 Reference 1.18 (1.06e1.31) 1.52 (1.33e1.73) 1.84 (1.61e2.12) 2.31 (1.89e2.82) 0.003 Reference 1.01 (0.92e1.10) 1.18 (1.04e1.34) !0.0005 Reference 0.73 (0.68e0.78) !0.0005 Reference 0.78 (0.71e0.85)
DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost; 95% CI 5 95% confidence interval; PSA 5 prostate-specific antigen.
to have more comorbidities. This was further supported as higher CharlsoneDeyo comorbidity scores were associated with the use of DE-EBRT vs. EBRT with BB. Some of these parameters have already been reported in the literature. Martin et al. (36) analyzed utilization of prostate brachytherapy as a whole and noted that patients more likely to receive brachytherapy were those with low CharlsoneDeyo scores, those with Medicare, earlier year of diagnosis, older age, and those from the southeast; those less likely to receive brachytherapy were Hispanics, those from the west, and those receiving care in academic institutions. With some slight differences, these factors are largely concordant with the factors we have identified in a cohort of boost-only patients. The differences seen between our analysis and that of Martin et al. (36) are likely explained by discrepancies between our cohorts as theirs was composed of patients predominantly treated with brachytherapy as a monotherapy, whereas those treated with BB were a small minority. Also confirmed by our analysis was the findings of Orio et al. (37, 38) who commented on the finding that academic centers were less likely to use BB than their nonacademic counterparts (adjusted odds
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ratio, 0.68; 95% CI 5 0.66e0.70; p ! 0.0001) and thus raised the concern about the potential lack of proper training within academic centers. Despite the apparent advantage of EBRT with BB over EBRT, there has been a statistically significant downward trend in the use of BB in patients in both the intermediateand high-risk groups. From 2004 to 2013, we calculated that utilization of BB decreased from 33.1% to 12.5% and 27.6e10.8% for intermediate- and high-risk patients, respectively (as compared with DE-EBRT). In addition, several articles have commented on this decline within the past decade or so (36, 38, 39). Martin et al. (36) specifically observed intermediate-risk patients experiencing the greatest decrease in BB followed by high- and then lowrisk patients. In fact, decreasing utilization of brachytherapy as a treatment modality has been documented in the literature in other cancers as well such as cervical cancer (40). An explanation for these observed trends in the treatment of prostate cancer is conceivably multifactorial including the more invasive nature of EBRT þ BB than DE-EBRT, changes in referral patterns where younger healthier patients are treated with radical prostatectomy, decreased training in brachytherapy, and pressures from health care reform and reimbursement trends. Limitations of our study include the potential for ascertainment bias, incomplete data, and coding error. Moreover, we were unable to collect information on disease recurrence or subsequent treatment as these data are not captured within the NCDB, and thus, we are unable to report on biological progression-free survival, disease-free survival, or salvage rates. Similarly, brachytherapy dose and isotope data were not included in the NCDB and thus are not reported in this study. There are no toxicity data in this analysis, although EBRT with BB has been shown to have limited Grade 3 or greater toxicities and acceptable levels of adverse events (8, 31, 41e45). Although we were not able to comment on endpoints that have been extensively discussed in prior literature, we were able to observe a less commonly seen trend in OS associated with use of BB because of our vast cohort.
Conclusion There has been a concerning decline in the utilization of EBRT plus BB for intermediate- and high-risk prostate cancer patients despite the associated survival advantage compared with DE-EBRT. In addition, this article has expanded on multiple factors associated with the utilization of BB. References [1] Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016;66:271e289. [2] Berge V, Thompson T, Blackman D. Use of additional treatment for prostate cancer after radical prostatectomy, radiation therapy,
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[19] Rosenbauum P, Armitage P, Colton T. Propensity score. In: Encyclopedia of biostatistics. 2nd ed. Chichester, England: Wiley; 2005. p. 4267e4272. [20] D’Agostino RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17:2265e2281. [21] Austin PC. Goodness-of-fit diagnostics for the propensity score model when estimating treatment effects using covariate adjustment with the propensity score. Pharmacoepidemiol Drug Saf 2008;17:1202e1217. [22] Watkins S, Jonsson-Funk M, Brookhart MA, et al. An empirical comparison of tree-based methods for propensity score estimation. Health Serv Res 2013;48:1798e1817. [23] Normand ST, Landrum MB, Guadagnoli E, et al. Validating recommendations for coronary angiography following acute myocardial infarction in the elderly: A matched analysis using propensity scores. J Clin Epidemiol 2001;54:387e398. [24] Ricco A, Manahan G, Lanciano R, et al. The comparison of stereotactic body radiation therapy and intensity-modulated radiation therapy for prostate cancer by NCCN risk groups. Front Oncol 2016;6:184. [25] D’Amico AV. Risk-based management of prostate cancer. N Engl J Med 2011;365:169e171. [26] Stone NN, Potters L, Davis BJ, et al. Multicenter analysis of effect of high biologic effective dose on biochemical failure and survival outcomes in patients with Gleason score 7-10 prostate cancer treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2009;73:341e346. [27] Stock RG, Cahlon O, Cesaretti JA, et al. Combined modality treatment in the management of high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2004;59:1352e1359. [28] Zelefsky MJ, Fuks Z, Hunt M, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001;166:876e881. [29] Stone NN, Stock RG, White I, et al. Patterns of local failure following prostate brachytherapy. J Urol 2007;177:1759e1763. discussion 1764. [30] Stone NN, Stock RG, Unger P. Intermediate term biochemical-free progression and local control following 125iodine brachytherapy for prostate cancer. J Urol 2005;173:803e807. [31] Borghede G, Hedelin H, Holm€ang S, et al. Combined treatment with temporary short-term high dose rate iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiother Oncol 1997;44:237e244. [32] Liss AL, Abu-Isa EI, Jawad MS, et al. Combination therapy improves prostate cancer survival for patients with potentially lethal prostate cancer: The impact of Gleason pattern 5. Brachytherapy 2015;14:502e510. [33] Kishan AU, Shaikh T, Wang PC, et al. Clinical outcomes for patients with Gleason score 9e10 prostate adenocarcinoma treated with radiotherapy or radical prostatectomy: A multi-institutional comparative analysis. Eur Urol 2016. http://dx.doi.org/10.1016/j.eururo. 2016.06.046 [Epub ahead of print]. [34] Amini A, Jones BL, Jackson MW, et al. Survival outcomes of combined external beam radiotherapy and brachytherapy vs. brachytherapy alone for intermediate-risk prostate cancer patients using the National Cancer Data Base. Brachytherapy 2016;15:136e146. [35] Amini A, Jones B, Jackson MW, et al. Survival outcomes of doseescalated external beam radiotherapy versus combined brachytherapy for intermediate and high risk prostate cancer using the National Cancer Data Base. J Urol 2016;195:1453e1458. [36] Martin JM, Handorf EA, Kutikov A, et al. The rise and fall of prostate brachytherapy: Use of brachytherapy for the treatment of localized prostate cancer in the National Cancer Data Base. Cancer 2014; 120:2114e2121. [37] Orio PF, Nguyen PL, Buzurovic I, et al. Prostate brachytherapy case volumes by academic and nonacademic practices: Implications for future residency training. Int J Radiat Oncol 2016;96:624e628.
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[38] Orio PF, Nguyen PL, Buzurovic I, et al. The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness. Brachytherapy 2016;15:701e706. [39] Mahmood U, Pugh T, Frank S, et al. Declining use of brachytherapy for the treatment of prostate cancer. Brachytherapy 2014;13:157e162. [40] Gill BS, Lin JF, Krivak TC, et al. National Cancer Data Base analysis of radiation therapy consolidation modality for cervical cancer: The impact of new technological advancements. Int J Radiat Oncol Biol Phys 2014;90:1083e1090. [41] Martinez AA, Kestin LL, Stromberg JS, et al. Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: The William Beaumont phase II dose-escalating trial. Int J Radiat Oncol Biol Phys 2000;47:343e352. [42] Hoskin PJ, Motohashi K, Bownes P, et al. High dose rate brachytherapy in combination with external beam radiotherapy in the radical
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treatment of prostate cancer: Initial results of a randomised phase three trial. Radiother Oncol 2007;84:114e120. [43] Kovacs G, Galalae R. Fractionated perineal high-dose-rate temporary brachytherapy combined with external beam radiation in the treatment of localized prostate cancer: Is lymph node sampling necessary? Cancer Radiother 2003;7:100e106. [44] Martin T, R€oddiger S, Kurek R, et al. 3D conformal HDR brachytherapy and external beam irradiation combined with temporary androgen deprivation in the treatment of localized prostate cancer. Radiother Oncol 2004;71:35e41. [45] Hiratsuka J, Jo Y, Yoshida K, et al. Clinical results of combined treatment conformal high-dose-rate iridium-192 brachytherapy and external beam radiotherapy using staging lymphadenectomy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2004;59: 684e690.
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Brachytherapy boost for prostate cancer: Trends in care and survival outcomes S.M. Glaser1, M.J. Dohopolski2, G.K. Balasubramani3, R.M. Benoit4, R.P. Smith1, S. Beriwal1,* 1 Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 3 Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 4 Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA
2
ABSTRACT
PURPOSE: Androgen suppression combined with elective nodal and dose-escalated radiation therapy recently demonstrated an improved biochemical failureefree survival in men who received external beam radiation therapy (EBRT) plus a brachytherapy boost (BB) compared with doseescalated external beam radiotherapy (DE-EBRT). We sought to analyze the factors predictive for use of EBRT þ BB as compared with DE-EBRT and report resulting survival outcomes on a national level using a hospital-based registry. METHODS AND MATERIALS: We identified 113,719 men from the National Cancer Database from 2004 to 2013 with intermediate- or high-risk prostate cancer who were treated with EBRT þ BB or DE-EBRT. We performed univariate and multivariate analyses of all available factors potentially predictive of receipt of treatment selection. Survival was evaluated in a multivariable model with propensity adjustment. RESULTS: For intermediate-risk patients, utilization of BB decreased from 33.1% (n 5 1742) in 2004 to 12.5% (n 5 766) in 2013 and for high-risk patients, utilization dropped from 27.6% (n 5 879) to 10.8% (n 5 479). Numerous factors predictive for use of BB were identified. Cox proportional hazards analysis was performeddadjusting for age, CharlsoneDeyo comorbidity score, T stage, prostatespecific antigen, Gleason score, and sociodemographic factorsdand demonstrated BB use was associated with a hazard ratio of 0.71 (95% confidence interval, 0.67e0.75; p ! 0.0005) and 0.73 (95% confidence interval, 0.68e0.78; p ! 0.0005) for intermediate- and high-risk patients, respectively. CONCLUSIONS: There has been a concerning decline in the utilization of BB for intermediateand high-risk prostate cancer patients despite an association with improved on overall survival. Numerous factors predictive for use of BB have been identified. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
EBRT; Brachytherapy boost; Prostate cancer; NCDB
Received 5 November 2016; received in revised form 12 December 2016; accepted 22 December 2016. Declaration: Data were presented in abstract format at the American Brachytherapy Society Annual Meeting/World Congress, San Francisco, 2016. The data used in the present study were derived from a deidentified National Cancer Data Base file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used or the conclusions drawn from these data by the investigators. The interpretation and reporting of these data are the sole responsibility of the authors. Financial disclosure/conflicts of interest: Acute or potential conflict of interest does not exist. The authors do not have anything to disclose. * Corresponding author. Department of Radiation Oncology, Magee Womens Hospital of UPMC, 300 Halket Street, Pittsburgh, PA 15213. Tel.: þ1-412-641-4600; fax: þ1-412-641-6601. E-mail address: [email protected] (S. Beriwal).
Introduction Prostate cancer is the most common cancer in males with an estimated 181,000 cases and 26,100 deaths in the United States during 2016 (1). Patients with prostate cancer are typically stratified into three risk groups (low, intermediate, and high) based on clinical T stage, Gleason score, and serum prostate-specific antigen (PSA) levels. Treatment selection, which can broadly include radiotherapy, surgery, and androgen deprivation therapy, is largely influenced by risk group stratification, provider preference, and patient preference (2). Treatment options for intermediateand high-risk groups include surgery or various modalities of radiotherapy, at times combined with androgen
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2016.12.015
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deprivation therapy. There are limited data, however, from randomized controlled trials comparing radical prostatectomy to radiation therapy for men with intermediate- or high-risk disease (3). For intermediate- to high-risk patients, multiple radiation therapy treatment options exist, including external beam radiation therapy (EBRT), EBRT with brachytherapy boost (BB), brachytherapy as monotherapy, and stereotactic body radiation therapy (the latter two typically reserved for loweintermediate-risk patients). Studies evaluating doseescalated EBRT (DE-EBRT) have demonstrated improved progression-free survival compared with lower dose treatment (3e7). The addition of low dose rate (LDR) or high dose rate (HDR) BB to EBRT has allowed for further dose escalation to the primary tumor site as the dosimetric properties of brachytherapy allow for the ultimate form of highly conformal dose escalation (3, 8e11). Moreover, both LDR and HDR boost have shown excellent toxicity profiles (8, 12). Recently, the androgen suppression combined with elective nodal and dose-escalated radiation therapy trial compared DE-EBRT to EBRT with iodine-125 LDR boost and demonstrated an improvement in 5-, 7-, and 9-year relapse-free survival for the EBRT plus BB arm
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compared with the EBRT arm (13). However, because of limited power and limited number of deaths in relatively short followup, they were unable to comment on overall survival (OS). Given these promising findings, we sought to investigate the trends in utilization of BBdincluding both LDR and HDR, factors predictive for utilization, and associated survival outcomes using a national data set.
Methods and materials Data source Deidentified data exempt from the National Cancer Database (NCDB) oversight were queried from 2004 to 2013 for men with nonoperative, nonmetastatic, and intermediate- or high-risk prostate cancer treated with EBRT þ BB (44e54 Gy of EBRT followed by a BB) or DE-EBRT (75.6e81 Gy of EBRT at 1.8e2.0 Gy per fraction). The NCDB is a nationally recognized clinical oncology database sourced by more than 1500 Commission on Cancereaccredited facilities maintained by the American College of Surgeons and the American Cancer Society.
Fig. 1. Consolidated Standards of Reporting Trials diagram for patient selection. NCCN 5 National Comprehensive Cancer Network.
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It captures more than 70% of newly diagnosed cancer in the United States (14, 15). Patient selection Within the NCDB, 113,719 men with nonoperative, nonmetastatic, and intermediate- to high-risk prostate cancer treated with DE-EBRT or EBRT þ BB were identified from an initial prostate cancer cohort of 1,208,180. Details of the patient selection process are given in Fig. 1. In accordance with the National Comprehensive Cancer Network, intermediate risk was defined as Gleason score of 7, PSA of 10e20 ng/mL but without any high-risk featuredclinical stage $T3a, PSA O20 ng/mL, Gleason score 8e10dor with clinical stage T2b or T2c (15, 16), and high risk was defined as T3a, Gleason score 8e10, or PSA O20 ng/mL (16). Definition of variables BB includes both LDR and HDR as NCDB does not reliably distinguish between the two. Race was defined as white, black, other, or unknown. Insurance was categorized as private, government (including Medicare, Medicaid, and other government), no insurance, or unknown. Charlsone Deyo comorbidity score was recorded as the summation of comorbid conditions and was scored as 0, 1, $2, with a score of 0 representing no comorbid conditions recorded (16e18). The 2013 U.S. Department of Agriculture RuralUrban Continuum was used to define metropolitan, urban, and rural areas. Counties in metropolitan areas were coded metropolitan, counties with an urban population of $2500 but not in a metropolitan area were termed urban, and counties with an urban population of !2500 were termed rural. Distance from residence to facility was calculated using the center of the patient’s zip code to the treating facilities mailing address. Facility location was defined as northeast: CT, MA, ME, NH, NJ, NY, PA, RI, and VT; south: AL, AR, DC, DE, FL, GA, KY, LA, MD, MS, NC, OK, SC, TN, TX, VA, and WV; midwest: IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, and WI; and west: AZ, AK, CA, CO, ID, HI, MT, NM, NV, OR, UT, WA, and WY.
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standard differences of less than !0.10 (21). By this method, the validity of the propensity model was successfully confirmed (22, 23). Parsimonious survival analysis was conducted both including and excluding propensity score. The multivariate portion of survival analysis was obtained from Cox proportional hazards modeling, whereas the univariate component was calculated from log-rank statistics.
Results Baseline characteristics Baseline patient demographics and characteristics are given in Table 1. The median age was 70 years, with an interquartile range of 64e75 years. Most patients were white (79%), lived in a metropolitan area (82%), had government insurance (67%), and had Stage T1 primary (59%). Of the final cohort (n 5 113,719), 68,886 (60.6%) were classified as intermediate-risk category and 44,833 (39.4%) were classified as high-risk category. Of the intermediate-risk patients, 41.3% received hormonal therapy, and 77% of the high-risk patients received hormonal therapy. BB was administered to 19.2% of those with intermediate-risk disease (80.8% received DE-EBRT), whereas 16.4% in the high-risk category received EBRT with BB (83.6% received DE-EBRT). Trends in BB utilization Both a relative and an absolute decline was observed in BB utilization from 2004 to 2013 in both intermediate-risk and high-risk categories compared with DE-EBRT. The use of BB for patients with intermediate-risk disease experienced a statistically significant ( p ! 0.001) decline from 33.1% (n 5 1742) in 2004 to 12.5% (n 5 766) in 2013 (Fig. 2a). Declining utilization was seen in both Gleason scores of 3 þ 4 and 4 þ 3. A similarly statistically significant ( p ! 0.001) trend was noted in high-risk patients treated with BB as usage declined from 27.6% (n 5 879) in 2004 to 10.8% (n 5 479) in 2013 (Fig. 2b). Factors predictive of preferential BB utilization
Statistical analysis IBM SPSS, version 22.0 (IBM, Armonk, NY) was used to analyze the data. Separately for intermediate- and highrisk patients, univariate analysis was performed on all available factors potentially predictive for receipt of each given treatment modality. Multivariable models of utilization were created from factors significant on univariate analysis, and from the multivariable models, propensity scores indicative of the likelihood of treatment utilization were generated to attempt to account for indication bias (19, 20). The distribution of propensity scores was evaluated using the binned quintiles method and the requirement of
Preferential use of EBRT plus BB was associated with earlier year of diagnosis, younger age, CharlsoneDeyo comorbidity score !2, race other than white or black, private insurance, higher residential area median income, treatment at a nonacademic facility, geographical location (south for both intermediate risk and high risk and west for high risk), higher facility volume, higher T stage (except 2C for high risk), PSA #10, Gleason score (7 for intermediate risk and 7e8 for high risk), and primary Gleason pattern of four for both groups on multivariate analysis. In addition, increased residential area graduation rate predicted preferential use of BB for intermediate-risk patients. For high-risk patients,
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Table 1 Baseline characteristics of all patients with intermediate- or high-risk prostate cancer who received DE-EBRT or EBRT plus BB (n 5 113,719)
Baseline characteristics Sociodemographic factors Year of diagnosis 2004e2007 2008e2010 2011e2013 Age (y) Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity score 0 1 $2 Race White Black Other Unknown Insurance status Private Government None Unknown Residential setting Metropolitan Urban Rural Unknown Median income (residential area) !$38,000 $38,000e$47,999 $48,000e$62,999 $$63,000 Unknown Without high school degree (residential area), % !7 7e12.9 13e20.9 $21 Unknown Distance from facility to residence, miles !5 5e9.9 10e24.9 25þ Unknown Facility type Nonacademic Academic/research Unknown Facility location Northeast South Midwest
Number of intermediate-risk patients (%)
Number of high-risk patients (%)
26,019 (37.8) 22,325 (32.4) 20,542 (29.8)
16,054 (35.8) 14,719 (32.8) 14,060 (31.4)
18,729 15,840 17,444 16,873
11,098 9211 10,645 13,879
(27.2) (23.0) (25.3) (24.5)
(24.8) (20.5) (23.7) (31.0)
59,647 (86.6) 7675 (11.1) 1564 (2.3)
38,705 (86.3) 5068 (11.3) 1060 (2.4)
54,702 11,480 1878 826
(79.4) (16.7) (2.7) (1.2)
35,064 7883 1373 513
(78.2) (17.6) (3.1) (1.1)
21,019 45,713 1022 1132
(30.5) (66.4) (1.5) (1.6)
12,390 30,919 809 715
(27.6) (69.0) (1.8) (1.6)
56,542 9361 1153 1830
(82.1) (13.6) (1.7) (2.7)
36,220 6519 870 1224
(80.8) (14.5) (1.9) (2.7)
12,190 15,581 18,195 22,234 686
(17.7) (22.6) (26.4) (32.3) (1.0)
8407 10,470 11,598 13,882 476
(18.8) (23.4) (25.9) (31.0) (1.1)
16,832 22,722 17,281 11,402 649
(24.4) (33.0) (25.1) (16.6) (0.9)
10,625 14,465 11,544 7753 446
(23.7) (32.3) (25.7) (17.3) (1.0)
22,274 16,486 17,772 11,748 606
(32.3) (23.9) (25.8) (17.1) (0.9)
14,593 10,675 11,495 7647 423
(32.5) (23.8) (25.6) (17.1) (0.9)
47,658 (69.2) 21,225 (30.8) 3 (0.0)
31,185 (69.6) 13,645 (30.4) 3 (0.0)
17,957 (26.1) 22,121 (32.1) 16,937 (24.6)
11,197 (25.0) 15,127 (33.7) 11,313 (25.2) (Continued)
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Table 1 (continued )
Baseline characteristics West Unknown Facility volume, cases !100 101e200 201e300 O300 Pathologic factors T stage 1 2A 2B 2C 3 PSA #10 10.1e20 20.1e40 O40 Total Gleason score #6 7 8 9 10 Primary Gleason pattern #3 4 5 Unknown Therapeutic factors Radiotherapy EBRT þ BB DE-EBRT Hormonal therapy No Yes Unknown
Number of intermediate-risk patients (%) 11,868 (17.2) 3 (0.0)
Number of high-risk patients (%) 7193 (16.0) 3 (0.0)
17,258 18,324 13,319 19,985
(25.1) (26.6) (19.3) (29.0)
12,213 12,246 8613 11,761
(27.2) (27.3) (19.2) (26.2)
45,085 9341 6337 8123 d
(65.4) (13.6) (9.2) (11.8)
22,642 4917 4336 6446 6492
(50.5) (11.0) (9.7) (14.4) (14.5)
50,018 (72.6) 18,868 (27.4) d d
19,087 8018 9359 8369
(42.6) (17.9) (20.9) (18.7)
10,711 (15.5) 58,175 (84.5) d d d
4137 9284 19,000 11,347 1065
(9.2) (20.7) (42.4) (25.3) (2.4)
48,441 18,688 6 1751
10,671 28,785 3998 1379
(23.8) (64.2) (8.9) (3.1)
(70.3) (27.1) (0.0) (2.5)
13,218 (19.2) 55,668 (80.8)
7370 (16.4) 37,463 (83.6)
38,463 (55.8) 28,448 (41.3) 1975 (2.9)
9547 (21.3) 34,529 (77.0) 757 (1.7)
DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost; PSA 5 prostate-specific antigen.
additional factors that predicted for BB use were metropolitan residential setting, increased distance from facility to residence, and no receipt of hormonal therapy. These results are depicted in Table 2. Survival outcomes Median followup was 54 months with 33e78 months as the interquartile range. Unadjusted 5-year OS for intermediate-risk patients receiving DE-EBRT vs. EBRT þ BB was 87.3% (95% confidence interval [95% CI] 5 86.9e87.7) vs. 91.6% (95% CI 5 91.0e92.2) and 58.0% (95% CI 5 56.4e59.6) vs. 71.6% (95% CI 5 69.4e73.8) for unadjusted 10-year OS ( p ! 0.0005; Fig. 3a). In a subset analysis of intermediate-risk patients receiving the highest radiotherapy doses (79.2e81 Gy) vs. EBRT þ BB, unadjusted 5-year OS was 89.5% (95%
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intermediate- and high-risk patients are given in Table 3. These findings persisted with incorporation of propensity scores for treatment selection into the Cox model with HRs of 0.73 (95% CI 5 0.68e0.77; p ! 0.0005) and 0.74 (95% CI 5 0.69e0.79; p ! 0.0005) for intermediateand high-risk patients, respectively.
Discussion
Fig. 2. Utilization of brachytherapy boost from 2004 to 2013 for men with (a) intermediate-risk and (b) high-risk prostate cancer. DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost.
CI 5 88.9e90.1) vs. 91.6% (95% CI 5 91.0e92.2) and unadjusted 10-year OS was 62.8% (95% CI 5 58.8e66.8) vs. 71.6% (95% CI 5 69.4e73.8) ( p ! 0.0005). Unadjusted 5year OS for high-risk patients receiving DE-EBRT vs. EBRT plus BB was 82.0% (95% CI 5 81.4e82.6) vs. 88.7% (95% CI 5 87.9e89.5) and 50.4% (95% CI 5 48.6e52.2) vs. 63.0% (60.0e66.0) for unadjusted 10-year OS ( p ! 0.0005; Fig. 3b). In a subset analysis of highrisk patients receiving the highest radiotherapy doses (79.2e81 Gy) vs. EBRT þ BB, unadjusted 5-year OS was 83.5% (95% CI 5 82.5e84.5) vs. 88.7% (95% CI 5 87.9e89.5) and unadjusted 10-year OS was 54.9% (95% CI 5 51.1e58.7) vs. 63.0% (95% CI 5 60.0e66.0) ( p ! 0.0005). For intermediate-risk patients, BB use was associated with a hazard ratio (HR) of 0.71 (95% CI 5 0.67e0.75, p ! 0.0005) on multivariate Cox proportional hazards analysis of factors predictive for survival. Similarly, for highrisk patients, the HR was 0.73 (95% CI 5 0.68e0.78; p ! 0.0005) in favor of EBRT þ BB. In subset analysis of only patients treated with the highest radiotherapy doses (79.2e81 Gy), the benefit was smaller but still present with an HR of 0.78 (95% CI 5 0.72e0.85; p ! 0.0005) and 0.78 (95% CI 5 0.71e0.85; p ! 0.0005) for intermediate risk and high risk, respectively. The complete models for
In this analysis, we have cohesively demonstrated a decline in the utilization of EBRT with BB in patients with intermediate- or high-risk prostate cancer despite our results indicating a small absolute survival advantage in both groups when compared with patients treated with DEEBRT. Intermediate-risk patients treated with EBRT plus BB experienced an absolute difference in 5- and 10-year OS of 4.3% and 13.6% compared with DE-EBRT. Highrisk patients saw a 6.7% absolute improvement in OS at 5 years and 12.6% at 10 years. Moreover, as significant imbalances existed between groups, adjusted multivariate analysis continued to demonstrate an associated OS benefit with use of BB in both groups. Our analysis also confirmed positive prognostic factors for OS, such as younger age, lower PSA, lower Gleason score, and others, which have been discussed extensively in the literature (24, 25). Consistent with other studies of dose escalation, our data suggest improved outcomes with the increased radiation doses permissible through BB (26e29). The importance of dose escalation has been described in the setting of brachytherapy monotherapy as well with increased doses correlated with improved outcomes (30). Furthermore, both retrospective and prospective data suggest that BB may be superior to DE-EBRT (13, 26, 31e33). Although since prior studies have been relatively small or had short followup, it is not surprising that differences in OS with the use of EBRT with BB have not been significant or reported until the recent large retrospective series published by Amini et al. (34, 35). They were able to observe an increase in OS in intermediate- and high-risk prostate cancer patients (n 5 20,279) treated from 2004 to 2006 with EBRT plus BB compared with those treated with DE-EBRT (75.6e 81 Gy). Yet, on subset analysis, they conceded that no significant difference was observed in OS when higher dose DE-EBRT (79.2e81 Gy) was used. In contrast, our analysis demonstrated an OS benefit with the use of BB even when compared with EBRT doses ranging from 79.2 to 81 Gy. We were able to show this persisting survival difference likely because of a broader inclusion criteria resulting in a higher number of patients and better powered analysis. We have also identified several factors associated with preferential use of EBRT with BB: earlier year of diagnosis, younger age, CharlsoneDeyo comorbidity score !2, treatment at a nonacademic facility, and others, all of which can be reviewed in Table 2. The two strongest predictors in our analysis that pointed toward decrease in use of BB were
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Table 2 Comparative utilization of DE-EBRT vs. EBRT plus BB for intermediate-risk and high-risk prostate cancer patients Intermediate risk Sociodemographic factors Year of diagnosisa 2004e2007 2008e2010 2011e2013 Age,a y Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity scorea 0 1 $2 Racea White Black Other Insurance statusa Private Government None Residential setting Metropolitan Urban Rural Median income (residential area)a !$38,000 $38,000e47,999 $48,000e62,999 $$63,000 Without high school degree (residential area),a % !7 7e12.9 13e20.9 $21 Distance from facility to residence, miles !5 5e9.9 10e24.9 25þ Facility typea Nonacademic Academic/research Facility locationa Northeast South Midwest West Facility volume,a cases !100 101e200 201e300 O300 Pathologic factors T stagea 1 2A 2B 2C
DE-EBRT (n 5 55,668)
EBRT þ BB (n 5 13,218)
Odds Ratio (95% CI)
p !0.0005
19,132 (73.5%) 18,676 (83.7%) 17,860 (86.9%)
6887 (26.5) 3649 (16.3) 2682 (13.1)
1 (Reference) 0.54 (0.52e0.57) 0.42 (0.40e0.44)
13,790 12,519 14,434 14,925
4939 3321 3010 1948
1 (Reference) 0.74 (0.70e0.78) 0.58 (0.55e0.61) 0.36 (0.34e0.39)
!0.0005 (73.6%) (79.0%) (82.7%) (88.5%)
(26.4%) (21.0%) (17.3%) (11.5%)
!0.0005 48,187 (80.8%) 6151 (80.1%) 1330 (85.0%)
11,460 (19.2%) 1524 (19.9%) 234 (15.0%)
1 (Reference) 1.04 (0.98e1.11) 0.74 (0.64e0.85)
44,314 (81.0%) 9230 (80.4%) 1472 (78.4%)
10,388 (19.0%) 2250 (19.6%) 406 (21.6%)
1 (Reference) 1.04 (0.99e1.09) 1.18 (1.05e1.32)
15,718 (74.8%) 38,071 (83.3%) 919 (88.9%)
5301 (25.2%) 7642 (16.7%) 103 (10.1%)
1 (Reference) 0.60 (0.57e0.62) 0.33 (0.27e0.41)
45,553 (96.7%) 7715 (95.7%) 939 (96.9%)
10,989 (19.4%) 1646 (17.6%) 214 (18.6%)
1 (Reference) 0.88 (0.84e0.94) 0.94 (0.81e1.10)
0.008
!0.0005
!0.0005
!0.0005 9967 12,643 15,076 17,474
(81.8%) (81.1%) (82.9%) (78.6%)
2233 2938 3119 4760
(18.2%) (18.9%) (17.1%) (21.4%)
1 (Reference) 1.04 (0.98e1.11) 0.93 (0.87e0.98) 1.22 (1.15e1.29) !0.0005
13,432 18,424 14,081 9254
(79.8%) (81.1%) (81.5%) (81.2%)
3400 4298 3200 2148
(20.2%) (18.9%) (18.5%) (18.8%)
1 (Reference) 0.92 (0.86e0.97) 0.90 (0.85e0.95) 0.92 (0.88e0.97) !0.0005
18,235 13,214 14,256 9520
(81.9%) (80.2%) (80.2%) (81.0%)
4039 3272 3516 2228
(18.1%) (19.8%) (19.8%) (19.0%)
1 (Reference) 1.12 (1.06e1.18) 1.11 (1.06e1.17) 1.06 (1.00e1.12)
37,946 (79.6%) 17,720 (83.5%)
9712 (20.4%) 3505 (16.5%)
1 (Reference) 0.77 (0.74e0.81)
14,678 16,917 14,283 9788
(81.7%) (76.5%) (84.3%) (82.5%)
3279 5204 2654 2080
(18.3%) (23.5%) (15.7%) (17.5%)
1 (Reference) 1.38 (1.31e1.45) 0.83 (0.79e0.88) 0.95 (0.90e1.01)
14,264 14,894 10,528 15,982
(82.7%) (81.3%) (79.0%) (80.0%)
2994 3430 2791 4003
(17.3%) (18.7%) (21.0%) (20.0%)
1 (Reference) 1.10 (1.04e1.16) 1.26 (1.19e1.34) 1.19 (1.13e1.26)
36,793 7433 4942 6500
(81.6%) (79.6%) (78.0%) (80.0%)
8292 1908 1395 1623
(18.4%) (20.4%) (22.0%) (20.0%)
1 (Reference) 1.14 (1.08e1.20) 1.25 (1.17e1.34) 1.11 (1.04e1.18)
!0.0005 !0.0005
!0.0005
!0.0005
(Continued)
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Table 2 (continued ) Intermediate risk
DE-EBRT (n 5 55,668)
High risk
DE-EBRT (n 5 37,463)
Sociodemographic factors Year of diagnosisa 2004e2007 2008e2010 2011e2013 Age,a y !65 65e69 70e74 $75 CharlsoneDeyo comorbidity scorea 0 1 $2 Racea White Black Other Insurance statusa Private Government None Residential settinga Metropolitan Urban Rural Median income (residential area)a !$38,000 $38,000e$47,999 $48,000e$62,999 $$63,000 Without high school degree (residential area), % !7% 7e12.9% 13e20.9% $21% Distance from facility to residence,a miles !5 5e9.9 10e24.9 25þ Facility typea Nonacademic Academic/research
EBRT þ BB (n 5 13,218)
Odds Ratio (95% CI)
p !0.0005
PSAa #10 10.1e20 Total Gleason scorea #6 7 Primary Gleason patterna #3 4 5 Therapeutic factors Hormonal therapy No Yes
39,878 (79.7%) 15,790 (83.7%)
10,140 (20.3%) 3078 (16.3%)
1 (Reference) 0.77 (0.73e0.80)
9122 (85.2%) 46,546 (80.0%)
1589 (14.8%) 11,629 (20.0%)
1 (Reference) 1.43 (1.35e1.52)
39,477 (81.5%) 14,800 (79.2%) 6 (100%)
8964 (18.5%) 3888 (20.8%) 0 (0%)
1 (Reference) 1.16 (1.11e1.21) N/A
31,020 (80.6%) 23,090 (81.2%)
7443 (19.4%) 5358 (18.8%)
1 (Reference) 0.97 (0.93e1.01)
!0.0005 !0.0005
0.093
EBRT þ BB (n 5 7370)
Odds Ratio (95% CI)
p !0.0005
12,403 (77.3%) 12,619 (85.7%) 12,441 (88.5%)
3651 (22.7%) 2100 (14.3%) 1619 (11.5%)
1 (Reference) 0.57 (0.53e0.60) 0.44 (0.41e0.47)
8616 7476 8922 12,449
2482 1735 1723 1430
1 (Reference) 0.81 (0.75e0.86) 0.67 (0.63e0.72) 0.40 (0.37e0.43)
!0.0005 (77.6%) (81.2%) (83.8%) (89.7%)
(22.4%) (18.8%) (16.2%) (10.3%)
0.001 32,312 (83.5%) 4222 (83.3%) 929 (87.6%)
6393 (16.5%) 846 (16.7%) 131 (12.4%)
1 (Reference) 1.01 (0.94e1.10) 0.71 (0.59e0.86)
29,406 (83.9%) 6585 (83.5%) 1059 (77.1%)
5658 (16.1%) 1298 (16.5%) 314 (22.9%)
1 (Reference) 1.02 (0.96e1.09) 1.54 (1.35e1.75)
9640 (77.8%) 26,443 (85.5%) 745 (92.1%)
2750 (22.2%) 4476 (14.5%) 64 (7.9%)
1 (Reference) 0.59 (0.56e0.63) 0.30 (0.23e0.39)
30,097 (83.1%) 5597 (85.9%) 735 (84.5%)
6123 (16.9%) 922 (14.1%) 135 (15.5%)
1 (Reference) 0.81 (0.75e0.87) 0.90 (0.75e1.09)
7159 8914 9835 11,178
1248 1556 1763 2704
1 (Reference) 1.00 (0.92e1.09) 1.03 (0.95e1.11) 1.39 (1.29e1.49)
!0.0005
!0.0005
!0.0005
!0.0005 (85.2%) (85.1%) (84.8%) (80.5%)
(14.8%) (14.9%) (15.2%) (19.5%)
!0.0005 8646 12,165 9768 6535
(81.4%) (84.1%) (84.6%) (84.3%)
1979 2300 1776 1218
(18.6%) (15.9%) (15.4%) (15.7%)
1 (Reference) 0.83 (0.77e0.88) 0.79 (0.74e0.85) 0.81 (0.75e0.88) 0.001
12,288 8943 9623 6277
(84.2%) (83.8%) (83.7%) (82.1%)
2305 1732 1872 1370
(15.8%) (16.2%) (16.3%) (17.9%)
1 (Reference) 1.03 (0.96e1.11) 1.04 (0.97e1.11) 1.16 (1.08e1.25)
5521 (17.7%) 1848 (13.5%)
1 (Reference) 0.73 (0.69e0.77)
!0.0005 25,664 (82.3%) 11,797 (86.5%)
(Continued)
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Table 2 (continued ) Intermediate risk Facility locationa Northeast South Midwest West Facility volume,a cases !100 101e200 201e300 O300 Pathologic factors T stagea 1 2A 2B 2C 3 PSAa #10 10.1e20 20.1e40 O40 Total Gleason scorea #6 7 8 9 10 Primary Gleason patterna #3 4 5 Therapeutic factors Hormonal therapya No Yes
DE-EBRT (n 5 55,668)
EBRT þ BB (n 5 13,218)
Odds Ratio (95% CI)
p !0.0005
9712 12,163 9756 5830
(86.7%) (80.4%) (86.2%) (81.1%)
1485 2964 1557 1363
(13.3%) (19.6%) (13.8%) (18.9%)
1 (Reference) 1.59 (1.49e1.71) 1.04 (0.97e1.13) 1.53 (1.41e1.66)
10,480 10,403 7071 9509
(85.8%) (85.0%) (82.1%) (80.9%)
1733 1843 1542 2252
(14.2%) (15.0%) (17.9%) (19.1%)
1 (Reference) 1.07 (1.00e1.15) 1.32 (1.22e1.42) 1.43 (1.34e1.53)
18,984 4034 3551 5509 5385
(83.8%) (82.0%) (81.9%) (85.5%) (82.9%)
3658 883 785 937 1107
(16.2%) (18.0%) (18.1%) (14.5%) (17.1%)
1 (Reference) 1.14 (1.05e1.23) 1.15 (1.05e1.25) 0.88 (0.82e0.95) 1.07 (0.99e1.15)
15,334 6830 7965 7334
(80.3%) (85.2%) (85.1%) (87.6%)
3753 1188 1394 1035
(19.7%) (14.8%) (14.9%) (12.4%)
1 (Reference) 0.71 (0.66e0.76) 0.72 (0.67e0.76) 0.58 (0.54e0.62)
3542 7711 15,634 9652 924
(85.6%) (83.1%) (82.3%) (85.1%) (86.8%)
595 1573 3366 1695 141
(14.4%) (16.9%) (17.7%) (14.9%) (13.2%)
1 (Reference) 1.21 (1.10e1.35) 1.28 (1.17e1.41) 1.05 (0.94e1.16) 0.91 (0.75e1.11)
8967 (84.0%) 23,923 (83.1%) 3421 (85.6%)
1704 (16.0%) 4862 (16.9%) 577 (14.4%)
1 (Reference) 1.07 (1.01e1.14) 0.89 (0.80e0.98)
7716 (80.8%) 29,131 (84.4%)
1831 (19.2%) 5398 (15.6%)
1 (Reference) 0.78 (0.74e0.83)
!0.0005
!0.0005
!0.0005
!0.0005
!0.0005
!0.0005
DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost; 95% CI 5 95% confidence interval; PSA 5 prostate-specific antigen; N/A 5 not available. a Indicates variable was significant on multivariable analysis and used to generate propensity score.
lack of health insurance and increasing age in both risk groups. We imagine that those without health insurance were less inclined to receive the more cost and resource-
intensive multimodality treatment, whereas older patients were less likely to be candidates for brachytherapy because of the requirements of anesthesia as they were more likely
Fig. 3. Unadjusted KaplaneMeier survival analysis for (a) intermediate-risk and (b) high-risk patients. NCCN 5 National Comprehensive Cancer Network; DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost.
S.M. Glaser et al. / Brachytherapy Table 3 Unadjusted multivariable Cox proportional hazard models for overall survival for intermediate-risk and high-risk prostate cancer patients who received DE-EBRT or EBRT plus BB Variable Significant factors (intermediate risk) Year of diagnosis 2004e2007 2008e2010 2011e2013 Age, y Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity score 0 1 $2 Race White Black Other Insurance status Private Government None Median income (residential area) !$38,000 $38,000e47,999 $48,000e62,999 $$63,000 Without high school degree (residential area), % !7 7e12.9 13e20.9 $21 Distance from facility to residence, miles !5 5e9.9 10e24.9 25þ Facility type Nonacademic Academic/research Facility location Northeast South Midwest West Facility volume, cases !100 101e200 201e300 O300
Hazard of death (95% CI)
p
0.052 Reference 1.05 (1.00e1.12) 1.11 (1.00e1.23) !0.0005 Reference 1.11 (1.02e1.21) 1.42 (1.31e1.54) 1.99 (1.84e2.16) !0.0005 Reference 1.47 (1.37e1.57) 2.36 (2.10e2.65) 0.008 Reference 0.99 (0.92e1.06) 0.77 (0.65e0.91) !0.0005 Reference 1.36 (1.28e1.46) 1.01 (0.79e1.28) !0.0005 Reference 0.97 (0.91e1.05) 0.89 (0.82e0.96) 0.83 (0.76e0.91) 0.004
Reference 1.06 (0.99e1.13) 1.08 (1.00e1.17) 1.19 (1.08e1.31) !0.0005
Reference 0.96 (0.90e1.01) 0.93 (0.88e0.99) 0.86 (0.80e0.92) 0.001 Reference 0.92 (0.87e0.97) !0.0005 Reference 1.08 (1.01e1.15) 1.03 (0.96e1.10) 0.80 (0.74e0.87) !0.0005 Reference 0.93 (0.88e0.99) 0.99 (0.93e1.06) 0.87 (0.82e0.93) (Continued)
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Table 3 (continued ) Variable T stage 1 2A 2B 2C PSA #10 10.1e20 Total Gleason score #6 7 Primary Gleason pattern #3 4 5 Radiotherapy DE-EBRT EBRT þ BB Hormonal therapy No Yes 79.2e81 Gy DE-EBRT EBRT þ BB Significant factors (high risk) Year of diagnosis 2004e2007 2008e2010 2011e2013 Age, y Younger than 65 65e69 70e74 75 and older CharlsoneDeyo comorbidity score 0 1 $2 Race White Black Other Insurance status Private Government None Median income (residential area) !$38,000 $38,000e47,999 $48,000e62,999 $$63,000 Facility type Nonacademic Academic/research Facility location Northeast South Midwest West
Hazard of death (95% CI)
p !0.0005
Reference 1.03 (0.96e1.10) 1.16 (1.07e1.25) 1.20 (1.13e1.28) !0.0005 Reference 1.28 (1.22e1.35) !0.0005 Reference 1.18 (1.10e1.26) 0.009 Reference 1.08 (1.03e1.14) 0.59 (0.08e4.19) !0.0005 Reference 0.71 (0.67e0.75) 0.006 Reference 0.94 (0.89e0.98) !0.0005 Reference 0.78 (0.72e0.85) 0.011 Reference 1.04 (0.98e1.10) 1.17 (1.05e1.29) !0.0005 Reference 1.11 (1.01e1.21) 1.29 (1.18e1.41) 2.01 (1.85e2.19) !0.0005 Reference 1.40 (1.30e1.51) 2.30 (2.03e2.61) 0.035 Reference 0.96 (0.89e1.03) 0.82 (0.69e0.97) !0.0005 Reference 1.18 (1.10e1.26) 0.81 (0.63e1.05) !0.0005 Reference 0.97 (0.90e1.04) 0.87 (0.81e0.94) 0.80 (0.74e0.87) 0.002 Reference 0.92 (0.87e0.97) !0.0005 Reference 1.11 (1.04e1.19) 1.13 (1.05e1.21) 0.89 (0.82e0.97) (Continued)
10
S.M. Glaser et al. / Brachytherapy
Table 3 (continued ) Variable Facility volume, cases !100 101e200 201e300 O300 T stage 1 2A 2B 2C 3 PSA #10 10.1e20 20.1e40 O40 Total Gleason score #6 7 8 9 10 Primary Gleason pattern #3 4 5 Radiotherapy DE-EBRT EBRT þ BB 79.2e81 Gy DE-EBRT EBRT þ BB
Hazard of death (95% CI)
p 0.001
Reference 0.93 (0.87e0.99) 0.99 (0.93e1.07) 0.88 (0.82e0.94) !0.0005 Reference 0.94 (0.86e1.02) 1.08 (0.99e1.17) 1.17 (1.09e1.25) 1.19 (1.10e1.28) !0.0005 Reference 1.21 (1.13e1.29) 1.36 (1.26e1.46) 1.29 (1.20e1.40) !0.0005 Reference 1.18 (1.06e1.31) 1.52 (1.33e1.73) 1.84 (1.61e2.12) 2.31 (1.89e2.82) 0.003 Reference 1.01 (0.92e1.10) 1.18 (1.04e1.34) !0.0005 Reference 0.73 (0.68e0.78) !0.0005 Reference 0.78 (0.71e0.85)
DE-EBRT 5 dose-escalated external beam radiotherapy; BB 5 brachytherapy boost; 95% CI 5 95% confidence interval; PSA 5 prostate-specific antigen.
to have more comorbidities. This was further supported as higher CharlsoneDeyo comorbidity scores were associated with the use of DE-EBRT vs. EBRT with BB. Some of these parameters have already been reported in the literature. Martin et al. (36) analyzed utilization of prostate brachytherapy as a whole and noted that patients more likely to receive brachytherapy were those with low CharlsoneDeyo scores, those with Medicare, earlier year of diagnosis, older age, and those from the southeast; those less likely to receive brachytherapy were Hispanics, those from the west, and those receiving care in academic institutions. With some slight differences, these factors are largely concordant with the factors we have identified in a cohort of boost-only patients. The differences seen between our analysis and that of Martin et al. (36) are likely explained by discrepancies between our cohorts as theirs was composed of patients predominantly treated with brachytherapy as a monotherapy, whereas those treated with BB were a small minority. Also confirmed by our analysis was the findings of Orio et al. (37, 38) who commented on the finding that academic centers were less likely to use BB than their nonacademic counterparts (adjusted odds
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ratio, 0.68; 95% CI 5 0.66e0.70; p ! 0.0001) and thus raised the concern about the potential lack of proper training within academic centers. Despite the apparent advantage of EBRT with BB over EBRT, there has been a statistically significant downward trend in the use of BB in patients in both the intermediateand high-risk groups. From 2004 to 2013, we calculated that utilization of BB decreased from 33.1% to 12.5% and 27.6e10.8% for intermediate- and high-risk patients, respectively (as compared with DE-EBRT). In addition, several articles have commented on this decline within the past decade or so (36, 38, 39). Martin et al. (36) specifically observed intermediate-risk patients experiencing the greatest decrease in BB followed by high- and then lowrisk patients. In fact, decreasing utilization of brachytherapy as a treatment modality has been documented in the literature in other cancers as well such as cervical cancer (40). An explanation for these observed trends in the treatment of prostate cancer is conceivably multifactorial including the more invasive nature of EBRT þ BB than DE-EBRT, changes in referral patterns where younger healthier patients are treated with radical prostatectomy, decreased training in brachytherapy, and pressures from health care reform and reimbursement trends. Limitations of our study include the potential for ascertainment bias, incomplete data, and coding error. Moreover, we were unable to collect information on disease recurrence or subsequent treatment as these data are not captured within the NCDB, and thus, we are unable to report on biological progression-free survival, disease-free survival, or salvage rates. Similarly, brachytherapy dose and isotope data were not included in the NCDB and thus are not reported in this study. There are no toxicity data in this analysis, although EBRT with BB has been shown to have limited Grade 3 or greater toxicities and acceptable levels of adverse events (8, 31, 41e45). Although we were not able to comment on endpoints that have been extensively discussed in prior literature, we were able to observe a less commonly seen trend in OS associated with use of BB because of our vast cohort.
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