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All content in this area was uploaded by Peter F Orio on Aug 03, 2016
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The decreased use of brachytherapy boost for intermediate and high-risk
prostate cancer despite evidence supporting its effectiveness
Peter F. Orio III
1,2,
*, Paul L. Nguyen
1,2
, Ivan Buzurovic
1,2
, Daniel W. Cail
1
, Yu-Wei Chen
1
1
Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA
2
Harvard Medical School, Boston, MA
ABSTRACT PURPOSE: The Canadian Androgen Suppression Combined with Elective Nodal and Dose Esca-
lated Radiation Therapy (ASCENDE-RT) randomized trial showed that brachytherapy boost
reduces recurrence by 50% compared to dose-escalated radiation. We examined how men with
identical inclusion criteria to the ASCENDE-RT trial were being treated in the United States.
METHODS AND MATERIALS: We used the National Cancer Database to identify prostate can-
cer patients treated with radiation from 2004 through 2012 who met the inclusion criteria of the
ASCENDE-RT trial (intermediate-/high-risk prostate cancer, excluding patients with prostate-
specific antigen O40 or tumor stage T3b/T4). The ManteleHaenszel test was used to investigate
the trend for type of radiation modality used over the study period.
RESULTS: A cohort of 156,411 patients was identified. Of those, 103,188 men (66%) were treated
with external beam radiation therapy (EBRT) alone, 31,129 (20%) with brachytherapy alone, and
22,094 (14%) with EBRT plus brachytherapy. EBRT plus a brachytherapy boost demonstrated a
significant decrease in utilization from 2004 to 2012 in both academic and nonacademic centers,
declining from 15% to 8% in academic centers and from 19% to 11% in nonacademic centers
(p-Value for trend !0.0001 for both). Academic centers were significantly less likely to use
brachytherapy boost than nonacademic centers (adjusted odds ratio: 0.68; 95% confidence interval:
0.66e0.70; p-Value: !0.0001).
CONCLUSIONS: Radiation oncology practices have demonstrated a significant reduction in the use
of brachytherapy boost from 2004 to 2012, and the lowest utilization was in academic centers. In light
of the superior results demonstrated for brachytherapy boost by the ASCENDE-RT trial, it is unclear
whether academic centers are prepared to train the next generation of residents in this critical modality.
Ó2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords: Prostate cancer; Brachytherapy boost; National cancer database; ASCENDE-RT; Radiation therapy
Introduction
The recently reported ASCENDE-RT trial explored the
use of 1 year of androgen deprivation therapy and external
beam radiation therapy (EBRT) to the pelvis, prostate,
and seminal vesicles followed by randomization to dose-
escalated EBRT or a low-dose-rate permanent transperineal
interstitial brachytherapy boost to the prostate for
intermediate- and high-risk prostate cancer (1). The addi-
tion of a low-dose-rate prostate brachytherapy boost re-
sulted in almost a 50% reduction in prostate-specific
antigen (PSA) progression-free survival (PFS) compared
to dose-escalated EBRT and an absolute difference in
PSA PFS at 9 years of almost 20% (1). This trial has the
potential to significantly change how higher risk prostate
cancer patients are treated. The importance of biochemical
control cannot be underestimated in prostate cancer treat-
ments, as it triggers a cascade of events that reduce quality
of life and that have high economic cost (2e5).
Although the ASCENDE-RT trial is not yet published,
the abstract and multiple oral presentations are convincing.
Given the proven benefit of this brachytherapy boost trial,
we sought to examine the national practice patterns for
radiation-managed men with prostate cancer who fit the
Received 10 April 2016; received in revised form 4 May 2016;
accepted 9 May 2016.
Conflict of interest: PLN, MD, consulted for Medivation, Ferring,
Genome DX, and Nanobiotix.
* Corresponding author. Department of Radiation Oncology, Dana-
Farber Cancer Institute, Brigham and Women’s Hospital, 75 Francis St.,
Boston, MA 02115. Tel.: 781-624-4700; fax: 781-624-4710.
E-mail address: PORIO@lroc.harvard.edu (P.F. Orio).
1538-4721/$ - see front matter Ó2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.brachy.2016.05.001
Brachytherapy -(2016) -
inclusion criteria of the ASCENDE-RT trial. Therefore, we
analyzed the National Cancer Database (NCDB) to
examine the use of brachytherapy boost among men with
the same inclusion criteria as patients in the ASCENDE-
RT trial from 2004 to 2012.
Methods and materials
Study population
We used the NCDB, a joint program of the Commission
on Cancer and the American Cancer Society, to select our
study population. NCDB is a hospital-based nationwide
database which captures 70% of newly diagnosed cancer
cases and is the largest cancer registry (6). We identified pa-
tients diagnosed with nonmetastatic prostate adenocarci-
noma between 2004 and 2012, further selecting patients
who met the inclusion criteria of the ASCENDE-RT trial
(1) (i.e., patients diagnosed with NCCNs intermediate-
and high-risk disease and excluded patients whose PSA
O40 or tumor stage was T3b or higher). We further
selected patients who received radiation therapy as the
definitive treatment. Our institutional review board
approved this study.
Primary end point and covariates
We aimed to investigate the trend of radiation modalities
for the period 2004 to 2012. The treatment modalities were
categorized as EBRT alone, brachytherapy alone, or EBRT
plus brachytherapy boost. The trend analysis was stratified
by the center type (academic/research program was defined
as academic, comprehensive community cancer center,
community cancer center and others were defined as nonac-
ademic). Other covariates included in this study were socio-
demographic variables such as age ($65, !65), race,
insurance status, year of diagnosis, household income, resi-
dence type, and the percent of education level less than
high school for each patient’s area of residence; clinical
variables included tumor stage (American Joint Committee
on Cancer sixth edition), PSA (coded as!10, 10e20, O20),
Gleason score (#6, 7, 8e10), and CharlsoneDeyo comor-
bidity score (0, 1, $2). The income (7) and education (8)
information were quartiles among all the U.S. zip codes
and were based on the 2012 U.S. census data; the residence
type (9) was determined with the 2003 USDA Economic
Research Service. All the information in our analysis was
provided by the NCDB.
Statistical analysis
The baseline patients’ characteristics were presented
with descriptive statistics and compared with chi-square
test as appropriate. ManteleHaenszel test was used to
investigate the trend for radiation modalities over the study
Table 1
Patient baseline characteristics
Category
Academic
hospital
(N546,765,
30%)
Nonacademic
hospital
(N5109,646,
70%) p-Value
Radiation modality (%)
EBRT alone 33,846 (72.4) 69,342 (63.2)
Brachytherapy alone 7551 (16.2) 23,578 (21.5)
EBRT þBrachy therapy 5368 (11.5) 16,726 (15.3)
Year of diagnosis !0.0001
2004e2006 14,781 (31.6) 38,292 (34.9)
2007e2009 15,524 (33.2) 37,268 (34.0)
2010e2012 16,460 (35.2) 34,086 (31.1)
Age !0.0001
!65 14,716 (31.5) 29,563 (27.0)
$65 32,049 (68.5) 80,083 (73.0)
Race !0.0001
Non-Hispanic White 32,910 (70.4) 86,025 (78.5)
Black 9309 (20.0) 15,489 (14.1)
Hispanic White 1763 (3.8) 3998 (3.7)
Other 1827 (3.9) 2949 (2.7)
Unknown 956 (2.0) 1185 (1.1)
PSA !0.0001
!10 31,878 (68.2) 73,289 (66.8)
10e20 11,139 (23.8) 27,394 (25.0)
O20 3748 (8.0) 8963 (8.2)
Gleason Score !0.0001
#6 7063 (15.1) 19,459 (17.8)
7 28,944 (61.9) 65,252 (59.5)
8e10 10,758 (23.0) 24,935 (22.7)
Tumor stage !0.0001
T1 27,464 (58.7) 63,015 (57.5)
T2 18,017 (38.5) 44,619 (40.7)
T3a 1284 (2.8) 2012 (1.8)
Charlson comorbidity score !0.0001
0 41,476 (88.7) 94,730 (86.4)
1 4,487 (9.6) 12,529 (11.4)
2þ802 (1.7) 2387 (2.2)
Insurance status !0.0001
None 955 (2.0) 1205 (1.1)
Private 16,418 (35.1) 33,848 (30.9)
Medicaid 1366 (2.9) 2340 (2.1)
Medicare 25,506 (54.5) 68,586 (62.6)
Other 1391 (3.0) 2241 (2.0)
Unknown 1129 (2.4) 1426 (1.3)
Income !0.0001
!$38,000 8007 (17.1) 19,427 (17.7)
$38,000e47,999 8781 (18.8) 27,245 (24.9)
$48,000e62,999 11,594 (24.8) 29,082 (26.5)
$63,000 17,813 (38.1) 32,074 (23.3)
Unknown 570 (1.2) 1818 (1.7)
Education !high school !0.0001
$21% 7217 (15.4) 18,059 (16.5)
13e20.9% 11,227 (24.0) 28,334 (25.8)
7e12.9% 14,304 (30.6) 36,637 (33.4)
!7% 13,471 (28.8) 24,833 (22.7)
Unknown 546 (1.2) 1747 (1.6)
Residence !0.0001
Metropolitan 40,720 (87.1) 82,208 (75.0)
Urban 4247 (9.1) 20,651 (18.8)
Rural 506 (1.1) 3150 (2.9)
Unknown 1292 (2.8) 3637 (3.3)
EBRT 5external beam radiation therapy; PSA 5prostate-specific
antigen.
2P.F. Orio et al. / Brachytherapy -(2016) -
period. Multivariable logistic regression analysis was used
to identify the independent predictors for treatment with
EBRT plus brachytherapy boost vs. treatment with EBRT
alone or brachytherapy alone. All statistical analyses were
performed using SAS version 9.4. (SAS Institute Inc., Cary,
NC). We used a two-sided p-Value !0.05 in all analyses as
criteria for statistical significance.
Results
Baseline characteristics stratified on academic vs.
nonacademic centers
Our study cohort consisted of 156,411 radiation-treated
prostate cancer patients. A total of 103,188 patients
(66%) were treated with EBRT alone, 31,129 (20%) were
treated with brachytherapy alone, and 22,049 (14%) were
treated with EBRT with brachytherapy boost. A total of
46,765 patients (30%) were treated at academic centers,
and 109,646 patients (70%) were treated at nonacademic
centers. Patient sociodemographic and clinical characteris-
tics stratified by center type are summarized in Table 1.
Trend of use of EBRT with brachytherapy boost
From 2004 to 2012, there was a steady rise in the use of
EBRT alone in both academic and nonacademic centers,
increasing from 66% to 80% and 56% to 72%, respectively;
during this same period, there was a steady decline in
brachytherapy alone being offered in academic and nonaca-
demic centers from 19% to 12% and 25% to 17%, respec-
tively. The use of EBRT and a brachytherapy boost
demonstrated the lowest utilization in this time period in
both academic and nonacademic centers from 15% to 8%
and 19% to 11%, respectively ( p-Value for trend !0.0001
for both academic and nonacademic hospitals). Academic
centers treated this patient cohort significantly more with
EBRT than with EBRT and a brachytherapy boost.
Figure 1 graphs the utilization rates over time.
Predictors for EBRT with brachytherapy boost
In the multivariable logistic regression model, patients
diagnosed from 2007 to 2009 (adjusted odds ratio
[AOR]: 0.72; 95% confidence interval [CI]: 0.69e0.74;
p-Value!0.0001) and 2010 to 2012 (AOR: 0.52; 95% CI:
0.50e0.54; p-Value!0.0001) were less likely to receive
EBRT plus brachytherapy boost than patients from 2004
to 2006. Compared with nonacademic centers, academic
centers were less likely to offer EBRT plus brachytherapy
boost (AOR: 0.68; 95% CI: 0.66e0.70; p-Value: !0.0001).
Patients with higher Gleason score, higher tumor
stage, black, or household income$75th percentile (i.e.,
$63,000) were more likely to receive EBRT plus brachy-
therapy boost, whereas patients age $65 years, with Charl-
son comorbidity score $2, nonprivate insurance status,
living in urban or rural areas were all less likely to receive
EBRT plus brachytherapy boost (Table 2).
Discussion
Analysis of the largest cancer database in the United
States found a significant decrease in the use of brachyther-
apy boost between 2004 and 2012 in the contemporary
population. Our results are consistent with earlier studies
(10, 11) and demonstrate that the United States is experi-
encing historic lows in the use of prostate brachytherapy
both as monotherapy and in the boost setting.
This finding is concerning as the randomized clinical
Phase 3 ASCENDE-RT trial (1) has shown a significant
PSA PFS benefit of adding a brachytherapy boost to EBRT
in treating intermediate- and high-risk prostate cancer
when compared to omitting brachytherapy in favor
Fig. 1. Trend of radiation modality use in 2004e2012. E, external beam radiation therapy; B, brachytherapy; E þB, external beam radiation
therapy þbrachytherapy boost.
3P.F. Orio et al. / Brachytherapy -(2016) -
of dose-escalated EBRT strategies. In addition to the
ASCENDE-RT trial, Hoskin et al. (12) also reported
improved biochemical and clinical relapse-free survivals
with the addition of a high-dose-rate brachytherapy boost
as a dose escalation strategy in higher risk patients. There
is also a large body of single institution and retrospective
data supporting dose escalation in higher risk patients
(13e16). Sylvester et al. (17) reported the 15 year biochem-
ical relapse-free survival of combined modality treatment by
risk group with excellent outcomes demonstrated in the
intermediate- and high-risk groups, 80.3% and 67.8%,
respectively. Dattoli et al. (18, 19) report similar results with
biochemical control of 82% in the intermediate-risk group
and 72% in the high-risk group at 14 years. Of grave concern
is that the rates of prostate brachytherapy utilization, both
monotherapy and in the boost setting, are decreasing in favor
of dose-escalated EBRT (10, 11), despite data suggesting
that this may not be the optimal treatment strategy, espe-
cially for higher risk patients (15, 17, 18, 20e23).
The trend toward underutilization of a brachytherapy
boost is even more prominent in academic centers, where
most of the nation’s residents are expected to receive
specialized training in these procedures. Radiation
oncology residents must emerge from their training pro-
grams comfortable and proficient in this cost-effective
and efficacious procedure while also being well versed in
this procedure as both a monotherapy and as a boost sec-
ondary to EBRT, as there are nuanced differences intrinsic
to each. The ASCENDE-RT (1) trial has reported a greater
urinary stricture rate with brachytherapy boost, which was
also seen in a CaPSURE database review (24); however,
the incidence is less than what has been reported for pros-
tatectomy and the literature suggests brachytherapy tech-
niques can be modified to further reduce this risk
(25, 26). This reinforces the critical need for academic pro-
grams to provide high case volumes and intense training in
brachytherapy techniques for their trainees.
Given the Level 1 evidence demonstrating a benefit to
the addition of a brachytherapy boost for intermediate-
and high-risk prostate cancer, current utilization trends will
need to reverse. Although an overall survival benefit has yet
to be reported, the biochemical control benefit at 9 years is
striking (1). Given the cascade of events creating a signifi-
cant quality of life reduction and economic cost that are
triggered in the event of biochemical failure, every effort
must be made to provide appropriate training opportunities
to the next generation of residents and leaders. The most
logical place to start is within residency training programs,
most often found at academic centers. Strategies are there-
fore needed to allow academic centers to bring forth the
necessary training and education required for residents to
be proficient in prostate brachytherapy in all settings. Addi-
tional training opportunities must also be brought forth to
our wider membership in the future.
In the early years of prostate brachytherapy, many resi-
dents and physicians learned the techniques of the proce-
dure first through lecture, followed by the implantation of
prostate phantoms before performing the procedure live.
MD Anderson Cancer Center published on the utilization
of a prostate brachytherapy simulator in their residency
program suggesting that it may be possible to incorporate
prostate brachytherapy simulators into academic programs
across the country (27). Surgical training programs in our
Table 2
Multivariable logistic regression for receipt of EBRT brachytherapy boost
Category AOR (95% CI) p-Value
Year of diagnosis
2004e2006 Ref
2007e2009 0.72 (0.69e0.74) !0.0001
2010e2012 0.52 (0.50e0.54) !0.0001
Hospital type
Nonacademic Ref
Academic 0.68 (0.66e0.70) !0.0001
Age
!65 Ref
$65 0.61 (0.58e0.63) !0.0001
Race
Non-Hispanic White Ref
Black 1.06 (1.01e1.11) 0.01
Hispanic White 0.90 (0.83e0.98) 0.01
Other 1.33 (1.23e1.44) !0.0001
PSA
!10 Ref
10e20 0.91 (0.88e0.94) !0.0001
O20 0.80 (0.75e0.84) !0.0001
Gleason Score
#6 Ref
7 1.81 (1.72e1.89) !0.0001
8e10 1.90 (1.80e2.00) !0.0001
Tumor stage
T1 Ref
T2 1.14 (1.11e1.18) !0.0001
T3a 1.54 (1.41e1.69) !0.0001
Charlson comorbidity score
0 Ref
1 1.09 (1.04e1.14) 0.0003
2þ0.79 (0.70e0.89) !0.0001
Insurance status
Private Ref
None 0.46 (0.39e0.54) !0.0001
Medicaid 0.61 (0.55e0.68) !0.0001
Medicare 0.87 (0.84e0.91) !0.0001
Other 0.44 (0.39e0.50) !0.0001
Income
!$38,000 Ref
$38,000e47,999 1.05 (0.99e1.11) 0.055
$48,000e62,999 1.00 (0.94e1.05) 0.91
$63,000 1.26 (1.18e1.33) !0.0001
Education !high school
$21% Ref
13e20.9% 0.96 (0.92e1.01) 0.14
7e12.9% 0.98 (0.93e1.04) 0.47
!7% 0.99 (0.94e1.06) 0.86
Residence
Metropolitan Ref
Urban 0.83 (0.79e0.86) !0.0001
Rural 0.70 (0.62e0.78) !0.0001
AOR 5adjusted odds ratio; CI 5confidence interval; EBRT 5
external beam radiation therapy; PSA 5prostate-specific antigen.
4P.F. Orio et al. / Brachytherapy -(2016) -
country are increasingly using surgical simulators to train
residents in a safe environment that compensates for
varying caseloads and decreased training hours (28).By
practicing surgical procedures on a simulator, resident sur-
geons accelerate their learning curve and are more profi-
cient in their skills once they begin live surgical cases
with their attending physicians providing guidance (28).
To bring prostate brachytherapy training to a wider audi-
ence, training opportunities exist through the American
Brachytherapy Society and at the annual meeting of the
American Society for Radiation Oncology, which also pro-
vides hands on simulator training courses in conjunction
with the American Brachytherapy Society.
Since practice patterns will need to shift due to findings
of the ASCENDE-RT trial, the question becomes whether
academic centers are prepared to train the next generation
of residents in this treatment modality. A recent resident
report of brachytherapy experience in ACGME-accredited
radiation oncology training programs has demonstrated a
25% reduction in interstitial procedures from 2006 to
2011 (29). If we do not change our training environments
to align with scientific findings, one of the most effective
treatments for prostate cancer may be lost secondary to a
lack of physician training in this procedure.
Limitations of this study include that the NCDB does
not provide data for every patient treated in the United
States, but it does capture approximately 70% of patients
in this country and as such is helpful in identifying trends
in treatments over time. Second, the Charlson comorbidity
score is a summary score for comorbidity profile, and thus,
we were not able to do a more granular analysis to deter-
mine whether certain specific comorbidities were associ-
ated with brachytherapy boost omission.
Conclusion
Despite the ASCENDE-RT trial providing Level 1
randomized evidence for a significant improvement in
biochemical control of intermediate- and high-risk prostate
cancer with the use of EBRT plus a brachytherapy boost,
both academic and nonacademic radiation oncology prac-
tices have demonstrated a significant reduction in the use
of brachytherapy utilization from 2004 to 2012. Even more
concerning is that the lowest utilization of prostate brachy-
therapy was found in academic centers. In time, we may
lose this efficacious and cost-effective treatment from our
armamentarium if residents are deprived of appropriate
training opportunities to bring forth this procedure to the
next generation of patients.
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