CARE DELIVERY

Hypofractionated Prostate Radiation Therapy:

original contributions
Adoption and Dosimetric Adherence Through
Clinical Pathways in an Integrated
Oncology Network
Michael D. Schad, BS1; Ankur K. Patel, MD2; Diane C. Ling, MD2; Ryan P. Smith, MD2; and Sushil Beriwal, MD, MBA2

QUESTION ASKED: Can clinical pathways (CPs), in
concert with institutional quality controls, facilitate
adoption of moderately hypofractionated external
beam radiotherapy (mHF-EBRT) for patients with low-
and intermediate-risk prostate cancer in a large, in-
tegrated cancer center, before release of national
guidelines supporting its use?
SUMMARY ANSWER: Rapid adoption of mHF-EBRT
was seen in our large, integrated cancer center after
a prostate CP modification in January 2018 making
mHF-EBRT the recommended treatment for patients
with low- and intermediate-risk disease pursuing cu-
rative EBRT monotherapy (Figure). In patients treated
with EBRT monotherapy, mHF-EBRT use increased
from 3.7% before the CP modification to 85.6% after
modification (P , .001)
WHAT WE DID: The prostate CP in our cancer network
was updated in January 2018 to make mHF-EBRT the
recommended treatment for patients with low- and
intermediate-risk disease seeking curative EBRT
monotherapy. This modification was supported by
institutional policies to monitor and audit compliance.
Use of mHF-EBRT before CP modification in 2015-
2017 was compared with use after CP modification in
2018, using the Cochran-Armitage test for trend.
Predictors of mHF-EBRT use were analyzed via binary
ASSOCIATED
logistic regression.
CONTENT WHAT WE FOUND: In 560 patients treated with EBRT
Appendix monotherapy, mHF-EBRT use increased from 3.7% be-
Author affiliations fore CP modification to 85.6% after CP modification (P ,
and disclosures are .001), whereas conventionally fractionated EBRT (CF-
available with the
complete article at
EBRT) use decreased from 96.3% to 14.4% (P , .001).
ascopubs.org/ Predictors of mHF-EBRT use included consultation year of
journal/op.
Accepted on
September 23, 2020 CORRESPONDING AUTHOR
and published at Sushil Beriwal, MD, MBA, UPMC Hillman Cancer Center,
ascopubs.org/journal/ Department of Radiation Oncology, 300 Halket St, Pittsburgh, PA
op on October 23, 15213; e-mail: beriwals@upmc.edu.
2020: DOI https://doi.
org/10.1200/OP.20.
00508
2018 (odds ratio [OR], 214.6; 95% CI, 94.5 to 484.6; P ,
.001), treatment at an academic facility (OR, 4.5; 95% CI,
1.8 to 11.3; P 5 .001), and smaller prostate (OR, 0.99;
95% CI, 0.97 to 1.00; P 5 .028).
BIAS, CONFOUNDING FACTORS: Patients treated with
active surveillance, radical prostatectomy, or stereo-
tactic body radiotherapy were not included in this
study. Reasons for “off pathway” selection of CF-EBRT
after CP modification were not stated in 13 of 18 cases,
which prevented full accounting of barriers to mHF-
EBRT in our network. Institutional policies to monitor
and audit compliance likely also facilitated adoption.
REAL-LIFE IMPLICATIONS: Updates to national guide-
lines recommending new, evidence-based treatments
may lag several years after evidence from clinical trials
demonstrating efficacy of these treatments. Moreover,
publication of new guidelines alone may fail to induce
rapid, large-scale changes in practice patterns. In this
study, a prostate CP amendment, in conjunction with
institutional quality controls to monitor CP compliance,
facilitated rapid adoption of mHF-EBRT in our large,
integrated cancer center, with use increasing from
, 5% to . 85% after CP modification. The success of
CPs in helping change practice patterns in this study,
as well as others, suggests CPs are a useful tool to
standardize care across an institution and encourage
timely adoption of the most up-to-date and evidence-
based treatments. Also, because this modification
was made before national guidelines supporting
routine mHF-EBRT use in patients with prostate
cancer, CPs may help bridge the gap between
publication of primary evidence and release of na-
tional guidelines.

198 Volume 17, Issue 4

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 CARE DELIVERY

original contributions
Hypofractionated Prostate Radiation Therapy:
Adoption and Dosimetric Adherence Through
Clinical Pathways in an Integrated
Oncology Network
Michael D. Schad, BS1; Ankur K. Patel, MD2; Diane C. Ling, MD2; Ryan P. Smith, MD2; and Sushil Beriwal, MD, MBA2
abstract

PURPOSE Updates to consensus guidelines in October 2018 recommending moderately hypofractionated

external beam radiotherapy (mHF-EBRT) in prostate cancer lagged several years after publication of evidence
supporting its efficacy. In January 2018, we amended our prostate cancer clinical pathway (CP) to facilitate
adoption of mHF-EBRT. Herein, we analyze patterns of care and changes in mHF-EBRT use after the CP
modification.
METHODS Our prostate CP was amended in January 2018 to make mHF-EBRT the recommended treatment for
patients with low- and intermediate-risk prostate cancer pursuing curative EBRT monotherapy. Normal-tissue
dose constraints accompanied the CP modification to guide planning. Use of mHF-EBRT from 2015 to 2017
was compared with use in 2018 after the CP modification, using the Cochran-Armitage test for trend. Predictors
of mHF-EBRT use and adherence to dose constraints were analyzed with binary logistic regression.
RESULTS In 560 patients treated with EBRT monotherapy, mHF-EBRT use increased from 3.7% in 2015-
2017 to 85.6% in 2018 (P , .001), whereas conventionally fractionated EBRT (CF-EBRT) use decreased from
96.3% to 14.4% (P , .001). Consultation year of 2018 (odds ratio [OR], 214.6; 95% CI, 94.5 to 484.6; P ,
.001), treatment at an academic facility (OR, 4.5; 95% CI, 1.8 to 11.3; P 5 0.001), and having a smaller prostate
(OR, 0.99; 95% CI, 0.97 to 1.00; P 5 .028) predicted for mHF-EBRT use. At least five of six recommended
bladder and rectal dose constraints were met in 89.4% of patients.
CONCLUSION Modification of our prostate cancer CP, in concert with institutional policies to monitor and audit CP
compliance, facilitated rapid adoption of mHF-EBRT in our large, integrated cancer center with good adherence
to dosimetric constraints.
JCO Oncol Pract 17:e537-e547. © 2020 by American Society of Clinical Oncology

INTRODUCTION weeks, whereas CF-EBRT regimens typically require

Definitive prostate external beam radiation (EBRT) is
an effective treatment for clinically localized prostate
cancer and provides outcomes comparable to radical
Author affiliations prostatectomy.1 Although conventionally fractionated
and support EBRT (CF-EBRT) regimens of 1.8-2 Gy/fraction have
information (if traditionally been used, the radiobiological basis of
applicable) appear
at the end of this
hypofractionated EBRT (HF-EBRT) is supported by
article. the low a/b ratio of prostate cancer relative to sur-
Accepted on rounding normal organs, such as the rectum,2-7 which
September 23, 2020 may reduce toxicity and improve tumor control with
and published at HF-EBRT compared with CF-EBRT. There are so-
ascopubs.org/journal/
cioeconomic advantages to HF-EBRT as well, in-
op on October 23,
2020: DOI https://doi.
cluding lower cost to payers and greater convenience
org/10.1200/OP.20. to patients. Moderately hypofractionated EBRT (mHF-
00508 EBRT) regimens may be completed in as little as 4-6
closer to 8 weeks of treatment. HF-EBRT, therefore,
may reduce time and travel burden on patients.
Several large, randomized controlled trials comparing
mHF-EBRT regimens of 2.5-3.4 Gy/fraction to CF-EBRT
regimens have demonstrated comparable disease control
with acceptable toxicity using mHF-EBRT.8-11 However,
although early clinical trial reports and editorials in the
early to mid-2010s lent support to the efficacy and safety
of mHF-EBRT8,12-14 and data from larger trials published
in 2016 and 2017 confirmed these results,8-11 it was not
until October 2018 that consensus recommendations
from the American Society for Radiation Oncology
(ASTRO), the American Urological Association (AUA) and
ASCO supported routinely offering mHF-EBRT (defined
as 2.4-3.4 Gy/fraction) to patients with prostate cancer of

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Schad et al

A CF-EBRT LDR-BT EBRT + HDR-BT

B CF-EBRT LDR-BT EBRT + HDR-BT
70 mHF-EBRT HDR-BT EBRT + LDR-BT 60 mHF-EBRT HDR-BT EBRT + LDR-BT
Patients (%) 60 50

Patients (%)
50
40
40
30
30
20
20
10 10
0 0
2015 2016 2017 2018 2015 2016 2017 2018
Year Year

C CF-EBRT LDR-BT EBRT + HDR-BT

D CF-EBRT LDR-BT EBRT + HDR-BT
70 mHF-EBRT HDR-BT EBRT + LDR-BT 70 mHF-EBRT HDR-BT EBRT + LDR-BT
60 60
Patients (%)

Patients (%)
50 50
40 40
30 30
20 20
10 10
0 0
2015 2016 2017 2018 2015 2016 2017 2018
Year Year

FIG 1. Use of radiation modalities from 2015 to 2018 for patients with (A) all, (B) low-risk, (C) favorable intermediate-risk, and (D) unfavorable
intermediate-risk prostate cancer. CF-EBRT, conventionally fractionated external beam radiotherapy; EBRT, external beam radiotherapy; HDR-BT,
high-dose-rate brachytherapy; LDR-BT, low-dose-rate brachytherapy; mHF-EBRT, moderately hypofractionated external beam radiotherapy.

all risk groups.15 Despite robust evidence and consensus
guidelines supporting mHF-EBRT in prostate cancer, the
adoption rate has been slow.16,17 This lag mirrors the slow
adoption of hypofractionation in other disease sites, such as
breast cancer.18-20
Clinical pathways (CPs) are a multidisciplinary, evidence-
based management tool that mitigates unnecessary variations
in practice patterns and has been associated with improved
patient outcomes.21 We have previously reported our expe-
rience with CPs increasing adoption of hypofractionation in
breast cancer.22-24 To increase adoption of mHF-EBRT in
prostate cancer, the national ClinicalPath prostate cancer CP
(Elsevier, Pittsburgh, PA) was modified with collaborative
input from our institution and other participating institutions to
make mHF-EBRT the first-choice option for patients with low-
and intermediate-risk prostate cancer who are pursuing EBRT
monotherapy. This CP change went into effect at our in-
stitution in January 2018. Herein, we analyze the adoption of
mHF-EBRT within our large, integrated cancer center and
analyze predictors of mHF-EBRT use and adherence to mHF-
EBRT dose constraints.
METHODS
mHF-EBRT compared with CF-EBRT, 8-11 the national
ClinicalPath committee, with input and support from our
institution, voted to modify the prostate CP in January 2018
to make mHF-EBRT, using either 70 Gy in 28 fractions or
60 Gy in 20 fractions, the first-choice recommended
treatment option for patients with National Comprehensive
Cancer Network (NCCN) low- and intermediate-risk pros-
tate cancer pursuing definitive EBRT monotherapy. Shortly
after, the staff at our institution were notified about the
prostate CP modification via e-mail. The menu-driven
decision-support tool at our institution was updated on
January 31, 2018, to reflect this CP modification. Before
this update, mHF-EBRT was listed as a treatment option
but not specifically recommended as the preferred option.
The CP modification included updating the decision-
support tool so that the term “preferred” appeared next
to mHF-EBRT, with accompanying citations of trials sup-
porting mHF-EBRT and consensus normal-tissue con-
straints for mHF-EBRT radiation planning. If physicians
chose to administer CF-EBRT after the CP modification,
they would need to communicate their rationale with
pathway directors. Additional details regarding the process
of CP modification, implementation, and institution-specific
CP policies are available in the online-only Appendix.

CP Modification Cohort Selection and Data Acquisition

In response to several large randomized trials demon- After obtaining a waiver of informed consent from our in-
strating comparable efficacy and acceptable toxicity with stitutional review board, ARIA (Varian Medical Systems,

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Clinical Pathways and Adoption of Prostate Hypofractionation
Palo Alto, CA) was queried for patients with International
Classification of Diseases, Ninth Revision (ICD-9) code 185.0
and ICD-10 code C61.0 and initial consultations in the De-
partment of Radiation Oncology between January 2015 and
December 2018. Patient charts were reviewed for de-
mographic, clinical, pathological, and treatment charac-
teristics. Patients with low-risk, favorable intermediate-risk,
or unfavorable intermediate-risk disease (per NCCN criteria)
who were treated with definitive radiation therapy, including
brachytherapy, were included in an analysis of patterns of
care.25 Patients treated with palliative intent, androgen-
deprivation therapy only, radical prostatectomy, or active
surveillance were excluded because we were interested in
treatment selection for patients pursuing curative radiation
therapy. Patients treated with stereotactic body radiother-
apy (SBRT) were also excluded, because SBRT was not
a standard treatment option for patients during this time but
was available on a prospective protocol.
EBRT and Dosimetry
In our prostate CP, mHF-EBRT consisted of 70 Gy in 28 or
60 Gy in 20 fractions delivered via intensity-modulated
radiation therapy. All regimens with , 2.5 Gy/fraction were
considered CF-EBRT. The median CF-EBRT dose was
77.4 Gy (interquartile range [IQR], 75.6-89.2 Gy), and the
median fraction number was 43 (IQR, 42-44). Dose-volume
histograms of mHF-EBRT plans were accessed to analyze
adherence to normal-tissue dose constraints that accompa-
nied the CP modification. For the 70 Gy in 28 fractions
scheme, recommended normal-tissue dose constraints for
the bladder were volume receiving 70 Gy (V70) , 10 cc, V65
, 15%, and V40 , 35%. Recommended dose constraints for
the rectum were V70 , 10 cc, V65 , 10%, and V40 , 35%.
Statistical Analysis
Our hypothesis was that mHF-EBRT use increased after the
CP modification in January 2018. The Cochran-Armitage (CA)
test for trend was used to evaluate changes in use of mHF-
EBRT in the period before CP modification (January 2015 to
December 2017) versus after (January 2018 to December
2018). The CA test for trend was also used to determine if
selection of other treatment options changed over time. Po-
tential predictors of mHF-EBRT use and adherence to mHF-
EBRT dose constraints were analyzed with binary logistic
regression. As a sensitivity analysis, all continuous variables
were tested as categorical variables dichotomized around the
median value. Predictors of mHF-EBRT use with P , 0.10
were entered into a multivariate logistic regression model,
which was run with backward conditional stepwise selection.
Statistical significance was set at P , .05. Data were analyzed
in SPSS, version 26 (IBM, Armonk, NY).
RESULTS
Patient Characteristics
A total of 1,037 patients with low-risk, favorable
intermediate-risk, or unfavorable intermediate-risk prostate
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cancer were treated with curative-intent radiation at our
institution from January 2015 to December 2018. Patient
characteristics are described in Table 1. Of these, 805
patients (77.6%) were treated before CP modification
(2015-2017) and 232 patients (22.4%) were treated after
CP modification (2018). Distribution by risk group was as
follows: low risk, 252 (24.3%); favorable intermediate risk,
274 (26.4%); and unfavorable intermediate risk, 511
(49.3%). A similar number of prostate cancer consultations
occurred each year during the study period. Most patients
were treated at a community center (76.2%). Patients with
low-risk disease were most frequently treated with low-
dose-rate brachytherapy (LDR-BT; 50.0%), followed by
EBRT monotherapy (46.4%). Most patients with favorable
intermediate-risk disease were treated with EBRT mono-
therapy (54.8%), followed by LDR-BT (33.9%). Patients
with unfavorable intermediate-risk disease were the most
likely to receive EBRT and brachytherapy boost (36.4%).
Patterns of Care Over Time
Patterns of care in the overall cohort of patients pursuing
definitive radiation from 2015 to 2018 are shown in Figure 1
and Appendix Table A1 (online only). Compared with 2015,
use of mHF-EBRT in 2018 significantly increased in the
overall cohort (from 0% to 46.1%; P , .001) whereas use of
CF-EBRT significantly decreased (from 51.0% to 7.8%;
P , .001); these trends retained statistical significance for
each risk group as well. Increased use of high-dose-rate BT
(HDR-BT) monotherapy occurred in patients with favorable
intermediate-risk disease (0% to 3.0%; P 5 .053), whereas
increased use of EBRT with HDR-BT boost occurred in
patients with unfavorable intermediate-risk disease
(8.6% to 16.9%; P 5 .009). Use of LDR-BT or EBRT with
LDR-BT boost did not change over time in the overall cohort
or in any risk group.
Patients who chose to pursue active surveillance or pros-
tatectomy after discussion with a urologist and who were
not referred formally to the Department of Radiation On-
cology were not captured in our departmental data set;
however, the number of patients seen for a radiation
consultation in 2015, 2016, 2017, and 2018 who sub-
sequently chose active surveillance was 31, 34, 28, and 44,
respectively, and the number of those who chose prosta-
tectomy in those years was 31, 24, 38, and 28, respectively.
Among 560 patients treated with EBRT monotherapy
during the study period, mHF-EBRT use significantly in-
creased from 3.7% in 2015-2017 to 85.6% in 2018 after
CP modification (P , .001), with a corresponding decrease
in CF-EBRT use from 96.3% to 14.4% (P , .001). An
increase in mHF-EBRT use was seen in patients with low-
risk (5.2% v 90.5%; P , .001), favorable intermediate-risk
(1.8% v 89.2%; P , .001), and unfavorable intermediate-
risk (4.0% v 82.1%; P , .001) prostate cancer. mHF-EBRT
use increased at community centers (2.5% v 83.7%; P ,
.001) and academic centers (10.1% v 95.2%; P , .001)
e539
 Schad et al

TABLE 1. Baseline Characteristics

Favorable Unfavorable
Low Risk Intermediate Risk Intermediate Risk All Patients
Baseline Characteristic (n 5 252) (n 5 274) (n 5 511) (N 5 1,037)
Year of consultation
2015 80 (31.7) 76 (27.7) 140 (27.4) 296 (28.5)
2016 66 (26.2) 64 (23.4) 124 (24.3) 254 (24.5)
2017 58 (23.0) 68 (24.8) 129 (25.2) 255 (24.6)
2018 48 (19.0) 66 (24.1) 118 (23.1) 232 (22.4)
Median age at consultation, years (range) 66.7 (47.1-84.0) 68.8 (52.7-96.5) 71.0 (55.1-85.8) 69.4 (47.1-96.5)
Median AUA score (range) 6 (0-30) 6 (0-30) 7 (0-27) 6 (0-30)
T stage
T1c-T2a 252 (100.0) 257 (93.8) 326 (63.8) 835 (80.5)
T2b-T2c 0 (0.0) 17 (6.2) 185 (36.2) 202 (19.5)
PSA concentration, median (range) 5.7 (0.5-9.9) 6.4 (0.6-18.0) 8.1 (0.9-19.7) 6.7 (0.5-19.7)
Gleason grade group
1 (313) 252 (100.0) 49 (17.9) 19 (3.7) 320 (30.9)
2 (314) 0 (0.0) 225 (82.1) 202 (39.5) 427 (41.2)
3 (413) 0 (0.0) 0 (0.0) 290 (56.8) 290 (28.0)
Pattern of care
CF-EBRT 93 (36.9) 115 (42.0) 229 (44.8) 437 (42.1)
mHF-EBRT 24 (9.5) 35 (12.8) 64 (12.5) 123 (11.9)
LDR-BT 126 (50.0) 93 (33.9) 31 (6.1) 250 (24.1)
HDR-BT 6 (2.4) 2 (0.7) 1 (0.2) 9 (0.9)
EBRT1HDR-BT 2 (0.8) 12 (4.4) 64 (12.5) 78 (7.5)
EBRT1LDR-BT 1 (0.4) 17 (6.2) 122 (23.9) 140 (13.5)
ADT use
None 240 (95.2) 194 (70.8) 168 (32.9) 602 (58.1)
3-6 months 4 (1.6) 63 (23.0) 291 (56.9) 358 (34.5)
. 6 months 3 (1.2) 12 (4.4) 37 (7.2) 52 (5.0)
Unknown 5 (2.0) 5 (1.8) 15 (2.9) 25 (2.4)
Facility type
Community 208 (82.5) 205 (74.8) 377 (73.8) 790 (76.2)
Academic 44 (17.5) 69 (25.2) 134 (26.2) 247 (23.8)

NOTE. Data presented as No. (%) unless otherwise indicated.

Abbreviations: ADT, androgen deprivation therapy; AUA, American Urological Association; CF-EBRT, conventionally fractionated external
beam radiotherapy; HDR-BT, high-dose-rate brachytherapy; LDR-BT, low-dose-rate brachytherapy; mHF-EBRT, moderately hypofractionated
external beam radiotherapy; PSA, prostate specific antigen; T stage, tumor stage.

after CP modification. All patients treated with mHF-EBRT
received 70 Gy in 28 fractions; no patient received 60 Gy in
20 fractions.
Of 18 patients treated with CF-EBRT monotherapy after CP
modification, 13 patients received CF on the basis of
physician preference, and inability to meet mHF-EBRT
dose constraints was cited for three patients. One patient
began EBRT with a plan for HDR-BT boost, but brachy-
therapy was subsequently cancelled because of surgical
risk from comorbidities, thus necessitating completion of
treatment with CF-EBRT. Another patient began a course of
mHF-EBRT but urinary retention developed that required
transurethral resection of the prostate; treatment was then
completed with CF-EBRT.
Predictors of mHF-EBRT Use and
Dose-Constraint Adherence
On univariate analysis (Table 2), statistically significant
predictors of mHF-EBRT use in patients treated with EBRT
monotherapy included year 2018 consultation, stage

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 Clinical Pathways and Adoption of Prostate Hypofractionation
T1a-T2a, and treatment at an academic facility. Smaller
prostate as a continuous variable showed a trend for
significance (OR 0.99; 95% CI, 0.98 to 1.00; P 5 .063).
On multivariate analysis (Table 3), 2018 consultation
year (OR, 214.6; 95% CI, 94.5 to 484.6; P , .001),
treatment at an academic facility (OR, 4.5; 95% CI, 1.8 to
11.3; P 5 .001), and smaller prostate (OR, 0.99; 95% CI,
0.97 to 1.00; P 5 .028) remained significant predictors
of mHF-EBRT use. Among patients treated with EBRT
monotherapy in 2018 (after the CP modification), no
variables predicted for mHF-EBRT use. Thus, the CP
modification increased use of mHF-EBRT in all patients,
regardless of practice setting, risk group, prostate size,
AUA score, or any other clinical or pathologic variables.
Among the 123 patients treated with mHF-EBRT, bladder
V70, V65, and V40 dose-constraint adherence rates and
median values were as follows: 82.1% (median, 5.60 cc;
IQR, 3.49 to 9.23 cc), 98.4% (median, 5.00%; IQR,
2.95%-8.17%), and 91.1% (median, 22.86%; IQR, 14.37-
29.67), respectively. All three bladder constraints were
met in 74.0% of patients, and at least two constraints
were met in 98.4%. Rectum V70, V65, and V40 dose-
constraint adherence rates and median values were as
follows: 99.2% (median, 1.89 cc; IQR, 1.09-2.57 cc),
87.8% (median, 6.29%, IQR, 4.21%-7.61%), and
85.6% (median, 27.50%; IQR, 20.71%-32.15%), re-
spectively. All three rectal constraints were met in 81.3% of
patients, and at least two constraints were met in 91.9%. All
six bladder and rectal constraints were met in 61.8% of
patients, and at least five constraints were met in 89.4%. A
larger prostate predicted for inability to meet the bladder
V70 constraint (OR, 0.94; 95% CI, 0.94 to 0.98; P , .001)
and rectum V65 constraint (OR, 0.98; 95% CI, 0.95 to
1.00; P 5 .032).
DISCUSSION
After our prostate CP was updated in January 2018 to list
mHF-EBRT as the first-choice recommended option for
patients with low- and intermediate-risk prostate cancer
pursuing EBRT monotherapy, mHF-EBRT use increased
from 3.7% to 85.6% (P , .001) in patients treated with
EBRT monotherapy. Increases in mHF-EBRT were seen in
all risk groups and at academic and community sites. In the
overall cohort of patients pursuing definitive radiation, in-
creases in use of mHF-EBRT (from 0% to 46.1%; P , .001)
were met by a decline in CF-EBRT use of approximately the
same magnitude (from 51% to 7.8%; P , .001). Thus,
mHF-EBRT replaced increasingly outdated CF-EBRT
regimens and did not detract from use of other standard-of-
care treatments such as brachytherapy. Although aware-
ness of emerging data supporting mHF-EBRT may have
contributed to moderate early adoption of mHF-EBRT
(5.9% use by 2017 in the overall cohort; Appendix
Table A1), it was not until the CP modification in 2018 that
mHF-EBRT use increased substantially and became the
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most commonly used treatment modality for patients
pursuing definitive EBRT. Because the implementation of
this national CP modification at our institution predated
updates in ASTRO consensus guidelines supporting mHF-
EBRT, these results demonstrate the effectiveness of CPs in
facilitating adoption of new, evidence-based care, bridging
the gap between publication of practice-changing clinical
trials and updates in consensus guidelines.
In 2016 and 2017, the publication of several key trials lent
support to the efficacy and safety of mHF-EBRT in prostate
cancer.8-11 More discussion of these trials is available in the
online-only Appendix. As a result of these trials, but with
a lag time of several years, consensus guidelines from
ASTRO, ASCO, and AUA were updated in October 2018 to
recommend routinely offering moderate HF-EBRT (defined
as 2.4-3.4 Gy/fraction) to patients with locally confined
prostate cancer, regardless of risk group, age, comorbidity,
anatomy, or urinary function.15 NCCN guidelines did not
recommend HF-EBRT routinely be offered, until January
2020, when HF-EBRT became the preferred fractionation
schedule for all risk groups.25 The update to our CP in
January 2018 predated these national guideline updates
and increased mHF-EBRT use within a large, integrated
comprehensive cancer center, helping bridge the gap
between publication of primary evidence and updates in
consensus guidelines.
CPs are a useful management tool to help facilitate early
implementation of new, evidence-based protocols. CP
modifications are a multi-institutional collaboration be-
tween academic and community physicians, including
those from our network, and the prostate CP modification
described in this study required a majority vote before
adoption. CPs may thus temper individual physician bias by
guiding treatment selection reached by multi-institutional
consensus. CP modification, in concert with quality controls
for pathway compliance at our institution, was likely in-
strumental in facilitating the rapid adoption of mHF-EBRT
for prostate cancer at our institution. CPs have also been
effective in increasing the adoption of hypofractionation for
women with breast cancer ages , 50,22 $ 50,23 and $
7024 years.
Adoption of hypofractionation has been slow for prostate
cancer16 as well as other disease sites such as breast
cancer18-20 and bone metastases.26 Several reasons may
explain the slow adoption of mHF-EBRT in prostate cancer,
including unfamiliarity with new clinical trials and tech-
niques, concerns with achieving normal-tissue dose con-
straints, lower reimbursement, concerns with relatively
shorter follow-up with mHF-EBRT trials compared with CF-
EBRT, and lagging updates in consensus guidelines. CPs
may reduce these barriers by recognizing evolving treat-
ment paradigms early on and implementing protocols
across an institution so patients are provided the most up-
to-date, evidence-based care that is safe, efficacious, and
cost effective.
e541
 Schad et al

TABLE 2. Univariate of Predictors of mHF-EBRT Use in Patients Treated With EBRT Monotherapy
CF-EBRT mHF-EBRT OR for mHF-EBRT
Baseline Characteristic (n 5 437) (n 5 123) (95% CI) P
Consultation year , .001
2015-2017 419 (96.3) 16 (3.7) Reference
2018 18 (14.4) 107 (85.6) 155.67 (76.83 to 315.40)
a
Median age at consultation, years (IQR) 70.39 (65.62-70.39) .383
# 70.39 215 (76.5) 66 (23.5) Reference
. 70.39 222 (79.6) 57 (20.4) 0.84 (0.56 to 1.25)
Median AUA score (IQR)a 7 (3-13) .657
, 20 285 (78.5) 78 (21.5) Reference
$ 20 27 (81.8) 6 (18.2) 0.81 (0.32 to 2.04)
T stage .009
T1a-T2 349 (75.9) 111 (24.1) Reference
T2b-T2 88 (88.0) 12 (12.0) 0.43 (0.23 to 0.81)
Median PSA level, ng/mL (IQR)a 7.2 (5.4-10.1) .436
# 7.2 210 (76.6) 64 (23.4) 1.17 (0.79 to 1.75)
. 7.2 227 (79.4) 59 (20.6) Reference
Gleason grade .357
1 (313) 130 (81.3) 30 (18.8) Reference
2 (314) 180 (78.3) 50 (21.7) 1.20 (0.73 to 2.00)
3 (413) 127 (74.7) 43 (25.3) 1.47 (0.87 to 2.48)
Risk group .856
Low 93 (79.5) 24 (20.5) Reference
Favorable intermediate 115 (76.7) 35 (23.3) 1.18 (0.66 to 2.12)
Unfavorable intermediate 229 (78.2) 64 (21.8) 1.08 (0.64 to 1.84)
Duration of ADT use, months .214
None 171 (73.1) 63 (26.9) Reference
3-6 234 (79.6) 60 (20.4) 0.70 (0.46 to 1.04)
.6 29 (100.0) 0 (0.0) NR
Facility type .046
Community 374 (79.6) 96 (20.4) Reference
Academic 63 (70.0) 27 (30.0) 1.67 (1.01 to 2.76)
Median prostate size on CT, cc (IQR)a,b 48.30 (34.40-66.50) .370
# 48.30 210 (76.1) 66 (23.9) Reference
. 48.30 218 (79.3) 57 (20.7) 0.83 (0.56 to 1.24)

NOTE. Data presented as No. (%) unless otherwise indicated.

Abbreviations: ADT, androgen deprivation therapy; AUA, American Urological Association; CF-EBRT, conventionally fractionated external
beam radiotherapy; CT, computed tomography; IQR, interquartile range; mHF-EBRT, moderately hypofractionated external beam radiotherapy;
NR, not reportable; OR, odds ratio; PSA, prostate-specific antigen; T stage, tumor stage.
a
Age, AUA score, PSA level, and prostate size were also tested as continuous variables.
b
Prostate size as a continuous variable showed a trend for significance (OR, 0.99; 95% CI, 0.98 to 1.00; P 5 .063).

At least five of the six bladder and rectal dose constraints
included with our prostate CP modification were met in
89.4% of patients, and rectum V70 , 10 cc was met in
99.2%, suggesting that concern about the inability to safely
deliver mHF-EBRT with 70 Gy in 28 fractions should not be
a barrier to adoption in the community. Of note, no patients
were treated with 60 Gy in 20 fractions, even though this
regimen was allowed, possibly due to difficulty achieving
rectal dose constraints with this more hypofractionated
regimen. As studies further elucidate appropriate dosi-
metric criteria for mHF-EBRT with 60 Gy in 20 fractions,27
adoption of this fractionation scheme may increase.

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 Clinical Pathways and Adoption of Prostate Hypofractionation

TABLE 3. Multivariate of Predictors of mHF-EBRT Use in Patients

Treated With EBRT Monotherapy
OR for mHF-EBRT
Baseline Characteristic (95% CI)
Consultation year , .001
2015-2017 Reference
2015
2016
2017
2018 214.56 (94.99 to 484.63)
Facility type
Community Reference
Academic 4.50 (1.79 to 11.31)
Prostate size on CT 0.99 (0.97 to 1.00)
Abbreviations: CT, computed tomography; mHF-EBRT, moderately
hypofractionated external beam radiotherapy; OR, odds ratio.
Furthermore, the emergence of rectal spacers,28,29 which
were not in widespread use in our network during the study
period, may make it easier to meet the high-dose rectal
constraints with this regimen and further encourage its
adoption.
This study has several limitations. Although emerging data
support the efficacy of radiosurgery in prostate cancer,
prostate SBRT was only offered as part of a protocol at
a limited number of centers because radiosurgery tech-
nology was not widely available throughout our network.
Therefore, data on percentage of patients treated with
SBRT were not collected. In addition, our data set consisted
only of patients seen by the Department of Radiation
Oncology for consideration of radiation treatment. Patients
who chose to pursue active surveillance after discussion
with a urologist and who were not referred formally to the
Department of Radiation Oncology were not captured in our
data set. However, the primary goal of this study was to
analyze radiation fractionation regimens used over time,
and given that use of CF-EBRT declined by approximately
the same amount as the increase in mHF-EBRT, it appears
that CF-EBRT was simply substituted with mHF-EBRT.
P Also, reasons for “off pathway” selection of CF-EBRT in
2018 after CP modification were not stated in 13 of 18
cases, which prevented full accounting of all barriers to
mHF-EBRT within our network. CP modification was
supported by institutional quality-control polices to monitor
and audit compliance; therefore, CP modification alone
may not have produced as rapid an uptake of mHF-EBRT.
Other factors, including dissemination of data supporting
.001 mHF-EBRT through the decision support tool and edu-
cational discussions between treating physicians and CP
directors when off-pathway treatment choices were cho-
sen, may have facilitated uptake of mFH-EBRT as well.
.028 Finally, the described CP modification was approved by
a national committee and implemented in other cancer
centers as well. Although a multi-institutional analysis of
practice patterns was outside of the scope of this in-
vestigation, it would be valuable to investigate whether
this CP modification produced similar results at other
institutions.
In conclusion, an update to our institution’s CP, which
made mHF-EBRT the recommended option for patients
with low- and intermediate-risk prostate cancer pursuing
definitive EBRT monotherapy, facilitated rapid adoption of
mHF-EBRT throughout a large integrated cancer center.
The update was supported by institutional policies to
monitor and audit CP compliance. Because this modifi-
cation was implemented ahead of guidelines recom-
mending routine use of mHF-EBRT in patients with
prostate cancer, CPs bridged the gap between publication
of primary evidence demonstrating efficacy of mHF-EBRT
and publication of updated consensus guidelines. CPs, in
concert with institutional quality controls, are a useful tool to
standardize care across an institution and can facilitate
timely adoption of the most up-to-date and evidence-based
treatment.

AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF

1
University of Pittsburgh School of Medicine, Pittsburgh, PA
2
Department of Radiation Oncology, UPMC Hillman Cancer Center,
University of Pittsburgh School of Medicine, Pittsburgh, PA
INTEREST
Disclosures provided by the authors are available with this article at DOI
https://doi.org/10.1200/JOP.20.00508.

CORRESPONDING AUTHOR AUTHOR CONTRIBUTIONS

Sushil Beriwal, MD, MBA, UPMC Hillman Cancer Center, Department of
Radiation Oncology, 300 Halket St, Pittsburgh, PA 15213; e-mail:
beriwals@upmc.edu.
PRIOR PRESENTATION
Presented in part at the American Society for Radiation Oncology Annual
Meeting, Miami, FL, October 25, 2020.
Conception and design: Ankur K. Patel, Ryan P. Smith, Sushil Beriwal
Provision of study material or patients: Ryan P. Smith
Collection and assembly of data: Michael D. Schad, Ankur K. Patel, Diane
C. Ling, Sushil Beriwal
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

SUPPORT
Supported by a grant from the Shadyside Hospital Foundation.

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 Schad et al

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14. Lee WR: Hypofractionation for prostate cancer: Tested and proven. Lancet Oncol 17:1020-1022, 2016
15. Morgan SC, Hoffman K, Loblaw DA, et al: Hypofractionated radiation therapy for localized prostate cancer: An ASTRO, ASCO, and AUA evidence-based
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16. Stokes WA, Kavanagh BD, Raben D, et al: Implementation of hypofractionated prostate radiation therapy in the United States: A National Cancer Database
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17. McClelland S III, Sandler KA, Degnin C, et al: Is moderate hypofractionation accepted as a new standard of care in North America for prostate cancer patients
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Oncol Biol Phys 90:1001-1009, 2014
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United States, 2008-2013. JAMA 312:2542-2550, 2014
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Oncol Biol Phys 93:854-861, 2015
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of radiation therapy fractionation. Int J Radiat Oncol Biol Phys 106:928-938, 2020
28. Hamstra DA, Mariados N, Sylvester J, et al: Continued benefit to rectal separation for prostate radiation therapy: Final results of a phase III trial. Int J Radiat Oncol
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n n n

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 Clinical Pathways and Adoption of Prostate Hypofractionation

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Hypofractionated Prostate Radiation Therapy: Adoption and Dosimetric Adherence Through Clinical Pathways in an Integrated Oncology Network
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/op/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Ryan P. Smith Sushil Beriwal

Consulting or Advisory Role: Elsevier Honoraria: Varian Medical Systems, XOFT
Open Payments Link: https://openpaymentsdata.cms.gov/physician/1136218 Consulting or Advisory Role: Elsevier
No other potential conflicts of interest were reported.

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 Schad et al
APPENDIX
Clinical Pathways at Our Institution
The University of Pittsburgh Medical Center Hillman Cancer Center is
a National Cancer Institute–designated comprehensive cancer center
operating as a hub-and-satellite system. The western Pennsylvania
network comprises central academic and regional community facilities
linked by an integrated electronic medical record system (ARIA, Varian
Medical Systems, Palo Alto, CA). Facilities staffed by faculty with roles
in research and/or overseeing radiation oncology resident instruction
and clinical care are considered academic centers, and all other fa-
cilities are considered community centers. Since 2001, the University
of Pittsburgh Medical Center Hillman Cancer Center has used clinical
pathways (CPs) to provide the most up-to-date, evidence-based
treatment guidelines for physicians within our network to minimize
unnecessary variations in care patterns. Each CP is a disease-specific
menu of treatment options developed by a collaborative group of
academic and community physicians from multiple institutions, in-
cluding ours, and is subject to semiannual revisions during which
newly published data are considered and CP modifications are pro-
posed. Potential CP modifications are disseminated in advance of
revision meetings, which are accessible to all members via telecon-
ference. During revision meetings, potential CP modifications are
discussed, and participating physicians are asked to vote for or against
a CP modification. Modifications passing a majority vote are in-
corporated into CPs across all participating institutions. Each institution
incorporates CP modifications on its own timeline, using institution-
specific systems to disseminate reports of CP modifications, update
CPs in decision-support tools, and audit CP use and compliance by
physicians. At our institution, a final report of all approved CP modi-
fications is made available to our staff.
At our institution, once a course of treatment is chosen for a given
patient, the treating physician enters this choice into a menu-driven
decision-support tool (ClinicalPath; Elsevier, Pittsburgh, PA) that
displays treatment options available on a given CP. Selected treatment
plans that are not a standard CP choice are flagged as “off pathway.”
Once an off-pathway treatment selection is entered, the disease-site
CP director is notified by e-mail and typically corresponds with the
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treating physician within 24-48 hours to discuss the rationale for the
off-pathway selection. In addition, treating physicians may reach out to
the pathway director independently. Treating physicians are asked to
justify their choice of an off-pathway plan, and if reasoning and evi-
dence are compelling, physicians can deliver the treatment while still
being considered as delivering pathway-compliant care. All efforts are
made to choose an appropriate treatment plan without delaying patient
care. At our institution, all radiation plans to be delivered at a specific
center are peer reviewed for quality before treatment delivery by other
radiation oncologists at that center or from a different center for sites
that have only one radiation oncologist.
All treatment plans chosen by physicians in our network must be
entered into the CP menu-driven decision-support tool. Physicians are
reminded daily if they have not chosen a CP for a given patient and
a quarterly report is generated regarding their compliance with CP
entry. Monthly audits are performed to record discordance between
CP entries and actual treatment plans delivered. As a component of the
CP initiative at our institution, delivery of pathway-compliant care is
monitored with a goal compliance rate of $ 90%. Meeting this
standard satisfies one component of a multifaceted quality-based
incentive.
Key Trials Lending Support to The Efficacy and Safety of
mHF-EBRT in Prostate Cancer
RTOG 0415, published in 2016, found that a hypofractionated scheme
of 70 Gy in 28 fractions was noninferior to a conventionally fractioned
scheme of 73.8 Gy in 41 fractions with regard to 5-year disease-free
survival.10 Publication of the HYPRO and CHHiP trials in 2016 showed
similar 5-year disease outcomes between conventionally fractionated
external beam radiotherapy and moderately hypofractionated external
beam radiotherapy (mHF-EBRT) schemes of 64.6 Gy in 19 fractions
and 60 Gy in 20 fractions, respectively.8,11 The PROFIT trial, published
in March 2017, found that 5-year biochemical control with 60 Gy in 20
fractions was noninferior to 78 Gy in 39 fractions.9 These trials also
demonstrated acceptable acute and late genitourinary and GI toxicity
with mHF-EBRT.
Volume 17, Issue 4
 Clinical Pathways and Adoption of Prostate Hypofractionation

TABLE A1. Patterns of Care From 2015 to 2018

2015 2016 2017 2018
Pattern of Care (N 5 296) (N 5 254) (N 5 255) (N 5 232) Pa
All patients (N 5 1,037)
CF-EBRT 151 (51.0) 146 (57.5) 122 (47.8) 18 (7.8) , .001
mHF-EBRT 0 (0.0) 1 (0.4) 15 (5.9) 107 (46.1) , .001
LDR-BT 83 (28.0) 59 (23.2) 55 (21.6) 53 (22.8) .121
HDR-BT 1 (0.3) 0 (0.0) 3 (1.2) 5 (2.2) .013
EBRT1HDR-BT 16 (5.4) 14 (5.5) 27 (10.6) 21 (9.1) .026
EBRT1LDR-BT 45 (15.2) 34 (13.4) 33 (12.9) 28 (12.1) .289
Low risk (n 5 252)
CF-EBRT 37 (46.3) 30 (45.5) 24 (41.4) 2 (4.2) , .001
mHF-EBRT 0 (0.0) 1 (1.5) 4 (6.9) 19 (39.6) , .001
LDR-BT 41 (51.2) 35 (53.0) 26 (44.8) 24 (50.0) .648
HDR-BT 1 (1.3) 0 (0.0) 3 (5.2) 2 (4.2) .113
EBRT1HDR-BT 1 (1.3) 0 (0.0) 1 (1.7) 0 (0.0) .706
EBRT1LDR-BT 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.1) .122
Favorable intermediate risk (n 5 274)
CF-EBRT 39 (51.3) 38 (59.4) 34 (50.0) 4 (6.1) , .001
mHF-EBRT 0 (0.0) 0 (0.0) 2 (2.9) 33 (50.0) , .001
LDR-BT 30.0 (39.5) 16 (25.0) 23 (33.8) 24 (36.4) .902
HDR-BT 0 (0.0) 0 (0.0) 0 (0.0) 2 (3.0) .053
EBRT1HDR-BT 3 (3.9) 4 (6.3) 4 (5.9) 1 (1.5) .527
EBRT1LDR-BT 4 (5.3) 6 (9.4) 5 (7.4) 2 (3.0) .452
Unfavorable intermediate risk (n 5 511)
CF-EBRT 75 (53.6) 78 (62.9) 64 (49.6) 12 (10.2) , .001
mHF-EBRT 0 (0.0) 0 (0.0) 9 (7.0) 55 (46.6) , .001
LDR-BT 12 (8.6) 8 (6.5) 6 (4.7) 5 (4.2) .111
HDR-BT 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.8) .164
EBRT1HDR-BT 12 (8.6) 10 (8.1) 22 (17.1) 20 (16.9) .009
EBRT1LDR-BT 41 (29.3) 28 (22.6) 28 (21.7) 25 (21.2) .122

NOTE. Data reported as annual No. (%) unless otherwise indicated.

Abbreviations: ADT, androgen deprivation therapy; CF-EBRT, conventionally fractionated external beam radiotherapy; HDR-BT, high-dose-rate
brachytherapy; LDR-BT, low-dose-rate brachytherapy; mHF-EBRT, moderately hypofractionated external beam radiotherapy.
a
Cochran-Armitage test for trend over time.

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