Research

JAMA Oncology | Original Investigation

Comparison Between Adjuvant and Early-Salvage

Postprostatectomy Radiotherapy for Prostate Cancer
With Adverse Pathological Features
William L. Hwang, MD, PhD; Rahul D. Tendulkar, MD; Andrzej Niemierko, PhD; Shree Agrawal, BS; Kevin L. Stephans, MD; Daniel E. Spratt, MD;
Jason W. Hearn, MD; Bridget F. Koontz, MD; W. Robert Lee, MD, MEd, MS; Jeff M. Michalski, MD; Thomas M. Pisansky, MD; Stanley L. Liauw, MD;
Matthew C. Abramowitz, MD; Alan Pollack, MD, PhD; Drew Moghanaki, MD, MPH; Mitchell S. Anscher, MD; Robert B. Den, MD; Anthony L. Zietman, MD;
Andrew J. Stephenson, MD; Jason A. Efstathiou, MD, DPhil

Supplemental content
IMPORTANCE Prostate cancer with adverse pathological features (ie, pT3 and/or positive
margins) after prostatectomy may be managed with adjuvant radiotherapy (ART) or
surveillance followed by early-salvage radiotherapy (ESRT) for biochemical recurrence. The
optimal timing of postoperative radiotherapy is unclear.

OBJECTIVE To compare the clinical outcomes of postoperative ART and ESRT administered to
patients with prostate cancer with adverse pathological features.

DESIGN, SETTING, AND PARTICIPANTS This multi-institutional, propensity score–matched

cohort study involved 1566 consecutive patients who underwent postprostatectomy ART or
ESRT at 10 US academic medical centers between January 1, 1987, and December 31, 2013.
Propensity score 1-to-1 matching was used to account for covariates potentially associated
with treatment selection. Data were collected from January 1 to September 30, 2016. Data
analysis was conducted from October 1, 2016, to October 21, 2017.

MAIN OUTCOMES AND MEASURES Freedom from postirradiation biochemical failure, freedom
from distant metastases, and overall survival. All outcomes were measured from date of
surgery to address lead-time bias.

RESULTS Of 1566 patients, 1195 with prostate-specific antigen levels of 0.1 to 0.5 ng/mL
received ESRT and 371 patients with prostate-specific antigen levels lower than 0.1 ng/mL
received ART. The median age (interquartile range) was 60 (55-65) years. After propensity
score matching, the median (interquartile range) follow-up after surgery was similar between
the ESRT and ART groups (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22).
Adjuvant RT, compared with ESRT, was associated with higher freedom from biochemical
failure (12-year actuarial rates: 69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect
size, 26%), freedom from distant metastases (95% [95% CI, 90%-97%] vs 85% [95% CI,
76%-90%]; effect size, 10%), and overall survival (91% [95% CI, 84%-95%] vs 79% [95% CI,
69%-86%]; effect size, 12%). Adjuvant RT, lower Gleason score and T stage, nodal irradiation,
and postoperative androgen deprivation therapy were favorable prognostic features on
multivariate analysis for biochemical failure. Sensitivity analysis demonstrated that the
decreased risk of biochemical failure associated with ART remained significant unless more
than 56% of patients in the ART group were cured by surgery alone. This threshold is greater
than the estimated 12-year freedom from biochemical failure rate of 33% to 52% after radical
prostatectomy alone, as determined by a contemporary dynamic nomogram.

CONCLUSIONS AND RELEVANCE Adjuvant RT, compared with ESRT, was associated with
reduced biochemical recurrence, distant metastases, and death for high-risk patients, Author Affiliations: Author
pending prospective validation. These findings suggest that a greater proportion of patients affiliations are listed at the end of this
article.
with prostate cancer who have adverse pathological features may benefit from
Corresponding Author: Jason A.
postprostatectomy ART rather than surveillance followed by ESRT.
Efstathiou, MD, DPhil, Massachusetts
General Hospital, Harvard Medical
School, 100 Blossom St, Cox Bldg,
JAMA Oncol. 2018;4(5):e175230. doi:10.1001/jamaoncol.2017.5230 Third Floor, Boston, MA 02114
Published online January 25, 2018. Corrected on February 22, 2018. (jefstathiou@partners.org).

(Reprinted) 1/8
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 Research Original Investigation Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer
T
he use of radical prostatectomy (RP) as the initial treat-
ment of high-risk and locally advanced prostate cancer
has increased in the past 2 decades.1 However, patients
with adverse pathological features, such as positive surgical mar-
gins, extraprostatic extension, and seminal vesicle invasion,
have a 40% to 70% risk of biochemical recurrence.2-6 Three ran-
domized clinical trials—European Organization for Research and
Treatment of Cancer (EORTC) 22911, Arbeitsgemeinschaft Ra-
diologische Onkologie (ARO) 9602, and Southwest Oncology
Group (SWOG) 8794—investigating the role of adjuvant radio-
therapy (ART) vs observation in patients with these high-risk
features demonstrated a progression-free survival benefit, but
only SWOG 8794 found a freedom from distant metastases
(FFDM) and overall survival (OS) advantage.3,5-10 On the basis
of these findings, the consensus guidelines of the American Uro-
logical Association and American Society for Radiation Oncol-
ogy and the European Association of Urology recommend phy-
sician-initiated, multidisciplinary discussions of the potential
benefits and risks of ART for patients with adverse pathologi-
cal features.11,12
Despite these recommendations, the use of ART in high-
risk patients is under 10% and on the decline, 13 likely
because of overtreatment concerns given that many patients
who receive ART would likely have never developed postop-
erative recurrence. Instead, a more common approach is to
monitor high-risk patients after RP until the prostate-
specific antigen (PSA) level becomes detectable and offer
early-salvage radiotherapy (ESRT) (initiated with PSA level
≤0.5 ng/mL). The ESRT strategy is supported by retrospec-
tive data suggesting it is often effective for long-term disease
control.14-18
Currently, no prospective randomized data are available
comparing ART with ESRT, pending 3 ongoing trials.19-21 Pre-
vious retrospective studies comparing ART and salvage RT
(SRT) yielded discrepant results regarding whether ART im-
proves post-RT freedom from biochemical failure (FFBF), free-
dom from androgen deprivation therapy, and FFDM, whereas
no studies showed an OS advantage for ART.4,22-26 Because the
optimal timing of postoperative RT for prostate cancer with ad-
verse pathological features remains controversial, we con-
ducted a large, multi-institutional analysis comparing the FFBF,
FFDM, and OS between ART and ESRT.
Methods
Study Design, Data Sources, Study Participants,
Exposures, and Outcomes
We pooled indiv idual data from 1566 patients w ith
pT2N0M0/R1 or pT3N0M0/R0-1 prostate adenocarcinoma
(American Joint Committee on Cancer’s Cancer Staging Manual,
7th edition) who underwent postprostatectomy ART or ESRT
at 10 academic medical centers between January 1, 1987,
and December 31, 2013. This study obtained institutional
review board approval from Massachusetts General Hospital
and Cleveland Clinic. Patient informed consent was waived
at these institutions because this is a minimal risk study
using data collected for routine clinical practice. Data
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Key Points
Question What is the optimal timing of postoperative
radiotherapy for prostate cancer with adverse pathological
features?
Findings In this multi-institutional cohort study of 1566
consecutive patients with prostate cancer with adverse
pathological features, adjuvant radiotherapy after prostatectomy
was associated with significantly greater freedom from
postirradiation biochemical failure, freedom from distant
metastases, and overall survival compared with early-salvage
radiotherapy.
Meaning Pending prospective validation, these findings suggest
that a greater proportion of patients with prostate cancer who
have adverse pathological features may benefit from
postprostatectomy adjuvant radiotherapy rather than surveillance
followed by early-salvage radiotherapy.
were collected from January 1 to September 30, 2016. Data
analysis was conducted from October 1, 2016, to October 21,
2017.
All patients were within a consecutive cohort of eligible
patients treated at each of the 10 institutions (Massachusetts
General Hospital, Cleveland Clinic, University of Michigan,
Duke University Medical Center, Washington University School
of Medicine, Mayo Clinic, University of Chicago, University of
Miami, Virginia Commonwealth University Medical Center, and
Sidney Kimmel Cancer Center at Thomas Jefferson Univer-
sity). Patients who had nodal involvement or received preop-
erative androgen deprivation therapy (ADT) were excluded.
The PSA-level detection limits varied over time and among
laboratories. In this study, PSA level was considered undetect-
able if it was less than 0.1 ng/mL or below the sensitivity limit
of the assay. Adjuvant RT was defined as RT delivered at an un-
detectable PSA level, whereas ESRT was defined as RT deliv-
ered at a detectable PSA level between and inclusive of 0.1 to
0.5 ng/mL, including those with a persistently detectable PSA
level after surgery. Use of ART or ESRT, RT technique, RT dose,
pelvic nodal RT, and postoperative ADT administered before
or concurrent with RT were at the discretion of the treating phy-
sicians.
The study outcomes were postirradiation FFBF, FFDM, and
OS. All outcomes were measured from the date of surgery to
address potential lead-time bias. Postirradiation biochemical
failure (BF) was defined as PSA level rising to 0.2 ng/mL or
higher. For patients in the ESRT group who never achieved a
PSA level lower than 0.2 ng/mL after radiation, BF was deter-
mined as the first documented rise in PSA level above 0.2 ng/
mL. Distant metastases was defined as radiographic evi-
dence of metastases. Overall survival was defined as death from
any cause.
Statistical Analysis
Patient and treatment characteristics were compared using
Fisher exact test and Wilcoxon rank sum test as appropriate.
Propensity score (PS) 1-to-1 matching27 using logistic regres-
sion and caliper width 0.01 was used to account for covari-
ates potentially associated with treatment selection: age at
jamaoncology.com
 Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer
surgery, year of surgery, Gleason score, T stage, margin sta-
tus, postoperative ADT, and pelvic nodal RT. Postirradiation
FFBF, FFDM, and OS outcomes after ART vs after ESRT were
compared using the Kaplan-Meier method. Multivariate
competing-risks regression analysis of FFBF accounting for
death as a competing risk was performed to compare the
outcomes of ART and ESRT when controlling for potential
confounders: age at surgery (continuous), year of surgery
(continuous), Gleason score (continuous), T stage (pT2/T3a/
T3b), margin status (dichotomous), RT dose (Gy; continu-
ous), pelvic nodal RT (dichotomous), and postoperative
ADT (dichotomous). Patients who died before developing
BF were censored in an informative manner, whereas
patients who were alive without BF at last follow-up were
censored in a noninformative manner.
A sensitivity analysis was completed to address the limi-
tation that an unknown proportion of patients in the ART group
who did not develop BF may have been cured by surgery alone.
Toward this end, we randomly removed from the PS-
matched ART cohort an increasing number of patients who did
not develop BF by the last follow-up visit to represent the as-
sumption that these patients were cured by surgery alone. Next,
we iteratively compared the BF rates between the PS-
matched ART and ESRT groups using the log-rank test. To
estimate FFBF after surgery alone for comparison to the sen-
sitivity analysis, we applied the dynamic postprostatectomy
nomogram developed at Memorial Sloan Kettering Cancer Cen-
ter (eAppendix in the Supplement).
Statistical analyses were performed using Stata, version 14.1
(StataCorp LLC). A 2-tailed P < .05 was considered statisti-
cally significant.
Results
Patient and Treatment Characteristics
Of the 1566 patients, 1195 received ESRT and 371 received ART.
The median age (interquartile range [IQR]) was 60 (55-65) years.
Baseline patient and treatment characteristics are provided in
Table 1. As expected, the median (IQR) time from surgery to
RT was longer for the ESRT group compared with the ART group
(22.9 [8.5-44.3] months vs 4.4 [3.5-6.4] months; P < .001),
which translated into a longer median (IQR) follow-up after sur-
gery (92.3 [55.3-134] months vs 65.4 [40-107] months; P < .001).
However, there was no difference in median (IQR) follow-up
after RT in the ESRT and ART cohorts (55.9 [26.6-96.1] months
vs 58.4 [32.0-101.2] months; P = .08).
The ESRT group, compared with the ART cohort, had an
earlier median (IQR) year of surgery (2002 vs 2006; P < .001),
lower pathological T stage (T3: 642 [52.7%] vs 273 [73.6%];
P < .001), lower Gleason score (8-10: 225 [18.8%] vs 107 [28.8%];
P < .001), lower rate of positive margins (721 [60.3%] vs 315
[84.9%]; P < .001), less use of intensity modulated RT (436
[36.5%] vs 174 [46.9%]; P < .001), and greater use of postop-
erative ADT (135 [11.3%] vs 23 [6.2%]; P = .004). The median
(IQR) pre-ESRT PSA level was 0.3 (0.2-0.4) ng/mL. Use of pel-
vic nodal RT was similar in the ESRT and ART groups (141
[11.8%] vs 43 [11.6%]; P = >.99).
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Original Investigation Research
Propensity Score–Matched Analysis
Propensity score matching yielded 366 matched pairs that were
well-balanced (Table 1). The mean standardized bias was re-
duced from 24.8% to 4.5% after matching (eTable and
eFigures 1 and 2 in the Supplement). As expected, the median
(IQR) time from surgery to RT remained longer in the ESRT
group than the ART group (14.1 [4.9-31.2] months vs 4.5 [3.5-
6.4] months; P < .001). However, the median (IQR) follow-up
after surgery was similar between the ESRT and ART cohorts
(73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22).
The median (IQR) RT dose to the prostate fossa was slightly
higher in the ESRT group than in the ART group (66.0 [64.8-
70.0] Gy vs 64.8 [61.2-66.0] Gy; P < .001 [to convert gray to
rad, mulitply by 100]).
After PS matching, all measured outcomes were signifi-
cantly better with ART compared with ESRT: FFBF (61 vs 140
events; P < .001), FFDM (14 vs 28 events; P = .03), and OS (20
vs 35 events; P = .01). The crude rate of prostate cancer–
specific death was higher in the ESRT than the ART cohort (6
vs 1 events), but the small number of events precluded addi-
tional statistical analysis. The 12-year actuarial rates for ART
vs ESRT were as follows: FFBF (69% [95% CI, 60%-76%] vs 43%
[95% CI, 35%-51%]; effect size, 26%), FFDM (95% [95% CI,
90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and
OS (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; ef-
fect size, 12%) (Figure).
Multivariate competing-risks analysis (Table 2) demon-
strated that the factors independently associated with risk of
BF were ART, pathological T stage, surgical Gleason score, nodal
RT, and postoperative ADT. Multivariate analyses for FFDM and
OS were not performed because of insufficient events.
Sensitivity Analysis
The sensitivity analysis revealed that the decreased risk of BF
associated with ART in the PS-matched analysis only lost sta-
tistical significance when more than 205 patients (56%) in the
ART cohort were assumed to have been cured by surgery alone.
In the ART group, the longest time to BF after surgery was 11.4
years. Because only overall Gleason scores were available, we
estimated the 12-year FFBF after surgery alone using the con-
temporary nomogram by accounting for patients with a Glea-
son score of 7 in 3 different ways: (1) all Gleason score 3 + 4, (2)
all Gleason score 4 + 3, and (3) one-third Gleason score 4 + 3 and
two-thirds Gleason score 3 + 4 based on previous population
studies of prostate cancer with a Gleason score of 7.28-30 For the
ART group, the 12-year FFBF estimates were 52%, 33%, and 46%,
respectively. All patients in the ESRT group had disease recur-
rence by definition, but for comparative purposes we also es-
timated the 12-year FFBF immediately after surgery for this
group, which was 61%, 38%, and 55%, respectively.
Discussion
In men with locally advanced T3N0 prostate adenocarcinoma,
the role of immediate postoperative RT after RP was
investigated in 3 randomized clinical trials.3,5-9 All 3 trials
demonstrated a progression-free survival outcome for imme-
(Reprinted) JAMA Oncology May 2018 Volume 4, Number 5 3/8
 4/8
Table 1. Summary of Patient and Treatment Characteristics

Before PS Matching After PS Matching

Characteristic ESRT (n = 1195) ART (n = 371) P Value ESRT (n = 366) ART (n = 366) P Value
Age at surgery, median (IQR), y 60.0 (55.0-64.7) 60.0 (55.2-65.0) .44a 61.0 (54.6-65.3) 60.0 (55.0-65.0) .90a
Year of surgery, median (IQR) 2002 (1998-2006) 2006 (2000-2008) <.001a 2005 (2001-2007) 2006 (2000-2008) .29a
a
Follow-up since surgery, median (IQR), mo 92.3 (55.3-134) 65.4 (40-107) <.001 73.3 (44.9-106.6) 65.8 (40-107) .22a
b
Pathological T stage, No. (%)
T2 553 (46.3) 98 (26.4) 109 (29.8) 98 (26.8)
Research Original Investigation

T3a 435 (35.4) 183 (49.3) <.001c 170 (46.4) 181 (49.5) .63c
T3b 207 (17.3) 90 (24.3) 87 (23.8) 87 (23.8)
Surgical Gleason score, No. (%)
6 248 (20.8) 50 (13.5) 33 (9.0) 50 (13.7)
7 722 (60.4) 214 (57.7) 209 (57.1) 210 (57.4)
8 108 (9.0) 46 (12.4) <.001c 54 (14.8) 45 (12.3) .18c
9 116 (9.7) 61 (16.4) 70 (19.1) 61 (16.7)
10 1 (0.1) 0 (0)

JAMA Oncology May 2018 Volume 4, Number 5 (Reprinted)

Margin status, No. (%)
Positive 721 (60.3) 315 (84.9) 318 (86.9) 313 (85.8)
Negative 462 (38.7) 53 (14.3) <.001c 48 (13.1) 53 (14.5) .67c

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Unknown 12 (1.0) 3 (0.8)
Time from surgery to RT, median (IQR), mo 22.9 (8.5-44.3) 4.4 (3.5-6.4) <.001a 14.1 (4.9-31.2) 4.5 (3.5-6.4) <.001a
Follow-up since RT, median (IQR), mo 55.9 (26.6-96.1) 58.4 (32.0-101.2) .08a 49.2 (22.2-80.0) 59.2 (32.0-101.2) <.001a
Pre-RT PSA level, median (IQR), ng/mL 0.3 (0.2-0.4) <0.1 NA 0.3 (0.2-0.4) <0.1 NA
RT technique, No. (%)
2-D 245 (20.5) 69 (18.6) 58 (15.8) 69 (18.9)
3-D CRT 311 (26.0) 64 (17.3) 70 (19.1) 63 (17.2)
<.001c .16c
IMRT 436 (36.5) 174 (46.9) 192 (52.5) 171 (46.7)
Unknown 203 (17.0) 64 (17.2) 46 (12.6) 63 (17.2)
RT node coverage, No. (%)
Yes 141 (11.8) 43 (11.6) 47 (12.8) 43 (11.7)

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>.99c .74c
No 1054 (88.2) 328 (88.4) 319 (87.2) 323 (88.3)
RT dose to prostate fossa, median (IQR), Gy 64.8 (64.8-68.1) 64.8 (61.2-66.0) <.001a 66.0 (64.8-70.0) 64.8 (61.2-66.0) <.001a
a
RT duration, median (IQR), d 50 (48-52) 49 (46-50) <.001 50 (48-52) 49 (46-50) <.001a
Postoperative ADT, No. (%)
Yes 135 (11.3) 23 (6.2) 19 (5.2) 23 (6.3)
.004c .63c
No 1060 (88.7) 348 (93.8) 347 (94.8) 343 (93.7)
a
Abbreviations: ADT, androgen deprivation therapy; ART, adjuvant radiation therapy; ESRT, early-salvage radiation Calculated using the Wilcoxon rank sum test.
therapy; IMRT, intensity-modulated radiation therapy; IQR, interquartile range; PS, propensity score; PSA, b
All patients with stage T2 had positive surgical margins.
prostate-specific antigen; RT, radiation therapy; 2-D, 2-dimensional; 3-D CRT, 3-dimensional conformal radiotherapy. c
Calculated using the Fisher exact test.
SI conversion factor: To convert PSA to micrograms per liter, multiply by 1.0; to convert gray to rad, multiply by 100.

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Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer
 Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer Original Investigation Research

Figure. Kaplan-Meier Curves After Adjuvant Radiotherapy (ART) Table 2. Multivariate Competing-Risks Regression Analyses of Factors
vs After Early-Salvage Radiotherapy (ESRT) in a Propensity Associated With Biochemical Failure After Radical Prostatectomy
Score–Matched Cohort of Patients With pT2N0M0/R1 and Postoperative Radiotherapy
or pT3N0M0/R0-1 Prostate Adenocarcinoma PS-Matched Patient Cohort,
Factor SHR (95% CI)a P Value
A Freedom from biochemical failure ART vs ESRT 0.34 (0.24-0.48) <.001

100 Age at surgery 1.00 (0.98-1.02) .65

Patients Free From Biochemical Failure, %

Year of surgery 1.02 (0.99-1.05) .24

Pathological T stage
75 ART
T2 1 [Reference]
T3a 1.14 (0.78-1.67) .51
50 T3b 1.87 (1.20-2.92) .005
ESRT Surgical Gleason score 2.06 (1.75-2.41) <.001
25 Surgical margin (±) 1.29 (0.82-2.04) .27

Log-rank P<.001 Omitting nodal RT 2.27 (1.33-3.87) .003

RT dose (Gy), prostate fossa 0.96 (0.91-1.01) .10
0
0 24 48 72 96 120 144 168 192 Postoperative ADT 0.30 (0.12-0.74) .009
Time From Surgery, mo
No. at risk Abbreviations: ADT, androgen deprivation therapy; ART, adjuvant radiation
ESRT 366 297 200 126 60 33 22 15 therapy; ESRT, early-salvage radiation therapy; PS, propensity score;
ART 366 314 216 140 97 60 37 26 RT, radiation therapy; SHR, subhazard ratio.
a
Subhazard ratios are reported for a 1-unit increase in the continuous variables.
B Freedom from distant metastases

100
superior with immediate RT than a wait-and-see approach, but
Patients Free From Distant Metastases, %

ART
there was no difference in OS in this combined analysis.10 There
ESRT
75 were several potential limitations in these trials. First, survival
was not a primary outcome, and the studies were therefore un-
derpowered for this end point. Second, fewer than half of pa-
50
tients who recurred in the observation arms received SRT, as sal-
vage therapy utilization was not prespecified in the trials.5,9,31
25 Third, roughly one-third of patients in the immediate RT arms
Log-rank P =.03 had low-detectable PSA levels before starting RT and therefore
technically received ESRT.3,7 Approximately 20% to 40% of men
0
0 24 48 72 96 120 144 168 192 in the observational arms of these trials never had disease re-
Time From Surgery, mo
currence, indicating the possibility of overtreatment with ART
No. at risk
ESRT 366 335 251 181 107 64 38 24 in this patient population.
ART 366 323 236 158 115 73 51 33 Improved FFBF after SRT is observed with a lower PSA level
at the time of treatment initiation.15,32-34 This observation was
C Overall survival
corroborated by a recent multi-institutional analysis, which
100 found a 5-year FFBF of 71% for patients with a pre-RT PSA level
ART of 0.01 to 0.20 ng/mL, 63% for 0.21 to 0.50 ng/mL, 54% for 0.51
to 1.0 ng/mL, 43% for 1.01 to 2.0 ng/mL, and 37% for greater than
75
2.0 ng/mL.18 Contemporary studies typically define ESRT as SRT
Overall Survival, %

ESRT
delivered at a PSA level of 0.5 ng/mL or lower.4,25,26,35 Impor-
50 tantly, the 3 randomized clinical trials of immediate RT vs ob-
servation do not inform whether the benefits of ART persist in
the context of more consistent use of ESRT, and therefore the
25
optimal timing of postoperative RT remains unclear.
Log-rank P =.01
To our knowledge, this report represents the largest multi-
0 institutional study comparing ART to ESRT in the literature to-
0 24 48 72 96 120 144 168 192
Time From Surgery, mo date. We measured all outcomes from the time of surgery to
No. at risk account for lead-time bias given the inherent difference in the
ESRT 366 338 265 188 112 68 40 25
ART 366 324 240 162 116 75 53 36 timing of ART and ESRT after surgery. Because treatment se-
lection was at the discretion of the treating physicians, it was
not surprising that the ESRT group featured less advanced dis-
diate radiotherapy over observation, but only SWOG 8794 dem- ease than the ART cohort did with less pathological T3, lower
onstrated an FFDM and OS improvement.3,9 A meta-analysis of Gleason score, and fewer positive margins. Furthermore, ap-
these 3 trials found that 10-year FFBF, FFADT, and FFDM were proximately twice as many patients in the ESRT group were

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 Research Original Investigation Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer
treated with salvage ADT compared with patients in the ART
group receiving adjuvant ADT. These differences contribut-
ing to treatment allocation were normalized with PS match-
ing. We found that ART was superior to ESRT for all out-
comes: postirradiation FFBF, FFDM, and OS.
To account for the unknown subset of patients in the ART
group who would never have developed recurrence after sur-
gery, we performed a sensitivity analysis that determined the
decreased risk of BF associated with ART only lost statistical
significance when more than 56% of patients in the ART group
were assumed to have been cured by surgery alone. This
threshold is greater than the estimated 12-year FFBF of 33%
to 52% after RP alone as determined by the contemporary no-
mogram, indicating that the difference in FFBF cannot be at-
tributed to successful surgery alone. In comparison, the esti-
mated 12-year FFBF after RP for the ESRT cohort is higher at
38% to 61%, suggesting that the improved outcomes seen in
the ART group, compared with the ESRT group, cannot be sim-
ply ascribed to more favorable clinicopathological features.
However, because all patients in the ESRT group had recur-
rent disease after surgery, there may be other unknown or
unmeasured factors in the ESRT group that predisposed
these patients to worse clinical outcomes. On multivariate
competing-risks regression analysis, ART remained signifi-
cantly associated with decreased BF. Other independent
favorable prognostic features were lower Gleason score, lack
of seminal vesicle invasion, pelvic nodal RT, and use of
postoperative ADT.
Previous retrospective series comparing ART and SRT gen-
erally showed increased FFBF but not OS with ART.4,22-26
Potential reasons for this difference include a smaller cohort
size, shorter follow-up, disparate end points, and varying PSA
thresholds at the time of SRT with inclusion of patients with a
PSA level greater than 0.5 ng/mL. Furthermore, positive mar-
gins have been correlated with better response to postopera-
tive RT5,8,15,32; 42% of men before PS matching and 28% after
PS matching had pT2/R1 disease in our cohort, which is a greater
proportion of margin-positive patients than in previous stud-
ies. In addition, the proportion of patients with Gleason scores
of 8 to 10 was 21% before PS matching and 31% after PS match-
ing, which is higher than in most previous studies4,22,23 and
similar to a recent study that also showed an FFDM advan-
tage with ART.26 Patients with high Gleason scores benefit from
ART,6,9 but this feature is strongly associated with a higher risk
of progression after SRT.15,16,22,23,32 Therefore, our study popu-
lation may have been enriched with patients more likely to ben-
efit from postoperative RT, especially after PS matching, for
whom there is increasing evidence that outcomes are im-
proved when treatment is initiated at lower PSA concentra-
tions with no clear lower bound.18 The median RT dose to the
prostate fossa in the ESRT cohort was 66 Gy, with 51% of men
receiving less than 66 Gy. An SRT dose of at least 66 Gy is as-
sociated with a decreased risk of BF36; hence, the use of higher
SRT doses may reduce the advantages with ART observed in
this study.
A subset of patients received pelvic nodal RT (12%) and/or
postoperative ADT (10%). Both treatment factors were asso-
ciated with reduced BF on multivariate analysis. Two recent
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randomized studies reported improved progression-free sur-
vival and/or OS with the addition of ADT to SRT.37,38 How-
ever, both studies included a substantial number of patients
with a PSA level greater than 0.5 ng/mL at the time of postop-
erative RT; therefore, it is unknown whether these results trans-
late to the early-salvage and adjuvant settings.
Limitations
The primary limitation of this study is its retrospective de-
sign and inherent selection bias associated with treatment as
rendered, which we attempted to address by performing PS
matching for the factors expected to influence decision mak-
ing. Nevertheless, PS matching cannot account for unmea-
sured confounders. The treatment center was deidentified dur-
ing primary data collection, and thus an imbalance in ART and
ESRT cases from each institution is a potential confounder. An-
other important limitation is that, although all patients in the
ESRT group had recurrent disease by definition, an unknown
subset of patients in the ART group may never have devel-
oped recurrence, which may overestimate the benefit of ART.
We addressed this limitation by performing a sensitivity analy-
sis. The median follow-up after surgery was significantly
longer in the ESRT group compared with the ART group, which
raises the possibility of insufficient time to observe distant me-
tastases and mortality events in the ART cohort. However, this
difference in follow-up between the 2 groups was no longer
present after PS matching, and the median follow-up after RT
was comparable between arms. The downward drifting thresh-
old of detectability for PSA over time led to the classification
of some men with a PSA level greater than 0.1 ng/mL as re-
ceiving ART; however, this should bias the results against ART
and therefore is unlikely to confound the validity of our re-
sults. Finally, data were unavailable regarding which patients
in the ESRT cohort had a persistently detectable PSA level
after RP. Nevertheless, identification of this subpopulation
is unlikely to be clinically significant given that (1) the
changing sensitivity of PSA assays over time renders the
definition of a detectable PSA level a moving target and (2)
previous multivariate analyses found that a persistently
elevated post-RP PSA level had a minimal association with
outcomes after SRT.15
This study provides important insights into the use of post-
operative RT for high-risk patients, but we acknowledge the
need for randomized prospective evidence to guide best clini-
cal practices. The Radiotherapy and Androgen Deprivation in
Combination After Local Surgery (RADICALS) trial assigns pa-
tients to either ART or ESRT and secondarily addresses the role
of concurrent ADT (none vs short-course or long-course).19
Similarly, the French Groupe d’Étude des Tumeurs Uro-
Génitales (GETUG-17) trial randomizes patients with pT3-
4N0/R1 carcinoma to ART vs ESRT, but both arms receive short-
course ADT.20 In contrast, the Radiotherapy–Adjuvant Versus
Early Salvage (RAVES) trial comparing ART and ESRT for pa-
tients with pT3N0/R1 carcinoma does not include ADT.21,39,40
The Radiation Therapy Oncology Group (RTOG) 0534 trial is
evaluating salvage pelvic nodal irradiation and ADT for pa-
tients with T2-3N0 prostate adenocarcinoma and a postop-
erative PSA level of 0.1 to 1.0 ng/mL using a 3-arm randomiza-
jamaoncology.com
 Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer Original Investigation Research

tion: (1) prostate fossa irradiation, (2) prostate fossa
irradiation + short-course ADT, and (3) prostate fossa/nodal ir-
radiation + short-course ADT.41
Conclusions
In this large, multi-institutional study, ART compared with
ESRT was associated with reduced biochemical recurrence,
DM, and death for patients with prostate cancer with adverse
pathological features (T3 disease and/or positive margins). The
12-year number needed to treat with ART vs ESRT to prevent
1 BF was 6 to 12 when accounting for the estimated surgical
cure rate based on a contemporary nomogram. The current use
of ART in high-risk patients is less than 10%.13 Our findings sug-
gest that a greater proportion of such men may benefit from
ART, especially those for whom the estimated risk of post-
prostatectomy recurrence is greater than 50%. Pending pro-
spective validation, contemporary practice patterns regard-
ing postoperative RT should be revisited. Further improvement
in risk stratification and patient selection for ART and ESRT
may be enabled by genomic biomarkers such as the Decipher
(GenomeDx) score. 42-44 Moreover, novel imaging tech-
niques, such as fluciclovine (18F) positron emission tomogra-
phy, may be useful for optimizing RT target coverage in the
early-salvage setting.45,46

ARTICLE INFORMATION Study supervision: Efstathiou. Michigan, Ann Arbor; and Skyler Johnson, MD, Yale
Accepted for Publication: November 16, 2017. Conflict of Interest Disclosures: Dr Spratt School of Medicine, New Haven, Connecticut.

Correction: This article was corrected on February
22, 2018, to fix a data presentation error in the
Results paragraph of the Abstract.
Published Online: January 25, 2018.
doi:10.1001/jamaoncol.2017.5230
Author Affiliations: Department of Radiation
Oncology, Massachusetts General Hospital, Harvard
Medical School, Boston, Massachusetts (Hwang,
Niemierko, Zietman, Efstathiou); Departments of
Radiation Oncology and Urology, Cleveland Clinic,
Cleveland, Ohio (Tendulkar, Stephans,
Stephenson); Department of Radiation Oncology,
Case Western Reserve University School of
Medicine, Cleveland, Ohio (Agrawal); Department
of Radiation Oncology, University of Michigan, Ann
Arbor (Spratt, Hearn); Department of Radiation
Oncology, Duke University Medical Center, Durham,
North Carolina (Koontz, Lee); Department of
Radiation Oncology, Washington University School
of Medicine, St Louis, Missouri (Michalski);
Department of Radiation Oncology, Mayo Clinic,
Rochester, Minnesota (Pisansky); Department of
Radiation Oncology, University of Chicago, Chicago,
Illinois (Liauw); Department of Radiation Oncology,
University of Miami, Miami, Florida (Abramowitz,
Pollack); Department of Radiation Oncology,
Hunter Holmes McGuire Veterans Affairs Medical
Center, Richmond, Virginia (Moghanaki);
Department of Radiation Oncology, Virginia
Commonwealth University Medical Center,
Richmond (Anscher); Department of Radiation
Oncology, Sidney Kimmel Cancer Center at Thomas
Jefferson University, Philadelphia, Pennsylvania
(Den).
Author Contributions: Drs Hwang, Tendulkar,
Niemierko, and Efstathiou had full access to all of
the data in the study and take responsibility for the
integrity of the data and the accuracy of the data
analysis.
Study concept and design: Hwang, Tendulkar,
Efstathiou.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Hwang, Niemierko,
Efstathiou.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Hwang, Niemierko, Efstathiou.
Obtained funding: Efstathiou.
Administrative, technical, or material support: All
authors.
reported serving on the advisory board of
Dendreon and being a member of the NRG
Oncology Genitourinary Core Committee. Dr
Koontz reported receiving research funding from
Janssen Pharmaceuticals and consulting for Blue
Earth Diagnostics, GenomeDx Biosciences, Laguna
Pharmaceuticals, and ChanRX. Dr Michalski
reported receiving travel accommodations and
expenses from Varian Medical Systems, Siemens
Healthcare Diagnostics, ViewRay, and General
Electric Systems. Dr Abramowitz reported receiving
research funding from Elekta, consulting for
General Electric Corporation, and being employed
by Artech. Dr Pollack reported receiving research
funding from GenomeDx Biosciences. Dr
Moghanaki reported receiving travel
accommodations and expenses from Varian
Medical Systems and honoraria from Augmenix and
Varian Medical Systems. Dr Den reported receiving
research funding from Medivation as well as
consulting honoraria for GenomeDx Biosciences
and Bayer Healthcare. Dr Stephenson reported
consulting for Bayer, receiving research funding
from Medivation/Astellas Pharma, and receiving
travel accommodations and expenses from Blue
Earth and Genomic Health. Dr Efstathiou reported
receiving research funding from the Prostate
Cancer Foundation and consulting for Medivation/
Astellas, Genentech, Bayer Healthcare, EMD
Serono/Pfizer, Blue Earth Diagnostics, and Taris
Biomedical. No other disclosures were reported.
Funding/Support: This work was supported by the
Prostate Cancer Foundation.
Role of the Funder/Sponsor: The funding source
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: Daniela Buscariollo, MD,
Brigham & Women’s Hospital, Boston,
Massachusetts, provided helpful discussions. The
following individuals assisted with the
data-collection process: Chandana Reddy, MS,
Cleveland Clinic, Cleveland, Ohio; Rebecca
Clayman, MS, Royal College of Surgeons, Dublin,
Ireland; Sigolene Galland, MD, Department of
Radiation Oncology, University of Bordeaux,
Bordeaux, France; Michael Drumm, BA, Feinberg
School of Medicine, Northwestern University,
Chicago, Illinois; William Jackson, MD, University of
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