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Outcomes of Observation vs Stereotactic Ablative Radiation
for Oligometastatic Prostate Cancer
The ORIOLE Phase 2 Randomized Clinical Trial
Ryan Phillips, MD, PhD; William Yue Shi, BS; Matthew Deek, MD; Noura Radwan, MD; Su Jin Lim, ScM; Emmanuel S. Antonarakis, MD;
Steven P. Rowe, MD, PhD; Ashley E. Ross, MD, PhD; Michael A. Gorin, MD; Curtiland Deville, MD; Stephen C. Greco, MD; Hailun Wang, PhD;
Samuel R. Denmeade, MD; Channing J. Paller, MD; Shirl Dipasquale, MS, RN; Theodore L. DeWeese, MD; Daniel Y. Song, MD; Hao Wang,PhD;
Michael A. Carducci, MD; Kenneth J. Pienta, MD; Martin G. Pomper, MD, PhD; Adam P. Dicker, MD, PhD; Mario A. Eisenberger, MD;
Ash A. Alizadeh, MD, PhD; Maximilian Diehn, MD, PhD; Phuoc T. Tran, MD, PhD
IMPORTANCE Complete metastatic ablation of oligometastatic prostate cancer may provide
an alternative to early initiation of androgen deprivation therapy (ADT).
OBJECTIVE To determine if stereotactic ablative radiotherapy (SABR) improves oncologic
outcomes in men with oligometastatic prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS The Observation vs Stereotactic Ablative Radiation for
Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants
from 3 US radiation treatment facilities affiliated with a university hospital from May 2016
to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened,
54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable
by conventional imaging who had not received ADT within 6 months of enrollment or 3 or
more years total were randomized.
INTERVENTIONS Patients were randomized in a 2:1 ratio to receive SABR or observation.
MAIN OUTCOMES AND MEASURES The primary outcome was progression at 6 months by
prostate-specific antigen level increase, progression detected by conventional imaging,
symptomatic progression, ADT initiation for any reason, or death. Predefined secondary
outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free
survival, Brief Pain Inventory (Short Form)–measured quality of life, and concordance
between conventional imaging and prostate-specific membrane antigen (PSMA)–targeted
positron emission tomography in the identification of metastatic disease.
RESULTS In the 54 men randomized, the median (range) age was 68 (61-70) years for patients
allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at
6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%)
undergoing observation (P= .005). Treatment with SABR improved median progression-free
survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P= .002). Total
consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months
(16%vs63%;P= .006). No toxic effects of grade 3 or greater were observed. T-cell receptor
sequencing identified significant increased clonotypic expansion following SABR and
correlation between baseline clonality and progression with SABR only (0.082085
vs 0.026051; P= .03).
CONCLUSIONS AND RELEVANCE Treatment with SABR for oligometastatic prostate cancer
improved outcomes and was enhanced by total consolidation of disease identified by
PSMA-targeted positron emission tomography. SABR induced a systemic immune response,
and baseline immune phenotype and tumor mutation status may predict the benefit from
SABR. These results underline the importance of prospective randomized investigation of the
oligometastatic state with integrated imaging and biological correlates.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02680587
JAMA Oncol. doi:10.1001/jamaoncol.2020.0147
Published online March 26, 2020.
Visual Abstract
Invited Commentary
Supplemental content
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author:
Phuoc T.Tran, MD, PhD, Department
of Radiation Oncology and Molecular
Radiation Sciences, Johns Hopkins
University School of Medicine,
1500 Orleans St, CRB2 Room 406,
Baltimore, MD 21231
(tranp@jhmi.edu).
Research
JAMA Oncology | Original Investigation
(Reprinted) E1
Downloaded From: https://jamanetwork.com/ on 03/26/2020
In the US, prostate cancer is the third most common can-
cer overall and the most common in men, accounting for
approximately 30000 deaths per year.
1
Metastatic pros-
tate cancer remains incurable despite advances in systemic
management for hormone-sensitive
2
and castration-
resistant disease.
3
The oligometastatic state described by Hellman and
Weichselbaum
4
may benefit from localized therapies,
and mounting prospective evidence supports the inclusion
of radiotherapy in the metastatic paradigm. Two trials
5,6
have shown that stereotactic ablative radiotherapy (SABR)
significantly improves progression-free survival (PFS)
and overall survival in patients with oligometastatic
non–small cell lung cancer when added to maintenance
systemic therapy, and the Stereotactic Ablative Radio-
therapy for the Comprehensive Treatment of Oligometa-
stases (SABR-COMET) trial
7
reported an overall survival ben-
efit with SABR in patients with oligometastases when used
in addition to standard-of-care systemic therapy across
histologies.
In the treatment of prostate cancer, radiotherapy has
demonstrated clinical benefits in both de novo and meta-
chronous low-volume metastatic disease. Parker et al
8
showed that the addition of prostate radiotherapy to stan-
dard systemic treatment improves overall survival for men
with de novo metastatic prostate cancer with low metastatic
burden. In the Surveillance or Metastasis-Directed Therapy
for Oligometastatic Prostate Cancer Recurrence (STOMP)
trial, to our knowledge the first phase 2 randomized clinical
trial of SABR vs observation in oligometastatic prostate can-
cer (OMPC), Ost et al
9
found significantly longer time to ini-
tiation of androgen deprivation therapy (ADT) in men
treated with SABR. Although the approach is controversial,
many men are interested in avoiding the unpleasant adverse
effects and potential health risks of ADT for as long as is rea-
sonable. With early clinical data suggesting the existence of
an oligometastatic state and the importance of local thera-
pies in management, strategies are now needed to define
who may benefit most from metastasis-directed therapy
(MDT).
10
This question is multifaceted, but 2 key components are
(1) determining which patients truly have oligometastaticdis-
ease and (2) ascertaining who is most likely to experience a
meaningful response to local consolidation. To answer the for-
mer, advanced imaging and circulating biomarkers, such as
microRNA
11-14
and circulating tumor DNA (ctDNA),
15-17
may im-
prove our ability to characterize disease burden and behav-
ior. Toaddress the latter requires a more complete understand-
ing of response to radiotherapy
18
and the complementary role
of the immune system.
19,20
This study reports the findings of a phase 2 randomized
clinical trial of observation vs SABR in men with hormone-
sensitive OMPC, to our knowledge the first in the western
hemisphere. The study also shows the value of the prostate-
specific membrane antigen (PSMA)–targeted positron emis-
sion tomography (PET) radiotracer
18
F-DCFPyL and liquid
biopsy correlatives in defining patients with oligometastasis
who would benefit the most from MDT.
Methods
Study Design and Participants
The Observation vs Stereotactic Ablative Radiation for Oligo-
metastatic Prostate Cancer (ORIOLE) 2-arm, phase 2 random-
ized clinical trial was approved by the Johns Hopkins Univer-
sity Institutional Review Board and performed across 3
affiliated centers in the US. Patients eligible forenrollment had
1 to 3 asymptomatic metastases that had arisen within the prior
6 months and were no larger than 5.0 cm in the largest axis or
250 cm
2
. The number of metastases was assessed by com-
puted tomography (CT), magnetic resonance imaging, and/or
radionuclide bone scan. All patients had histologic confirma-
tion of prostate cancer and prior definitive treatment of the pri-
mary tumor with surgery or radiotherapy. Salvage radio-
therapy to the prostate bed or pelvis was allowed. Patients were
allowed to have received ADT or other systemic therapy dur-
ing initial management or salvage treatment but not within 6
months of enrollment. The trial protocol is available in Supple-
ment 1. Additional inclusion criteria and full exclusion crite-
ria are available in eMethods in Supplement 2. All study par-
ticipants provided written informed consent approved bythe
institutional review board. This study followed the Consoli-
dated Standards of Reporting Trials (CONSORT) reporting
guideline.
Randomization and Blinding
Participants were randomized to the SABR or observation arm
in a 2:1 ratio using an interactive web response system.
Minimization
21
was applied to balance assignment based on
stratification by initial treatment (surgery or radiotherapy),his-
tory of prior ADT or lack thereof, and prostate-specific anti-
gen (PSA) doubling time (<6 months vs 6-14.9 months)
(eMethods in Supplement 2). Neither the treating physician,
the participants, nor the personnel responsible for data analy-
sis were blinded to assignment. The trial radiologist assess-
ing response by CT size criteria and by
18
F-DCFPyL uptake was
blinded to the participant treatment arm and to the treat-
ment fields used (eMethods in Supplement 2).
Key Points
Question How effectively does stereotactic ablative radiotherapy
prevent progression of disease compared with observation
in men with recurrent hormone-sensitive prostate cancer
with 1 to 3 metastases?
Findings In this phase 2 randomized clinical trial of 54 men,
progression of disease at 6 months occurred in 7 of 36 participants
(19%) treated with stereotactic ablative radiotherapy and in 11 of
18 participants (61%) undergoing observation, a statistically
significant difference.
Meaning Stereotactic ablative radiotherapy is a promising
treatment approach for men with recurrent hormone-sensitive
oligometastatic prostate cancer who wish to delay initiation of
androgen deprivation therapy.
Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer
E2 JAMA Oncology Published online March 26, 2020 (Reprinted) jamaoncology.com
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Procedures
For assessment of eligibility, patients provided a comprehen-
sive medical history, underwent a physical examination, and
had blood drawn for analysis of complete blood count, serum
chemistry measurements, and PSA level. Radiographic stud-
ies were performed as necessary to complete staging. After ran-
domization, participants underwent routine laboratory test-
ing on days 1, 90, and 180 as well as collection of blood for
correlative studies and PSMA-targeted PET-CT (performed at
baseline and day 180 for patients randomized to SABR)
(eMethods in Supplement 2).
Participants underwent CT-based simulation with cus-
tomized immobilization. Magnetic resonance imaging–based
simulation and 4-dimensional CT were performed at the dis-
cretion of the treating physician. Gross tumor volume delin-
eation was performed by the treating radiation oncologist with
the addition of a variable expansion of up to 5 mm to gener-
ate the planning target volume. Adjacent organs at risk were
delineated by the treating radiation oncologist. A stereotactic
body radiotherapy plan was then generated with dose and frac-
tionation determined based on the size and location of each
lesion, with prescription doses ranging from 19.5 to 48.0 Gy
in 3 to 5 fractions (eTable 1 in Supplement 2) and normal tis-
sue constraints per American Association of Physicists in
Medicine Task Group 101 recommendations.
22
Treatment was
initiated within 3 weeks of simulation. Image guidance
with daily cone beam CT prior to treatment was used for all
participants.
Outcomes
The primary outcome was the proportion of men in each arm
with disease progression at 6 months. Progression was a com-
posite end point that included any of the following: a PSA rise
of at least 2 ng/dL (to convert to micrograms per liter, multi-
ply by 0.01) and 25% above nadir; concern for radiologic pro-
gression by CT, magnetic resonance imaging, or bone scan as
determined by the reading radiologist; symptomatic progres-
sion of disease; initiation of ADT for any reason; or death.
Withdrawal from the study after randomization was consid-
ered progression.
Predefined secondary outcomes included the adverse ef-
fects of SABR as defined by the Common Terminology Crite-
ria for Adverse Events (version 4.0), local control at 6 months
for lesions treated with SABR, PFS, quality of life as measured
by the Brief Pain Inventory (Short Form), the concordance be-
tween conventional imaging and PSMA-targeted PET in the
identification of metastatic disease, and sequencing of T-cell
receptor repertoires from peripheral blood mononuclear cells
using ImmunoSEQ (Adaptive Biotechnologies).
For radiologic evaluation of lesions that did not meet for-
mal Response Evaluation Criteria in Solid Tumors (RECIST) ver-
sion 1.1 criteria, progression by imaging was assessed based on
the blinded professional assessment of the primary radiolo-
gist reading the images combined with application of the
RECIST version 1.1 size criteria to all measurable lesions,
including those not meeting formal size criteria. To minimize
the risk of underestimating local progression, any evidence of
progression by size was counted as a progression.
Statistical Analysis
Briefly, comparisons of progression at 6 months and presence
of new metastases at 6 months were performed using the
2-sided Fisher exact test. PFS curves were generated using
the Kaplan-Meier method, and Pvalues were calculated using
the log-rank test. Brief Pain Inventory responses were com-
pared between and within arms across time using the Holm-
Sidak method for multiple ttests. Differential clonotype abun-
dance and ctDNA allele fraction comparisons between arms
were performed using 2-tailed Mann-Whitney tests. Statisti-
cal significance was defined as P< .05. Statistical analysis was
performed using Prism version 8 (GraphPad Software) and
Rstudio version 1.2.5 (Rstudio Inc). All analysis was per-
formed on an intention-to-treat basis, and further details are
available in eMethods in Supplement 2.
Results
Between May 25, 2016, and March 5, 2018, a total of 80 men
were screened and 54 were randomized in a 2:1 ratio to SABR
or observation (Figure 1). Of the 54 men randomized, the me-
dian (range) age was 68 (61-70) years for patients allocated to
SABR and 68 (64-76) years for those allocated to observation.
The follow-up period for each participant extended from the
date of randomization to the most recent clinical contact as of
May 20, 2019 (median [range] follow-up of 18.8 [5.8-35.0]
months), and the trial was completed 6 months after random-
ization of the final participant. The Table and eTable 2 in
Supplement 2 summarize participant and lesion characteris-
tics, respectively. Gleason grade was higher in the observa-
tion arm than in the SABR arm with mean values of 8 and 7,
respectively. The arms were otherwise well balanced.
The proportion of men with disease progression by com-
posite end point at 6 months was 7 of 36 patients (19%;
95% CI, 9.6-35.4)treated with SABR and 11 of 18 patients (61%;
95% CI, 38.5-79.6) in the observation arm (P= .005). The pro-
portion of participants with disease progression by PSA level
at 6 months was 4 of 36 patients (11%;95% CI, 3.9-26.1) treated
with SABR and 9 of 18 patients (50%; 95% CI, 29.1-70.9) in the
observation arm (P= .005). The median PFS for participants
treated with SABR was not reached compared with 5.8 months
for those undergoing observation (hazard ratio [HR], 0.30;
95% CI, 0.11-0.81; P= .002) (Figure 2A). Median biochemical
PFS was not reached for patients treated with SABR and was
6.4 months for those undergoing observation (HR, 0.31;
95% CI, 0.13-0.75; P= .002) (Figure 2B). Local control was ex-
cellent as expected (98.9%) at 6 months (eResults, eFigure 1,
and eTable 1 in Supplement 2).
Because of blinding of the investigative team to the PSMA-
targeted PET data during treatment planning, 16 of 36 partici-
pants treated with SABR had baseline PET-avid lesions that
were not included in the treatment fields. The proportion of
men with no untreated lesions with progression at 6 months
was 1 of 19 (5%; 95% CI, 0-26.8) compared with 6 of 16 (38%;
95% CI, 18.5-61.5) for those with any untreatedlesions (P= .03).
The median PFS was unreached among participants with no
untreated lesions vs 11.8 months among participants with any
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untreated lesions (HR, 0.26; 95% CI, 0.09-0.76; P= .006)
(Figure 2C). The proportion of men who developed new meta-
static lesions at 180 days was 3 of 19 (15.8%; 95% CI, 4.9-38.6)
with no untreated lesions and 10 of 16 (62.5%; 95% CI, 38.5-
81.5) with any untreated lesions (P= .006). Median distant me-
tastasis–free survival was 29.0 months in men with no un-
treated lesions at baseline and 6.0 months in men with any
untreated lesions at baseline (HR, 0.19; 95% CI, 0.07-0.54;
P< .001) (Figure 2D; eResults in Supplement 2).
No grade 3 or higher adverse events were identified
(eTables 3 and 4 in Supplement 2). No differences in Brief Pain
Inventory (Short Form) scores were observed between arms
or within either arm across time.
Peripheral blood mononuclear cells were collected at base-
line and day 90 from participants in both arms for deep se-
quencing of T-cell receptor DNA. Differential clonotype abun-
dance appeared more pronounced in the SABR arm (Figure 3A),
with significantly more expanded clones and a nonsignifi-
cantly greater amount of contracted clones at 90 days com-
pared with observation. Greater peripheral baseline clonality
was associated with composite end point progression at 180
days in participants receiving SABR (0.082085 vs 0.026051;
P= .03) but not with observation (0.084299 vs 0.060002;
P= .68)(Figure 3B). At baseline, no participant had clusters of
similar expanded T-cell receptors within their repertoire, but
at day 90, clusters of similar expanded T-cell receptors were
identified in 3 participants, all in the SABR arm (Figure 3C).
Plasma and matched leukocyte DNA samples collected at
baseline from 54 participants were profiled by the CAPP-Seq
(cancer personalized profiling by deep sequencing) method for
analysis of ctDNA. Nonsynonymous mutations were present
in 20 participants (37%) with a mean of 1.3 mutations per par-
ticipant and a median allele fraction of 0.25%. No significant
differences in ctDNA concentration were noted between par-
ticipants whose disease did or did not progress in either the
SABR or observation arm (eFigure 2 in Supplement 2).
Based on prior sequencing studies
23-25
that identified mu-
tations associated with outcomes in metastatic prostate can-
cer, we defined a high-risk mutation signaturew ithtr uncating/
pathogenic germline mutations identified via a Color Genomics
assay and confirmed by CAPP-Seq (Figure 4A; eTables 5 and 6
in Supplement 2). To avoid false negatives owing to undetect-
able ctDNA, we limited our analyses to participants with de-
tectable ctDNA or truncating/pathogenic germline mutations
in high-risk genes (n = 22). PFS was significantly longer among
participants receiving SABR than among those in the obser-
vation arm in the high-risk mutation–negative subgroup
(Figure 4B) but not in the high-risk mutation–positive sub-
group (Figure 4C).
Discussion
This phase 2 randomized clinical trial showed that among men
with OMPC, those treated with SABR were significantly less
likely to have disease progression than those undergoing ob-
servation alone. Local control for SABR-treated lesions was ex-
cellent, and the adverse effects associated with SABR were mild
and did not appear to affect quality of life. These results are
consistent with prior reports validating the existence of the
oligometastatic state in prostate cancer and the utility of SABR
as MDT in this condition.
With a median (interquartile range) follow-up of 3.0 (2.3-
3.8) years, Ost et al
9
reported a median ADT-free survival of
21 months (80% CI, 14-29 months) with SABR compared with
13 months (80% CI, 12-17 months)w ithobser vation (HR, 0.60;
80% CI, 0.40-0.90; log-rank P= .11). Criteria for initiation of
ADT were defined as “symptomatic progression, progression
to more than three metastases, or local progression of baseline-
detected metastases.”
9(p448)
Importantly, progression by PSA
increase alone was not an indication to start ADT, nor was de-
velopment of additional metastases amenable to MDT as long
Figure 1. CONSORT Diagram
80 Patients assessed for eligibility
54 Randomized
26 Excluded
19 Did not meet inclusion criteria
5Declined to participate
2Insurance denied
36 Randomized to treatment arm
36 Received allocated intervention
0Lost to follow-up
7Discontinued intervention because
of progression prior to 180 days
0Lost to follow-up
0Discontinued intervention
18 Analyzed36 Analyzed
18 Randomized to observation arm
17 Received allocated intervention
1Withdrew and did not receive
allocated intervention
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as the patient still had 3 or fewer total metastases.
9
In the
present cohort, 2 of 7 men with disease progression in the SABR
arm and 7 of 11 men with disease progression in the observa-
tion arm experienced biochemical progression alone. Further-
more, additional SABR was the next intervention in 14 of 15
men in the observation arm who ultimately received subse-
quent treatment and 6 of 14 men in the SABR arm. These dif-
ferences inform the limitations of direct comparison of these
trials.
Another important consideration is that SABR in the
STOMP trial
9
included all concerning lesions identified by cho-
line PET-CT. The ORIOLE trial enrolled participants with less-
sensitive conventionalimaging and still demonstrated a posi-
tive benefit for MDT, suggesting that the oligometastatic state
is heterogeneous and that better biomarkers are needed to
define participants who would benefit most from MDT. Post
hoc analysis of PFS based on extent of disease appreciable by
PSMA-targeted PET-CT found significant PFS and distant
metastasis–free survival advantages among men who re-
ceived consolidation of all detectable disease. These data sup-
port the use of molecular imaging in conjunction with MDT
for patients with OMPC.
The key question that remains incompletely answered is
whether we can alter the natural history of OMPC with MDT.
Clearly, SABR is a safe and effective way to forestall progres-
sion of treated metastases and improves oncologic outcomes
in certain patients.
6,7
Furthermore, complete consolidation of
detectable metastases improves time to progression. Most men
with oligometastatic disease do not experience a complete PSA
response after SABR, which suggests that residual microme-
tastases are present but undetectable. The consolidation of
macroscopic disease may simply reset the clock on time to de-
tectable metastases, and micrometastatic disease may con-
tinue to grow unchecked until it reaches sufficient size to be-
come clinically actionable. Alternatively, consolidation of
macroscopic metastases may remove or significantly affect sig-
nals that promote the development of remaining micro-
metastases. Our finding that total consolidation of disease de-
tectable by PSMA-targeted PET-CT was associated with lower
risk of new metastases at 6 months is consistent with this lat-
ter explanation, as is the recent overall survival improve-
ment observed in the SABR-COMET trial.
7
A deeper under-
standing of this process may be obtained through sequencing
of biopsy or liquid biopsy specimens to explore the relation-
ships and lineages of specific metastases in these patients
14,26
or through advances in analysis of circulating readouts, such
as circulating tumor cells, ctDNA, and exosomes.
Our analysis of ctDNA revealed several key findings. First,
ctDNA concentrations in patients with OMPC were signifi-
cantly lower than those reported in prior studies
17,27
of
more advanced metastatic castration-resistant or hormone-
sensitive prostate cancer.This suggests that ultrasensitive strat-
egies, such as tumor-informed ctDNA monitoring, will be re-
quired for reliable detection and monitoring of ctDNA in
patients with OMPC. Second, we did not find an association
of baseline ctDNA concentration with outcome. However, our
analysis was limited by the small fraction of participants with
detectable ctDNA, so further exploration in future cohorts using
tumor-informed monitoring or alternative methods is war-
ranted. Third, the results of the study suggest that the pres-
ence of mutations associated with worse prognosis may iden-
tify a subset of patients who do not benefit from MDT.If these
findings are confirmed in independent cohorts, the absence
of high-risk mutations could potentially serve as a predictive
biomarker for benefit from MDT.
The benefit of early ADT initiation remains a controver-
sial question,
28-30
and rigorous evaluation of men who un-
dergo multiple rounds of MDT rather than proceeding to sys-
temic therapy at first progression may shed light on the effect
of SABR on the natural history of this disease. If a single round
of MDT arrests the progression of some but not all lesions, sub-
sequent rounds of MDT might salvage the remaining disease
until what remains is inadequate to support a metastatic phe-
Table. Baseline PatientCharacteristics
Characteristic
No. (%)
SABR (n = 36) Observation (n = 18)
Age, median (range), y 68 (61-70) 68 (64-76)
Initial T stage
cT1c 3 (8) 1 (6)
cT2a 2 (6) 0
cT2b 0 1 (6)
cT3a 1 (3) 1 (6)
pT2 12 (33) 6 (33)
pT3a 10 (28) 8 (44)
pT3b 8 (22) 1 (6)
Initial N stage
N0 31 (86) 16 (89)
N1 2 (6) 1 (6)
NX 3 (8) 1 (6)
Margin status
R0 20 (56) 10 (56)
R1 10 (28) 5 (28)
Gleason grade
3+3=6 3(8) 0
3+4=7 8(22) 4 (22)
4+3=7 14(39) 4 (22)
4+4=8 4(11) 1 (6)
4+5=9 4(11) 8 (44)
5+4=9 3(8) 0
5+5=10 0 1(6)
Initial management
Surgery 30 (83) 15 (83)
Radiotherapy 6 (17) 3 (17)
Time to first recurrence,
median (range), mo
22 (9-42) 22 (9-51)
Had received prior ADT 15 (42) 5 (28)
Baseline, median (range)
PSA, ng/dL 6 (2-13) 7 (3-17)
PSADT, mo 8 (4-11) 6 (4-11)
Abbreviations: ADT, androgen deprivation therapy; PSA, prostate-specific
antigen; PSADT,prostate-specific antigen doubling time; SABR, stereotactic
ablative radiotherapy.
SI conversion factor: Toconvert PSA to μg /L, multiply by 0.01.
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notype. The utility of repeated MDT may also vary by patient
and the response of individual; therefore, well-selected pa-
tients for MDT may have intrinsic predictive value for guid-
ing subsequent management.
The effect of radiotherapy on the immune system is also
an area of interest with the promise of using SABR to induce
an in situ vaccine response.
20,31
We observed enhanced dif-
ferential clonotype expansion, clusters of similar expanded
T-cell receptors, and a clinical benefit to greater baseline clon-
ality seen only in participants treated with SABR. Future stud-
ies assessing the association of these findings with T-cell char-
acteristics or relatedness to tumor-infiltrating lymphocytes
may help further characterize this systemic immune response.
Soldatov et al
32
described patterns of failure following
PSMA-ligand–based, conventionally fractionated radio-
therapy for OMPC and found that recurrences are bone tro-
phic. This suggests a role for aggressive management of mi-
crometastatic osseous disease with ADT and/or radium 223,
the latter of which will be the center of investigation for the
Radium-223 and SABR vs SABR for Oligometastatic Prostate
Cancers (RAVENS) trial (ClinicalTrials.gov identifier:
NCT04037358). Soldatov et al
32
also found that 17% of recur-
rences after MDT were in pelvic nodes. The best manage-
ment approach for pelvic recurrences is currently being stud-
ied in the Salvage Treatment of Oligorecurrent Nodal Prostate
Cancer Metastases (STORM) trial (ClinicalTrials.gov identi-
fier: NCT03569241).
Limitations
While these results are promising, this trial is limited by its rela-
tively small sample size; subsequent phase 3 validation would
strengthen the argument in favor of this approach. Addition-
ally,our ability to study the long-term implications of this treat-
ment approach was limited by high rates of crossover occur-
ring after the predefined 6-month primary end point, with 15
of 18 men randomized to observation ultimately seeking SABR.
It should also be noted that the correlative datapresented
herein are hypothesis generating and require further prospec-
Figure 2. Clinical Outcomes of Stereotactic Ablative Radiotherapy (SABR)
Compared With Observation and Benefit of Total Consolidation of Prostate-Specific Membrane Antigen Radiotracer-Avid Lesions
100
80
60
40
20
0
No. at risk
0
26
8
36
18
12
7
1
18
2
0
24
Progression-free survival, %
Time from randomization, mo
6
13
1
SABR
Observation
Composite PFS stratified by study arm
A
100
80
60
40
20
0
No. at risk
0
28
9
36
18
12
10
4
18
4
1
24
Biochemical progression-free survival, %
Time from randomization, mo
6
20
7
SABR
Observation
Biochemical PFS stratified by study arm
B
100
80
60
40
20
0
No. at risk
0
14
7
19
16
12
6
1
18
2
0
24
Progression-free survival, %
Time from randomization, mo
6
10
1
No untreated
Any untreated
PFS stratified by presence of untreated lesions
C
100
80
60
40
20
0
No. at risk
0
14
6
19
16
12
8
2
18
4
0
24
Distant metastasis-free survival, %
Time from randomization, mo
6
12
2
No untreated
Any untreated
DMFS stratified by presence of untreated lesions
D
SABR SABR
Observation
No untreated lesions
No untreated lesions
Any untreated lesions Any untreated lesions
Observation
HR, 0.30; 95% CI, 0.11-0.81; P
=
.002 HR, 0.31; 95% CI, 0.13-0.75; P
=
.002
HR, 0.26; 95% CI, 0.09-0.76; P
=
.006 HR, 0.19; 95% CI, 0.07-0.54; P
<
.001
A, Composite progression-free survival (PFS) stratified by study arm. B, Biochemical PFS stratified by study arm. C, Composite PFS and (D) distant metastasis–free
survival (DMFS) for patients treated by SABR stratified by presence of untreated lesions detected by prostate-specific membrane antigen–positron emission
tomography.
Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer
E6 JAMAOncology Published online March 26,2020 (Reprinted) jamaoncology.com
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tive validation. Although we have identified a systemic im-
mune response to SABR, we do not yet understand the nature
of this response, and additional studies are needed to better
characterize the interactions between immune cells, tumor,
and the microenvironment. A limitation of our ctDNA analy-
sis was the lack of available biopsy specimens to confirm the
presence or absence of mutations. Thus, although we se-
quenced matched leukocyte DNA to identify mutations ow-
Figure 3. Baseline and Dynamic Immunologic Features Suggesting Interplay Between Stereotactic Ablative Radiotherapy (SABR)
and the Immune System
–100
100
50
Clones, No.
0
–50
1 1014182224293336384347485253
Patient
2
T-cell clonotype abundance
A
0.4
0.3
Baseline Simpson clonality
0.2
0.1
0
Patient
Baseline Simpson clonality
B
T-cell receptor sequences
C
–100
100
50
Clones, No.
0
–50
Patient
356 7 8 91112 13 16 17 19 20 21 23 25 26 27 28 31 32 34 35 37 39 40 41 42 44 45 46 50 51 54 55
No progression Progression No progression Progression
Control SABR Patient
13
CASSPRLYEQYF
Yes
CASSPRLNEQYF
40
CASSYSTTGSSYEQYF
No
CASSYSTRGSSYEQYF
50
CASSLVPAGTNTGELFF
No
CASSLLPAGTNTGELFF
Amino acid sequence Progression at 180 days
Patients in SABR group
Control patients
Expanded clones
Contracted clones
Expanded clones
Contracted clones
A, Changes in T-cellclonotype abundance at day 90 from baseline. B, Baseline Simpson clonality stratified by progression at 180 days. C, Clustered T-cell receptor
sequences identified at day 90 in 3 patients treated with SABR.
Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Original Investigation Research
jamaoncology.com (Reprinted) JAMA Oncology Published online March 26, 2020 E7
Downloaded From: https://jamanetwork.com/ on 03/26/2020
ing to clonal hematopoiesis, it is possible that some of the mu-
tations we detected did not originate from tumor cells. Future
studies in this area should prioritize acquisition of tissue
samples for molecular analysis.
Conclusions
In conclusion, SABR is a safe and effective modality for MDT
in OMPC that improves PFS compared with observation and
results in a systemic adaptive immune response. Complete con-
solidation of metastatic disease detectable by molecular
imaging decreases the risk of subsequent metastases, sug-
gesting an alteration in the natural history. Finally, baseline
immune phenotype and a tumor mutation signature may
predict clinical response to SABR, pending validation in inde-
pendent cohorts. Although SABR alone may or may not be suf-
ficient as curative management, the combination of SABR with
systemic therapies may provide the multipronged attack re-
quired to cure this disease.
ARTICLE INFORMATION
Accepted for Publication: January 21, 2020.
Published Online: March 26, 2020.
doi:10.1001/jamaoncol.2020.0147
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2020 Phillips R et al. JAMA Oncology.
Author Affiliations: Department of Radiation
Oncology and Molecular Radiation Sciences,
Johns Hopkins University School of Medicine,
Baltimore, Maryland (Phillips, Deek, Radwan, Deville,
Greco, H. Wang, Dipasquale,DeWeese, Song, Tran);
Stanford Cancer Institute, Department of Radiation
Oncology,School of Medicine, Stanford University,
Stanford, California (Shi, Diehn); Department of
Medical Oncology,Johns Hopkins University School
of Medicine, Baltimore, Maryland (Lim, Antonarakis,
Denmeade, Paller,DeWeese, Song, H. Wang,
Carducci, Pienta, Eisenberger,Tran);
The Russell H. Morgan Department of Radiology
and Radiological Science, Johns Hopkins University
School of Medicine, Baltimore, Maryland (Rowe,
Gorin, Pomper); The James Buchanan Brady
Urological Institute and Department of Urology,
Johns Hopkins University School of Medicine,
Baltimore, Maryland (Rowe, Ross, Gorin, DeWeese,
Song, Pienta, Pomper,Tran); Sidney Kimmel Cancer
Center,Depar tment of Radiation Oncology, Thomas
Jefferson University,Philadelphia, Pennsylvania
Figure 4. Association of High-Risk Mutation Status With Progression-Free Survival (PFS) After Stereotactic Ablative Radiotherapy(SABR)
0
30
PFS, mo
High-risk mutations
20
10
1.0
0.8
0.6
0.4
0.2
0
0 12 18 3024
PFS, %
Time from randomization, mo
6
PFS for patients without high-risk mutations
B
1.0
0.8
0.6
0.4
0.2
0
0 12 18 3024
PFS, %
Time from randomization, mo
6
PFS for patients with high-risk mutations
C
Log-rank P
=
.01 Log-rank P
=
.62
SABR
SABR
Observation Observation
Treatment arm
Progression
Other mutations
TP53
ATM
BRCA2
BRCA1
RB1
Observation
Treatment arm Progression
SABR
Yes
No
High-risk mutation positive High-risk mutation negative
Missense-near-splice
Nonsense
Germline truncating/pathogenic
None
Missense
Mutation type
Patient and tumor characteristics
A
No. at risk
Observation
SABR
6
9
00 00
2
63 02
8
No. at risk
Observation
SABR
2
5
00 00
1
00 00
3
A, Patient characteristics and tumor mutations for patients with detectable circulating tumor DNA via CAPP-Seq or pathogenic germline mutations. B, PFS stratified
by treatment arm for patients without high-risk mutations (n = 15). C, PFS stratified by treatment arm for patients with high-risk mutations (n = 7).
Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer
E8 JAMAOncology Published online March 26, 2020 (Reprinted) jamaoncology.com
Downloaded From: https://jamanetwork.com/ on 03/26/2020
(Dicker); Stanford Cancer Institute, Division of On-
cology,Depar tment of Medicine,School of Medi-
cine, Stanford University,Stanford, California (Aliza-
deh).
Author Contributions: Drs Phillips and Tran 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: Rowe, Hao Wang,
Carducci, Pienta, Pomper, Dicker, Eisenberger,
Diehn, Tran.
Acquisition, analysis, or interpretation of data:
Phillips, Shi, Deek, Radwan, Lim, Antonarakis,
Rowe, Ross, Gorin, Deville, Greco, Hailun Wang,
Denmeade, Paller, Dipasquale,DeWeese,
Song, Hao Wang, Carducci, Dicker, Eisenberger,
Alizadeh, Diehn, Tran.
Drafting of the manuscript: Phillips, Shi, Deville,
Hailun Wang, Dipasquale, Carducci, Pienta, Pomper,
Dicker, Diehn, Tran.
Critical revision of the manuscript for important
intellectual content: Shi, Deek, Radwan, Lim,
Antonarakis, Rowe, Ross, Gorin, Deville, Greco,
Denmeade, Paller, DeWeese,Song, Hao Wang,
Carducci, Pienta, Dicker, Eisenberger, Alizadeh,
Diehn, Tran.
Statistical analysis: Phillips, Shi, Deek, Lim, Hao
Wang, Alizadeh, Diehn.
Obtained funding: Pomper, Diehn, Tran.
Administrative, technical, or material support:
Phillips, Deek, Radwan, Antonarakis, Ross, Gorin,
Deville, Greco, Paller,Eisenberger, Diehn, Tran.
Study supervision: Antonarakis, Deville, Greco,
Denmeade, Hao Wang, Pienta, Dicker, Alizadeh,
Diehn, Tran.
Conflict of Interest Disclosures: Dr Phillips
reported receiving consulting fees and honoraria
from RefleXion Medical outside the submitted
work. Mr Shi reported receiving support from the
Alpha Omega Alpha Carolyn L. Kuckein Student
Research Fellowship. Dr Antonarakis reported
receiving research grants to his institution from
Dendreon, Genentech, Novartis, Janssen, Johnson
& Johnson, Sanofi, Bristol-Myers Squibb, Pfizer,
AstraZeneca, Celgene, Merck & Co, Bayer, and
Clovis; serving as a paid consultant/advisor to
Astellas Pharma, Janssen, Pfizer, Sanofi, Dendreon,
Bayer, Bristol-MyersSquibb, Amgen, Merck & Co,
AstraZeneca, and Clovis outside the submitted
work; and holding a patent to a biomarker
technology licensed to Qiagen. Drs Rowe and Gorin
reported receiving research funding and consulting
fees from Progenics Pharmaceuticals, the licensee
of
18
F-DCFPyL, outside the submitted work.
Dr Carducci reported receiving personal fees from
Pfizer and Roche/Genentech for serving on data
safety monitoring boards outside the submitted
work. Dr Pienta reported receiving grants from
Progenics Pharmaceuticals and the Prostate Cancer
Foundation, consulting fees and stock options from
Cue Biopharma, and consulting fees from
GloriousMed Technology outside the submitted
work. Dr Pomper reported receiving grants and
other from Progenics Pharmaceuticals and grants
from the National Institutes of Health during the
conduct of the study, as wellas holding a patent
(US 8,778,305 B2) covering
18
F-DCFPyL with
royalties paid (Progenics Pharmaceuticals).
Dr Dicker reported receiving grants from the
Prostate Cancer Foundation, the National Cancer
Institute, and NRG Oncology during the conduct of
the study; receiving advisor fees from Janssen,
Cybrexa Therapeutics, Self Care Catalysts,
OncoHost, ThirdBridge, Noxopharm, Celldex
Therapeutics, EMD Serono, and Roche; providing
expert testimony on intellectual property for
Wilson Sonsini; and serving as an unpaid advisor for
Google LaunchPad Accelerator,Dreamit Ventures,
and Evolution Road outside the submitted work.
Dr Alizadeh reported receiving consulting fees from
Roche, Genentech, Chugai Pharmaceutical Co, and
Pharmacyclics outside the submitted work; having
equity in Forty Seven and CiberMed; and being a
coinventor on patent applications related to
CAPP-Seq. Dr Diehn reported receiving grants and
personal fees from Illumina; receiving consulting
fees from Roche, AstraZeneca, BioNTech, Novartis,
Varian Medical Systems, and Quanticel
Pharmaceuticals; receiving honoraria from
RefleXion Medical; and having equity in CiberMed
outside the submitted work, as well as being a
coinventor and having pending and issued patents
related to CAPP-Seq. Dr Tran reported receiving
grants from RefleXion Medical, the Prostate Cancer
Foundation, and Movember Foundation during the
conduct of the study; receiving grants from Astellas
Pharma and Bayer and personal fees from
Noxopharm and RefleXion Medical outside the
submitted work; and holding a licensed patent
related to ablative radiotherapy compounds and
methods (Natsar Pharmaceuticals).
Funding/Support: This work was supported by the
Nesbitt-McMaster Foundation, Ronald Roseand
Joan Lazar, the MovemberFoundation and Prostate
Cancer Foundation, and the National Cancer
Institute (grants R01CA166348, U01CA212007,
U01CA231776, and R21CA223403) (Dr Tran); the
National Cancer Institute (grants R01CA188298
and 1R01CA233975) (Drs Diehn and Alizadeh);
SDW/DT and Shanahan Cancer Research Funds
(Dr Alizadeh); the US National Institutes of Health
Director’s New Innovator Award (grant
1-DP2-CA186569) (Dr Diehn); the Virginia and D.K.
Ludwig Fund for Cancer Research (Drs Diehn and
Alizadeh); the CRK Faculty Scholar Fund(Dr Diehn);
and the Transdisciplinary Integration of Population
Science Program of Sidney Kimmel Cancer Center–
Jefferson Health and a Challenge Grant from the
Prostate Cancer Foundation (Dr Dicker).
Role of the Funder/Sponsor:The funders 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: We acknowledge
Terrence Caldwell, BS,and Colby Yu, BS,
Department of Radiation Oncology and Molecular
Radiation Sciences, Johns Hopkins University
School of Medicine, Baltimore, Maryland, as study
coordinators. They were compensated for their
contributions.
Data Sharing Statement: See Supplement 3.
REFERENCES
1. Surveillance, Epidemiology, and End Results
Program. Cancer stat facts: prostate cancer.
Accessed January 28, 2020. https://seer.cancer.
gov/statfacts/html/prost.html
2. Damodaran S, Lang JM, Jarrard DF. Targeting
metastatic hormone sensitive prostate cancer:
chemohormonal therapy and new combinatorial
approaches. J Urol. 2019;201(5):876-885.
doi:10.1097/JU.0000000000000117
3. Nuhn P, De Bono JS, Fizazi K, et al. Update on
systemic prostate cancer therapies: management of
metastatic castration-resistant prostate cancer in
the era of precision oncology. EurUrol. 2019;75(1):
88-99. doi:10.1016/j.eururo.2018.03.028
4. HellmanS, Weichselbaum RR. Oligometastases. JClin
Oncol. 1995;13(1):8-10.doi:10.1200/JCO.1995.13.1.8
5. Iyengar P, Wardak Z, Gerber DE, et al.
Consolidative radiotherapy for limited metastatic
non–small-cell lung cancer: a phase 2 randomized
clinical trial. JAMA Oncol. 2018;4(1):e173501.
doi:10.1001/jamaoncol.2017.3501
6. Gomez DR, Tang C, Zhang J, et al. Local
consolidative therapy vs maintenance therapy or
observation for patients with oligometastatic
non–small-cell lung cancer: long-term results of a
multi-institutional, phase II, randomized study.
J Clin Oncol. 2019;37(18):1558-1565. doi:10.1200/
JCO.19.00201
7. Palma DA, Olson R, Harrow S, et al. Stereotactic
ablative radiotherapy versus standard of care
palliative treatment in patients with oligometastatic
cancers (SABR-COMET): a randomised, phase 2,
open-label trial. Lancet. 2019;393(10185):2051-2058.
doi:10.1016/S0140-6736(18)32487-5
8. Parker CC, James ND, Brawley CD, et al;
Systemic Therapy for Advanced or Metastatic
Prostate Cancer: Evaluation of Drug Efficacy
(STAMPEDE) Investigators. Radiotherapyto the
primary tumour for newly diagnosed, metastatic
prostate cancer (STAMPEDE): a randomised
controlled phase 3 trial. Lancet. 2018;392(10162):
2353-2366. doi:10.1016/S0140-6736(18)32486-3
9. Ost P, Reynders D,Decae steckerK, et al.
Surveillance or metastasis-directed therapy for
oligometastatic prostate cancer recurrence:
a prospective, randomized, multicenter phase II
trial. J Clin Oncol. 2018;36(5):446-453. doi:10.
1200/JCO.2017.75.4853
10. Loo BW Jr, Diehn M. SABR-COMET: harbinger of
a new cancer treatment paradigm. Lancet. 2019;
393(10185):2013-2014.doi:10.1016/S0140-6736(19)
30278-8
11. Lussier YA, Xing HR, Salama JK, et al. MicroRNA
expression characterizes oligometastasis(es). PLoS
One. 2011;6(12):e28650. doi:10.1371/journal.pone.
0028650
12. Lussier YA, Khodarev NN, Regan K, et al.
Oligo- and polymetastatic progression in lung
metastasis(es) patients is associated with specific
microRNAs. PLoS One. 2012;7(12):e50141. doi:10.
1371/journal.pone.0050141
13. Uppal A, Wightman SC, Mallon S, et al.
14q32-Encoded microRNAs mediate an
oligometastatic phenotype. Oncotarget. 2015;6(6):
3540-3552. doi:10.18632/oncotarget.2920
14. Pitroda SP, Khodarev NN, Huang L, et al.
Integrated molecular subtyping defines a curable
oligometastatic state in colorectal liver metastasis.
Nat Commun. 2018;9(1):1793. doi:10.1038/
s41467-018-04278-6
15. Chaudhuri AA, Chabon JJ, Lovejoy AF,et al.
Early detection of molecular residual disease in
localized lung cancer by circulating tumor DNA
profiling. Cancer Discov. 2017;7(12):1394-1403.
doi:10.1158/2159-8290.CD-17-0716
16. Tie J, Cohen JD, Wang Y, et al. Serial circulating
tumour DNA analysis during multimodality
treatment of locally advanced rectal cancer:
Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Original Investigation Research
jamaoncology.com (Reprinted) JAMA Oncology Published online March 26, 2020 E9
Downloaded From: https://jamanetwork.com/ on 03/26/2020
a prospective biomarker study.Gut. 2019;68(4):
663-671. doi:10.1136/gutjnl-2017-315852
17. Wyatt AW, Annala M, Aggarwal R, et al.
Concordance of circulating tumor DNA and
matched metastatic tissue biopsy in prostate
cancer. J Natl Cancer Inst.2017;109(12). doi:10.
1093/jnci/djx118
18. Hong JC, Ayala-Peacock DN, Lee J, et al.
Classification for long-term survival in
oligometastatic patients treated with ablative
radiotherapy: a multi-institutional pooled analysis.
PLoS One. 2018;13(4):e0195149. doi:10.1371/journal.
pone.0195149
19. Weichselbaum RR. The 46th David A.
Karnofsky Memorial Award Lecture:
oligometastasis—from conception to treatment.
J Clin Oncol. 2018;36(32):3240-3250. doi:10.1200/
JCO.18.00847
20. Formenti SC, Rudqvist NP, Golden E, et al.
Radiotherapy induces responses of lung cancer to
CTLA-4 blockade. Nat Med. 2018;24(12):1845-1851.
doi:10.1038/s41591-018-0232-2
21. Vickers AJ. How to randomize. J Soc Integr Oncol.
2006;4(4):194-198. doi:10.2310/7200.2006.023
22. Benedict SH, Yenice KM, Followill D, et al.
Stereotactic body radiation therapy: the report of
AAPM Task Group 101.Med Phys. 2010;37(8):
4078-4101. doi:10.1118/1.3438081
23. Abida W, Cyrta J, Heller G, et al. Genomic
correlates of clinical outcome in advanced prostate
cancer. Proc Natl Acad SciUSA. 2019;116(23):
11428-11436. doi:10.1073/pnas.1902651116
24. Annala M, Vandekerkhove G, Khalaf D, et al.
Circulating tumor DNA genomics correlate with
resistance to abiraterone and enzalutamide in
prostate cancer. Cancer Discov.2018;8(4):44 4-457.
doi:10.1158/2159-8290.CD-17-0937
25. Na R, Zheng SL, Han M, et al. Germline
mutations in ATM and BRCA1/2 distinguish risk for
lethal and indolent prostate cancer and are
associated with early age at death. Eur Urol. 2017;7 1
(5):740-747. doi:10.1016/j.eururo.2016.11.033
26. Gundem G, Van Loo P, KremeyerB, et al; ICGC
Prostate Group. The evolutionary history of lethal
metastatic prostate cancer. Nature. 2015;520
(7547):353-357.doi:10.1038/nature14347
27. Vandekerkhove G, Struss WJ, Annala M, et al.
Circulating tumor DNA abundance and potential
utility in de novo metastatic prostate cancer.Eur U rol.
2019;75(4):667-675. doi:10.1016/j.eururo.2018.
12.042
28. Duchesne GM, Woo HH, Bassett JK, et al.
Timing of androgen-deprivation therapy in patients
with prostate cancer with a rising PSA (TROG 03.06
and VCOG PR 01-03 [TOAD]): a randomised,
multicentre, non-blinded, phase 3 trial. Lancet Oncol.
2016;17(6):727-737. doi:10.1016/S1470-2045(16)
00107-8
29. Moul JW, Wu H, Sun L, et al. Early versus
delayed hormonal therapy for prostate specific
antigen only recurrence of prostate cancer after
radical prostatectomy.J Urol. 2004;171(3):1141-1147.
doi:10.1097/01. ju.0000113794.34810.d0
30. Studer UE, Whelan P, Albrecht W, et al.
Immediate or deferred androgen deprivation for
patients with prostate cancer not suitable for local
treatment with curative intent: European
Organisation for Research and Treatment of Cancer
(EORTC) trial 30891. J Clin Oncol. 2006;24(12):
1868-1876. doi:10.1200/JCO.2005.04.7423
31. Golden EB, Chhabra A, Chachoua A, et al. Local
radiotherapy and granulocyte-macrophage
colony-stimulating factor to generate abscopal
responses in patients with metastatic solid
tumours: a proof-of-principle trial. Lancet Oncol.
2015;16(7):795-803.doi:10.1016/S1470-2045(15)
00054-6
32. Soldatov A, von Klot CAJ, Walacides D, et al.
Patterns of progression after
68
Ga-PSMA-ligand
PET/CT-guided radiation therapy for recurrent
prostate cancer. Int J RadiatOncol Biol Phys. 2019;
103(1):95-104. doi:10.1016/j.ijrobp.2018.08.066
Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer
E10 JAMA Oncology Published online March 26, 2020 (Reprinted) jamaoncology.com
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