original reports

Prostate-Only Versus Whole-Pelvic Radiation

Therapy in High-Risk and Very High-Risk Prostate
Cancer (POP-RT): Outcomes From Phase III
Randomized Controlled Trial
Vedang Murthy, MD1; Priyamvada Maitre, MD1; Sadhana Kannan, MSc2; Gitanjali Panigrahi, MSc1; Rahul Krishnatry, MD1;
Ganesh Bakshi, MCh3; Gagan Prakash, DNB3; Mahendra Pal, DNB3; Santosh Menon, MD4; Reena Phurailatpam, MSc5;
Smruti Mokal, MSc2; Dipika Chaurasiya, BSc1; Palak Popat, DNB6; Nilesh Sable, MD6; Archi Agarwal, DNB7;
Venkatesh Rangarajan, DNB7; Amit Joshi, DM8; Vanita Noronha, DM8; Kumar Prabhash, DM8; and Umesh Mahantshetty, MD1
abstract

PURPOSE We report the clinical outcomes of a randomized trial comparing prophylactic whole-pelvic nodal
radiotherapy to prostate-only radiotherapy (PORT) in high-risk prostate cancer.
METHODS This phase III, single center, randomized controlled trial enrolled eligible patients undergoing radical
radiotherapy for node-negative prostate adenocarcinoma, with estimated nodal risk $ 20%. Randomization was
1:1 to PORT (68 Gy/25# to prostate) or whole-pelvic radiotherapy (WPRT, 68 Gy/25# to prostate, 50 Gy/25# to
pelvic nodes, including common iliac) using computerized stratified block randomization, stratified by Gleason
score, type of androgen deprivation, prostate-specific antigen at diagnosis, and prior transurethral resection of
the prostate. All patients received image-guided, intensity-modulated radiotherapy and minimum 2 years of
androgen deprivation therapy. The primary end point was 5-year biochemical failure-free survival (BFFS), and
secondary end points were disease-free survival (DFS) and overall survival (OS).
RESULTS From November 2011 to August 2017, a total of 224 patients were randomly assigned (PORT 5 114,
WPRT 5 110). At a median follow-up of 68 months, 36 biochemical failures (PORT 5 25, WPRT 5 7) and 24
deaths (PORT 5 13, WPRT 5 11) were recorded. Five-year BFFS was 95.0% (95% CI, 88.4 to 97.9) with WPRT
versus 81.2% (95% CI, 71.6 to 87.8) with PORT, with an unadjusted hazard ratio (HR) of 0.23 (95% CI, 0.10 to
0.52; P , .0001). WPRT also showed higher 5-year DFS (89.5% v 77.2%; HR, 0.40; 95% CI, 0.22 to 0.73; P 5
.002), but 5-year OS did not appear to differ (92.5% v 90.8%; HR, 0.92; 95% CI, 0.41 to 2.05; P 5 .83). Distant
metastasis-free survival was also higher with WPRT (95.9% v 89.2%; HR, 0.35; 95% CI, 0.15 to 0.82; P 5 .01).
Benefit in BFFS and DFS was maintained across prognostic subgroups.
CONCLUSION Prophylactic pelvic irradiation for high-risk, locally advanced prostate cancer improved BFFS and
DFS as compared with PORT, but OS did not appear to differ.
ASSOCIATED
CONTENT J Clin Oncol 39:1234-1242. © 2021 by American Society of Clinical Oncology
See accompanying
Oncology Grand INTRODUCTION serum prostate-specific antigen (PSA) levels at diag-
Rounds on page 1196 nosis and tumor Gleason score (GS).3 Potential clinical
Data Supplement External beam radiotherapy combined with androgen
gain with prophylactic pelvic irradiation is likely to be
Protocol deprivation therapy (ADT) is the recommended radical
relevant in patients with Roach nodal risk of 20%-
Author affiliations treatment for nonmetastatic, locally advanced prostate
40%. Under-representation of this group in the pre-
and support cancer. For patients without regional pelvic nodal in-
information (if vious randomized trials studying pelvic radiotherapy,
volvement, the benefit of prophylactically treating
applicable) appear along with variable use of ADT, possibly explains their
pelvic lymph nodes with radiotherapy has been de-
at the end of this inconclusive results.
article. bated for decades. The rationale for pelvic radio-
Accepted on therapy is the eradication of nodal micrometastases, The present randomized trial of prostate-only or whole-
December 8, 2020 providing better regional control and potentially im- pelvic radiation therapy in high-risk prostate cancer
and published at proving survival outcomes. However, long-term clinical (POP-RT) evaluated the benefit of treating the pelvic
ascopubs.org/journal/ outcomes from two large randomized trials exploring nodes for node-negative, high-risk prostate adeno-
jco on January 26,
this question have failed to provide a conclusive carcinoma undergoing dose-escalated and moder-
2021: DOI https://doi.
org/10.1200/JCO.20. answer.1,2 Risk of pelvic nodal involvement is esti- ately hypofractionated radiotherapy. Although the
03282 mated clinically using the Roach formula, based on secondary outcomes of toxicities and patient-reported

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 Pelvic or Prostate RT in High-Risk Prostate Cancer

CONTEXT
Key Objective
To address the longstanding question regarding the efficacy of prophylactic pelvic nodal irradiation in high-risk prostate
cancer. The present trial incorporates the contemporary standards of staging, radiotherapy dose, technique, nodal
volumes, and duration of androgen deprivation therapy.
Knowledge Generated
Prophylactic pelvic radiotherapy resulted in significantly improved biochemical failure-free survival and disease-free survival
as compared with prostate-only radiotherapy. Modest increase was observed in the incidence of grade $ 2 late
genitourinary toxicity with pelvic radiotherapy, with low incidence of GI toxicity in both the arms.
Relevance
Prophylactic pelvic irradiation using contemporary dose and technique of radiation along with long-term androgen dep-
rivation for high-risk and very high-risk prostate cancer should be routinely considered as standard for these patients.

quality of life (QOL) have been reported previously,4 long- prostate (yes or no). Investigators and participants were not
term clinical outcomes of this trial are reported here. masked to the assignment.

METHODS
Study Design and Participants
This phase III randomized trial was undertaken within the
Uro-oncology Disease Management Group of Tata Me-
morial Centre, India, after approval of the institutional ethics
committee (IEC ID 932). Men with histopathological di-
agnosis of prostate adenocarcinoma and staged as non-
metastatic and node-negative were screened for trial
eligibility. Magnetic resonance imaging for prostate,
contrast-enhanced computed tomography (CT) scan of
abdomen and pelvis, technetium-99 bone scan, or positron
emission tomography (PET) CT with fluoride-18 or gallium-
68 prostate-specific membrane antigen (PSMA) scans
were allowed for staging. Key eligibility criterion was the risk
of pelvic node involvement of at least 20%, estimated using
Roach formula (Table 1). Patients with clinical stage
T1-T3a with Gleason 8-10 and any PSA, Gleason 7 with
PSA . 15 ng/mL, Gleason 6 with PSA . 30 ng/mL; or stage
T3b-T4a with any GS and any PSA were eligible for in-
clusion. Other inclusion criteria were estimated life ex-
pectancy of at least 5 years and ability to receive long-term
ADT or undergo surgical castration. Patients with a history
of prior pelvic radiation, prior malignancy within 5 years of
present diagnosis, or if deemed unsuitable for pelvic ra-
diotherapy were excluded. All patients signed informed
consent before being enrolled in the trial.
Enrolled patients were randomly assigned to receive either
prostate-only radiotherapy (PORT) or whole-pelvic radio-
therapy (WPRT) in 1:1 ratio using computerized stratified
block randomization method with a block size of four,
stratified according to GS (6-7 or 8-10), type of androgen
deprivation (medical or surgical), PSA at diagnosis (# 50
or . 50 ng/mL), and prior transurethral resection of the
Treatment Procedures
Detailed radiotherapy procedures have been previously
published.4 In brief, patients were simulated in the supine
position with pelvis immobilized using knee rest. Uniform
filling of the urinary bladder and rectal emptying were
ensured for radiotherapy planning and delivery. Radio-
therapy planning CT scan was acquired without intrave-
nous contrast or intraprostatic fiducials. Clinical target
volume (CTV) included entire prostate gland along with any
extracapsular extension and base of seminal vesicles if
clinicoradiologically free or entirely if involved. CTV was
uniformly expanded by 7 mm (5 mm posteriorly) to gen-
erate the primary planning target volume (PTV), which was
prescribed a dose of 68 Gy in 25 fractions. In WPRT arm,
pelvic nodal CTV was delineated starting at L4-5 junction to
include bilateral common iliac, external iliac, internal iliac,
presacral, and obturator nodes as per guidelines by Ra-
diation Therapy Oncology Group (RTOG).5 It was uniformly
expanded by 7 mm to obtain nodal PTV, which was pre-
scribed 50 Gy in 25 fractions.
Inverse planning method was used to plan intensity-
modulated radiotherapy (IMRT) with a fixed field, dy-
namic arc, or helical tomotherapy techniques, ensuring
coverage of at least 95% of PTV within 95% prescription
isodose. In WPRT arm, radiotherapy to pelvic nodes and
prostate was delivered as a simultaneous integrated boost.
One of the two authors (V.M. or U.M.) approved all the
contours and treatment plans. Each finalized plan under-
went patient-specific quality assurance for plan delivery
before beginning the treatment course. Daily volumetric
image guidance using on-board kilovoltage cone-beam CT
or megavoltage CT was obtained to verify patient position.
Androgen suppression was either medically using lutei-
nizing hormone-releasing hormone analogs or surgically

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 Murthy et al

TABLE 1. Baseline Characteristics

Characteristic All Patients (N 5 222), N (%) PORT (n 5 112), N (%) WPRT (n 5 110), N (%)
Median age, years 66 66 66
Median PSA, ng/mL 28.2 27.4 29.9
a
Nodal risk, %
# 40% 119 (53.6) 60 (53.6) 59 (53.6)
. 40% 103 (46.4) 52 (46.4) 51 (46.4)
Gleason grade group
1 22 (9.9) 11 (9.8) 11 (10)
2 38 (17.1) 20 (17.9) 18 (16.4)
3 53 (23.9) 25 (22.3) 28 (25.5)
4 53 (23.9) 26 (23.2) 27 (24.5)
5 56 (25.3) 30 (26.8) 26 (23.6)
ADT
Orchiectomy 42 (18.9) 26 (23.2) 16 (14.5)
Medical 180 (81.1) 86 (76.8) 94 (85.5)
History of TURP
Yes 60 (27) 30 (26.8) 30 (27.3)
No 162 (73) 82 (73.2) 80 (72.7)
Tumor stage
T1 2 (0.9) 1 (0.9) 1 (0.9)
T2 46 (20.7) 19 (17) 27 (24.5)
T3a 70 (31.5) 38 (33.9) 32 (29.1)
T3b 86 (38.7) 44 (39.3) 42 (38.2)
T4 18 (8.1) 10 (8.9) 8 (7.3)

Abbreviations: ADT, androgen deprivation therapy; PORT, prostate-only radiotherapy; PSA, prostate-specific antigen; TURP, transurethral resection of
prostate; WPRT, whole-pelvic radiotherapy.
a
By Roach formula, risk 5 2/3 PSA 1 ([Gleason score 2 6] 3 10).

with bilateral orchiectomy, at least 8 weeks before radio-
therapy, continued concurrently, and later for a total du-
ration of 2 years. Patients were followed up at 6-12 weeks
after completing radiotherapy and every 3 to 6 months
thereafter. Acute and late genitourinary (GU) and GI tox-
icities were evaluated as per RTOG scale. QOL assessment
was done using the European Organisation for Research
and Treatment of Cancer Quality-of-Life Questionnaire-
Core 30 (EORTC QLQ-C30) and Prostate module PR-25.
Clinical examination, serum PSA measurement, review of
toxicities, and QOL assessment were performed as defined
in the protocol, with additional investigations at physician’s
discretion as clinically indicated. At the time of biochemical
failure, restaging was done with CT or PSMA PET CT.
Study Outcomes
The primary objective was biochemical failure-free survival
(BFFS) at 5 years, estimated from the time of randomization
to the first recorded date of biochemical failure. Bio-
chemical failure was defined by the Phoenix criteria of
serum PSA exceeding nadir PSA 12 ng/mL.6 Secondary
objectives included disease-free survival (DFS), overall
survival (OS), acute and late toxicities, and patient-reported
QOL. DFS was calculated from the time of randomization to
the first biochemical or clinicoradiological recurrence of
disease at any site, or death due to any cause, whichever
occurred earlier. OS was calculated from the time of ran-
domization till death because of any cause. After devel-
oping the primary end point event of biochemical failure,
patients were continued on follow-up within the trial for
secondary outcomes. The exploratory outcome of distant
metastasis-free survival (DMFS) was defined as the time
from randomization till the development of first distant
metastasis outside the irradiated pelvic field. For the end
points of BFFS and DMFS, patients were censored at either
the date of last follow-up or date of death. For DFS and OS,
censoring was at the date of the last follow-up.
Statistical Analysis
Given the higher risk profile of the included patients, the
5-year BFFS was estimated to be 45% with PORT, to be
improved to 62% with WPRT. With a two-sided alpha error
of .05 and 80% statistical power, a total of 120 events were
required to detect the effect. Totally, 224 patients were

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Pelvic or Prostate RT in High-Risk Prostate Cancer
required to be randomly assigned (112 in each arm),
allowing for a 5% rate of loss to follow-up.
After a study period of 9 years, only 36 events of bio-
chemical failure were observed, which was considerably
lower than anticipated and statistically planned for. It was
considered by the trial steering committee that the planned
number of events for the primary end point may need an
inordinately long time to occur or may never be reached.
Therefore, it was deemed prudent to analyze the study data
for the outcomes as specified in this study design.
Median follow-up time was calculated using reverse
Kaplan-Meier method. Survival rates for primary and sec-
ondary outcomes were estimated using Kaplan-Meier
method. The difference in survival curves was tested us-
ing a two-sided log-rank test. Cumulative incidence func-
tion for BFFS was estimated with death due to any cause as
a competing event for biochemical failure and compared
using Gray’s test. Cox regression method was used to es-
timate hazard ratios (HRs). Multivariable analysis was
performed using Cox proportional hazards method for the
primary end point. The proportional hazards assumption
was tested and found to hold true. Subgroup analysis for
BFFS and secondary end points was performed in sub-
groups defined by the prespecified stratification factors
and other known prognostic factors. DMFS was analyzed
post hoc following its emergence as a validated surrogate
end point for OS in prostate cancer.7 Updated cumulative
late GU and GI toxicities were compared using chi-square
test or Fisher’s exact test. All analyses were intention-to-
treat, performed on SPSS version 24 (IBM Inc, Armonk,
New York) and STATA 14.
Trial data were regularly monitored by independent insti-
tutional data and safety monitoring committee. This trial
was registered at Clinical Trials Registry of India (CTRI/
2012/12/003181) and ClinicalTrials.gov (identifier:
NCT02302105).
RESULTS
From November 25, 2011, to August 22, 2017, 336 pa-
tients were screened for trial eligibility, and totally 224
patients were enrolled after written informed consent
(Fig 1). They were randomly assigned 1:1 to WPRT (n 5
110) or PORT (n 5 114) arms. In the PORT arm, two
patients withdrew consent and one received pelvic radio-
therapy. Baseline features were balanced well in both the
arms (Table 1). Median patient age was 66 years, and
median baseline serum PSA was 28.2 ng/mL. About half of
the patients had Gleason grade group four or five. Median
estimated Roach nodal risk was 37.8% (interquartile range,
25.1 to 53.4) for the entire cohort. Advanced tumor stage of
T3b or T4 was diagnosed in just under half the patients, and
about 80% of the patients underwent PSMA PET CT scan
for staging. Median follow-up was 68 months, and the last
enrolled patient has completed 3 years of follow-up.
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Totally, 36 biochemical failures were observed (WPRT 5 7,
PORT 5 29), with corresponding 5-year BFFS of 95.0%
(95% CI, 88.4 to 97.9) and 81.2% (95% CI, 71.6 to 87.8),
respectively, with an unadjusted HR for biochemical failure
being 0.23 (95% CI, 0.10 to 0.52, P , .0001) favoring
WPRT (Fig 2). Competing risk analysis for the primary end
point also showed significant difference in the cumulative
incidence of primary events favoring WPRT (5% v 19%,
Gray’s test, P , .0001; Data Supplement, online only).
Total events for DFS were 51 (WPRT 5 15, PORT 5 36),
with a 5-year DFS of 89.5% (95% CI, 81.9 to 94.1) versus
77.2% (95% CI, 67.6 to 84.3) and an HR of 0.40 (95% CI,
0.22 to 0.73; P 5 .002). Totally, 24 deaths were observed
(WPRT 5 11, PORT 5 13), with a 5-year OS being 92.5%
(95% CI, 85.6 to 96.2) versus 90.8% (95% CI, 83.5 to
94.9) and an HR of 0.92 (95% CI, 0.41 to 2.05; P 5 .83).
Distant metastasis (outside the pelvis) developed in 27
patients (WPRT 5 7, PORT 5 20). For the exploratory end
point of DMFS, the 5-year rate was 95.0% (95% CI, 88.4 to
97.9) versus 87.9% (95% CI, 79.0 to 93.2) and an HR of
0.35 (95% CI, 0.15 to 0.82; P 5 .01).
On multivariable analysis of prognostic factors, WPRT and
GS showed statistically significant association with BFFS
(Data Supplement). Subgroup analyses showed that the
benefit of WPRT was maintained across all the subgroups
analyzed for BFFS (Fig 3) and DFS (Data Supplement). Of
note, younger patients (age , 66 years) seemed to derive a
greater benefit for BFFS and DFS with WPRT (for inter-
action, P 5 .03 and .02, respectively).
Patterns of disease recurrence at the time of biochemical
failure are detailed in Data Supplement. Recurrent disease
in regional pelvic nodes, with or without other sites of
disease, accounted for 15/29 (52%) recurrences in the
PORT arm and 1/8 (12.5%) recurrences in the WPRT arm
(P 5 .05 for comparison).
Acute GU and GI toxicities have been reported in detail
earlier, which did not show any significant difference be-
tween the two arms.4 Late bowel and bladder toxicities were
updated at median follow-up of 68 months (Table 2).
Cumulative $ grade II late GU toxicity was significantly
higher with WPRT (20.0% v 8.9%, P 5 .02), while no
statistically significant difference was observed for $ grade
II late GI toxicity (8.2% v 4.5%, P 5 .28). No RTOG grade IV
GU or GI toxicity was observed in either of the arms.
DISCUSSION
This randomized trial reports the long-term clinical out-
comes with prophylactic pelvic nodal irradiation in patients
with high-risk and very high-risk, locally advanced, node-
negative prostate cancer. WPRT resulted in a significant
improvement in BFFS and DFS at 5 years. An increase in
late $ grade II bladder toxicity observed with pelvic ra-
diotherapy could possibly be a result of a larger volume of
the bladder being exposed to mid-range dose of 30-40 Gy,
1237
 Murthy et al
Assessed for eligibility
(N = 336)
Randomized
(n = 224)
Allocated to whole-pelvis radiotherapy (n = 110)
Withdrawn consent (n = 0)
Did not receive allocated intervention (n = 0)
Received allocated intervention (n = 110)
Discontinued intervention (n = 0)
Analyzed for outcomes (n = 110)
FIG 1. CONSORT diagram. RT, radiotherapy.
as detailed previously.4 Late bowel toxicity, however, was
similar between the two arms, attributable to the meticulous
bowel sparing achieved by the universal use of IMRT.
Two published randomized trials from the nineties have
previously explored the benefit of adding pelvic radio-
therapy for localized prostate cancer. The GETUG-01 trial
compared survival in 446 patients with cT1b-T3N0M0
prostate cancer treated with 66-70 Gy to the prostate
with or without 46 Gy to the pelvic nodes.2 No difference
was observed in event-free survival or OS with pelvic ra-
diotherapy at more than 11 years follow-up. Unexpectedly,
a post hoc subgroup analysis favored pelvic radiotherapy in
patients with , 15% Roach nodal risk. The RTOG 9413
trial used a 2 3 2 factorial design to compare WPRT versus
PORT and neoadjuvant or adjuvant ADT.1 Conventionally
fractionated dose of 70.2 Gy was delivered to the prostate,
with 50.4 Gy to the pelvic nodes in WPRT. All patients
received only 4 months of ADT, before or after the radio-
therapy as per assignment. Although initial results sug-
gested improved biochemical control with WPRT, long-
term outcomes have shown no clear difference between
the PORT and WPRT.1,8,9 Lack of optimal patient selection,
radiotherapy technique, volume and dose, along with the
inadequate duration of ADT for high-risk disease, and its
unanticipated interaction with radiotherapy have left
the question in equipoise. Three ongoing trials have
addressed the above shortcomings but are likely to
report only in the next 5-15 years. The RTOG 0924
1238 © 2021 by American Society of Clinical Oncology
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
Excluded (n = 112)
Not meeting inclusion (n = 51)
Declined to participate (n = 27)
Other reasons (n = 34)
Allocated to prostate-only radiotherapy (n = 114)
Withdrawn consent (n = 2)
Did not receive allocated intervention
(Received Pelvic RT) (n = 1)
Received allocated intervention (n = 111)
Discontinued intervention (logistics) (n = 1)
Analyzed for outcomes (n = 112)
(ClinicalTrials.gov identifier: NCT01368588) and the Piv-
otalBoost (ISRCTN80146950) trials include patients with un-
favorable intermediate risk and favorable high-risk patients
rather than the cohort reported in this trial. The French GETUG-
AFU-23 trial (ClinicalTrials.gov identifier: NCT01952223) has a
similar cohort of patients with unfavorable high-risk cancer but
is a 2 3 2 factorial design studying the value of neoadjuvant
cabazitaxel in addition to pelvic radiotherapy.
Eligibility criteria for the present trial ensured the selection
of uniformly higher risk cohort, with pelvic nodal involve-
ment risk at least 20% as estimated by the Roach formula.
In fact, just over half of our patients would be classified as
very high risk as per National Comprehensive Care Network
risk stratification of 2019.10 This is in contrast to the eli-
gibility criteria of the previous trials (Table 3). Functional
imaging (PSMA PET CT) with higher sensitivity was used for
staging in 80% of the patients to identify and exclude
metastatic disease both within and outside the pelvis.
A moderately hypofractionated dose of 68 Gy in 25 fractions
at 2.72 Gy per fraction corresponds to about 78-81 Gy at
2 Gy per fraction (a/b 5 3-1.5 Gy), which conforms to the
dose-escalation recommendation.11,12 Concerns regarding
higher bowel toxicity with WPRT were addressed with the
use of IMRT to optimize small bowel sparing. It also allowed
the safe inclusion of common iliac nodes into the pelvic
treatment volume, as compared with the previous trials
which limited their pelvic field portals to L5/S1 or S1/S2
Volume 39, Issue 11
 Pelvic or Prostate RT in High-Risk Prostate Cancer

A B
Biochemical Failure-Free Survival
1.0 1.0

Disease-Free Survival
0.8 0.8

0.6 0.6

0.4 0.4

HR 0.23 (95% CI, 0.10 to 0.52) Pelvic RT Pelvic RT

0.2 0.2 HR 0.40 (95% CI, 0.22 to 0.73)
P < .0001 Prostate RT Prostate RT
P = .002

0 12 24 36 48 60 72 84 96 0 12 24 36 48 60 72 84 96
Months Months
No. at risk No. at risk
WPRT 110 106 104 100 81 64 40 20 10 WPRT 110 107 105 102 82 66 42 20 10
PORT 112 106 104 97 77 55 34 22 10 PORT 112 108 106 99 79 56 39 19 10

C D
1.0 1.0
Distant Metastasis-Free Survival

0.8 0.8
Overall Survival
0.6 0.6

0.4 0.4
Pelvic RT Pelvic RT
HR 0.92 (95% CI, 0.41 to 2.05)
HR 0.35 (95% CI, 0.15 to 0.82) Prostate RT P = .83 Prostate RT
0.2 P = .01 0.2

0 12 24 36 48 60 72 84 96 0 12 24 36 48 60 72 84 96
Months Months
No. at risk No. at risk
WPRT 110 107 105 100 80 64 41 20 9 WPRT 110 108 105 101 83 67 43 21 10
PORT 112 108 107 99 80 56 39 21 10 PORT 112 110 108 102 85 65 47 29 15

FIG 2. Kaplan-Meier estimates of (A) biochemical failure-free survival, (B) disease-free survival, (C) distant metastasis-free survival, and (D) overall
survival. HR, hazard ratio; PORT, prostate-only radiotherapy; RT, radiotherapy; WPRT, whole-pelvic radiotherapy.

vertebral junction, possibly missing a substantial proportion
of lymph nodes draining the prostate.13,14
Guidelines generally recommend ADT for at least 2 years
rather than a shorter duration of treatment for high-risk
disease.11,15,16 Benefits of longer ADT persist despite using
a high radiation dose.17 There has been a long-standing
question of whether WPRT is necessary in the setting of
long-term ADT, as prolonged testosterone suppression
after radiotherapy may compensate for the exclusion of
pelvic fields.18 The present trial clearly shows that the
failure events in the PORT arm start at about 36 months,
corresponding to the recovery of testosterone in these
patients. Importantly, the predominance of pelvic failures in
PORT arm seems to be driving the differences in clinical
outcomes between the two arms, suggesting the necessity
of WPRT for the long-term control of microscopic disease in
regional nodes. Moreover, a pelvic dose of 50 Gy in 2 Gy
fractions in the present trial is somewhat higher than
45-50.4 Gy in 1.8 Gy fractions in the previous trials
(Table 3), which may have contributed to improved disease
control. In any case, the cytostatic effect of prolonged ADT
may not be an adequate replacement for WPRT to provide
long-term control of regional microscopic disease, espe-
cially in higher risk patients.
Some limitations of the present trial are acknowledged.
First, the choice of BFFS as the primary end point is not
ideal. Although OS may be an impractical end point in trials
of localized prostate cancer, the secondary end point of DFS
is more acceptable to define practice. In this trial, the large
early difference in BFFS is the main contributor to improved

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 Murthy et al

No. of events/ Total no.

Pelvic Prostate-only P value for
Subgroup radiotherapy radiotherapy Hazard Ratio (95% CI) interaction

Age (years)
≤ 66 2/59 22/58 0.08 (0.02 to 0.35) .03
> 66 5/51 7/54 0.66 (0.21 to 2.10)

Nodal Risk
≤ 40% 4/59 11/60 0.36 (0.12 to 1.14) .28
> 40% 3/51 18/52 0.15 (0.04 to 0.50)

T stage
< T3b 3/60 14/58 0.18 (0.05 to 0.64) .59
≥ T3b 4/50 15/54 0.30 (0.10 to 0.90)

Gleason Score
6-7 2/57 9/56 0.22 (0.05 to 1.01) .88
8-10 5/53 20/56 0.24 (0.09 to 0.64)

PSA (ng/mL)
≤ 50 5/80 21/81 0.22 (0.08 to 0.58) .96
> 50 2/30 8/31 0.25 (0.05 to 1.16)

Risk Group (NCCN 2019)

High risk 2/55 12/51 0.14 (0.03 to 0.63) .37
Very high risk 5/55 17/61 0.32 (0.12 to 0.88)

Androgen Suppression
Medical 6/94 23/86 0.22 (0.09 to 0.54) .90
Orchiectomy 1/16 6/26 0.26 (0.03 to 2.14)

Overall 110 112 0.23 (0.10 to 0.52)

0.2 1.0
Pelvic Radiotherapy Better Prostate-Only Radiotherapy Better

FIG 3. Subgroup analysis for biochemical failure-free survival. NCCN, National Comprehensive Care Network; PSA, prostate-specific antigen.

DFS. DMFS has recently emerged as a robust surrogate end efficacy of WPRT for disease control. Second, although the
point for OS,7,19 and hence it was included as a post hoc clinical outcomes in both arms were considerably better
exploratory outcome in statistical analysis. The observed than anticipated, the resultant absolute benefit of 14% in
significant improvement in the DMFS further supports the BFFS with WPRT closely matched with the difference of

TABLE 2. Cumulative Late Toxicity (RTOG)

RTOG Grade All Patients (N 5 222), N (%) PORT (n 5 112), N (%) WPRT (n 5 110), N (%) P (grade 0-1 v grade ‡ II)
GU
0 85 (38.3) 45 (40.2) 40 (36.4) .02
I 105 (47.3) 57 (50.9) 48 (43.6)
II 28 (12.6) 8 (7.1) 20 (18.2)
III 4 (1.8) 2 (1.8) 2 (1.8)
GI
0 138 (62.2) 74 (66.1) 64 (58.2) .28
I 70 (31.5) 33 (29.5) 37 (33.6)
II 12 (5.4) 5 (4.5) 7 (6.4)
III 2 (0.9) 0 (0) 2 (1.8)

Abbreviations: GU, genitourinary; PORT, prostate-only radiotherapy; RTOG, Radiation Therapy Oncology Group; WPRT, whole-pelvic radiotherapy.

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 Pelvic or Prostate RT in High-Risk Prostate Cancer

TABLE 3. Comparison With Previous Randomized Trials of Pelvic Radiotherapy

Parameter RTOG 9413 GETUG-01 POP-RT
T Stage T2c-T4: 67% T3: 25.5% T3b-T4: 46.4%
Estimated pelvic nodal risk . 35% risk in 24.5% . 35% risk in 9.8% Median 38%
. 35% risk in 55%
. 50% risk in 29%
GS GS 7-10: 72% GS 7-10: 50.7% GS 7-10: 90.2%
GS 8-10: 10.9% GS 8-10: 49.1%
Baseline median PSA 22.6 ng/mL 12 ng/mL 28.2 ng/mL
Staging imaging Chest x-ray, CT pelvis or CT thorax abdomen and pelvis, bone scan MRI pelvis, PETCT (F-18 or
lymphangiogram, bone scan Ga-68 PSMA)
80% had PSMA PETCT
Pelvic field upper limit L5-S1 S1-S2 L4-L5 including common iliac
nodes
Pelvic dose 50.4 Gy 46 Gy 50 Gy
Prostate dose (biologically 70.2 Gy, 1.8 Gy per fraction (112.32 Gy) 66.25-72 Gy, 1.8-2 Gy per fraction (110-122 68 Gy, 2.72 Gy per fraction
effective dose) Gy) (129.6 Gy)
Radiotherapy technique Conventional 2-dimensional box fields Conventional 2-dimensional box fields and Image-guided IMRT
3-dimensional conformal radiotherapy
ADT 4 months 4-8 months $ 24 months

Abbreviations: ADT, androgen deprivation therapy; CT, computed tomography; GS, Gleason score; IMRT, intensity-modulated radiotherapy; MRI,
magnetic resonance imaging; PET, positron emission tomography; POP-RT, prostate-only or whole-pelvic radiation therapy in high-risk prostate cancer; PSA,
prostate-specific antigen; PSMA, prostate-specific membrane antigen; RTOG, Radiation Therapy Oncology Group.

17% as hypothesized during trial design. To see the ob-
served difference in the two arms (5-year BFFS 95% v
81%) with 80% statistical power and .05 two-sided alpha, a
total of 18 events would have been required, which are
fewer than actually observed. Third, while the trial protocol
allowed for multicentric accrual, a single-center approach
was necessitated in the absence of national collaborative
research groups supporting or funding prostate cancer
research. Finally, brachytherapy, which has evolved as an
important component of local treatment for dose escalation
in high-risk prostate cancer, was not used in this trial since
it had not been established as a standard of care for the
high- and very high-risk cohort when this trial was com-
menced. Also, a significant number of patients were
expected to undergo transurethral resection of prostate
based on national practice patterns, which would have
made them unsuitable candidates for a brachytherapy
boost. However, an adequately high radiation dose
equivalent to 78-81 Gy (biologically effective dose, 129.6
Gy) was delivered to the prostate to achieve local control.
In conclusion, prophylactic WPRT using a contemporary
dose and technique along with long-term ADT for high-risk
and very high-risk prostate cancer resulted in a large and
significantly improved BFFS and DFS as compared with
PORT, but did not impact OS. Until the long-term outcomes
of the ongoing trials are reported, prophylactic pelvic ra-
diotherapy should be routinely considered for these patients.

AFFILIATIONS
1
Department of Radiation Oncology, Tata Memorial Hospital and
Advanced Centre for Treatment Research and Education in Cancer
(ACTREC), Homi Bhabha National Institute (HBNI), Mumbai, India
2
Clinical Research Secretariat, Tata Memorial Hospital and Advanced
Centre for Treatment Research and Education in Cancer (ACTREC), Homi
Bhabha National Institute (HBNI), Mumbai, India
3
Department of Surgery, Tata Memorial Hospital and Advanced Centre for
Treatment Research and Education in Cancer (ACTREC), Homi Bhabha
National Institute (HBNI), Mumbai, India
4
Department of Pathology, Tata Memorial Hospital and Advanced Centre
for Treatment Research and Education in Cancer (ACTREC), Homi
Bhabha National Institute (HBNI), Mumbai, India
5
Department of Medical Physics, Tata Memorial Hospital and Advanced
Centre for Treatment Research and Education in Cancer (ACTREC), Homi
Bhabha National Institute (HBNI), Mumbai, India
6
Department of Radiodiagnosis, Tata Memorial Hospital and Advanced
Centre for Treatment Research and Education in Cancer (ACTREC), Homi
Bhabha National Institute (HBNI), Mumbai, India
7
Department of Nuclear Medicine and Molecular Imaging, Tata Memorial
Hospital and Advanced Centre for Treatment Research and Education in
Cancer (ACTREC), Homi Bhabha National Institute (HBNI), Mumbai,
India
8
Department of Medical Oncology, Tata Memorial Hospital and Advanced
Centre for Treatment Research and Education in Cancer (ACTREC), Homi
Bhabha National Institute (HBNI), Mumbai, India
CORRESPONDING AUTHOR
Vedang Murthy, MD, Department of Radiation Oncology, Tata Memorial
Hospital, Ernest Borges Road, Parel, Mumbai, India 400 012; Twitter:
@VedangMurthy, @ACTREC_TMC, @TataMemorial; e-mail: vmurthy@
actrec.gov.in.

Journal of Clinical Oncology 1241

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

PRIOR PRESENTATION Provision of study materials or patients: Gitanjali Panigrahi, Ganesh

The results of secondary outcomes of acute and late toxicities and
patient-reported quality of life from this study have been published
previously (doi.org/10.1016/j.radonc.2019.12.006). The results of final
survival outcomes have been presented as a Plenary Lecture at the annual
meeting of the European Society of Therapeutic Radiology and Oncology
(ESTRO39), Vienna, Austria, November 30, 2020.
SUPPORT
The POP-RT trial is supported by intramural funding from Tata Memorial
Center and the Terry Fox Foundation.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF
INTEREST
Disclosures provided by the authors are available with this article at DOI
https://doi.org/10.1200/JCO.20.03282.
AUTHOR CONTRIBUTIONS
Conception and design: Vedang Murthy, Sadhana Kannan, Ganesh
Bakshi, Reena Phurailatpam, Palak Popat, Kumar Prabhash, Umesh
Mahantshetty
Administrative support: Dipika Chaurasiya, Kumar Prabhash
Bakshi, Mahendra Pal, Smruti Mokal, Venkatesh Rangarajan, Amit Joshi,
Vanita Noronha, Umesh Mahantshetty
Collection and assembly of data: Vedang Murthy, Priyamvada Maitre,
Sadhana Kannan, Gitanjali Panigrahi, Rahul Krishnatry, Ganesh Bakshi,
Gagan Prakash, Mahendra Pal, Dipika Chaurasiya, Palak Popat, Archi
Agarwal, Venkatesh Rangarajan, Amit Joshi, Vanita Noronha, Kumar
Prabhash, Umesh Mahantshetty
Data analysis and interpretation: Vedang Murthy, Priyamvada Maitre,
Sadhana Kannan, Rahul Krishnatry, Mahendra Pal, Santosh Menon,
Smruti Mokal, Palak Popat, Nilesh Sable, Vanita Noronha, Kumar
Prabhash
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
ACKNOWLEDGMENT
We are grateful to the Tata Memorial Centre and Terry Fox Foundation for
the funding support to this trial. Critical inputs and review of manuscript
draft by Dr Sudeep Gupta is deeply appreciated. We also thank Ms Pooja
Gurav and Ms Sujata Ghonge for assisting in patient follow-up, collection
of trial data, and maintenance of patient records.

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n n n

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 Pelvic or Prostate RT in High-Risk Prostate Cancer

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Prostate Only Versus Whole Pelvic Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer (POP-RT): Outcomes From Phase III Randomized
Controlled Trial
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/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Vanita Noronha Umesh Mahantshetty

Research Funding: Amgen, Sanofi/Aventis, Dr Reddy’s Laboratories, Intas, Research Funding: Varian Medical Systems
AstraZeneca
No other potential conflicts of interest were reported.
Kumar Prabhash
Research Funding: Biocon, Dr Reddy’s Laboratories, Fresenius Kabi, Alkem
Laboratories, Natco Pharma, BDR Pharmaceutics, Roche

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