Radiotherapy and Oncology 145 (2020) 71–80

Contents lists available at ScienceDirect

Radiotherapy and Oncology

journal homepage: www.thegreenjournal.com

Original Article

Late toxicity and quality of life with prostate only or whole pelvic
radiation therapy in high risk prostate cancer (POP-RT): A randomised
trial
Vedang Murthy a,⇑, Priyamvada Maitre a, Jatin Bhatia a, Sadhana Kannan b, Rahul Krishnatry a,
Gagan Prakash c, Ganesh Bakshi c, Mahendra Pal c, Santosh Menon d, Umesh Mahantshetty a
a
Department of Radiation Oncology; b Department of Biostatistics; c Department of Uro-Oncology; and d Department of Pathology, Tata Memorial Hospital and Advanced Centre for
Treatment Research and Education in Cancer (ACTREC), Homi Bhabha National Institute (HBNI), Mumbai, India

a r t i c l e i n f o a b s t r a c t

Article history: Aim: To report toxicity and quality of life (QOL) outcomes from a randomised trial of prostate only versus
Received 3 October 2019 whole pelvic radiotherapy in high risk, node negative prostate cancer.
Received in revised form 9 December 2019 Materials/methods: Patients with localised prostate adenocarcinoma and nodal involvement risk > 20%,
Accepted 11 December 2019
were randomised to prostate only (PORT, 68 Gy/25# to prostate) and whole pelvis (WPRT, 68 Gy/25#
Available online 7 January 2020
to prostate and 50 Gy/25# to pelvis) arms with stratification for TURP, Gleason score, baseline PSA,
and type of androgen deprivation therapy (ADT). Image guided intensity modulated radiotherapy
Keywords:
(IG-IMRT) and two years of ADT were mandatory. Acute and late genitourinary (GU) and gastrointestinal
Prostate cancer
Pelvic radiotherapy
(GI) toxicities were graded using RTOG grading. QOL was assessed using EORTC QLQ-C30 and PR-25
Radiotherapy toxicity questionnaire pre-treatment and every 3–6 months post RT.
Quality of life Results: Total 224 patients were randomised (PORT 114, WPRT 110) from November 2011 to August
2017. Median follow up was 44.5 months. No RTOG grade IV toxicity was observed. Acute GI and GU tox-
icities were similar between both the arms. Cumulative  grade II late GI toxicity was similar for WPRT
and PORT (6.5% vs. 3.8%, p = 0.39) but GU toxicity was higher (17.7% vs. 7.5%, p = 0.03). Dosimetric anal-
ysis showed higher bladder volume receiving 30–40 Gy in the WPRT arm (V30, 60% vs. 36%, p < 0.001;
V40, 41% vs. 25%, p < 0.001). There was no difference in QOL scores of any domain between both arms.
Conclusion: Pelvic irradiation using hypofractionated IG-IMRT resulted in increased grade II or higher late
genitourinary toxicity as compared to prostate only RT, but the difference was not reflected in patient
reported QOL.
Clinicaltrials.gov NCT02302105: Prostate Only or Whole Pelvic Radiation Therapy in High Risk Prostate
Cancer (POP-RT).
Ó 2019 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 145 (2020) 71–80

Prostate cancer is a leading cause of male cancer globally, with
incidence increasing parallel to rise in life expectancy [1]. Patients
in unscreened populations in developing nations present with
more locally advanced and high risk disease [2]. Such patients
are currently treated with a combination of high dose radiation
and long course androgen deprivation therapy (ADT).
Prophylactic regional nodal irradiation in high risk cases has
improved survival outcomes in cancers of breast, and head and
neck. However, the benefit of irradiating pelvic nodes in node neg-
ative prostate cancer is yet to be determined conclusively even
after two randomised trials [3,4]. Radiotherapy dose and delivery
⇑ Corresponding author at: Department of Radiation Oncology, Tata Memorial
Hospital, Ernest Borges Road, Parel, Mumbai 400 012, India.
E-mail address: vmurthy@actrec.gov.in (V. Murthy).
techniques in these trials may be considered less than optimal by
the current standards. Evolution of intensity modulated radiation
therapy (IMRT) with image guidance and hypofractionation has
improved the therapeutic ratio by more accurate dose delivery
and shortened overall treatment time [5,6]. Recently, safety of
dose-escalated pelvic lymph nodal irradiation (PLNI) with IMRT
was demonstrated in a phase II multicentre randomised trial from
the United Kingdom [7].
The randomised trial Prostate Only or Whole Pelvic Radiation
Therapy in High Risk Prostate Cancer (POP-RT) aims to establish
the efficacy, toxicity and impact on quality of life (QOL) of PLNI
compared to prostate only radiation using image guided, moder-
ately hypofractionated, dose escalated radiotherapy. While long-
term survival outcomes are awaited, we report the late toxicities
and QOL outcomes from this trial.

https://doi.org/10.1016/j.radonc.2019.12.006
0167-8140/Ó 2019 Elsevier B.V. All rights reserved.

Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
72 RCT of Prostate only vs. Pelvic RT
Materials and methods
Trial design
POP-RT is a randomised single institution trial comparing pros-
tate only and whole pelvis irradiation in patients with high risk,
node negative prostate cancer. The study was approved by the
Institutional Ethics Committee and is registered at clinicaltrials.gov
(NCT02302105). It was conducted in accordance with the principles
of good clinical practice. Safety and efficacy data were reviewed
regularly by an independent institutional data monitoring
committee.
Patient selection and randomisation
All patients with high risk, node negative, non-metastatic,
biopsy proven prostate adenocarcinoma with >20% risk of pelvic
nodal involvement (Roach formula) were screened for the study.
Inclusion criteria were stage T3b-T4a; T1-T3a with Gleason Score
(GS) 8–10; T1-T3a with GS 7 and serum Prostate Specific Antigen
(PSA) > 15 ng/ml; T1-T3a with GS 6 and PSA > 30 ng/ml. Patients
had to be fit for androgen suppression with either medical or sur-
gical castration, with physician estimated life expectancy >5 years.
Patients unsuitable for high dose, moderately hypofractionated
radiation therapy or with history of prior pelvic surgery or inflam-
matory bowel disease were excluded.
The enrolled patients provided written informed consent prior
to randomisation. Randomisation was carried out by the trial
statistician (SK) in Clinical Research Secretariat within the hospital
by phone or email. Patients were allocated randomly to either
Prostate Only Radiation Therapy (PORT) or Whole Pelvis Radiation
Therapy (WPRT) arms using stratified block randomisation method
with block size of 4. Stratification factors were GS (6–7/8–10), type
of ADT (medical castration/orchiectomy), PSA (>50 or 50 ng/mL),
and history of transurethral resection of prostate (TURP) (yes/no).
Treatment planning and delivery
All patients were treated with IMRT with daily volumetric
image guidance. Empty rectum (using a low residue diet without
routine laxatives) and adequate bladder filling were ensured for
simulation and daily treatment, using a bladder protocol of
500 ml water drunk 45 minutes before simulation and each frac-
tion. Non-contrast planning computed tomography (CT) scan was
acquired with patient positioned supine and three external mark-
ers were placed at the level of pubic symphysis to align the lasers.
Intraprostatic fiducials were not used. A short scan was taken at
the level of prostate to check adequately full bladder (250–
300 ml) and empty rectum (rectal diameter < 4 cm) before pro-
ceeding with the simulation scan. Target volume and organs at risk
(OARs) were delineated as per Radiation Therapy Oncology Group
(RTOG) guidelines and International Commission on Radiation
Units [8]. The CTV prostate included the entire prostate gland
and the base of seminal vesicles, with a 7 mm expansion (5 mm
posteriorly) for PTV prostate. The CTV for pelvic nodes included
common iliac, internal iliac, external iliac, presacral, and the obtu-
rator nodes delineated as per RTOG guidelines. Nodal PTV was gen-
erated with a 7 mm expansion around the nodal CTV. Detailed
description of target volume and OARs with the dose constraints
used is provided in Appendix 1.
Dose prescription was 68 Gy in 25 fractions to the prostate in
both arms and 50 Gy in 25 fractions to the pelvic nodes in WPRT
arm as simultaneous integrated boost (SIB). Using inverse planning
method, step-and-shoot or rotational IMRT was planned on
Eclipse planning system (Varian Medical Systems), or helical
tomotherapy-based IMRT on proprietary tomotherapy planning
system (Tomotherapy Inc.). All the plans used 6 MV photon energy,
Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
aiming to cover 95% of the PTV by the 95% isodose. For step-and-
shoot IMRT, seven equally-spaced beams were typically used. All
contours and treatment plans were reviewed and finalised by a
single radiation oncologist. Occasional patient with dose con-
straints exceeding the tolerance was replanned. Patient-specific
plan delivery quality assurance was performed for each final plan
before commencing treatment.
Patients were aligned with skin tattoos for treatment, following
the same bladder protocol as during simulation. On board imaging
using cone beam CT or megavoltage CT was taken daily before each
fraction for set-up verification and confirming the empty rectum.
Patients were advised low residue diet in general but no daily lax-
ative was routinely advised. If the rectal gas prevented a good
match, the patient was prescribed a mild laxative. Patients were
reviewed weekly during RT by the treating physician and acute
genitourinary (GU) and gastrointestinal (GI) toxicities were graded
using RTOG scale.
All patients received ADT with Luteinizing Hormone Releasing
Hormone analogue (LHRHa) or bilateral orchiectomy at least
8 weeks prior to starting radiotherapy. Medical castration contin-
ued concomitantly with radiation and later for a total duration of
two years.
Objectives and assessments
The primary objective was 5-year biochemical failure free sur-
vival (BFFS) using the Phoenix criteria to define biochemical failure
(nadir PSA + 2 ng/mL). The secondary objectives were disease free
survival (DFS), overall survival (OS), acute and late GI and GU tox-
icities, and quality of life (QOL).
Baseline assessment prior to randomisation included complete
history and physical examination, serum PSA < 3 weeks of randomi-
sation, laboratory investigations (complete blood counts, renal and
liver function tests, serum electrolytes) and staging imaging (CT
scan of abdomen and pelvis, MRI pelvis, bone scan or Ga-68 PSMA
PET scan) <8 weeks from randomisation. All patients were assessed
weekly during RT, 6–8 weeks after RT completion and 3–6 monthly
thereafter in clinic. Follow up included clinical evaluation (digital
rectal examination, PSA), toxicities (GI and GU; RTOG criteria) and
QOL documentation (EORTC QLQC-30 and PR-25).
Statistical considerations
For the primary endpoint of 5-year BFFS, the sample size calcu-
lations assumed a 5-year BFFS of 62% with WPRT and 45% with
PORT. To detect this difference with a 5% two-sided significance
and 80% power, a total of 224 patients were randomised to both
arms equally (112 in each arm). Toxicities till three months post
radiation were considered acute, and those beyond as late toxici-
ties. Late toxicities were reported both as cumulative and at last
follow up. Intention to treat analysis was done using SPSS version
21 (IBM Inc.). Incidence of toxicities (Grade 0-I versus  Grade II)
was estimated with 95% confidence intervals for both the arms
separately and compared using chi square test or Fisher’s exact
test. Hazards ratio was estimated for actuarial toxicities using
cox regression method to assess the difference in toxicity plots
between both arms. A p value of <0.05 was considered statistically
significant. An unplanned analysis of bladder and rectal dosimetry
was performed by comparing the medians across both arms using
independent samples test.
EORTC QLQ-C30 and PR25 questionnaires were used for QOL
assessment. QLQ-C30 assesses six function scales (physical, role,
emotional, cognitive, social, and global health status) and eight
symptom scales (fatigue, nausea/vomiting, pain, dyspnoea, insom-
nia, appetite loss, constipation, diarrhoea, and financial difficul-
ties). The prostate specific QLQ-PR25 assesses three symptom
 V. Murthy et al. / Radiotherapy and Oncology 145 (2020) 71–80 73

scales (urinary, bowel, and hormone treatment-related symp-
toms), sexual activity, sexual functioning, and bother due to incon-
tinence aid. All items and scales scores were linearly transformed
to 0–100 points scale according to the EORTC guidelines. Means
and standard deviation of QOL scores for each arm at different time
points were estimated. Linear mixed model with repeated mea-
sures was used to test the differences in serial QOL scores between
the arms, to control for intra-subject correlation of responses. A 10-
point difference in QOL scores between the two arms was consid-
ered clinically significant. Statistical significance for each time
point was considered as p < 0.007 (correcting for multiple time
points). Only available data was used for statistical analyses with-
out imputation for the missing data.
Results
Between November 2011 and August 2017, total 336 patients
were screened for the study, of which 224 patients were eligible
for randomisation (Fig. 1). Of 114 patients allocated in the PORT
arm, two patients withdrew consent and one patient received
whole pelvis radiation, whereas all 110 patients in the WPRT
arm received the allocated treatment. Baseline patient and disease
characteristics were well balanced in both the arms (Table 1).
Majority (78.3%) of patients were locally advanced (stage T3a),
with median nodal involvement risk of 42% by Roach formula. Half
of the patients had GS  8, and over a quarter of patients had prior
history of TURP (27.6%) or had diabetes (28.4%). Median follow up
was 44.5 months.
Maximal acute toxicity developed is shown in Table 2. There
were no acute grade IV GI toxicities in any arm. Most patients
experienced grade I-II toxicities with no significant difference
between both arms. Two patients in WPRT arm and none in
the PORT arm experienced acute grade III GI toxicity. At three
months follow-up post RT, overall residual GI toxicity was grade
II in 0.9% (WPRT 1.8% vs. PORT 0%) and grade I in 5.8% (WPRT
6.5% vs. PORT 5.6%) patients. No patient in the study experienced
acute grade III/IV GU toxicity. Compared to PORT arm, more
patients in WPRT arm experienced mild to moderate acute GU
toxicities (grade II 24.3% vs. 32.7%) however the difference was
not statistically significant. Residual grade II GU toxicity was
2.8% (2.8% each in WPRT and PORT) and grade I was 10.8%
(WPRT 12.1% vs. PORT 10.2%).
The crude toxicity rates are shown in Fig. 2. No patient experi-
enced late grade IV GI or GU toxicity in either arm (Table 2). One
patient in WPRT arm and none in the PORT arm showed grade III
late GI toxicity. Grade II GI toxicities were 6.5% in the WPRT
arm and 3.8% in the PORT arm (p = 0.39). Cumulative late GI toxi-
city showed no significant difference between the two arms
(Fig. 2C). Late  grade II GI toxicity at last follow up was 2.7% in
the WPRT arm and 0.9% in the PORT arm (p = 0.32). Grade III late
GU toxicity was observed in five patients (PORT = 2, WPRT = 3).
GU toxicity  grade II was significantly higher with WPRT (17.7%
vs. 7.5%; p = 0.03) (Fig. 2D). At last follow up, two patients of WPRT
arm reported grade III toxicity but grade II GU toxicity was statis-
tically similar between the two arms (5.5% vs. 1.9%; p = 0.32).
Post hoc dose volume histogram (DVH) analysis was done for a
subset of half the patients in each arm (n = 50 each) for differences
in the planned dose for bladder and rectum during WPRT or PORT
(Fig. 3). Volume of bladder receiving 30–40 Gy was larger in the
WPRT arm (V30, 60% vs. 36%, p < 0.001; V40, 41% vs. 25%,
p < 0.001). There was no significant difference in the volume of
bladder and rectum exposed to 60–65 Gy between both arms.

Fig. 1. CONSORT diagram.

Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
74 RCT of Prostate only vs. Pelvic RT

Table 1
Baseline patient and disease characteristics.

Characteristic Overall PORT WPRT

n = 224 (100%) n = 114 (50.9%) n = 110 (49.1%)
Median Age (years) 66 66 66
Median PSA (ng/ml, median) 32.2 29 33.3
Median Nodal Risk %* 42 43 41
Gleason Score 6 22 (9.8) 11 (9.6) 11 (10)
7 (3 + 4) 39 (17.4) 21 (18.4) 18 (16.4)
7 (4 + 3) 53 (23.7) 25 (21.9) 28 (25.5)
8 54 (24.1) 27 (23.7) 27 (24.5)
9 49 (21.9) 25 (21.9) 24 (21.8)
10 7 (3.1) 5 (4.4) 2 (1.8)
Androgen Deprivation Therapy Orchiectomy 44 (19.8) 24 (21.1) 20 (18.2)
LHRHa 178 (80.2) 88 (78.6) 90 (81.8)
History of TURP Yes 62 (27.6) 32 (28) 30 (27.2)
No 162 (72.3) 82 (72) 80 (72.7)
Diabetes Yes 63 (28.4) 35 (31.3) 28 (25.5)
No 159 (71.6) 77 (68.8) 82 (74.6)
Tumour Stage T1 2 (0.9) 1 (0.9) 1 (0.9)
T2 48 (21.6) 20 (17.9) 28 (25.5)
T3a 69 (31.1) 38 (33.9) 31 (28.2)
T3b 85 (38.3) 43 (38.4) 42 (38.2)
T4 18 (8.1) 10 (8.9) 8 (7.3)

* Calculated as per Roach formula = 2/3  PSA + [Gleason Score 6]  10).

(PORT = Prostate Only Radiation Therapy; WPRT = Whole Pelvis Radiation Therapy; PSA = Prostate Specific Antigen; LHRHa = Luteinizing Hormone Releasing Hormone
analogue; TURP = Transurethral Resection of Prostate).

Table 2
Acute and late toxicities (RTOG).

Acute Toxicity
Grade Overall PORT WPRT P value
n = 214 (100%) n = 107 (50%) n = 107 (50%) (gr 0-I vs. gr  II)
Gastrointestinal 0 93 (43.4) 48 (44.8) 45 (42.1) 0.23
I 59 (27.5) 32 (29.9) 27 (25.2)
II 60 (28.0) 27 (25.2) 33 (30.8)
III 2 (0.9) 0 (0) 2 (1.8)
Genitourinary 0 74 (34.5) 44 (41.1) 30 (28.1) 0.17
I 79 (36.9) 37 (34.6) 42 (39.2)
II 61 (28.5) 26 (24.3) 35 (32.7)
Late Toxicity
Grade Overall PORT WPRT P value
n = 211 (100%) n = 104 (49.2%) n = 107 (50.2%) (gr 0-I vs. gr  II)
Gastrointestinal
Cumulative 0 142 (67.2) 73 (70.1) 69 (64.4) 0.39
I 59 (27.9) 27 (25.9) 32 (29.9)
II 9 (4.2) 4 (3.8) 6 (5.6)
III 1 (0.4) 0 (0.0) 1 (0.9)
At Last Follow up 0 191 (90.5) 97 (93.2) 94 (87.8) 0.17
I 16 (7.5) 6 (5.7) 10 (9.3)
II 3 (1.4) 1 (0.9) 2 (1.8)
III 1 (0.4) 0 (0.0) 1 (0.9)
Genitourinary
Cumulative 0 95 (45.0) 48 (46.1) 47 (43.9) 0.03
I 88 (41.7) 48 (46.1) 40 (37.3)
II 23 (10.9) 6 (5.7) 16 (14.9)
III 5 (2.3) 2 (1.8) 3 (2.8)
At Last Follow up 0 173 (81.9) 88 (84.6) 85 (79.4) 0.32
I 30 (14.2) 14 (13.4) 16 (14.9)
II 6 (2.8) 2 (1.9) 4 (3.7)
III 2 (0.9) 0 (0.0) 2 (1.8)

Total 217 patients (PORT = 105; WPRT = 112) completed 1068
QOL questionnaires over a median assessment period of 18 months
(range 1–73 months). Each patient completed an average of 5
(range 1–11) assessments. No statistically or clinically significant
change was observed in any functional or symptom domain of
EORTC QLQ C-30 between both arms over the follow up period.
The symptom scores of PR-25 including bowel and urinary symp-
toms were also similar between the two arms (Appendix 2), as also
the responses to specific items of urinary and bowel symptoms
subscales (Appendix 3). Scores for subscales of treatment-related
symptoms as well as sexual functioning also showed no significant
difference for the two arms.
Discussion
POP-RT incorporates the currently recommended dose escala-
tion for prostate radiotherapy delivered with image guided inverse
planning IMRT. Overall incidence of grade III toxicities was low,

Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
 V. Murthy et al. / Radiotherapy and Oncology 145 (2020) 71–80 75

Fig. 2. Crude toxicity rates and cumulative late toxicities (Grade II or higher) – Gastrointestinal (A, C) and Genitourinary (B, D) (time points calculated from the date of
randomisation).

Fig. 3. Dosimetric analysis for bladder (A) and rectum (B).

with no significant difference in acute GI or GU toxicities between (p = 0.03), corresponding to the larger volume of bladder exposed
both arms. Addition of PLNI delivered using IG-IMRT did not to 30–50 Gy dose in this arm.
increase late GI toxicity. Late GU toxicity was higher with WPRT

Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
 76
Table 3
Randomised trials of prostate only versus pelvic irradiation in node negative prostate cancer.

RTOG 9413 GETUG-01 PIVOTAL Present Study

Duration of April 1995 to June 1999 December 1998 to June 2004 May 2011 to March 2013 November 2011 to August 2017
accrual
Lymph node risk Clinically localised prostate cancer with nodal Clinically localised prostate cancer with Clinically localised prostate cancer with Clinically localised prostate cancer with
risk > 15% stage T1b-T3, cN0pNx stage T3b/T4 or nodal risk  30% nodal risk > 20%
Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.

Hormonal Therapy NHT 2 months before Only for high risk – NHT (LHRHa) for 4 to NHT (LHRHa) for 6 to 9 months before RT NHT at least 2 months + concomitantly
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

RT + concomitantly + AHT for 4 months 8 months before RT + concomitant + AHT for total 2–3 years.
Arms 4 arms: 2 arms: 2 arms: 2 arms:
NHT + WP (n = 320); WP (n = 225); PO (n = 62) WP (n = 110);
NHT + PO (n = 319); PO (n = 221) P&P (n = 62) PO (n = 112)
WP + AHT (n = 319);
PO + AHT (n = 321)
Technique Conventional box field. WP upper border at L5- Conventional portals for WP. IMRT (image guidance allowed). IG-IMRT. WP upper border at L4-L5.
S1. WP upper border at S1/S2. 3DCRT for PO WP upper border at L5-S1.
Dose Fractionation Pelvic LN: 50.4 Gy in 28 fractions Pelvic LN: 45–46.8 Gy in 20–26 fractions Pelvic LN – 60 Gy in 37 fractions (55 Gy in Pelvic LN – 50 Gy in 25 fractions
(BED3 = 80.64 Gy) (BED3 = 74.88 to 78.75 Gy) 37 fractions if mandatory dose (BED = 83.33 Gy)
Prostate: 70.2 Gy in 39 fractions Prostate: 65.25–68.4 Gy in 29–38 constraints not met) (BED3 = 92.4 Gy) Prostate – 68 Gy in 25 fractions
(BED3 = 112.32 Gy) fractions (BED3 = 110–114.19 Gy; After Prostate – 74 Gy in 37 fractions (BED3 = 129.65 Gy)

RCT of Prostate only vs. Pelvic RT

March 2000 two fractions increased for (BED3 = 123.33 Gy)
prostate, BED3 = 116.67–122.06 Gy)
Acute toxicity Any  Grade III: - Grade III GI: n = 1 (P&P) No Grade IV GI/GU toxicity
9% (NHT + WPRT) Grade II GI: Grade III GI: n = 2 (WP)
8% (NHT + PORT) Week 6: 7% (PO) vs. 25% (P&P) Grade II GI: 25.2% (PO) vs. 30.8% (WP)
7% (WPRT + AHT) Week 18: 3.3% (PO) vs. 4.8% (P&P) Grade II GU: 24.3% (PO) vs. 32.7% (WP)
5% (PORT + AHT) Grade IV GU: n = 1 (PO)
Grade III GU: n = 5 (PO) vs. 2 (P&P)
Grade II + and I + GU: Similar in both
arms
Late toxicity Any Grade III + GU: - Grade IV GI: n = 1 each in PO and P&P Grade IV GI/GU: nil
6% (NHT + WPRT) Grade IV GU: nil Grade III:
5% (NHT + PORT) Grade II + toxicity: GI: n = 1 (WP)
7% (WPRT + AHT) GI: 16.9% (PO) vs. 24% (P&P) GU: n = 2 (PO) vs. 3 (WP)
4% (PORT + AHT) GU: 5.1% (PO) vs. 5.6% (P&P) Grade II + toxicity:
GI: 3.8% (PO) vs. 6.5% (WP)
Any Grade III + GU: GU: 7.5% (PO) vs. 17.7% (WP)
7% (NHT + WPRT)
2% (NHT + PORT)
3% (WPRT + AHT)
2% (PORT + AHT)
QOL addressed No No Yes Yes
Remarks  Highest failures and deaths.in WP + AHT  EFS favoured WP in low risk with < 15%  Peak acute toxicity at 8 weeks in both  Grade II + late GU toxicity significantly
 Late GI toxicity highest in NHT + WPRT risk of nodal involvement groups worse in WPRT arm
 Late GU toxicities similar in all four arms  EFS favoured PO in > 15% risk of nodal  Higher acute grade II GI toxicity in  Mean QOL scores for GI and GU symp-
 Complicated results, straightforward inter- involvement P&P group toms higher in WPRT arm at most
pretation difficult.  Low incidence of late grade II + GI/GU time points, but difference not statisti-
toxicities cally significant

(NHT = Neoadjuvant Hormone Therapy; AHT = Adjuvant Hormone Therapy; RT = Radiation Therapy; WP = Whole Pelvis RT; PO = Prostate Only RT; P&P = Pelvis and Prostate; IG-IMRT = Image Guided Intensity Modulated Radiation
Therapy; LHRHa = Luteinizing Hormone Releasing Hormone analogue; QOL = Quality of Life; GI = Gastrointestinal; GU = Genitourinary; EFS = Event Free Survival).
 V. Murthy et al. / Radiotherapy and Oncology 145 (2020) 71–80
The benefit of PLNI in radical intent radiotherapy for locally
advanced prostate cancer has been debated for decades [9,10]. It
is even more relevant with near universal adoption of IMRT for
prostate cancer globally. While long term outcomes from ongoing
phase III trials are awaited, toxicity concerns especially to the
bowel need to be addressed before they can be weighed vis-à-vis
potential benefits in tumour control.
Till date, three RCTs have compared outcomes with whole pel-
vis irradiation versus prostate only radiotherapy (Table 3). Of
these, only phase II PIVOTAL trial used IMRT [7]. Long term results
of PLNI are available from the randomised trials RTOG 9413 and
GETUG 01. RTOG 9413 randomised patients with >15% risk of
nodal involvement in 2  2 factorial design for hormone sequenc-
ing and radiation portals. In the latest update, WPRT and PORT
showed no difference in biochemical control and late GU toxicity
[3]. Late GI toxicity was the highest in WPRT arm of NHT cohort,
but similar in the other three arms. Interaction between ADT and
radiotherapy did not allow straightforward assessment of the
impact of WPRT on toxicities. Overall, results were still not conclu-
sive for benefit of PLNI [11]. Meanwhile, GETUG 01 used 3DCRT for
prostate but conventional four fields for WPRT, beginning from S1-
S2 interspace [4]. Over 50% patients in both arms of GETUG 01 had
nodal involvement risk < 15%, and it was underpowered to show
survival benefit with WPRT in the high risk subgroup. Again,
detailed toxicity outcomes were not reported in GETUG 01, while
the impact on patient QOL was not addressed in both these ran-
domised trials.
Recently, phase II PIVOTAL study from the UK reported a non-
comparative analysis of toxicity with IMRT-based PLNI, with acute
lower GI toxicity at 18 weeks post RT as the primary endpoint [7].
Acute and 2-year GI toxicity showed no difference between the
two arms of PIVOTAL, similar to POP-RT. However, unlike the PIVO-
TAL trial, we observed higher late GU toxicity with WPRT. While
the PORT arms of both trials show similar grade 2 + late GU toxicity
(PIVOTAL 5.1%, POP-RT 7.5%), the WPRT arms show a difference
(PIVOTAL 5.6%, POP-RT 17.7%); possibly due to use of hypofraction-
ation and longer follow up in the present trial (median follow up
37.6 months versus 44.5 months respectively).
Patient-reported QOL scores showed no difference between
both arms for any domain. Higher RTOG late GU toxicity with
WPRT did not show a corresponding increase in PR-25 urinary
symptoms scores. This could be attributable partly to the absence
of haematuria as a symptom in the urinary subscale of PR-25
questionnaire. We did an exploratory dosimetric analysis for pos-
sible reasons of increased late urinary toxicity in the WPRT arm.
Post hoc DVH analysis from our trial showed higher bladder vol-
ume receiving planned dose of 30–50 Gy (V30, V40 and V50) for
WPRT, the difference being statistically significant and clinically
relevant. We hypothesise that this could account for more grade
II toxicity with WPRT, particularly gross haematuria. It would
be interesting to see the planning constraints for urinary bladder
achieved in PIVOTAL for doses in 30–50 Gy range between the
two arms.
Urinary toxicity is known to be associated with higher dose to
the bladder neck and trigone [12], and history of previous TURP
[13]. Late cystitis rates were higher post IMRT in high risk patients
when larger volume of bladder neck received >75 Gy [12], and
widespread use of TURP in India could account for higher GU tox-
icity in both arms of the present study [2]. However, TURP or dose
to bladder trigone/neck are unlikely to be responsible for the dif-
ference in bladder toxicity between the two randomised groups
here as TURP was an a priori stratification factor. Previous studies
in dose escalated prostate IMRT show association of late grade
2+ GU toxicity with WPRT [14]. Higher bladder DVH range has
been associated with worse urinary obstruction and incontinence
[15]. The observed difference in urinary toxicity could also be
Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
77
incidental, and may even change with longer follow up. However,
the contribution of bladder volume exposed to moderate RT doses
towards late cystitis is a hypothesis worth exploring, which to our
knowledge has not been reported previously in literature.
Similar findings were observed in rectal dosimetric analysis,
with larger rectal volume receiving 30–40 Gy in the WPRT arm
(V30, 69% vs. 58%, p < 0.001; V40, 47% vs. 41%, p = 0.02). However,
it did not translate into clinically measurable change in acute or
late GI toxicity. While bowel dosimetry was not separately anal-
ysed, both physician-graded lower GI toxicity and patient-
reported PR-25 bowel subscale were similar for both arms.
Improved bowel and rectum sparing by universal use of IG-
IMRT may be responsible for this, since the rectal dose volume
parameters achieved in both the arms were well below the plan-
ning constraints. A study correlating HRQOL outcomes in prostate
3DCRT dosimetry showed higher incidence of rectal bleeding and
incontinence with higher DVH distribution range, but the
reported DVH range was far higher than the one achieved with
IMRT in our trial [15]. Upper extent of pelvic field in POP-RT
was at the level of aortic bifurcation, which is higher than the
other randomised trials of WPRT (Table 3). No increase in the
bowel toxicity was observed, demonstrating excellent bowel
sparing achievable with IMRT.
Although this is the largest report of prospectively assessed
patient-reported QOL and treatment toxicities, these are not the
primary end points of this trial. Toxicities were assessed with
RTOG grading only, which may be subject to interpretation and
documentation bias [16] and does not differentiate between vari-
ous symptoms. Addition of CTCAE may have improved the qualita-
tive toxicity assessment. International Prostate Symptom Score
(IPSS) questionnaire was not used in this trial, however the
patients were screened for any pre-existing symptoms at baseline.
Dosimetry was available for analysis in about half of the patients,
and was not retrievable for the remaining patients. This is however
unlikely to change the results significantly, as the missing dosimet-
ric data was not subject to any selection bias. QOL assessment
using EORTC PR-25 module without additional dedicated question-
naires might have impacted the sensitivity of assessments. The
results reported presently at median follow up of 44 months may
evolve differently with even longer follow-up.
While the long-term survival outcomes are awaited from POP-
RT trial, two other randomised trials are exploring the question
of benefit of PLNI in high risk node negative prostate cancer. RTOG
0924 is recruiting patients with unfavourable intermediate risk or
favourable high-risk prostate cancer, allowing brachytherapy boost
for prostate (NCT01368588). Phase III trial PIVOTAL boost is
expected after the feasibility demonstrated in the phase II PIVOTAL
trial. The benefit of PLNI for advanced localised prostate cancer is
expected to be conclusively answered with the results of these tri-
als. It remains to be seen, however, if the trade-off in terms of
increased toxicities is worthwhile.
To conclude, whole pelvic RT delivered with hypofractionated
IG-IMRT resulted in increased grade II or higher late genitourinary
toxicity as compared to prostate only RT. This was not reflected in
the patient reported QOL. Final results of clinical outcomes are
awaited.
Financial disclosure
POP-RT trial is supported by intramural funding from Tata
Memorial Hospital and the Terry Fox Foundation.
Conflict of interest statement
None.
78 RCT of Prostate only vs. Pelvic RT

Acknowledgements Dipika Chourasiya, Ms. Gitanjali Panigrahi, Ms. Pooja Gurav, and
Ms. Sujata Ghonge for their valuable help in collection and mainte-
We are grateful to Tata Memorial Centre and Terry Fox Founda- nance of the trial related data and meticulous follow-up of
tion for the funding support of this trial. We sincerely thank Ms. patients.

Appendix 1. Target volume and OARs delineation and their dose constraints

Target Volume Delineation and Dose Prescription

CTV Prostate Entire prostate gland including any extracapsular extension and the base of seminal vesicles defined as the
proximal 1.5 seminal vesicles.
PTV Prostate Expansion of 7 mm around the CTV prostate in all directions except posteriorly (5 mm). 68 Gy in 25 fractions
(2.72 Gy per fraction)
CTV Pelvic Nodes Pelvic nodal stations included were common iliac, internal iliac, external iliac, obturator and presacral nodes.
Contouring began at the level of aortic bifurcation drawn around major vessels by giving 7 mm margin, edited
from bone, muscles, bowel and bladder.
PTV Pelvic Nodes Generated by 7 mm margin all around the CTV pelvic nodes. 50 Gy in 25 fractions (2 Gy per fraction)

OAR Delineation and Dose Constraints

Rectum Solid structure starting from recto sigmoid flexure up to the bottom of ischial V40 60%
tuberosity. V50 35%
V60 25%
V65 15%
V70 0.1%
Bladder Solid structure from the dome to the base including the wall. V30 65%
V40 45%
V50 25%
V60 15%
Bowel Bag Single solid structure encompassing the peritoneal cavity and any pelvic bowel loops; Grade I II
upper extent was kept constant at 5 cm superior to the uppermost extent of the PTV V45 78 cc 158 cc
pelvic nodes to have comparability of the dose volume data. V50 17 cc 110 cc
V55 14 cc 28 cc
V60 0.5 cc 6 cc
V65 0 cc 0 cc
Femoral heads Drawn within the acetabulum without including the neck of femur. V50 5%

Appendix 2. Patient-reported quality of life outcomes for EORTC PR-25 urinary and bowel symptom domains. The mean composite
scores for urinary symptoms domain (8 questions, Q31-37 and Q39 of PR-25) and bowel symptoms domain (4 questions, Q40-43 of
PR-25), along with the standard deviation from the mean score are shown. Threshold of significance for p-value is 0.007 to correct
for QOL assessment being done at multiple time points

Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
 V. Murthy et al. / Radiotherapy and Oncology 145 (2020) 71–80 79

Appendix 3. Patient-reported item-wise responses for urinary and bowel functions of EORTC PR-25

Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
80 RCT of Prostate only vs. Pelvic RT

References prostate and pelvic node intensity modulated radiation therapy. Int J Radiat
Oncol Biol Phys 2015;92:874–83. https://doi.org/10.1016/j.ijrobp.2015.03.021.
[9] Kaidar-Person O, Roach M, Créhange G. Whole-pelvic nodal radiation therapy
[1] Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al.
in the context of hypofractionation for high-risk prostate cancer patients: a
Estimating the global cancer incidence and mortality in 2018: GLOBOCAN
step forward. Int J Radiat Oncol Biol Phys 2013;86:600–5. https://doi.org/
sources and methods. Int J Cancer 2018;144:ijc.31937.
10.1016/j.ijrobp.2013.02.006.
[2] Murthy V, Mallick I, Arunsingh M, Gupta P. Prostate radiotherapy in india:
[10] Dirix P, Haustermans K, Junius S, Withers R, Oyen R, Van Poppel H. The role of
evolution, practice and challenges in the 21st century. Clin Oncol
whole pelvic radiotherapy in locally advanced prostate cancer. Radiother
2019;31:492–501. https://doi.org/10.1016/j.clon.2019.05.020.
Oncol 2006;79:1–14. https://doi.org/10.1016/j.radonc.2006.03.011.
[3] Roach M, Moughan J, Lawton CAF, Dicker AP, Zeitzer KL, Gore EM, et al.
[11] Delouya G, Taussky D. Pelvic radiotherapy in prostate cancer: an unresolved
Sequence of hormonal therapy and radiotherapy field size in unfavourable,
question. Lancet Oncol 2018;19:1428–9. https://doi.org/10.1016/S1470-2045
localised prostate cancer (NRG/RTOG 9413): long-term results of a
(18)30588-6.
randomised, phase 3 trial. Lancet Oncol 2018;19:1504–15. https://doi.org/
[12] Inokuchi H, Mizowaki T, Norihisa Y, Takayama K, Ikeda I, Nakamura K, et al.
10.1016/S1470-2045(18)30528-X.
Correlation between urinary dose and delayed radiation cystitis after 78 Gy
[4] Pommier P, Chabaud S, Lagrange JL, Richaud P, Le Prise E, Wagner JP, et al. Is
intensity-modulated radiotherapy for high-risk prostate cancer: a 10-year
there a role for pelvic irradiation in localized prostate adenocarcinoma?
follow-up study of genitourinary toxicity in clinical practice. Clin Transl Radiat
Update of the long-term survival results of the GETUG-01 randomized study.
Oncol 2017;6:31–6. https://doi.org/10.1016/j.ctro.2017.09.005.
Int J Radiat Oncol Biol Phys 2016;96:759–69. https://doi.org/10.1016/j.
[13] Byrne K, Hruby G, Kneebone A, Whalley D, Guo L, McCloud P, et al. Late
ijrobp.2016.06.2455.
genitourinary toxicity outcomes in 300 prostate cancer patients treated with
[5] Bruner DW, Hunt D, Michalski JM, Bosch WR, Galvin JM, Amin M, et al.
dose-escalated image-guided intensity-modulated radiotherapy. Clin Oncol
Preliminary patient-reported outcomes analysis of 3-dimensional radiation
2017;29:617–25. https://doi.org/10.1016/j.clon.2017.03.006.
therapy versus intensity-modulated radiation therapy on the high-dose arm of
[14] Pederson AW, Fricano J, Correa D, Pelizzari CA, Liauw SL. Late toxicity after
the Radiation Therapy Oncology Group (RTOG) 0126 prostate cancer trial.
intensity-modulated radiation therapy for localized prostate cancer: an
Cancer 2015;121:2422–30. https://doi.org/10.1002/cncr.29362.
exploration of dose-volume histogram parameters to limit genitourinary and
[6] Ferreira MR, Thomas K, Truelove L, Khan A, Parker C, Dearnaley DP, et al.
gastrointestinal toxicity. Int J Radiat Oncol Biol Phys 2012;82:235–41. https://
Dosimetry and gastrointestinal toxicity relationships in a phase II trial of pelvic
doi.org/10.1016/j.ijrobp.2010.09.058.
lymph node radiotherapy in advanced localised prostate cancer. Clin Oncol
[15] Boladeras A, Ferrer F, Navarro V, De Blas R, Cunillera O, Mateo D, et al.
2019;31:374–84. https://doi.org/10.1016/j.clon.2019.02.012.
Association between EBRT dose volume histograms and quality of life in
[7] Dearnaley D, Griffin CL, Lewis R, Mayles P, Mayles H, Naismith OF, et al.
prostate cancer patients. Rep Pract Oncol Radiother 2018;23:360–8. https://
Toxicity and patient-reported outcomes of a phase 2 randomized trial of
doi.org/10.1016/j.rpor.2018.07.009.
prostate and pelvic lymph node versus prostate only radiotherapy in advanced
[16] Huynh-Le M-P, Zhang Z, Tran PT, DeWeese TL, Song DY. Low inter-rater
localised prostate cancer (PIVOTAL). Int J Radiat Oncol Biol Phys
reliability in grading of rectal bleeding using NCI CTC and RTOG toxicity scales:
2019;103:605–17. https://doi.org/10.1016/j.ijrobp.2018.10.003.
a survey of radiation oncologists. Int J Radiat Oncol Biol Phys 2014;90:1076.
[8] Harris VA, Staffurth J, Naismith O, Esmail A, Gulliford S, Khoo V, et al.
https://doi.org/10.1016/j.ijrobp.2014.08.014.
Consensus guidelines and contouring atlas for pelvic node delineation in

Downloaded for Anonymous User (n/a) at CK Mobile App Test from ClinicalKey.com by Elsevier on July 25, 2023.
For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.