Randomised Controlled Trial of Prostate Radiotherapy In High Risk and Node Positive Disease Comparing Moderate and Extreme Hypo-fractionation (PRIME Trial)
Phase: NA
Conditions: Prostate Adenocarcinoma
Sponsor: Tata Memorial Centre

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 1 
 
Randomised controlled trial of Prostate Radiotherapy In high risk and node 
positive disease comparing Moderate and Extreme hypofractionation  
 
[PRIME Trial] 
 
 
Principal Investigator: Vedang Murthy 
Co Investigators: Ganesh Bakshi, Rahul Krishnatry, Gagan Prakash, Mahendra Pal, Santosh    
Menon, Palak Popat, Venkatesh Rangarajan, Archi Agrawal, Sheetal Kulkarni 
Statistician: Sadhana Kannan 
Location: Tata Memorial Hospital and ACTREC, Tata Memorial Centre, Mumbai, India 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 2 
 
TRIAL SUMMARY 
 
PROTOCOL TITLE 
Randomised controlled trial of Prostate Radiotherapy In high risk 
and node positive disease comparing Moderate and Extreme 
hypofractionation (PRIME trial). 
 
RATIONALE 
Extreme hypofractionated radiotherapy is a shorter duration 
treatment with probable similar clinical efficacy as moderately 
hypofractionation Radiotherapy. Given the potential positive 
economic impact with shorter duration treatment with similar 
clinical outcomes and probable similar toxicity profile, SBRT 
(extreme hypo-fractionation) in prostate cancer can be offered as 
a treatment option, especially in a limited-resource setting. 
 
AIM 
The aim of the study is to compare the efficacy with SBRT and 
moderate hypo-fractionation in high risk and node positive 
prostate cancer 
 
PRIMARY STUDY OBJECTIVES 
To assess whether extreme hypo-fractionation with SBRT in high 
risk prostate cancer is non inferior to moderately hypo-
fractionated standard radiotherapy 
 
STUDY DESIGN 
Two arm, Prospective Randomized Trial with a non-inferiority 
design 
 
TRIAL POPULATION 
Inclusion criteria: 
1. Age: above 18 years.  
2. Participants must be histologically proven, 
adenocarcinoma prostate 
3.Localised to the prostate or pelvic lymph 
nodes 
4. High risk prostate cancer as per NCCN definition 
clinical stage T3a  or Gleason score 8/Gleason grade group4 or 
Gleason score 9-10/gleason grade group 5,  PSA > 20 ng/mL. or 
Very high risk prostate cancer as per NCCN definitioni.e T3b-T4 or 
Primary Gleason pattern 5/Gleason grade group 5  or > 4cores 
Gleason score 8-10/Gleason grade group 4 or5  
 
5. Ability to receive long term hormone therapy/ orchidectomy 
6. KPS >70 (see appendix 
7. No prior history of therapeutic irradiation to  
pelvis 
8. Patient willing and reliable for follow-up 
and QOL. 
 9.Signed study specific consent form 
 
Exclusion criteria: 
1. Evidence of distant metastasis  at any time since presentation 
2. Life expectancy <2 year 
3. Previous RT to prostate or prostatectomy. 
4. Severe urinary symptoms or with severe IPSS score inspite of 
being on hormonal therapy for 6mnths which in the opinion of the 
physician precludes RT  
5. Patients with known obstructive symptoms with stricture. 
6. Any contraindication to radiotherapy like inflammatory bowel 
disease. 
7. Uncontrolled comorbidities including, but not limited to 
diabetes or hypertension 
8. Unable to follow up or poor logistic or social support 
 
Arm 1-[standard arm] 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 3 
 
 
 
 
TREATMENT REGIMEN 
Moderate hypofractionated RT, 
Will receive a total dose of 68Gy in 25# to the primary over 5 
weeks, with treatment being delivered daily. Patients with node 
positive disease will receive a dose of 50Gy in 25# to the pelvic 
nodes.Boost to gross nodal disease will be considered based on 
the response to hormonal therapy to a dose of 60-66Gy/25# as a 
simultaneous integrated boost (SIB). An option of equivalent 
biological dose using 60-62.5 Gy in 20# may be allowed for multi-
centric accrual in the future. 
Arm 2 –[Experimental Arm] 
Extreme hypofractionation with SBRT, will receive a course of 5 
fractions of radiation; each fraction size will be 7.25 Gy. The total 
dose will be 36.25 Gy. Patients with node positive disease will 
receive a dose of 25Gy in 5 # to the pelvic nodes. The 5 treatments 
will be scheduled to be delivered alternate day over approximately 
7-10 days. An option of equivalent biological dose using 35-36.25 
Gy in 5 weekly fractions may be allowed for multicentric accrual in 
the future. 
Dose Coverage  
The 95% isodose line used for the prescription dose should cover a 
minimum of 95% of the PTV 
RECRUITMENT TARGET 
434 total number of patients with 217 patients in experimental 
arm and 217 patients in standard arm. 
65 patients to be accrued per year in the project with a total study 
duration of about 8 years, with a 4-year follow up period and a 
uniform accrual rate. 
   PRIMARY ENDPOINT  
 
1. To assess the 4 year Biochemical Failure free Survival (BFFS) 
between the two arms. 
  KEY SECONDARY ENDPOINTS  
 
1. To evaluate acute and late toxicity with both treatments. 
2. To find theProstate cancer specific survival and overall survival 
of patients receiving moderately hypofractionated RT and SBRT. 
3. To estimate the out of pocket expenditureinvolved in 
patientsreceiving the two treatment schedules. 
4. To assess quality of life 
  FOLLOW UP  
 
• All patients will follow up 3-6 weeks from end of radiotherapy, 
followed by 3-6 monthly for the first two years depending on the 
clinical need and 6 monthly thereafter. At baseline and every 
follow-up data will be collected and recorded in CRF 
• Physician assessment of toxicity with RTOG toxicity criteria and 
CTCAE ver4.03 criteria for proctitis, rectal pain, rectal bleeding 
and urinary complaints at baseline and follow up. 
• Physician assessment during and end of RT with scoring of 
toxicity and IPSS scoring 
• Physician assessment with clinical examination and serum PSA. 
• QOL will be assessed at baseline and 6 monthly using the 
QLQC30 and PR25 EORTC Questionnaire.  

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 4 
 
Background 
Prostate cancer is one of the most common cancers seen in the western population and is 
also seen on a rising trend in India. It is the fourth most common cancer in both sexes 
combined and the second most common cancer in men worldwide[1] [GLOBOCON 2012] 
and is the second leading site of cancer among males in large Indian cities like Delhi, Kolkata, 
Pune and Thiruvananthapuram, third leading site of cancer in cities like Bangalore and 
Mumbai and it is among the top ten leading sites of cancers in the rest of the PBRCs of 
India.[2] 
High risk prostate cancer is an aggressive form of prostate cancer,defined by NCCN as cases 
with at least one of thefollowing features: Gleason score of 8–10, clinical stage T3a or 
higher,or PSA > 20 ng/mL[3][NCCN]. The standard of care for locally advanced high risk 
cancer is external beam radiotherapy alongwithlong term hormonal therapy. [4-6].Long 
term clinical and biochemical control is achievable with dose escalation in radiotherapy in 
prostate cancer. With advances in high precision technology in radiotherapy, it is possible to 
target and deliver higher doses to the tumour with sparing of the normal tissue. 
The radiobiological studies have shown that prostate cancer has a low alpha / beta ratio in 
the 
range 
of 
(0.9-2.2) 
[7,8].Thismeans 
increased 
fraction 
size 
may 
improve 
biochemicalcontrol without significantly increased toxicity tonearby tissues (bladder, 
rectum).Thus a low α:β ratio of prostate cancer has high sensitivity to dose per fraction. This 
makes hypo-fractionated radiotherapy radio-biologically superior than conventional 
fractionated schedules as it leads to a considerably higher biologically equivalent dose 
delivery. 
Various prospective randomised trials have studied the safety and efficacy of moderate 
hypo-fractionation in prostate cancer and has been now considered as the standard of care 
[9-11]. With the benefit shown with moderate hypofractionation, there has been a growing 
interest in the role of extreme hypofractionation in prostate cancer. 
 Extreme hypofractionation with stereotactic body radiation therapy (SBRT) has an emerging 
role as an alternative technique to deliver high dose radiotherapy to the prostate through a 
non-invasive approach, comparable to HDR brachytherapy, but with a non-invasiveapproach 
[12-15].SBRT is defined by the American Society for Radiation Oncology and the American 
College of Radiology as a treatment method to deliver a high dose of radiation to the target, 
utilizing either a single dose or a small number of fractions with a high degree of precision 
within the body. 
Multiple single-institution studies on the use of SBRT as the primary treatment for prostate 
cancer have suggested the treatment to be safe and quicker alternative to 
prolongedfractionation schedules [17-26]. However the number of patients with high risk 
prostate cancer included in these studies was low. This is predominantly because of large 
numbers of low and intermediate risk cancer in the west as opposed to the high risk group 
prostate cancer patients commonly seen in Indian scenario. 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 5 
 
Table 1 gives a brief summary of various moderate and extreme hypofractionation 
schedules used in prostate cancer radiotherapy. The safety and toxicity evaluated in 
extreme hypofractionationin these studies have been comparable to moderate 
hypofractionation.  
Therefore with advance techniques in radiotherapy planning and delivery, it is imperative to 
use SBRT in the treatment of prostate cancer. 
The standard duration of treatment with radiotherapy is 8weeks in conventional 
fractionation; 5-6 weeks with moderate hypo-fractionation, while it is only 1- 2weeks with 
extreme hypo-fractionation (SBRT).The health costs and out of pocket expenditure involved 
in the conventional hypo-fractionated radiotherapy treatmentlargely depends on the overall 
treatment duration. This involves expenditure not only for the patient but also the 
caretaker.Moreover most of these patients presenting to a tertiary care centre from 
different parts of the country, have logistic issues of accommodation, food, travelalong with 
the treatment costs. Also for patients staying away from family, 5weeks treatment without 
considerable family support has a psychological impact, especially on elderly group of 
patients commonly seen with prostate cancer.This further leads to a major cause of distress 
among these patients, especially in a resource limited setting as ours. [27] 
Extreme hypo-fractionation with a total duration of 2weeks, would offer an opportunity 
tooptimize the therapeutic ratio taking advantage of the potential therapeutic gain due to 
low alpha/beta for prostate to higher dose/fraction(compared to surrounding organs at 
risk). Moreover, shortened overall treatment time,would lead to less distressing and early 
recommencement of their daily activities for the patients,with an obvious impact in 
improving the quality of life andhealth costs. 
Given the potential positive economic impact with shorter duration treatment with similar 
clinical outcomesand probable similar toxicity profile, SBRT (extreme hypo-fractionation) in 
prostate cancer is an attractive treatment option, especially in a limited-resource setting 
and can have a large and positive impact on the patient care. 
 
 
 
 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 6 
 
Table no 1: Reported studies using moderate and extreme hypofractionation dose schedules 
in prostate cancer. 
 
 
Study 
No 
of 
patient
s 
Median 
Follow-
up 
(months) 
Total 
dose 
(Gy) 
Dose 
/fractio
n (Gy) 
Free from PSA 
failure 
Definition of 
failure 
Late toxicity 
 
Hormo
ne (%) 
GU 
≥2 
(%) 
GI ≥2 
 (%) 
Extreme hypofractionation with SBRT 
Madsen 
[20] 
40 
41 
33.5 
6.7 
Low, 90% (4 
years) 
Nadir+2/AST
RO# 
20 
8 
No 
Freeman 
[19] 
41 
60 
36.25 
7.25 
Low, 92.7% (5 
years) 
Nadir+2 
9.5 
2.5 
No 
Tang [21] 
30 
12 
35‡‡ 
7 
NA 
NA 
13 at 6 
months 
13 at 
6 mo 
3 
Friedland[
22] 
112 
24 
35–36 
7–7.2 
NA 
NA 
0 
0.9 
19 
Katz[23] 
50, 
254§§ 
17, 30 
35, 
36.25 
7, 7.25 
Low, 99%, Int, 
100%, 
High,83% (last 
follow-up) 
Nadir+2 
2, 6.3 
0, 2.9 
19 
Bolzicco[2
4] 
45 
20 
35 
7 
Low and Int, 
100% 
NA 
2.2 
2.2 
38 
Jabbari 
[27] 
20 
18.3 
38 
9.5 
All risk groups, 
100% 
NA 
13¶¶ 
8¶¶ 
47% 
Boike [25] 
15, 15, 
15## 
30, 
18, 
12 
45, 
47.5, 50 
9, 9.5, 
10 
100% 
Nadir+2 
13, 20, 
7 
7,7, 0 
22 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 7 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate hypofractionation 
Pollack 
[13-14] 
50 
39 
70.2 
2.7 
Int and High, 83% (5 
years) 
Nadir+2 
25(5years 
6(5years) 
44 
Kupelian 
770 
45 
70 
2.5 
Low, 94; Int, 83%; High, 
72% (5 years 
Nadir+2/ASTRO# 
7 (5 years) 
6 (5 years) 
60 
CHHiP 
Dearnale
y et al. 
[25-26] 
1065/37 # 
1074/20 # 
1077/19 # 
 
74 Gy/37# 
60 Gy/20# 
57 Gy/19 # 
2 
3 
3 
15 % low 
73 % intermediate 
12 % high 
NA 
5 years G 2 
+ GU 
(RTOG, NS) 
9.1 % (37 
#) 
11.7 % (20 
#) 
6.6 % (19 
#) 
Acute G2 + 
GI (p < 
0.0001) 
25 % (37 #) 
38 % (20 #) 
38 % (19 #) 
 
5 years G 2+ 
GI 
(RTOG, NS) 
13.7% 
(37#x) 
11.9% (20 #) 
11.3% (19 #) 
97 
HYPRO 
Aluwini 
et al. 
[12] 
 
397 
 
407 
60 
 
78 Gy/39 # 
 
64.6 
Gy/19 
fx 
2G 
 
3.4Gy 
27 % intermediate  
73 % high 
NA 
3 
years 
G2+ GU 
39 % 
3 
years 
G3+ 
GU12.9 % 
 (3 
years 
G3+ GU p = 
0.02) 
 
3years G2+ 
GU41.3 % 
3 
years 
G3+ GU 
19.0 % 
3 
years 
G2+ GI 
17.7 % 
3 
years 
G2+ GI 
21.9 % 
66% 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 8 
 
 
Hypothesis for present study: 
Extremehypo-fractionation with SBRT in high risk prostate cancer is non inferior to 
moderately hypo-fractionated standard radiotherapy while producing acceptable toxicity 
and advantage in terms of shortening of treatment duration 
Aim 
The aim of the study is to compare the efficacy with SBRT and moderate hypo-fractionation 
in high risk and node positive prostate cancer 
Objectives: 
Primary Endpoint 
ü The primary objective of the study is to assess the 4 year biochemical Failure free 
Survival (BFFS) between the two arms 
 
Secondary Endpoints 
ü To evaluate acute and late toxicity with both treatments. 
ü To find the Prostate cancer specific survivaland overall survival of patients receiving 
moderately hypofractionated RT and SBRT. 
ü To estimate the out of pocket expenditure involved in patientsreceiving the two 
treatment schedules. 
ü To assess quality of life 
 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 9 
 
Methodology: 
Trial design 
This will be a 2 arm, Prospective Randomized Trial with anon-inferiority design 
Patients will be randomized to one of these below mentioned arms using stratified block 
randomization method. 
 
Arm 1[standard arm]:  
Moderatelyhypofractionated 
Radiotherapy 
(217 patients) 
 
Arm 2 [Experimental arm]:  
Extreme 
hypofractionation 
with 
Stereotactic 
body 
radiotherapy 
(217 patients) 
 
 
Eligibility criteria 
Inclusion criteria-  
1. 
Age: above 18 years.  
2. 
Participants must be histologically proven, adenocarcinoma prostate 
3. 
Localised to the prostate or pelvic lymph nodes 
4. 
High risk prostate cancer as per NCCN definition 
clinical stage T3a  or Gleason score 8/Gleason grade group4 or Gleason score 9-
10/gleason grade group 5,  PSA > 20 ng/mL.orVery high risk prostate cancer i.e 
T3b-T4 or Primary Gleason pattern 5/Gleason grade group 5 or > 4cores Gleason 
score8-10/Gleason grade group 4 or5 
5. 
Ability to receive long term hormone therapy/ orchidectomy 
6. 
KPS ≥ 70 (see appendix) 
7. 
No prior history of therapeutic irradiation to pelvis 
8. 
Patient willing and reliable for follow-up and QOL 
9. 
Signed study specific consent form 
 
 
Exclusion criteria-  
1. 
Evidence of distant metastasis  at any time since presentation 
2. 
Life expectancy < 2 year 
3. 
Previous RT to prostate or prostatectomy.  
4. 
Severe urinary symptoms or with severe IPSS score (>15)inspite of being on 
hormonal therapy for 6months which in the opinion of the physician precludes RT. 
5. 
Patients with known obstructive symptoms with stricture. 
6. 
Any contraindication to radiotherapy like inflammatory bowel disease. 
7. 
Uncontrolled co-morbidities including, but not limited to diabetes or hypertension 
8. 
Unable to follow up or poor logistic or social support. 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 10 
 
Pre-treatment evaluation:  
All patients with biopsy proven Adenocarcinoma of the prostate (TRUS guided) after 
screening will undergo the following investigations prior to enrolment and randomization 
• Complete history and physical examination 
• Serum PSA < 3 weeks of randomization 
• Laboratory investigations undertaken routinely (complete blood counts, Renal 
function test, Liver function test and Serum Electrolytes) 
• Staging investigation including CT scan of the abdomen- pelvis / bone scan/ MRI 
pelvis/ PSMA PETCTto rule out distant metastasis. 
• IPSS scoring  
• Documentation of pre-treatment urinary and rectal symptoms and quality of life. 
 
 
Interventions 
Registration 
Patients with high risk carcinoma prostate on presentation will be screened for eligibility 
criteria. They must meet all of the inclusion criteria and have none of the exclusion criteria 
to be eligible for the trial. Written, informed consent will be obtained from all these patients 
at the time of registration. 
Subjects must be registered before starting study treatment. Once the registration process 
has been completed, the subject will be assigned a subject study number. Individuals will 
only be registered once in this trial following which the patient would be randomized.  
Randomisation 
Patients will be randomized to one of the below mentioned arms using stratified block 
randomization method.  
Arm 1 (Standard arm): Moderate hypo-fractionated RT 68Gy/25# 
Arm 2 (Test arm): Extreme hypo-fractionated RT with SBRT 36.25Gy/5# 
Stratification 
Stratification will be done for the following parameters 
1. Nodal status: N0 Vs N+ 
2. LHRH agonist/antagonists Vs Bilateral orchidectomy 
 
Radiotherapy details 
In arm 1 of the study, patients who are randomized to receive moderatelyhypofractionated 
RT will receive a total dose of 68Gy in 25# to the primary over 5 weeks, with treatment 
being delivered daily. Patients with node positive disease will receive a dose of 50Gy in 25# 
to the pelvis. Boost to gross nodal disease will be considered based on the response to 
hormonal therapy to a dose of 60-66Gy/25# as a simultaneous integrated boost(SIB). An 
option of equivalent biological dose using 60-62.5 Gy in 20# may be allowed for multicentric 
accrual in the future. 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 11 
 
In Arm 2 of the study, patients who are scheduled to receive SBRT will receive a course of 5 
fractions of radiation; each fraction size will be 7.25Gy. The total dose will be 36.25Gy. 
Patients with node positive disease will receive a dose of 25Gy in 5 # to the pelvis. Boost to 
gross nodal disease will be considered based on the response to hormonal therapy to a dose 
of 30-35Gy/5# as a simultaneous integrated boost (SIB).The 5 treatments will be scheduled 
to be delivered alternate day over approximately 7-10 days. An option of equivalent 
biological dose using 35-36.25 Gy in 5 weekly fractions may be allowed as per institutional 
practice for multicentric accrual in the future. 
 
 
Dose Coverage  
The 95% isodose line used for the prescription dose should cover a minimum of 95% of the 
PTV.  
 
Treatment Planning 
Preparation 
• Bladder: Patients will be asked to have a comfortably full urinary bladder both during 
simulation and treatment.  Consistent bladder filling procedure should be used for 
an individual patient for simulation and for each treatment. Bladder filling may be 
achieved by asking patients to drink 500 ml of water 45 minutes prior to treatment 
and to not urinate between this time and treatment.  
• Bowel: Patients will be advised to adhere to a low gas, low motility diet commencing 
2 days prior to the simulation and treatment. One tablespoon of Milk of Magnesia 
will be taken the night before the simulation. 
 
 
Simulation  
Computed Tomography (CT)  
• Patients will be asked to empty the rectum before the planning CT scan. About 45 
min prior of acquiring the helical CT scan; all participants will be asked to void 
completely and to drink 500 ml of plain water. This protocol of bladder filling will be 
followed during every day treatment to ensure constant partial bladder filling to 
achieve lesser volume of bowel in irradiated area and least displacement of internal 
organs due to variable bladder filling. Patients will be simulated in supine position 
with hands over chest. Knee rest will be used for immobilisation and reproducibility. 
Three markers will be placed over skin at laser intersections; one at symphysis pubis 
and two laterally. CTscans will be taken with contrast from 1st Lumber vertebra to 5 
cm below ischial tuberosity with a slice thickness of 2.5mm. Lasermarks will be 
permanently tattooed for set up. 
 
Magnetic Resonance Imaging (MRI)  
MRI images are not required but may be used for fusion if available. 
 
Contouring: 
• Target Volumes: CTV prostate (and SV): For patients without clinical or radiological 
involvement of SV, CTV will consist of the whole of prostate gland including any ECE 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 12 
 
and the base of seminal vesicles defined as the proximal 0.5 seminal vesicles will be 
included in the CTV.  
• CTV nodes: For patients with node positive disease, will receive radiotherapy to 
pelvic nodes. Contouring will begin from the level of L4-5.  Contour will be drawn 
around the major vessels with margins of about 7 mm and then modified depending 
on the anatomical boundaries like bone, muscles and peritoneum. The external iliac 
vessel contouring will be stopped at the top level of the femoral head. The upper 
external iliac region delineation will also include the lateral and medial pre-sacral 
nodal area from S1-3 with a thickness of 8-10mm.  The internal iliac lymph node 
contouring (including the obturator node) will stop at the beginning of the obturator 
foramen. The caudal part of the volume will include the distal part of the SV when it 
is uninvolved clinico-radiologically. The prophylactic lymph nodal delineations follow 
the pattern shown at the RTOG. The whole nodal CTV (bilateral) will be drawn as a 
single structure and 1cm thick pre sacral space will be included by joining bilateral 
nodal CTV up to caudal border of S3, posterior border being the anterior sacrum and 
anterior border approximately 10 mm anterior to the anterior sacral bone carving 
out bowel, bladder, and bone. 
• PTV nodes: A margin of 5mm will be grown isotropically over CTV nodes 
• PTV Prostate (and SV): A margin of 5mm will be grown in all directions over 
theCTVprostate. 
• Organs at risk: Whole of rectum will be drawn as a solid structure starting from recto 
sigmoid flexure up to the bottom of ischial tuberosity. The rectal wall will not be 
drawn separately. The entire bladder will be drawn as a solid structure from the 
dome to the base including the wall. 
• Bowel will be represented by a single solid structure encompassing the peritoneal 
cavity and any loops of bowel in the pelvis. The upper extent will be kept constant at 
2 cm superior to the uppermost extent of the PTV to have comparability of the dose 
volume data.  
• Penile bulb will be contoured on the CT image below the pelvic diaphragm with 
reference to the MRI of pelvis. Both femoral heads will be drawn within the 
acetabulum without including the neck of the femur. 
 
Treatment planning: 
This protocol requires the use of IMRT (DMLC or SMLC) or related techniques 
(Tomotherapy/VMAT). The recommended photon energies for this protocol are 6-15 MV 
with or without a flattening filter. All patients will undergo daily image guided radiotherapy. 
Planning will be done as a single phase simultaneous integrated boost (SIB) technique. The 
dose volume constraints are given below in Table 2 and Table 3 for the two dose 
fractionation schedules and the 2 Gy equivalent doses (EQD2)of each dose fractionation 
schedule is given in table 4. 
 
 
 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 13 
 
Table 2: Dose constraints with moderate hypofractionation in Arm 1 (Standard arm) 
 
Organ 
V30 
V40 
V45 
V50 
V60 
V65 
V70 
Bowel 
(cc) 
 
 
80 
30 
 
 
 
Bladder 
(%) 
65 
45 
 
25 
15 
 
 
Rectum 
(%) 
80 
60 
 
35 
25 
15 
0.1 
 
 
Table No 3: Dose constraints with extreme hypofractionation with SBRT in Arm 2 
(Experimental arm) 
 
Organ  
V14 
V17.5 
V28 
V31.5 
V35 
Bladder 
<40% 
(N+) 
<20% 
(<27% in 
N+) 
 
 
<3% 
Rectum 
 
<40% 
<15% 
<8% 
<3% 
Femoral 
head 
<5% 
 
 
 
 
 
 
 
Table 4:EQD2for the different dose-fractionation schedules. 
 
Dose 
 (Gy) 
Fractions Dose/Fraction 
       (Gy) 
EQD2 (Gy) 
Alpha/beta@3Gy 
EQD2(Gy) 
Alpha/beta 
@1.5Gy 
68 
25 
2.72 
78 
81 
66 
25 
2.64 
74.5 
78 
64 
25 
2.56 
70 
74 
60 
25 
2.4 
64.8 
66.86 
50 
25 
2 
50 
50 
62.5 
20 
3.125 
76.56 
82.59 
60 
20 
3 
72 
77.14 
36.25 
5 
7.25 
78 
94 
35 
5 
7 
74 
85 
30 
5 
6 
54 
64.29 
25 
5 
5 
40 
46 
 
 
 
 
 
 
Hormone therapy 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 14 
 
All patients will receive hormone therapy starting at least 8 weeks prior to the beginning of 
radiotherapy (LHRH agonist/antagonist). They will continue the hormone therapy during the 
radiotherapy and later for a total duration of  2 years. Patients who have undergone 
orchidectomy will also be eligible in this study. The first LHRH agonist/antagonist injection 
will be covered with a 3-4 week course of anti-androgen to prevent testosterone flare. 
 
Clinical Assessment: 
1. Objective criteria for toxicity evaluation. 
The RTOG will be used to document acute and late toxicities (appendix 2-3) 
National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 will also be used for documentation of proctitis, rectal pain, rectal 
bleeding, rectal ulcer; and urinary tract toxicities such as frequency, urgency, 
retention, pain, obstruction. 
 
a. RTOG toxicity criteria at baseline, 3-6 weeks post RT and at 6 monthly thereafter. 
b. Physician assessment during and end of RT with scoring of toxicity and IPSS 
scoring. 
c. QOL will be assessed at baseline and 6 monthly using theQLQC30 and PR25 EORTC 
Questionnaire.  
 
2. Disease evaluation: Clinical evaluation of the disease will be done at each follow up 
visit with a serum PSA and clinical examination. 
 
3. Out of pocket expenditure of the patient and caregiver on food, travel, 
accommodation and for management of treatment related side-effects will be 
captured using a structured record form during treatment and each follow- up upto 
2years. 
 
4. All patients will follow up 3-6 weeks from end of radiotherapy. Thereafter follow up 
visits would be scheduled three to six monthly for the first two years depending on 
the clinical need and 6 monthly thereafter as per standard practice. Clinical data will 
be recorded prospectively in the Case Record Form. 
Statistical consideration: Study Sample Size 
 
The primary endpoint for this study is 4 year BFFS. The power calculations assume a 4-year 
BFFS of 80% in the moderate hypo fractionation arm (Arm1). On this basis, with a 5% one 
sided significance and 80% power, a total of 434 patients will be randomized to both arms 
equally (217 in each arm) and the trial will have the ability to demonstrate non-inferiority of 
extreme hypo fractionation with SBRT arm (Arm 2), defining non-inferiority as “no worse 
than 12%‟ below moderate hypo fractionation arm. This also accounts for a 5% 
noncompliance rate as anticipated from experience in previous studies. 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 15 
 
Interim Analysis 
A planned interim analysis for toxicity is built in. The timing of the interim analyses will be 
based on accrual of patients (25%, n=108) completing 2 years of follow up. At the planned 
interim analysis, the p-value from the chi-square or fisher exact test assessing treatment 
efficacy with respect to grade III or higher combined GI and GU RTOG toxicity will be 
compared in the two arms at one sided alpha of 2.5% and a power of 80%. If the computed 
p-value is less than or equal to 0.025, then accrual to the trial will be discussed with the 
DSMC for stopping (if applicable). Otherwise, accrual to the trial or follow-up (as applicable) 
will continue until the planned sample size (n=434) 
Data collection methods 
The data of the study would be collected in a pre designed case record form. The data will 
be filled in excel sheets and then would be transferred in SPSS and/or R studio for requisite 
analysis.  
Data monitoring– 
The institutional data monitoring and safety board (DSMSC) will be responsible for oversight 
of the data. 
Analysis of population  
Patient disposition and efficacy analyses will be performed on data from the intent-to-treat 
(ITT) population and per protocol analysis. All patients randomized into the study will be 
classified according to their assigned treatment group, regardless of the actual treatment 
received. The primary efficacy analysis will be on the ITT basis and per protocol basis. 
Statistical Analysis  
Qualitative data will be expressed as percentages and compared between the treatment 
groups using the chi-square test (or the Fisher exact test). Quantitative data will be 
expressed as means and standard deviation (or medians and range) and compared between 
the treatment groups using the Student t test (or the Wilcoxon test).  
Prostate cancer specific survival and overall survival will be estimated using the Kaplan-
Meier method with 95% confidence Intervals. The log-rank test will be used to compare the 
treatment groups. The comparison will be adjusted on stratification factors using the Cox 
model. The median follow-up will be estimated using the  reverse Kaplan-Meier method.  
Outcome measures 
Freedom from biochemical failure [BFFS]: Freedom from biochemical failure will be defined 
as duration from date of nadir PSA to PSA>2ng/ml over the nadir PSA 
Overall survival (OS) is defined as the time from randomization to the time of death from 
any cause  
The prostate cancer-specific survival will be calculated from the date of randomization to 
the date of the death due to prostate cancer. 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 16 
 
Quality of life will be assessed using the EORTC QLQ c30 and PR25 questionnaire 
Patient accrual  
Patients will be identified and checked for eligibility from the OPDs at TMH and ACTREC. 
Suitable patients will be considered for the study by a member of the investigating team 
after thoroughly explaining the study process and giving at least 24 hours for thinking over if 
they need.  
We expect 65 patients to be accrued per year in the project with total study duration of 
about 8 years, with a 4-year follow up period and a uniform accrual rate. 
Multicentric approach: The trial will be opened to other centers with access to IMRT/IGRT 
who may be encouraged to join the study in due course. The choice of conventional 
fractionation to 60-62.5 Gy in 20# will be allowed with appropriate stratification for 
individual centres. 
Adverse Event reporting guidelines  
In order to assure prompt and complete reporting of toxicities, the following general 
guidelines are to be observed.  
The principal Investigator will report the details of any unusual, significant, fatal or life- 
threatening protocol treatment reaction to the Data Monitoring Committee and Data 
Management Staff in the CRS within 24 hours of discovery. When reporting it is required 
that the Principal Investigator should have a relevant material available. A written report, 
including all relevant study forms, containing all relevant clinical information concerning the 
reported event will be sent to the DSMSC by the Principal Investigator. This will be sent 
within 10 working days of the discovery of the toxicity unless specified sooner by the 
protocol. The Principal Investigator in consultation with other Investigators will take 
appropriate and prompt action to inform the IEC of any protocol modifications and/or 
precautionary measures if this is warranted.  
Translational Research  
The accrual of patients in the prospective randomized trial will be an excellent opportunity 
to collect bio-specimen (urine, serum, and paraffin blocks) from the patients for correlative 
studies in the future with the outcome and toxicity data. Patients will be consented for the 
same and IEC will be informed before undertaking any future correlative studies using the 
bio-specimen.  
Research ethics approval - This protocol and the template informed consent forms 
contained in Appendix will be reviewed and approved by the institutional IRB with respect 
to scientific content and compliance with applicable research and human subjects’ 
regulations. The protocol, site-specific informed consent forms (local language and English 
versions), participant education and recruitment materials, and other requested 
documents—and any subsequent modifications — also will be reviewed and approved by 
the IRB. Subsequent to initial review and approval, the IRB will review the protocol at least 
annually. The Investigator will make safety and progress reports to the IRB at 12 monthly 
intervals and within three months of study termination or completion. These reports will 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 17 
 
include the total number of participants enrolled and summaries of each DSMSC [data 
safety and monitoring committee] review of safety and/or efficacy.  
Protocol amendments - Any modifications to the protocol which may impact on the 
conduct of the study, potential benefit of the patient or may affect patient safety, including 
changes of study objectives, study design, patient population, sample sizes, study 
procedures, or significant administrative aspects will require a formal amendment to the 
protocol. Any and all such amendments will be communicated to the institutional IRB for 
review and approval. Administrative changes of the protocol are minor corrections and/or 
clarifications that have no effect on the way the study is to be conducted. These may be 
communicated to the IRB at the investigator's’ discretion.  
Consent 
Patients will be given the patient information sheet by the trial investigators / nurses. The 
purpose and reasons behind the study will be communicated to the patient. All patients will 
be provided with a copy of the written informed consent as well as the patient information 
sheet. Consent will be on as per institutional IRB guidelines.  
Confidentiality 
 All study-related information will be stored securely at the study site. All participant 
information will be stored in locked file cabinets in areas with limited access. All laboratory 
specimens, reports, data collection, process, and administrative forms will be identified by a 
coded ID [identification] number only to maintain participant confidentiality. All records that 
contain names or other personal identifiers, such as locator forms and informed consent 
forms, will be stored separately from study records identified by code number. All local 
databases will be secured with password-protected access systems. Forms, lists, logbooks, 
appointment books, and any other listings that link participant ID numbers to other 
identifying information will be stored in a separate, locked file in an area with limited 
access. 
Access to data  
The Principal Investigator and Co investigators will be given access to the data sets. Project 
data sets will be housed on the project specific database created for the study, and it will be 
password protected. 
 
 

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Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 19 
 
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radiotherapy for localized prostate cancer: interim results of a prospective phase II 
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17. Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, Corman J: Stereotactic 
hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five 
fractions for localized disease: first clinical trial results. Int J Radiat Oncol Biol Phys 
2007, 67:1099-1105. 
18. Tang CI, Loblaw DA, Cheung P et al. Phase I/II study of a five-fraction 
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737 (2008). 
19. Bolzicco G, Favretto MS, Scremin E, Tambone C, Tasca A, Guglielmi R. Image-guided 
stereotactic body radiation therapy for clinically localized prostate cancer: 
preliminary clinical results. Technol. Cancer Res. Treat. 9(5), 473–477 (2010. 
20. Boike TP, Lotan Y, Cho LC et al. Phase I dose-escalation study of stereotactic body 
radiation therapy for low- and intermediate-risk prostate cancer. J. Clin. Oncol. 
29(15), 2020–2026 (2011). 
21. Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M. Stereotactic body radiotherapy 
as boost for organ-confined prostate cancer. Technol. Cancer Res. Treat. 9(6), 575–
582 (2010). 
22. Jabbari S, Weinberg VK, Kaprealian T et al. Stereotactic body radiotherapy as 
monotherapy or post-external beam radiotherapy boost for prostate cancer: 
technique, early toxicity, and PSA response. Int. J. Radiat. Oncol. Biol. Phys. DOI: 
10.1016/j.ijrobp.2010.10.026 (2010).  
23. Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: 
five-year outcomes. Radiat Oncol, 6, 3 (2011. 
24. Townsend NC, Huth BJ, Ding W, Garber B, Mooreville M, Arrigo S, Lamond J, Brady 
LW: Acute toxicity after Cyber Knife-delivered hypofractionated radiotherapy for 
treatment of prostate cancer. Am JClinOncol 2010. 
25. Dearnaley DP, Sydes MR, Langley RE, et al. The early toxicity of escalated versus 
standard dose conformal radiotherapy with neo-adjuvant androgen suppression 
for patients with localised prostate cancer: results from the MRC RT01 trial 
(ISRCTN47772397). Radiother Oncol 2007; 83: 31–41.. 
26. Dearnaley D, Syndikus I, Sumo G, et al. Conventional versus hypofractionated high-
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21(1):93-98 · February 2017.DOI: 10.1188/17.CJON.93-98. 
 
 
 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 20 
 
Appendix 1:Karnofsky Performance Scale 
100- Normal, no complaints, no evidence of disease 
90 - Able to carry on normal activity: minor symptoms of disease 
80 - Normal activity with effort: some symptoms of disease 
70 - Cares for self: unable to carry on normal activity or active work 
60 - Requires occasional assistance but is able to care for needs 
50 - Requires considerable assistance and frequent medical care 
40 - Disabled: requires special care and assistance 
30 - Severely disabled: hospitalization is indicated, death not imminent 
20 - Very sick, hospitalization necessary: active treatment necessary 
10 - Moribund, fatal processes progressing rapidly 
Appendix 2:RTOG Acute Toxicity 
Organ 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
LOWER G.I. 
INCLUDING 
PELVIS 
No change 
Increased 
frequency 
or 
change in quality 
of bowel habits 
not 
requiring 
medication/ 
rectal discomfort 
not 
requiring 
analgesics 
Diarrhea requiring 
parasympatholytic 
drugs 
(e.g., 
Lomotil)/ mucous 
discharge 
not 
necessitating 
sanitary 
pads/ 
rectal 
or 
abdominal 
pain 
requiring 
analgesics 
Diarrhea requiring 
parenteral 
support/ 
severe 
mucous or blood 
discharge 
necessitating 
sanitary 
pags/abdominal 
distention 
(flat 
plate 
radiograph 
demonstrates 
distended 
bowel 
loops) 
Acute or subacute 
obstruction, 
fistula 
or perforation; GI 
bleeding 
requiring 
transfusion; 
abdominal pain or 
tenesmus requiring 
tube decompression 
or bowel diversion 
GU 
No change 
Frequency 
of 
urination 
or 
nocturia 
twice 
pretreatment 
habit/ 
dysuria, 
urgency 
not 
requiring 
medication 
Frequency 
of 
urination 
or 
nocturia which is 
less frequent than 
every 
hour. 
Dysuria, 
urgency, 
bladder 
spasm 
requiring 
local 
anesthetic 
(e.g., 
Pyridium) 
Frequency 
with 
urgency 
and 
nocturia hourly or 
more 
frequently/ 
dysuria, pelvis pain 
or bladder spasm 
requiring 
regular, 
frequent 
narcotic/gross 
hematuria 
with/ 
without 
clot 
passage 
Hematuria requiring 
transfusion/ 
acute 
bladder obstruction 
not secondary to clot 
passage, 
ulceration 
or necrosis 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 21 
 
Appendix 3:RTOG Late Toxicity 
Organ 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Small/ 
Large 
intestine 
 
No change  
Mild diarrhoea; 
mild 
cramping; 
bowel 
movement 
5 
times 
daily; 
slight 
rectal 
discharge 
or 
bleeding 
Moderate 
diarrhoea 
and 
colic; 
bowel 
movement 
> 
5 
times 
daily; 
excessive 
rectal 
mucus 
or 
intermittent 
bleeding 
Obstruction 
or 
bleeding, requiring 
surgery 
Necrosis 
/ 
perforation fistula 
Bladder  
No change 
 
Slight epithelial 
atrophy; 
minor 
telangiectasia 
(microscopic 
hematuria) 
Moderate 
frequency; 
generalized 
telangiectasia; 
intermittent 
macroscopic 
hematuria 
Severe 
frequency 
& dysuria; severe 
telangiectasia 
(often 
with 
petechiae); 
frequent 
hematuria; 
reduction 
in 
bladder 
capacity 
(<150 cc) 
Necrosis/contracted 
bladder (capacity < 
100 
cc); 
severe 
hemorrhagic cystitis 
 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 22 
 
Appendix 4:Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
 
Adverse event  
1 
2 
3 
4 
5 
Proctitis 
Definition: 
A 
disorder 
characterized by 
inflammation of 
the rectum. 
Rectal 
discomfort, 
intervention 
not indicated 
Symptoms 
(e.g., 
rectal 
discomfort, 
passing blood or 
mucus); 
medical 
intervention 
indicated; limiting 
instrumental 
ADL 
Severe symptoms; 
fecal 
urgency or stool 
incontinence; 
limitingself-care 
ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Rectal 
hemorrhage  
Definition: 
A 
disorder 
characterized by 
bleeding 
from 
the rectal wall 
and 
discharged 
from the anus. 
Mild; 
intervention not 
indicated 
Moderate 
symptoms; 
medical 
intervention 
or 
minor 
cauterization 
indicated 
Transfusion, 
radiologic, 
endoscopic, 
or 
elective 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Rectal mucositis 
Definition: 
A 
disorder 
characterized by 
inflammation of 
the 
mucous 
membrane 
of 
the rectum. 
 
Asymptomatic or 
mild 
symptoms; 
intervention not 
indicated 
Symptomatic; 
medical 
intervention 
indicated; limiting 
instrumental ADL 
Severe symptoms; 
limiting self 
care ADL 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
Death 
Rectal pain  
Definition: 
A 
disorder 
characterized by 
a sensation of 
marked 
discomfort in the 
rectal region 
Mild pain 
Moderate 
pain; 
limiting 
instrumental ADL 
Severe 
pain; 
limiting self care 
ADL 
- 
- 
Rectal ulcer  
Definition: 
A 
disorder 
characterized by 
a circumscribed, 
inflammatory 
and 
necrotic 
erosive lesion on 
the 
mucosal 
surface of the 
rectum. 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
altered GI 
function 
(e.g. 
altered dietary 
habits, 
vomiting, 
diarrhea) 
Severely altered GI 
function;TPN 
indicated; elective 
operative 
or 
endoscopic 
intervention 
indicated; 
disabling 
Life-threatening 
consequences; 
urgent operative 
intervention 
indicated 
 
death 
Urinary 
frequency  
Definition: 
A 
disorder 
characterized by 
urination 
at 
short intervals. 
Present 
Limiting 
instrumental ADL; 
medical 
management 
indicated 
- 
- 
- 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 23 
 
Urinary 
incontinence  
Definition: 
A 
disorder 
characterized by 
inability 
to 
control the flow 
of urine from the 
bladder. 
Occasional (e.g., 
with coughing, 
sneezing, 
etc.), 
pads not 
indicated 
Spontaneous; pads 
indicated 
limiting 
instrumental ADL 
Intervention 
indicated (e.g., 
clamp, 
collagen 
injections); 
operative 
intervention 
indicated; 
limiting self care 
ADL 
- 
- 
Urinary 
retention  
Definition: 
A 
disorder 
characterized by 
accumulation of 
urine within the 
bladder because 
of the inability to 
urinate. 
Urinary, 
suprapubic or 
intermittent 
catheter 
placement 
not 
indicated; 
able to void with 
some residual 
Placement 
of 
urinary, 
suprapubic 
or 
intermittent 
catheter 
placement 
indicated; 
medication 
indicated 
Elective operative 
or radiologic 
intervention 
indicated; 
substantial loss of 
affected 
kidney function or 
mass 
 
Life-threatening 
consequences; 
organ 
failure; 
urgent operative 
intervention 
indicated 
Death 
Urinary urgency  
Definition: 
A 
disorder 
characterized by 
a 
sudden 
compelling urge 
to urinate. 
Present  
 
Limiting 
instrumental ADL; 
medical 
management 
indicated 
- 
- 
- 
Urinary 
tract 
pain  
Definition: 
A 
disorder 
characterized by 
a sensation of 
marked 
discomfort in the 
urinary tract. 
Mild pain  
Moderate 
pain; 
limiting 
instrumental ADL 
Severe 
pain; 
limiting self care 
ADL 
- 
- 
Urinary 
tract 
obstruction  
Definition: 
A 
disorder 
characterized by 
blockage of the 
normal flow of 
contents of the 
urinary tract. 
Asymptomatic; 
clinical or 
diagnostic 
observations only 
Symptomatic 
but 
no 
hydronephrosis, 
sepsis or renal 
dysfunction; 
urethral dilation, 
urinary 
or 
suprapubic 
catheter 
indicated 
Symptomatic and 
altered organ 
function 
(e.g., 
hydronephrosis, 
or 
renal 
dysfunction); 
elective 
radiologic, 
endoscopic or 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 24 
 
Appendix 5: IPSS score 
International Prostate Symptom Score (I-PSS) 
 
Patient Name: ______________________ Date of birth: ________ Date completed 
_______ 
 
  
In the past month: 
Not 
at all 
Less 
than 
1 
in 
5times  
 
Less than
half 
the
time 
About 
half the 
time 
 
More than 
half 
the 
time 
Almost 
always  
Your 
score  
1. Incomplete Emptying 
 
 
 
 
 
 
 
 
How often have you had the 
0 
1 
 
2 
3 
 
4 
5 
 
 
 
sensation of not emptying 
 
 
 
 
 
 
 
 
 
 
 
 
 
your bladder? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Frequency  
 
 
 
 
 
 
 
 
How often have you had
tourinate less than every two 
hours? 
0 
1 
 
2 
3 
 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Intermittency 
 
 
 
 
 
 
 
 
How often have you found 
0 
1 
 
2 
3 
 
4 
5 
 
 
 
you stopped and started
again 
 
 
 
 
 
several times when you 
 
 
 
 
 
 
 
 
urinated? 
 
 
 
 
 
 
 
 
 
4. Urgency 
 
 
 
 
 
 
 
 
How often have you found it
difficult 
to 
postpone
urination? 
0 
1 
 
2 
3 
 4 
5 
 
 
5. Weak Stream 
0 
1 
 
2 
3 
 
4 
5 
 
 
How often have you had a
weak urinary stream 
 
 
 
 
6. Straining 
 
0 
1 
 
2 
3 
 
4 
5 
 
 
How often have you had to
strain to start urination? 
 
 
 
 
None 
1 Time 
2 Times 
3 Times 4 Times 
5 Times 
 
 
 
7. Nocturia 
 
 
 
 
 
 
 
 
 
How many times did you 
0 
1 
 
2 
3 
 
4 
5 
 
 
typically get up at night to
urinate? 
 
 
 
 
 
 
 
 
 
 
 
Total I-PSS 
 
 
 
 
Score 
 
 
 
 
 
 
Score: 
1-7: Mild 
8-19: Moderate 
20-35: Severe 
 
 

Randomised controlled trial of Prostate Radiotherapy In high risk and node positive disease 
comparing Moderate and Extreme hypofractionation [PRIME Trial] 
PRIME trial_ PI: Dr Vedang Murthy, Protocol version 1.2 Dated: 18.12.2017 
Page 25 
 
 
 
 
 
 
 
 
 
 
Quality of Life Due to 
Urinary Symptoms 
Delighted 
Please
d 
Mostly 
Satisfied 
Mixed Mostly 
Dissatisfied 
Unhappy 
Terrible 
If you were to spend the rest of 
your life with your urinary 
condition just the way it is now, 
how would you feel about that? 
0 
1 
 
2 
3 
4 
5 
6 
 
About the I-PSS 
 
The International Prostate Symptom Score (I-PSS) is based on the answers to seven 
questions concerning urinary symptoms and one question concerning quality of life. Each 
question concerning urinary symptoms allows the patient to choose one out of six answers 
indicating increasing severity of the particular symptom. The answers are assigned points 
from 0 to 5. The total score can therefore range from 0 to 35 (asymptomatic to very 
symptomatic). 
The questions refer to the following urinary symptoms: 
Questions 
Symptom 
 
1 
Incomplete emptying  
2 
Frequency  
 
3 
Intermittency  
4 
Urgency  
5 
Weak Stream  
6 
Straining  
7 
Nocturia 
Question eight refers to the patient’s perceived quality of life. 
The first seven questions of the I-PSS are identical to the questions appearing on the 
American Urological Association (AUA) Symptom Index which currently categorizes 
symptoms as follows: 
Mild (symptom score less than of equal to 7) 
Moderate (symptom score range 8-19) 
Severe (symptom score range 20-35) 
The International Scientific Committee (SCI), under the patronage of the World Health 
Organization (WHO) and the International Union Against Cancer (UICC), recommends the 
use of only a single question to assess the quality of life. The answers to this question range 
from “delighted” to “terrible” or 0 to 6. Although this single question may or may not 
capture the global impact of benign prostatic hyperplasia (BPH) Symptoms or quality of life, 
it may serve as a valuable starting point for a doctor-patient conversation. 
The SCI has agreed to use the symptom index for BPH, which has been developed by the 
AUA Measurement Committee, as the official worldwide symptoms assessment tool for 
patients suffering from prostatism. 
 
Appendix 6: QOL questionnaire (Attached) 
Appendix 7: Out of pocket expenditure(Attached)