A Prospective Randomized Phase II Clinical Trial of Moderately Hypofractionated Radiotherapy (70 Gy in 28 Fractions vs 60 Gy in 20 Fractions) Using Helical Tomotherapy.
Phase: NA
Conditions: Prostatic Neoplasms, Genital Neoplasms
Sponsor: Tatarstan Cancer Center

 
 
 
 
 
 
STUDY PROTOCOL 
Version 1.0 
Date 25.01.2019 
 
A Prospective Randomized Phase II Clinical Trial of Moderately 
Hypofractionated Radiotherapy (70 Gy in 28 Fractions vs 60 Gy 
in 20 Fractions) Using Helical Tomotherapy. 
 
 
The following Amendment(s) have been made to this protocol since the date of preparation: 
 
Amendment No. 
 Date of Amendment 
Local Amendment No: 
 
Date of Local 
 
 
 
 
 
 
Amendment 
 
  
 
 
  
 
  
 
 
  
 
  
 
 
  

TABLE OF CONTENTS 
 
 
1. Introduction. 
1.1 The rationale for the use of hypofractionation. 
1.2 Calculation of biologically effective doses. 
1.3 Randomized studies of hypofractional regimens. 
1.4 Selection of patients. 
2. Study objectives. 
2.1 Primary objective. 
2.2 Secondary objectives. 
3. Eligibility 
3.1 Inclusion criteria 
3.2 Exclusion criteria 
4. Actions before radiotherapy. 
5. Radiotherapy. 
5.1 Technical aspects. 
5.2 Simulation and immobilization. 
5.3 Treatment planning. 
6. Observation after the end of radiation therapy. 
7. Statistical analysis plan. 
7.1 Primary Endpoint. 
7.2 Secondary Endpoints. 
7.3 Patient Groups. 
7.4 Sample Size. 
7.5 Analysis of the Primary Endpoint. 
7.6 Analysis of the Secondary Endpoint. 
7.7 Incidence of GU and GI Acute and Late Adverse Events. 
7.8 Analysis for Endpoints Related to HRQOL. 
7.9 Interim Reports. 
7.10 
Analysis for Reporting Initial Treatment Result 
 
 
LIST OF ATTACHMENTS: 
1. EPIC 
2. EQ5D 
3. IPSS 
7. ECOG 

8. TNM 8th edition. 
9. Roach formula. 
10. The formula for assessing the risk of lesions of the seminal vesicles. 
 
 
1.0 Introduction. 
1.1 The rationale for the use of hypofractionation. 
The optimal radiation pattern for radical treatment of prostate cancer is currently 
under discussion.1  Patients suffering from prostate cancer, as a rule, receive 
EXTERNAL BEAM radiation therapy (EBRT) 5 times a week for 7-8 weeks (76 
Gy in 38 farctions).2  Based on recent research, some practitioners increased the 
total radiation dose by adding additional fractions. In some large centers, for this 
cohort of patients, the standard of EBRT is treatment for 9–10 weeks.3 Increasing 
the duration of the course increases the cost of treatment and is less convenient for 
the patient. Over the past 5 years, a large number of studies have been published 
confirming the comparability of shortened irradiation courses with an increase in 
the dose per fraction compared to the irradiation with the traditional regime. 4-7 
The death of mammalian cells from radiation is described by a linear-quadratic 
model. (LQE). According to this model, the survival curve of the irradiated cells 
depends on the total dose of radiation, a single dose of radiation and the duration of 
the course of treatment. In a linear-quadratic model, the reaction of a tumor and 
normal tissues to fractionated irradiation can be described by the alpha / beta ratio 
(α / β). The alpha / beta ratio determines the fractional sensitivity to irradiation of a 
particular cell type. The alpha / beta ratio is high enough (> 10Gy) for early 
responsive irradiation of normal tissues (skin, mucous membranes) and most 
tumors, and low (<5Gy) for late reacting normal tissues (spinal cord, bones). One 
consequence of the different ratio of alpha / beta of normal tissues and tumors is the 
possibility of using non-conventional fractionation schemes. 
In 1999, Brenner and Hall published an article in which they first described the low 
α / β ratio in prostate cancer cells. They concluded that the α / β ratio is 1.5 Gy, 
which is an argument for using hypofractionation.8 In 2001, Fowler and others 
updated this study with the participation of 1020 patients from 11 centers and came 
to the same conclusions. The same data was confirmed in the work of Miralbell and 
co-authors, who retrospectively analyzed data on 6000 patients stratified by risk 
groups and androgen deprivation.9 

Recent years have published articles showing very low alpha / beta ratios for 
prostate tumors. The safety and comparability of the schemes of hypofractionated 
irradiation of prostate cancer (60Gy in 20 farctions; 70 Gy in 28 farctions) in 
comparison with the conventional radiation regime (78 Gy in 39 farctions) has been 
proven. However, there is not a single prospective randomized study comparing the 
hypofractional modes of prostate cancer among themselves. The purpose of this 
study is to compare the modes of hypofractional irradiation of prostate cancer. 
1.2  Calculation of biologically effective doses (BED) 
To facilitate a comparison between the different fractionation regimes discussed in 
this protocol, biologically effective doses (BED) will be calculated and isoeffective 
regimes will be used according to the LQE model. The convention used in this 
protocol to indicate the alpha-beta relationship used in calculating the BED, will be 
indicated by an index; for example, BED1.5 indicates that the BED provided is 
calculated based on the alpha-beta ratio of 1.5. 
Tota
l 
Dos
e 
(Gy
) 
Dose 
per 
fractio
n (Gy) 
Numbe
r 
of 
fractio
ns 
Equivalent dose of 2 Gy at alpha / beta ratio 
1.0 
1.5 
2.0 
3.0 
5.0 
10.0 
70 
2,5 
28 
81,6
7 
80 
78,7
5 
77 
75 
72,9
2 
50,4 
1,8 
28 
47,0
4 
47,5
2 
47,8
8 
48,3
8 
68,5
4 
49,5
6 
60 
3 
20 
80 
77,1
4 
75 
72 
68,5
7 
65 
50 
2,5 
20 
58,3
3 
57,1
4 
56,2
5 
55 
53,5
7 
52,0
8 
44 
2,2 
20 
46,9
3 
46,5
1 
46,2 
45,7
6 
45,2
6 
44,7
3 
Table 1 
1.3 Randomized studies of hypofractional regimens. 
The three largest studies, PROFIT, CHHiP and NRG Oncology 0415, demonstrate 
the comparability of the hypofractional irradiation regimes with those of the 
classical fractionation, both in local control and in toxicity, the results of which 
were obtained from patients after 5 years. 
In the CHHiP study, 3216 men, predominantly with intermediate-risk prostate 
cancer, were randomized (1: 1: 1) into 3 groups. The first group is the classical 

fractionation group (74 Gy in 37 fractions), the second and third groups are 
hypofraction modes (60 Gy in 20 fractions or 57 Gy in 19 fractions for 4 weeks) 
using intensively modulated radiotherapy (IMRT) and 3- 6 months of therapy for 
androgen deprivation (ADT). The mode of irradiation up to 60 Gy was found to be 
not inferior to 74 Gy with respect to biochemical or clinical disease-free survival. 
In the PROFIT study, the 1206 fractions and the hypofractionation (60 Gy in the 20 
fractions for 4 weeks) were randomized to the classical fractionation group (IGRT). 
The treatment results were also comparable. 
In the NRG Oncology 0415 study, 1,115 men with low-risk prostate cancer were 
randomized to the traditional fractionation group (73.8 Gy in 41 fractions) and 
hypofractionation (70 Gy in 28 fractions). Comparable irradiation results were 
obtained.10 
1.4  Selection of patients. 
To participate in this study, patients with localized prostate cancer stage I-III (T1-
3N0M0) will be selected, who will receive radical radiotherapy (helical-IG-IMRT) 
on the TomoHD. 
2.0 Study objectives. 
2.1 Primary objective.  
Determine what regime of hypofractionation will be the best 5-10 year biochemical 
relapse free survival. Compare the results of hypofractional regimes (60Gy in 20 
farctions; 70 Gy in 28 farctions). 
2.2 Secondary objectives. 
2.2.1. Determine which of the hypofractionation regimes will have the best 5-10 
year survival rate without a local progression and overall survival. 
2.2.2. Compare the frequency of acute and late genitourinary and gastrointestinal 
toxicity in patients in 2 groups using the scale ctcae v4, eortc/rtog. 
2.2.3 Compare quality of life of patients in 2 groups using the scale EPIС СP 
(Expanded Prostate Cancer Index Composite for Clinical Practice), EQ5D 
(European Quality of Life Questionnaire). 
 
3.0  Eligibility 
3.1 Inclusion criteria  

3.1.1. Histologically confirmed adenocarcinoma of the prostate. 
3.1.2 The presence of the following studies: TRUS of the prostate gland, pelvis 
MRI, OSG. 
3.1.3 Histological evaluation of prostate biopsy with assignment of the Gleason 
index. 
3.1.4 Clinical stage T1-3N0-1M0 (AJCC 7th edition). 
3.1.5 ECOG performance status 0-1 
3.1.6 Age limit 18 years. 
3.1.7 Patient consent to participate in a clinical study. 
3.2. Exclusion criteria 
3.2.1. Prior or concurrent lymphomatous/hematogenous malignancy or other 
invasive malignancy except nonmelanomatous skin cancer or any other cancer for 
which the patient has been continually disease-free for ≥ 5 years (e.g., carcinoma in 
situ of the bladder or oral cavity) 
 3.2.2. Distatnt metastases. 
3.2.3. Metastases in the lymph nodes of prostate cancer. 
3.2.4. Radical prostatectomy or cryodestruction of the prostate gland in history. 
3.2.5. Radiation of a small pelvis in the anamnesis. Bilateral orchectomy history. 
3.2.6. Unstable angina and/or congestive heart failure requiring hospitalization 
within the past 6 months, transmural myocardial infarction within the past 6 
months, acute bacterial or fungal infection requiring IV antibiotics, chronic 
obstructive pulmonary disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study treatment, hepatic insufficiency resulting in 
clinical jaundice and/or coagulation defects. 
4.0 Actions before radiotherapy. 
4.1. Assessment of the patient's quality of life according to the following EPIC, 
EQ5D scales. 
4.2. Evaluation of the maximum flow rate of urine by urofluometry, assessment of 
urination on the IPSS scale. 
5.0 Radiotherapy. 

5.1 Technical aspects. Radiotherapy will be carried out using the iMRT method on 
a 6 MeV linear accelerator TomoHD. 
5.2 Simulation and immobilization. 
To determine the tumor, clinical and planning volumes of normal critical structures, 
topometric CT is required. CT scan is performed in the same position as for daily 
treatment. Each patient is in the supine position. Computed tomography of the 
pelvis should begin with the 2nd lumbar vertebra and end with the perineal region, 
i.e. all tissues to be irradiated must be included in the CT scan. The thickness of the 
sections should be no more than 0.5 cm. The bladder must be filled, and the rectum 
is empty. On the skin should be applied 3 marks. 
5.3 Treatment planning. 
The target volumes will be determined according to ICRU 83 report. 
5.3.2 Gross tumor volume (GTV). GTV is a visually detectable tumor volume. 
5.3.3. Clinical target volume (CTV) - is the area of microscopic spread of the tumor 
around GTV. 
The prostate will be defined as CTV for T1-T2. At the discretion of the attending 
physician at T3 CTV will be a prostate or an area of about 3 mm around the 
prostate gland. In T3b, CTV will be a prostate with seminal vesicles. 
In patients with T1-T3a with a risk of damage to the seminal vesicles of more than 
15% (according to the formula for assessing the risk of damage to the seminal 
vesicles.), A separate CTV will be isolated, including the bases of the seminal 
vesicles. 
In patients with a risk of lymph node damage of more than 15% (according to 
Roach's formula), a separate CTV will be allocated, including obstructive, external 
iliac, internal iliac, and general iliac lymph nodes to the level of the lumbar-cretzal 
joint. 
5.3.4. Planning target volume (PTV) is a volume around CTV, compensating for 
inaccuracies arising in the treatment of the patient, the movement of internal 
organs. For this study, PTV indents will be 0.5 cm anteriorly, laterally, and 0.4 cm 
toward the rectum. 
5.3.5.  Planning will be carried out on the TomoProvider planning system. 
Treatment is carried out by the method of helical-IG-IMRT. 

The treatment plan used for each patient will be based on the analysis of the volume 
dose, including the analysis of the volume histogram (DVH) of PTV and critical 
normal structures. 
5.3.6 Critical normal structures 
The bladder, rectum, intestine, femoral heads, penis bulbs, penis and skin should be 
outlined. The bladder should be contoured from the base to the dome, the rectum 
from the anus to the rectosigmoid bend. 
 
 
Arm 2,5 Gy 
Arm 3 Gy 
Dose per 
fraction  
Gy 
Total 
Dose Gy 
Dose per 
fraction  
Gy 
Total Dose 
Gy 
Prostate 
2,5 
70 
3 
60 
Seminal 
vesicles 
2 
56 
2,5 
50 
Pelvic 
lymph 
nodes * 
1,8 
50,4 
2,2 
44 
Table 2 
* According to testimony 
 
 
Low risk  
Intermediate 
risk 
High risk 
GTV70/60 
visually 
detectable tumor 
volume 
visually 
detectable tumor 
volume 
visually detectable 
tumor volume 
CTV70/60 
prostate 
prostate 
prostate 
CTV56/50 
- 
seminal vesicles 
base 
seminal 
vesicles 
base /for T3b, the 
seminal 
vesicles 
and the area of 5 
mm around them 
CTV50,4/44 
- 
- 
Pelvic 
lymph 
nodes 
PTV70/60 
 
CTV+5мм( 
posterior 4мм) 
CTV+5мм( 
posterior 4мм) 
CTV+5мм( 
posterior 4мм) 
PTV56/50 
- 
CTV+5мм( 
posterior 4мм) 
CTV+5мм( 
posterior 4мм) 
PTV50,4/44 
- 
- 
CTV+5мм 

Table 3 
6.0 Observation after the end of radiation therapy. 
6.1 Control of PSA every 3 months within six months after the end of radiation 
therapy. 
6.2 Control of PSA every six months for 5 years after the end of radiation therapy. 
6.3. Control PSA every year after 5 years after the end of radiation therapy. 
6.4 Toxicity assessment after 3 months, six months after the end of radiation 
therapy. 
6.5 Toxicity assessment every year after the end of radiation therapy. 
6.6 Assessment of the patient's quality of life on the EPIC, EQ5D scales after 3 
months, six months, and then every year after the end of radiation therapy. 
7.0 Statistical analysis plan. 
7.1Primary Endpoint 
Percentage of patients with 5-10 year biochemical relapse free survival in the groups 
with 3Gy/60Gy and 2,5Gy/70Gy. (PSA failure) 
7.2 
Secondary Endpoints 
7.2.1 Local progression and overall survival 
7.2.2.Acute and late GI and GU toxicity 
7.2.3 EPIC QOL measurements 
7.2.4 EQ-5D measurements 
7.3 Patient Groups 
There are two separate and independent patient groups as defined by the 
Hypofractionation schedule: Arm 1 patients treated with 70 Gy (28 daily fractions of  
2,5 Gy over five and a half weeks) and Arm 2 patients treated with 60 Gy (2 daily  
fractions of 3 Gy over four weeks). 
7.4 Sample Size  
7.4.1 Randomization 
Patients will be randomized to the two hypofractionated group 3Gy/60Gy and 
2,5Gy/70Gy. 
7.4.2 Sample Size 

 
The sample size is estimated based on Schoenfeld‘s sample size formula.11 This 
formula is used to calculate the sample size when the log rank test is used. We assume 
that the disease-free survival function follows an exponential distribution for each 
arm. Accrual to the study is assumed to be uniformly distributed. The null hypothesis 
(H0) of this test is that the hazard rate of Arm 2 (2) is worse than the hazard rate of 
Arm 1 (1). The alternative hypothesis (H A) is that the hazard rate of Arm 2 is not 
worse than the hazard rate of Arm 1. 
H0:   ≥ 0 
vs. 
HA:   < 0 
where  = -ln ( 1/ 2 ) and 0 is a non-inferiority margin. 
the final targeted accrual for this study will be 300 patient 
 
 
7.4.3 Accrual and Duration 
Patient accrual is projected to be 20 cases per month. We expect to complete accrual 
in 1 year. The total duration of the study is expected to be 11 years from the time the 
first patient is entered to the final analysis. 
 
7.5 Analysis of the Primary Endpoint. 
The primary endpoint, 5 and 10-years biochemical relapse free survival, is measured 
from the date of randomization to the date of the biochemical failure defined by the 
RTOG Phoenix definition, or death from any cause. We assume that the distribution 
of biochemical relapse free survival for each arm is an exponential distribution. The 
survival distribution of biochemical relapse free survival will be estimated by the 
Kaplan-Meier method. 
 
7.6 Analysis of the Secondary Endpoints 
We assume that the distribution of failure times of secondary endpoints related to time 
to failure for each arm is an exponential distribution. In a trial of local radiation 
therapy, disease-specific survival, local progression provide relevant measures of the 
treatment effect. However, the treatment effect on other types of failure may impact 
the observable measures of local failure, and other competing risks may dilute the 
sensitivity of local failure. We will use the cause-specific hazard rate (the 
instantaneous rate of cause-specific failure in the presence of competing failure types 
as a function of time) approach to consider the competing events. Freidlin and Korn 
show that the cause-specific hazard rate approach is better than other approaches (e.g., 
the survival distribution of the time to first failure, cumulative incidence method, etc.) 
in most of cases. The log-rank test on times to the specific type of failure will be used 
to test secondary endpoints related to time to failure (local progression, disease-

specific survival the presence of competing failure types as a function of time) 
approach to consider the competing events 12,13. 
The overall survival, local progression, disease-specific survival distribution will be 
estimated by the Kaplan-Meier method. 
7.7   Incidence of GU and GI Acute and Late Adverse Events 
Adverse events are scored according to eortc/rtog, CTCAE version 4.0. An acute 
adverse event will be defined as an adverse event occurring less than or equal to 90 
days from the completion of RT. A multivariate logistic regression will be used to 
model the distribution of acute adverse events for each arm. Both unadjusted and 
adjusted odds ratios and the respective 95% confidence interval will be computed. 
PSA, Gleason score, and age (as appropriate) will be adjusted for in this analysis. A 
late adverse event will be defined as an adverse event occurring more than 90 days 
from the completion of RT. The time to late adverse events will be measured from the 
time that protocol treatment is completed (i.e., the completion of radiation) to the time 
of the worst late adverse event. If no such late adverse event is observed until the time 
of the analysis, the patient will be censored at the time of the analysis. The distribution 
of time to late adverse events (observed severities of adverse events over time) will be 
estimated using the Kaplan-Meier method using a two-sided log-rank test with a 
significance level of 0.05. 
A multivariate Cox regression model will be used to compare the treatment 
differences for time to late adverse events between the two arms. Both unadjusted and 
adjusted hazard ratios and the respective 95% confidence interval will be computed. 
PSA, Gleason score, and age (as appropriate) will be adjusted for in this analysis. 
7.8 Analysis for Endpoints Related to HRQOL  
 
We will use four instruments to measure QOL: the Expanded Prostate Cancer Index 
Composite (EPIC) and EQ-5D. Protocol eligible patients will be included in the QOL 
analysis only if they have provided baseline and at least one subsequent measurement. 
All QOL instruments (EPIC and EQ-5D) will be collected on all cases participating in 
the trial. 
The EPIC and EQ-5D will be collected at pretreatment (baseline) and after 3 months, 
six months, and then every year after the end of radiation therapy. 
Patient self-assessment of symptoms will be performed using three primary EPIC 
scales: urinary, bowel, and sexual symptoms. The EQ-5D is a two-part self-
assessment questionnaire. The first part consists of five items covering five 
dimensions 
(mobility, 
self 
care, 
usual 
activities, 
pain/discomfort, 
and 
anxiety/depression). Each dimension is measured by a three-point likert scale (1-no 
problems, 2-moderate problems and 3-extreme problems). The second part is a visual 
analog scale (VAS) valuing the current health state measured by a 100-point scale 
with a 10-point interval. (0-worst imaginable health state, 100-best imaginable health 

state). We will transform the five-item index score and VAS score into a utility score 
between 0 (Worst health state) and 1 (Best health state) for comparative purposes. 
For all QOL analyses we will conduct a comparison between the two treatment 
arms with a significance level of 0.05 and a two-sided test. To address the non-
ignorable missing data caused by censoring survival time, the data analysis will 
also be done with patients who have not died. 
We will describe the distributions of QOL data collection patterns over all collection 
points in each treatment arm. Longitudinal data analysis, specifically the general 
linear mixed-effect model,15 will be performed to describe the change trend of the 
EPIC, and EQ-5D scores over time across the two treatments. The primary objective 
in the HRQOL analysis is to determine the QOL differences. The response will be the 
change of measurement from baseline for each measurement. z- test statistics will be 
used to test the null hypothesis that responses are the same across the two treatment 
arms versus the alternative hypothesis that they are different. To maintain the overall 
significance level for testing six HRQOL instruments, the Bonerroni-adjusted 
significance level is 0.05/6 = 0.0083. The model will include the baseline and 
stratification variables (Gleason score, PSA). 
To examine trade-offs between the survival time and QOL, we will combine them for 
each patient into two single measurements: QALY and QADFSY. QALY and 
QADFSY are defined by the weighted sum of different time episodes added up to a 
total quality-adjusted survival time and a total quality-adjusted disease-free survival 
time, respectively. 
These health state-based methods of quality-adjusted survival analysis are 
known as Q-TWiST, the quality-adjusted time without symptoms and toxicity 
method. 
Q-TWiST = ∑i=1k qi si 
 
where qi is the quality (the utility coefficient) of health state i , si is the duration spent 
in each health state, and k is the number of health states. We will use Glasziou‘s 
multiple health-state (Q-TWiST) models16 to use the repeated measures of EQ-5D. 
Because Glasziou‘s method incorporates longitudinal QOL data into an analysis of 
quality-adjusted survival, the health-stated model must be constructed on the 
following assumptions: 
 
A1) QOL is independent from treatment 
A2) A health state is independent from previous states 
 
A3) Proportionality of quality-adjusted duration and duration of the actual state of a 
health state. 
 

Assumption A1 can be checked by plotting QOL over time according to treatment, 
and the t-test can be used to compare the mean QOL scores of each treatment arm. 
Assumption A2 can be checked by comparing the QOL for patient groups in a given 
health state where the groups are defined by duration of previous health state 
experience using a regression model. Suitable checks for assumption A3 at minimum 
would be a simple plot. If data does not support these assumptions, we will use a 
method which uses the longitudinal QOL data directly. 
 
7.9 Interim Reports  
In general, the interim reports will contain information about the patient accrual rate 
with a projected completion date for the accrual phase; data quality; compliance rate 
of treatment delivery with the distributions of important prognostic baseline variables; 
and the frequencies and severity of adverse events. The interim reports will not 
contain results from the treatment comparisons with respect to the primary or 
secondary endpoints. 
 
7.10 Analysis for Reporting Initial Treatment Result 
The final analysis will include tabulation of all cases entered and those excluded from 
the analyses with the reasons for such given; the distribution of the important 
prognostic baseline variables; and observed results with respect to the primary and 
secondary endpoints. All eligible patients randomized will be included in the 
comparison and will be grouped by assigned treatment in the analysis (intent-to-treat 
analysis). In addition, exploratory analyses of treatment comparisons of biochemical 
disease free survival, local progression, overall survival will be tested using the Cox 
proportional hazard model that includes age, clinical tumor stage, PSA, Gleason 
score/. Also, where feasible, treatment comparisons with respect to the primary 
endpoint (biochemical relapse free survival) and secondary endpoints (local 
progression 
and 
overall 
survival) 
will 
be 
compared.

 
Study design 
Patients with localized prostate cancer, stage cT1-3N0M0. 
 
Scheduled definitive radiotherapy (helical-IG-IMRT) using TomoHD. 
                                          
                                                            Randomization.      
 
                      Arm 1 (2,5Gy/70Gy)                                 Arm 2 (3Gy/60Gy) 
                        
 
 
                                                      Simulation and immobilization 
Evaluation of the rectum, bladder. 
                                                                                Radiotherapy 
Evaluation of acute toxicity (at the end of EBRT). 
Evaluation of PSA after 1.5 months completion of EBRT. 
                                                
                                                          Observation after treatment. 
Estimation of PSA level every six months. 
Evaluation of late toxicity. 
Assessment of relapse-free survival. 
                                                                        
Study objectives 
 Oncological results (5th, 10th summer) 

Biochemical relapse free survival rate 
Survival rate without a local progression  
Overall survival. 
 Negative effects 
Early and late genitourinary (GU) toxicity 
Early and late gastrointestinal (GI) toxicity 
 
 
 
References:  
1. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate 
carcinoma. Int J Radiat Oncol Biol Phys 1999; 43:1095-1101. 
2. Zietman A, Moughan J, Owen J, Hanks G. The Patterns of Care Survey of radiation 
therapy in localized prostate cancer: similarities between the practice nationally and in 
minority-rich areas. Int J Radiat Oncol BiolPhys 2001; 50:75-80. 
3. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy 
for prostate cancer:early toxicity and biochemical outcome in 772 patients. Int J Radiat 
Oncol Biol Phys 2002; 53:1111-1116. 
4. Fowler JF, Ritter MA, Chappell RJ, Brenner DJ. What hypofractionated protocols 
should be tested forprostate cancer? Int J Radiat Oncol Biol Phys 2003; 56:1093-1104. 
5. Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors 
show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding 
normal tissue. Int J Radiat Oncol Biol Phys 2002; 52:6-13. 
6. D'Souza WD, Thames HD. Is the alpha/beta ratio for prostate cancer low? Int J Radiat 
Oncol Biol Phys 2001; 51:1-3. 
7. King CR, Fowler JF. A simple analytic derivation suggests that prostate cancer 
alpha/beta ratio is low. Int J Radiat Oncol Biol Phys 2001; 51:213-214. 

8. Despina Spyropoulou, Dimitrios Kardamakis Review of Hypofractionated Radiotherapy 
for Prostate Cancer ISRN Oncol. 2012; 2012: 410892. 
9. M. Mangoni,  , I. Desideri.  Hypofractionation in Prostate Cancer: Radiobiological Basis 
and Clinical Appliance Biomed Res Int. 2014; 2014: 781340.  
10. David I Pryor, Sandra L Turner. Moderate hypofractionation for prostate cancer: A 
user's guide. Journal of Medical Imaging and Radiation Oncology. 2018; 232-239. 
11. Schoenfeld D. Sample-size formula for the proportional-hazards regression model. 
Biometrics 1983; 39:499-503. 
12. Freidlin B, Korn EL. Testing treatments effects in the presence of competing risks. Stat 
Med 2004; 24:1703-1712. 
13. Mantel N. Evaluation of survival data and two new rank order statistics arising in its 
consideration. Cancer Chemother Rep 1966; 50:163-170. 
14. Kim K, Tsiatis AA. Study duration for clinical trials with survival response and early 
stopping rule. Biometrics 1990; 46:81-92. 
15. Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. 2000; New 
York: Springer-Verlag, Inc. 
16. Glasziou PP, Cole BF, Gelber RD, et al. Quality adjusted survival analysis with 
repeated quality of life measures. Stat Med 1998; 17:1215-1229. 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
ATTACHMENTS. 
 
 
 
 
 
 
 
 

1. EPIC. 
       Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) 
 
Prostate Cancer Quality of Life (QOL) 
Patient Name: 
Date of Birth: 
Physician: 
Date of Visit:
 
Patients: Please answer the following questions by circling the appropriate answer. All questions are 
about 
your health and symptoms in the LAST FOUR WEEKS. 
Select ONE answer for each question: 
 
В 
Overall, how much of a problem has your urinary function been for you? 
No Problem 
Very small problem 
Small problem 
Moderate problem 
Big problem 
 
 
2. Which of the following best describes your urinary control? 
0-Total control 
1-Occasional dribbling 
2-Frequent dribbling 
4- No urinary control 
3. How many pads or adult diapers per day have you been using for urinary leakage? 
0-None 
1-One pad per Day 
2-Two pads per Day 
4- Three or more pads 
4. How big a problem, if any has urinary dripping or leakage been for you? 
 
0-No problem 
1-Very small problem 
2-Small problem 
3-Moderate problem 
4-Big problem 
 
CLINICIANS: Add the answers from questions 2-4 to calculate the Urinary Incontinence Symptom Score (out of 12) 
 
 
5. How big a problem, if any, has each of the following been for you? 
 
No problem 
Very small problem 
Small problem 
Moderate 
Big problem 
problem 
a. Pain or burning with urination 
0 
1 
2 
3 
4 
b. Weak urine stream/incomplete bladder 
0 
1 
2 
3 
4 
emptying 
c. Need to urinate frequently 
0 
1 
2 
3 
4 
 
CLINICIANS: ADD the answers from questions 5a-5c to calculate the Urinary Irritation/Obstructive Symptom Score (out of 12) 
 
 
6. How big a problem, if any, has each of the following been for you? 
No problem 
Very small problem 
Small problem 
Moderate 
Big problem 
problem 
a. Rectal pain or urgency of bowel 
0 
1 
2 
3 
4 
movements 
b. Increased frequency of your bowel 
0 
1 
2 
3 
4 
movements 
c. Overall problems with your bowel 
0 
1 
2 
3 
4 
movements 
d. Bloody stools 
0 
1 
2 
3 
4 
CLINICIANS: ADD the answers from questions 6a-6d to calculate the Bowel Symptom Score (out of 16) 
 
 
7. How do you rate your ability to reach orgasm (climax)? 
0- Very good 
1-Good 
2-Fair 
3-Poor 
4-Very poor to none 
 
 
8. How would you describe the usual quality of your erections? 
0- Firm enough for 
1-firm enough for masturbation 
2-Not firm enough for any 
4-None at 
intercourse 
and foreplay 
sexual activity 
all 
 
 

9. Overall, how much of a problem has your sexual function or lack of sexual function been for you? 
0-No problem 
1-Very small problem 
2-Small problem 
3-Moderate problem 
4-Big problem 
10. How big a problem, if any, has each of the following been for you? 
 
No problem 
Very small problem 
Small problem 
Moderate 
Big problem 
problem 
a. Hot flashes or breast 
0 
1 
2 
3 
4 
tenderness/enlargement 
b. Feeling depressed 
0 
1 
2 
3 
4 
c. Lack of energy 
0 
1 
2 
3 
4 
 
CLINICIANS: ADD the answers from question s10a-10c to calculate the Vitality/Hormonal Symptom Score(out of 12) 
 
 
CLINICIANS: ADD the five domain summary scores to calculate the Overall Prostate Cancer QOL Score (out of 60) 

 
2. EQ 5D. 
Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY 
 I have no problems in walking about                           
 I have slight problems in walking about  
 I have moderate problems in walking about 
   I have severe problems in walking about 
 I am unable to walk about 
 
 
SELF-CARE 
 I have no problems washing or dressing myself   
 I have slight problems washing or dressing myself 
 I have moderate problems washing or dressing myself 
 I have severe problems washing or dressing myself 
   I am unable to wash or dress myself 
 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
 
I have no problems doing my usual activities  
 
I have slight problems doing my usual activities 
I have moderate problems doing my usual activities 
I have severe problems doing my usual activities 
I am unable to do my usual activities 
 
 
  
 PAIN / DISCOMFORT 
I have no pain or discomfor                                        
I have slight pain or discomfort 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 

I have extreme pain or discomfort 
 
 
 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
I am slightly anxious or depressed 
I am moderately anxious or depressed  
 
I am severely anxious or depressed 
I am extremely anxious or depressed 
 
 
 
We would like to know how good or bad your health is TODAY.

 
This scale is numbered from 0 to 100.

 
100 means the best health you can imagine.

 
0 means the worst health you can imagine. 

 
Mark an X on the scale to indicate how your health is 
TODAY.

Now, please write the number you marked 
on the scale in the box below 
YOUR HEALTH TODAY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

3. IPSS 
 
International Prostate Symptom Score (IPSS)SS) 
 
Patient Name: ______________________ Date of birth: ________ Date completed _______ 
 
In the past 
Less than 
Less than 
About 
More 
Your 
Not at 
Half 
Almost 
1 in 5 
Half the 
than Half 
month: 
All 
the 
Always 
score 
Times 
Time 
the Time 
Time 
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 to 
0 
1 
2 
3 
4 
5 
urinate less than every two 
hours? 
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 
0 
1 
2 
3 
4 
5 
difficult to postpone 
urination? 
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 
Quality of Life Due to 
Delighted 
Pleased 
Mostly 
Mixed 
Mostly 
Unhappy 
Terrible 
Urinary Symptoms 
Satisfied 
Dissatisfied 
If you were to spend the rest of 
your life with your urinary 
0 
1 
2 
3 
4 
5 
6 
condition just the way it is now, 
how would you feel about that? 

 
 
4. ECOG. 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

5.  TNM 8th edition 
 
 

 
 
 
 
 

 
 
6. Roach Formula = [(2/3) ( *) PSA + (Gleason score - 6) ( *) 10] 
7. Evaluation formula for involvement of the seminal vesicles = PSA + (Gleason score - 6) (*) 10]