A First Step Towards Ultra-hypofractionation for Unfavourable Intermediate and High-risk Prostate Cancer: a Prospective Safety and Feasibility Study in Patients With Metastatic Prostate Cancer
Phase: NA
Conditions: Prostate Cancer
Sponsor: Erasmus Medical Center

 
 
 
 
 
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Cover Page: 
 
OFFICIAL TITLE: A first step towards ultra-hypofractionation for unfavourable intermediate 
and high-risk prostate cancer: a prospective safety and feasibility study in patients with 
metastatic prostate cancer. 
 
NCT-number: not yet assigned 
 
Document date: 23rd of December 2021 
 

 
 
 
 
 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ................................................................................. 8 
2. 
OBJECTIVES .................................................................................................................. 10 
3. 
STUDY DESIGN ............................................................................................................. 11 
4. 
STUDY POPULATION .................................................................................................... 13 
4.1 
Population (base) ..................................................................................................... 13 
4.2 
Inclusion criteria ....................................................................................................... 13 
4.3 
Exclusion criteria ...................................................................................................... 13 
4.4 
Sample size calculation ........................................................................................... 13 
5. 
TREATMENT OF SUBJECTS ........................................................................................ 14 
6. 
INVESTIGATIONAL PRODUCT ..................................................................................... 15 
7. 
NON-INVESTIGATIONAL PRODUCT ............................................................................ 16 
8. 
METHODS ...................................................................................................................... 17 
8.1 
Study parameters/endpoints .................................................................................... 17 
8.1.1 
Main study parameter/endpoint ........................................................................ 17 
8.1.2 
Secondary study parameters/endpoints (if applicable) ..................................... 17 
8.1.3 
Other study parameters (if applicable) .............................................................. 17 
8.2 
Randomisation, blinding and treatment allocation ................................................... 17 
8.3 
Study procedures ..................................................................................................... 18 
8.4 
Withdrawal of individual subjects ............................................................................. 18 
8.4.1 
Specific criteria for withdrawal (if applicable) .................................................... 18 
8.5 
Replacement of individual subjects after withdrawal ............................................... 18 
8.6 
Follow-up of subjects withdrawn from treatment ...................................................... 19 
8.7 
Premature termination of the study .......................................................................... 19 
9. 
SAFETY REPORTING .................................................................................................... 20 
9.1 
Temporary halt for reasons of subject safety ........................................................... 20 
9.2 
AEs, SAEs and SUSARs ......................................................................................... 20 
9.2.1 
Adverse events (AEs) ....................................................................................... 20 
9.2.2 
Serious adverse events (SAEs) ........................................................................ 20 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .......................... 21 
9.3 
Annual safety report ................................................................................................. 21 
9.4 
Follow-up of adverse events .................................................................................... 21 
9.5 
Data Safety Monitoring Board (DSMB) .................................................................... 21 
10. 
STATISTICAL ANALYSIS ........................................................................................... 22 
10.1 
Primary study parameter(s) ..................................................................................... 22 
10.2 
Secondary study parameter(s) ................................................................................. 22 
10.3 
Other study parameters ........................................................................................... 22 
10.4 
Interim analysis (if applicable) .................................................................................. 22 
11. 
ETHICAL CONSIDERATIONS .................................................................................... 23 
11.1 
Regulation statement ............................................................................................... 23 
11.2 
Recruitment and consent ......................................................................................... 23 

 
 
 
 
 
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11.3 
Objection by minors or incapacitated subjects (if applicable) .................................. 23 
11.4 
Benefits and risks assessment, group relatedness .................................................. 23 
11.5 
Compensation for injury ........................................................................................... 24 
11.6 
Incentives (if applicable) .......................................................................................... 24 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .......................... 25 
12.1 
Handling and storage of data and documents ......................................................... 25 
12.2 
Monitoring and Quality Assurance ........................................................................... 25 
12.3 
Amendments ............................................................................................................ 26 
12.4 
Annual progress report ............................................................................................ 26 
12.5 
Temporary halt and (prematurely) end of study report ............................................ 26 
12.6 
Public disclosure and publication policy ................................................................... 27 
13. 
STRUCTURED RISK ANALYSIS ................................................................................ 28 
13.1 
Potential issues of concern ...................................................................................... 28 
13.2 
Synthesis ................................................................................................................. 28 
14. 
REFERENCES ............................................................................................................ 29 

 
 
 
 
 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
ART 
Adaptive Radiotherapy 
CT 
Computed Tomography 
CTV 
Clinical Target Volume 
DSMB 
Data Safety Monitoring Board 
DVH 
Dose Volume Histogram 
EBRT 
External Beam Radiation Therapy 
GCP 
Good Clinical Practice 
Gy 
Gray 
IC 
Informed Consent 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
OAR 
Organ at risk 
PET 
Positron Emission Tomography 
PSMA 
Prostate-Specific Membrane Antigen 
PTV 
Planning Target Volume 
(S)AE 
(Serious) Adverse Event  
Sponsor The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SV 
Seminal Vesicles 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
WMO 
 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 
 
 

 
 
 
 
 
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SUMMARY 
 
Rationale:  
One of the key treatment modalities for prostate cancer is external beam radiation therapy. 
Considering the relatively low alpha/beta ratio of prostate cancer, increasing the dose per 
fraction could yield higher tumour control rates with acceptable toxicity in a reduced number of 
treatment fractions (hypofractionation). Ultrahypofractionation (fraction dose > 5 Gy) has 
shown promising results for low- and intermediate risk prostate cancer. 
    Ultrahypofractionation for high-risk prostate cancer however is challenging as the seminal 
vesicles (SV) are included in the target volume, which is not the case for intermediate and low-
risk prostate cancer patient. These SV belong to the male reproduction system and their exact 
shape and size can differ substantially. The SV are attached bilaterally to the prostate and, 
similarly to the prostate, their motion is caused by changes in bladder and rectal filling status. 
However, although the cause of motion is similar for both the prostate and the SV, multiple 
studies report that the inter- and intra-fraction motion of the SV remain significant and largely 
uncorrelated to the prostate motion.  
    Considering the SV must be included in the target volume, the significant SV motion has to 
be accounted for during treatment. A solution is to use safety margins to extend the clinical 
target volume (CTV) to the planning target volume (PTV). Due to their substantial inter- and 
intra-fraction motion, the SV require a relatively large PTV-margin of 8 mm, which causes the 
bladder and rectum to receive more dose per fraction, which in combination with a higher 
fraction dose could result in unacceptable genitourinary and gastrointestinal toxicity rates.   
    This means that to safely introduce ultra-hypofractionation for high-risk prostate cancer 
patients, strategies to minimize PTV-margins around the SV are required. To account for the 
inter-fraction motion of the SV, adaptive radiotherapy (ART) in the form of online re-planning 
could be the solution. Online re-planning is a workflow in which a new treatment plan is 
generated for each fraction, optimized on the anatomy of the day. ART accounting for the intra-
fraction motion of the prostate has been studied well, for example by tracking the intra-prostatic 
markers with the CyberKnife system. Using the in-room Computed Tomography (CT) scan of 
our institution’s CyberKnife, it is feasible to combine online re-planning with intra-fraction 
fiducial tracking. 
   A few papers have recently been published regarding the feasibility of ultra-hypofractionation 
when including the SV in the target volume, using different methods than we are proposing 
here. And while they showed feasibility in principle, the overall conclusions were that further 
research is needed.  

 
 
 
 
 
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   To summarize, this study aims to make a first step towards ultra-hypofractionation for high-
risk prostate cancer by proving the technical feasibility of margin reduction of the SV by 
combining the intra-fraction fiducial tracking with an online re-planning workflow for each 
fraction to account for the inter-fraction SV motion.  
Objective: to take a first step towards ultrahypofractionation for high-risk prostate cancer by 
showing the technical feasibility of PTV-margin reduction around the SV using adaptive 
radiotherapy.  
Primary: To assess the feasibility of reducing the PTV-margins around the SV using online 
adaptive re-planning.  
Secondary:  
 
To assess treatment tolerance using a standardized questionnaire.  
 
To assess possibilities for further treatment optimisation, regarding organs at risk dose, 
for patients  without clinical or radiological SV involvement 
Study design: Non-randomized single arm prospective phase II Study. 
Study population: Patients (n=61) with histologically proven prostate cancer with 
radiologically proven limited metastatic disease, referred to the Erasmus MC, after 
multidisciplinary consensus, for local radiotherapy treatment, similar to the STAMPEDE trial. 
Intervention (if applicable): Patients will be treated according to current clinical practice and 
following the procedures and protocols derived from the STAMPEDE trial. Six weekly fractions 
of 6 Gy will be given and before and after each fraction a CT-scan will be made.  
The target volume will be defined according to our standard current practice, i.e. the whole 
prostate and the basis of or the whole SV. For these patients a treatment plan will be generated 
using the pre-fraction CT-scan and online re-planning to account for differences in daily 
anatomy, hence justifying treatment with reduced SV PTV-margins. By means of a post-
fraction CT-scan dose volume histograms (DVH) parameters will be extracted to estimate the 
achieved intra-fraction coverage of the SV. 
In patients without SV involvement on imaging and no clinical need for including the SV, the 
SV will be excluded from the target volume. This group of patients will receive an un-adapted 
treatment plan based on the original planning CT. A pre- and post-treatment CT scan will be 
made, to simulate offline SV target coverage and gather data for potential Organ at risk (OAR) 
sparing. 
Main study parameters/endpoints: Main endpoint: Percentage of patients for which in 0 or 
1 fraction out 6 fractions the SV were underdosed. Underdosage being defined as 95% of the 
volume of SV receiving < 95% of prescribed dose. In the case of unavoidable underdosage of 
the target on the reference plan, coverage below the achieved coverage in the reference plan 
will be seen as an underdosed fraction. The margin reduction of the SV is considered feasible 

 
 
 
 
 
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when ≥90% of patients received successful treatments. Secondary endpoints: Quantify and 
assess toxicity using questionnaires. Quantify and assess target coverage and OAR dose 
when only the prostate is targeted. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The additional burden for the patients consists of a longer treatment 
fraction duration and filling out questionnaires at regular intervals. The additional risks 
associated with partaking in this study are, firstly, the added radiation dose associated with the 
extra CT-scans at the start and end of each fraction (175mGy). Secondly, the possible 
underdosage of the target volume in the SV. However, considering the SV were not included 
in the target volume for the STAMPEDE trial, the effect of this underdosage on the efficacy of 
the treatment is expected to be minimal. The benefits are (1) a significant reduction from 20 to 
6 treatment fractions, and thus fewer hospital appointments for a palliative group of patients. 
(2) A smaller margin for prostate and SV, which we expect to correspond to less toxicity. 

 
 
 
 
 
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1. INTRODUCTION AND RATIONALE 
Prostate cancer is shown to be the second most diagnosed cancer and sixth highest cause of 
cancer-related death in men worldwide in 2018 [1]. One of the key treatment modalities for 
prostate cancer is external beam radiation therapy (EBRT) [2]. Considering the relatively low 
alpha/beta ratio of prostate cancer [3, 4], increasing the dose per fraction, could yield higher 
tumour control rates with acceptable toxicity in a reduced number of treatment fractions 
(hypofractionation) [5]. Multiple randomized trials on low- and favourable intermediate risk 
prostate cancer reported a non-inferiority of moderate hypofractionation [6, 7] and ultra-
hypofractionation [8] compared to conventional fractionation schemes. For unfavourable 
intermediate and high-risk Prostate cancer patients, large randomized trials using moderate 
hypofractionation have shown non-superiority [9, 10].  
A next logical step would be to introduce ultra-hypofractionation (fraction dose > 5 Gy) for high-
risk prostate cancer patients to possibly improve outcomes and/or reduce the number of 
hospital visits. This ultra-hypofractionation for these patients however is challenging as the 
seminal vesicles (SV) are included in the target volume [11] as opposed to the previously 
mentioned favourable and low-risk Prostate cancer patients where the SV are not included in 
the target volume.  
Regarding the SV, they belong to the male reproduction system and are about 3-5 cm long 
and 1 cm in diameter [12], however their exact shape and size can differ substantially. The SV 
are attached bilaterally to the prostate on the cranioposterior side and they lie superior to the 
rectum, inferior to the fundus of the bladder and posterior to the prostate [12]. The motion of 
the SV, similarly to the prostate, is caused by changes in bladder and rectal filling status. 
However, although the cause of motion is similar for both the prostate and the SV, multiple 
studies report that the inter- and intra-fraction motion of the SV remain significant and largely 
uncorrelated to the prostate motion [13-23].  
Considering the SV must be included in the target volume, the significant SV motion has to be 
accounted for during treatment. A widely used solution to account for these motions and, lesser 
so, for other treatment uncertainties, is to use safety margins to extend the clinical target 
volume (CTV) to the planning target volume (PTV) and thereby insuring that the planned dose 
is actually delivered to the target [24]. Due to their substantial inter- and intra-fraction motion, 
the SV require a relatively large PTV-margin of 8 mm [25-28], which causes the bladder and 
rectum to be, partially, inside the PTV. Which means that the higher the margin, the more dose 
the rectum and bladder will receive [29], which in combination with a higher fraction dose could 
result in unacceptable genitourinary and gastrointestinal toxicity rates.  
This means that to safely introduce ultra-hypofractionation for high-risk prostate cancer 
patients, strategies to minimize PTV-margins around the SV are required, as a reduction in 
PTV-margin should lower the probability of developing genitourinary or gastrointestinal side-
effects [30]. As mentioned, these margins mainly correct for the inter- and intra-fraction motion 
of the SV and prostate [24]. When trying to account for these motions, adaptive radiotherapy 
(ART) could be the solution. ART has been described as being a closed-loop treatment 
process in which systematically monitoring treatment variations and incorporating the findings 
leads to re-optimization of the treatment plan during treatment and thereby improving the 
treatment [31].  

 
 
 
 
 
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When looking at the inter-fraction motion of the SV specifically, ART could provide a solution. 
ART for prostate has been extensively studied and reported [32-38]. Fuelled by the 
developments around MR linear accelerators (Linacs), recent publications on ART for prostate 
cancer focused on online re-planning [39, 40]. Online re-planning is a workflow in which a new 
treatment plan is generated for each fraction, optimized on the anatomy of the day [40]. 
However, ART for SV is a relatively new topic.  
ART accounting for the intra-fraction motion of the prostate has been studied as well [39, 41-
43], for example by tracking the intra-prostatic markers with the CyberKnife system. This has 
been studied previously for localized prostate cancers with excellent results [42]. This led to 
the current clinical application of the CyberKnife system in our institution, which is to treat low-
risk prostate cancer patients (without SV in target volume), using 3 mm PTV-margins around 
the prostate. These relatively small margins are made possible by the intra-fraction tracking of 
the intra-prostatic markers.  
Using the in-room CT-scan of our institution’s CyberKnife, it is feasible to combine online re-
planning with intra-fraction fiducial tracking. This has been shown in dummy runs by our 
department for pancreatic cancer and abdominal lymph node metastasis already. 
A few papers have recently been published regarding the feasibility of ultra-hypofractionation 
when including the SV in the target volume, using different methods than we are proposing 
here. Using an MR-Linac, 5 fractions of 7 Gy has shown excellent tolerability in the 21 patients 
with SV in the target volume. The data on technical feasibility of the adaptive radiotherapy 
approach used were promising as well, however they conclude that more data is warranted 
[44]. Similarly, using an IMRT-approach ultra-hypofractionation (5 x 7 Gy) was shown to be 
well tolerated in patients with node-positive Prostate cancer and SV involvement. Relatively 
small margins were used (5mm) in this study and they also concluded that prospective 
validation of these retrospective results are necessary [45].  
To summarize, this study aims to make a first step towards ultra-hypofractionation for high-risk 
prostate cancer by proving the technical feasibility of margin reduction of the SV by combining 
the intra-fraction fiducial tracking with an online re-planning workflow for each fraction to 
account for the inter-fraction SV motion.  
 
 

 
 
 
 
 
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2. OBJECTIVES 
 
Primary Objective:  
 
To assess the feasibility of reducing the PTV-margins around the SV without 
compromising coverage using an online re-planning approach 
Secondary Objective(s):  
 
To measure Genitourinary and Gastrointestinal toxicity rates  
 
To assess possibilities for further treatment optimisation, regarding organs at risk dose, 
for patients without clinical or radiological SV involvement 

 
 
 
 
 
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3. STUDY DESIGN 
This is a single-centre prospective interventional cohort study evaluating the feasibility of 
margin reduction for the SV in patients with limited metastatic prostate cancer. 
Eligible for this study, will be the patients with limited metastasised prostate cancer, who are 
deemed eligible for local radiotherapy treatment by a multidisciplinary team of specialists. This 
group of patients are currently treated with a combination of systemic and local treatments, 
based on the results of the STAMPEDE trial [46]. The STAMPEDE trial has shown that the 
addition of EBRT on the primary tumour of the prostate to lifelong systemic androgen 
deprivation therapy leads to improved survival for the subgroup of patients with limited 
metastatic burden [46]. By a possible reduction in PTV-margins, a reduction in genitourinary 
and gastrointestinal toxicity rates could be achieved [47]. Furthermore, underdosing the SV 
likely has little impact on the efficacy of the treatment, as the SV are, in contrast to local clinical 
practice, not included in the target volume in the STAMPEDE trial [46]. 
The standard of care for limited metastasised prostate cancer in the Erasmus MC is a 
combination of systemic and local treatment, in line with the results of the STAMPEDE trial 
[46]. The systemic treatment consists of lifelong androgen deprivation therapy (ADT). The sole 
focus of this research is however the local treatment: EBRT. The current clinical workflow is 
as follows. The CTV consists of the prostate and the entire SV, when the SV show tumour 
ingrowth on imaging or physical examination. Before the treatment all patients receive 4 fiducial 
markers, placed in the prostate, and 4 days later a planning CT-scan in treatment position, 
without contrast, is made. After delineation by a radiation oncologist, a treatment plan is 
generated in the Monaco treatment planning system. The treatment is delivered on an Elekta 
Linac in 20 daily fractions of 3 Gy using a fixed PTV-margin around the prostate (5mm) and 
the SV (8mm). Before each fraction patients are asked to adhere to “full” bladder instructions. 
Lastly, before each fraction a Cone-Beam CT is made for position verification. 
In this study the standard of care regarding the systematic treatment will be upheld. The local 
treatment, will be delivered on the CyberKnife Linac using a fractionation scheme of 6 weekly 
fractions of 6 Gy each (according to the fractionation scheme that has been used in the 
STAMPEDE trial) [46]. At the start of treatment two groups are defined: with (part of the) SV 
and without the SV in the target volume. For both groups the treatment preparation will be in 
line with the current clinical practice, including the fiducial placement and the full bladder 
instructions before the planning CT-scan and before each treatment. A treatment plan based 
on the planning CT will be generated using margins of 3 mm around the prostate and 5 mm 
around the (basis of the) SV, in the case of SV being part of the target volume. These PTV-
margins are derived from the standard of care protocols in our institution regarding CyberKnife 
treatment, based on the work of Van de Water et al. [48], and ultrahypofractionated treatment 
with curative intent, based on the work of De Muinck Keizer et al. [49]. Before each fraction the 
patient will be aligned to the correct treatment position and receive a non-contrast CT-scan 
using the in-room CT of the CyberKnife.  
At this point the treatment for both groups will start to differ. For the patient group with (part of 
the) SV in the target volume plan adaptation will be applied (see figure 1). Using artificial 
intelligence software the contours of the reference plan will be propagated onto the fraction 
scan after which these contours will be adapted manually where needed by or under 

 
 
 
 
 
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supervision of a radiation oncologist. Based on the CT scan and contours a new treatment 
plan will be generated and approved by the radiation oncologist. Subsequently, quality 
assurance of the new plan will be carried out before the start of treatment.  
The group without any part of the SV in the target volume receives the un-adapted treatment 
plan (see figure 2). After treatment we will simulate an adaptive treatment plan offline with the 
SV in the target to assess intra-fraction target coverage.  
Both groups receive a final CT-scan without contrast directly after treatment in treatment 
position. 
During the course of and after the treatment the patient will be asked to fill out a questionnaires 
regarding the toxicity experienced. 
 
 
Figure 1: Flowchart for patients with (the base of the) SV in the target volume. Blue steps are done once at the 
start of treatment, red steps are repeated every fraction. SV = seminal vesicle; CT = Computed Tomography; Plan 
CT = planning CT-scan; Pre-CT = pre-fraction CT-scan; post CT = Post-fraction CT-scan; QA = quality 
assurance. 
Figure 2: Flowchart for patients without SV in the target volume. Blue steps are done once at the start of 
treatment, red steps are repeated every fraction, green steps are simulated/offline. CT = Computed Tomography; 
Plan CT = planning CT-scan; Pre-CT = pre-fraction CT-scan; Post CT = Post-fraction CT-scan; QA = quality 

 
 
 
 
 
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4. STUDY POPULATION 
4.1 Population (base)  
This study will focus on male patients with recently diagnosed limited metastatic prostate 
cancer, eligible for local treatment at Erasmus MC. The number of patients per year fitting this 
criteria is approximately 100. Estimated inclusion rate is around 50 patients per year.  
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
 
Histologically proven prostate cancer 
 
Limited metastatic disease as confirmed on Bone scintigraphy or on soft-tissue 
imaging: CT-scan or by means of a prostate-specific membrane antigen (PSMA) 
positron emission tomography (PET)-CT scan 
 
Deemed a candidate for local radiotherapy by a multidisciplinary team of medical 
specialists. 
 
Willing to and capable of personally filling out online questionnaire 
 
Signed written informed consent 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
 
Previous pelvic radiotherapy or surgery for prostate cancer (excluding surgery to 
improve urinary function in benign prostate hyperplasia, i.e. trans-urethral resection 
of the prostate or prostatectomy according to Millin or Hryntschak). 
 
According to current clinical protocols, at discretion of the treating physician, patients 
can be excluded in case of, for example, an IPSS score of more than 20 or a prostate 
volume of more than 90ml, expecting an unacceptable rise in toxicity 
 
4.4 Sample size calculation 
A patient’s treatment will be considered a success if at least 5 out of the 6 planned (online or 
offline) fractions have sufficient coverage of the SV as defined in section 8.1.1 below. The 
sample size was calculated for an A'Hern one-stage phase-2 design. The null hypothesis will 
be that the success probability is 90% (any lower probability would not warrant further 
investigation of the new margin recipe). If the true probability of success is 98%, then an exact 
binomial test with a one-sided alpha of 0.05 will have 80% power if the sample size is 61 or 
more patients. If the sample size is 61 patients (counting only evaluable patients), then the test 
will reject the null hypothesis if at least 59 successes are observed among the 61 patients. 
Evaluable in this instance is defined as underwent all 6 fractions with CT-scans before and 
after. 

 
 
 
 
 
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5. TREATMENT OF SUBJECTS 
Not applicable 
 

 
 
 
 
 
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6. INVESTIGATIONAL PRODUCT 
Not applicable 
 

 
 
 
 
 
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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable. 

 
 
 
 
 
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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Feasibility of margin reduction will be measured using the post-fraction CT-scan. The dose of 
the online re-planned treatment plan or the offline simulated treatment plan will be copied, 
based on a fiducial match, to the post-fraction CT-scan after which dose volume histograms 
will be calculated and relevant DVH parameters will be extracted. For every fraction the 
coverage of the SV will be calculated, as well as the dose on the OARs. A coverage of ≥95% 
of the SV volume received 95% of the prescribed dose is accepted, any less will be seen as a 
failure to reduce margins. Patients for whom 95% coverage cannot be achieved in the 
reference plan, further coverage loss below the coverage achieved on the reference plan will 
be seen as a failure. Considering all patients receive 6 fractions of 6 Gy, we will consider 
margin reduction feasible if at most one out of six fractions is considered underdosed on the 
SV. To conclude we consider margin reduction to be feasible when >90% of patients have 
received a successful treatment (i.e. coverage of ≥95% for 5 or 6 out of 6 fractions given). 
8.1.2 Secondary study parameters/endpoints (if applicable) 
To measure the tolerance of the patients for this treatment, multiple questionnaires (see 
appendix 1: EPIC, EORTC-Q and EQ5D) will be given to the patients before treatment starts 
as a baseline. The questionnaire regarding the acute toxicity (EORTC-Q) will then be given in 
the last week of treatment and on month 1 and 3 after the end of treatment. The questionnaires 
regarding the late toxicity (EPIC and EQ5D) will be given on 6, 12, 24 and 36 months after end 
of treatment. These questionnaires will be used, along with information in HiX, to assign toxicity 
scores (according to the RTOG/EORTC system) to each patient during the treatment.  
8.1.3 Other study parameters (if applicable) 
Relevant patient and tumour characteristics will be collected form HiX. Patient characteristics 
include age, start of systematic treatment, ECOG performance status, relevant medical history, 
etc… Tumour characteristics include TNM-stage, imaging data (images and reports), etc…  
 
8.2 Randomisation, blinding and treatment allocation 
Not applicable 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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8.3 Study procedures 
Online re-planning: See chapter 3 for the detailed rundown. The treatment plan aims to achieve 
a target coverage of 95% of the target volume (SV) to receive 95% of the prescribed dose of 
36Gy (34.2Gy). The prescribed dose will be given on the 90% isodoseline, thereby accepting 
a maximum dose of 40Gy. The OAR constraints used during the planning and re-planning 
process are in adherence to current clinical standards in our institute as well as the constraints 
used in the PACE-trial, albeit converted to a 6 fraction-schedule using the linear-quadratic 
model. These converted constraints will undergo extensive validation during upcoming 
Dummy-runs to check whether it is feasible to obtain clinically acceptable plans, also in the 
case of quite extreme daily anatomical differences in especially bladder- and/or rectal filling. 
CT-scans: Before and after each fraction a CT-scan without contrast will be made using the 
in-room CT-scan of our institution’s CyberKnife Linac system. This differs from the standard of 
care in which 1 cone beam CT is made before each fraction.  
Questionnaires: All questionnaires will be distributed though the Gemstracker application, 
which is coordinated by the Outcome Unit. The patient will receive emails to notify the patient 
that he is asked to fill out an online questionnaire on the moments mentioned in 8.1.2. 
Toxicity scores: Acute toxicity scores (according the RTOG system) will be assigned, based 
on the acute questionnaires and information in Hix. For this purpose, an acute toxicity form will 
be implemented in Castor. Late toxicity scoring according CTCAE will be included in standard 
clinical care and extracted from the Gemstracker system for the study patients for research 
purposes. Late toxicity scoring according RTOG/EORTC will be done retrospectively (in 
Castor), based on the assigned CTCAE scores, questionnaires, and information in Hix. 
Informed consent: Patients participating in this study are asked to sign informed consent before 
being included in the study population. All patients have received detailed information about 
this study beforehand through a patient information form (PIF) as well as verbal information. 
The investigators of this study are at all times willing to answer any remaining questions of the 
patients. The patient can withdraw consent at any time. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
Not applicable 
 
8.5 Replacement of individual subjects after withdrawal 
Any subject that withdraws form the study will be replaced as to make sure the calculated 
number of evaluable patients is met. 
 

 
 
 
 
 
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8.6 Follow-up of subjects withdrawn from treatment 
No further follow-up within the scope of this study will be conducted. 
 
8.7    Premature termination of the study 
When the treatment of three patients with SV involvement is unsuccessful, the hypothesis 
cannot be rejected and therefore the study will be put on hold. The data up to that point will be 
analysed to determine whether an increase of the PTV-margin around the SV, e.g. from 5 mm 
to 6 mm, would lead to successful treatments. If this does not prove a solution, this study will 
be terminated prematurely. 
 

 
 
 
 
 
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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or safety.  
The sponsor will notify the accredited METC without undue delay of a temporary halt including 
the reason for such an action. The study will be suspended pending a further positive decision 
by the accredited METC. The investigator will take care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the  study procedures. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
The investigator will report only SAEs that are related to the study procedures to the sponsor 
without undue delay after obtaining knowledge of the events.  
The sponsor will report the SAEs related to study procedures through the web portal 
ToetsingOnline to the accredited METC that approved the protocol, within 7 days of first 
knowledge for SAEs that result in death or are life threatening followed by a period of maximum 
of 8 days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious adverse 
events. 

 
 
 
 
 
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9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable. 
 
9.3 Annual safety report 
 
Not applicable. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol.  
 
9.5 Data Safety Monitoring Board (DSMB) 
For this study a DSMB will not be installed. 
 

 
 
 
 
 
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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter(s) 
The primary endpoint will be, as discussed in Chapter 8.1, the percentage of patients with 
successful treatments, which will be analysed with an exact one-sided test with significance 
level alpha of 0.05. If the null hypothesis of 90% can be rejected, the treatment will be 
considered feasible. This data will be collected using the DVH parameters obtained after 
copying the adapted treatment plan onto the post-fraction CT-scan and adapting the contours 
to the anatomy. Patients with missing CT-scans or treatments will not be evaluable and will 
therefore be removed from the analysis of the primary endpoint and replaced (see Chapter 8).  
 
10.2 Secondary study parameter(s)  
The assessment of tolerance will be done using questionnaires and information in HiX to 
determine toxicity scores (according to RTOG/EORTC) per patient on different time points. 
The evolution of toxicity scores through time will be visually represented using a graph and 
depending on the distribution of the data, a student’s t-test or a Wilcoxon signed-ranked test 
will be used to determine statistical significance between time points. Patients with missing 
data at a time point will be removed from the analysis of that particular time point. 
 
10.3 Other study parameters 
Data collection will be done in the electronic patient dossier in HiX. From here all the relevant 
patient and tumour characteristics are gathered and entered in Castor EDC, in co-operation 
with the outcome unit. These will be summarized in the form of a table, using means of medians 
where necessary. 
 
10.4 Interim analysis (if applicable) 
Not applicable 

 
 
 
 
 
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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (World 
Medical Association, 2013) and in accordance with the Medical Research Involving Human 
Subjects Act (WMO) and appropriate other guidelines, regulations and Acts. 
 
11.2 Recruitment and consent 
All newly referred prostate cancer patients will be assessed for study eligibility at their first 
outpatient clinic in Erasmus MC, and eligible patients will be asked to participate by their 
treating radiation oncologist. Patients will be given one week consideration time. After all 
questions of the patient are answered satisfactorily by their treating physician, patients will be 
asked to sign the informed consent form. After obtaining written informed consent, a unique 
study subject ID number will be assigned by the Datacenter. This unique identifier will be used 
on the patient questionnaires and in the study database. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable. 
 
11.4 Benefits and risks assessment, group relatedness 
The benefits of participation are twofold. The number of hospital visits decreases significantly 
from 20 to 6, which should improve patient convenience and hospital logistics. Secondly, the 
reduction of the PTV-margin from 5 to 3 mm, around the prostate and, for the patient group 
with (the base of the) SV in the target volume, from 8 to 5 mm around the SV is expected to 
reduce toxicity rates [47]. Additional burdens for all the patients will be the 6 questionnaires 
they are asked to fill out. Another burden for the patients, will be the longer on-couch time for 
each treatment. For the group without SV involvement an on-couch time of 45 min is expected, 
for the group with involvement the on-couch time is expected to be 60-70 min. 
The risks associated with participation are twofold. As mentioned in Chapter 8.3, each patient 
will receive 1 planning CT-scan, 6 pre- and 6 post-fraction CT-scans (total radiation dose of 
311 mGy) instead of 1 planning CT-scan and 20 Cone-beam CT-scans (total radiation dose of 
136 mGy). In this study the patients will receive a small amount of extra radiation dose from 
the imaging required: 175 mGy. See “details on radiation exposure”, enclosed in this 
submission, for more information on the radiation exposure. Secondly, there is a risk of 
underdosing the SV for the patients which have SV involvement. However, the effect 

 
 
 
 
 
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underdosing has on the overall efficacy of the treatment is likely negligible, considering the SV 
were not included in the target volumes in the STAMPEDE trial.    
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the 
WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 years 
after the end of the study. 
 
11.6 Incentives (if applicable) 
Not applicable 
 

 
 
 
 
 
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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
After checking eligibility criteria and availability of written informed consent, candidate patients 
may be enrolled in the study after registration at the Datacenter. Each patient will receive a 
unique study subject ID number from the Datacenter after inclusion in the trial. This unique 
study subject ID number will be used as identifier for clinical data, lab samples and tissue 
samples. 
 
In this study clinical data will be collected from the electronic patient dossier HiX to Castor 
EDC. Computer generated data will be merged with other study data by adding the unique 
study subject ID number to these datasets, and after validation of the completeness and 
correctness by the investigator, and secured against accidental loss or changes after merging. 
All data will be processed according to the General Data Protection Regulation (“Algemene 
Verordening Gegevensbescherming”) and the General Data Protection Regulation 
Implementation Act (“Uitvoeringswet Algemene Verordening Gegevensbescherming”). 
 
Essential Documents are those documents that permit evaluation of the conduct of a trial and 
the quality of the data produced. The essential documents may be subject to, and should be 
available for, audit and inspection by the regulatory authority. The Sponsor will file all essential 
documents relevant to the overall conduct of the trial. Essential documents should be filed in 
such a manner that they are protected from accidental loss and that they can be easily 
retrieved for review. 
 
Essential documents will be retained for 15 years after the end of the study. Source documents 
(i.e. medical records) of patients should be retained for at least 15 years after the end of the 
study.   
 
12.2 Monitoring and Quality Assurance  
Based on the guideline by the NFU (Dutch Federation of University Medical Centers) about 
quality insurance in human research (“Kwaliteitsborging van mensgebonden onderzoek”) we 
qualify the risk of this study as “low”.  
 
The independent Monitoring Team assigned by the Sponsor will perform on-site monitoring 
visits to verify that the rights and well-being of patients are protected, the reported trial data 
are accurate, complete, and verifiable from source documents and the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with GCP, and with the 
applicable regulatory requirement(s). Monitoring visits will take place according to the study 
specific monitoring plan. On-site monitoring includes checking the informed consent 
procedure, and the verification of completeness of the Trial Master File, conform the study 
specific monitoring plan. Minor and major findings of the monitor will be discussed with the 
investigator, and documented in a standard monitoring report that will be provided to the 

 
 
 
 
 
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Sponsor. The Sponsor may decide to increase the monitoring frequency or intensity if the 
results of monitoring require this to ensure patient safety and/or data quality.  
 
All clinical data that will be collected in the e-CRF will be checked by the principal investigator 
before they are marked as final. 
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a period 
of 8 weeks. The end of the study is defined as the last patient’s last visit.  
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC. 
 

 
 
 
 
 
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12.6 Public disclosure and publication policy 
Erasmus MC Research Code “guidelines on publishing and authorship” will be applicable. The 
main results of the trial will be presented in international meetings and medical journals by the 
principal investigator. Before that moment, the results will be presented to the co-investigators 
who will have the rights to make their comments. Those who have contributed to the 
development of the protocol and the conduct of the study can be considered also as co-
authors. 
 

 
 
 
 
 
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13. STRUCTURED RISK ANALYSIS  
 
13.1 Potential issues of concern 
Not applicable. 
 
 
13.2 Synthesis 
Based on the guideline by the NFU (Dutch Federation of University Medical Centres) about 
quality insurance in human research (“Kwaliteitsborging van mensgebonden onderzoek”) we 
qualify the risk of this study as ‘low’, meaning it has a small chance of serious damage.  
 
 

 
 
 
 
 
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14. REFERENCES 
1. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, et al. Global cancer 
observatory: cancer today. Lyon, France: International Agency for Research on Cancer. 
2018. 
2. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, et al. EAU-
ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local 
Treatment with Curative Intent. Eur Urol. 2017;71(4):618-29. 
3. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. 
Int J Radiat Oncol Biol Phys. 1999;43(5):1095-101. 
4. Fowler JF. The radiobiology of prostate cancer including new aspects of fractionated 
radiotherapy. Acta Oncologica. 2005;44(3):265-76. 
5. Mangoni M, Desideri I, Detti B, Bonomo P, Greto D, Paiar F, et al. Hypofractionation in 
prostate cancer: radiobiological basis and clinical appliance. BioMed research international. 
2014;2014. 
6. Incrocci L, Wortel RC, Alemayehu WG, Aluwini S, Schimmel E, Krol S, et al. 
Hypofractionated versus conventionally fractionated radiotherapy for patients with localised 
prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, 
phase 3 trial. Lancet Oncol. 2016;17(8):1061-9. 
7. Dearnaley D, Syndikus I, Mossop H, Khoo V, Birtle A, Bloomfield D, et al. Conventional 
versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-
year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 
2016;17(8):1047-60. 
8. Widmark A, Gunnlaugsson A, Beckman L, Thellenberg-Karlsson C, Hoyer M, Lagerlund 
M, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate 
cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. 
Lancet. 2019;394(10196):385-95. 
9. De Vries KC, Wortel RC, Oomen-de Hoop E, Heemsbergen WD, Pos FJ, Incrocci L. 
Hyprofractionated Versus Conventionally Fractionated Radiation Therapy for Patients with 
Intermediate- or High-Risk, Localized, Prostate Cancer: 7-Year Outcomes From the 
Randomized, Multicenter, Open-Label, Phase 3 HYPRO Trial. International Journal of 
Radiation Oncology*Biology*Physics. 2020;106(1):108-15. 
10. 
Arcangeli G, Saracino B, Arcangeli S, Gomellini S, Petrongari MG, 
Sanguineti G, et al. Moderate Hypofractionation in High-Risk, Organ-Confined Prostate 
Cancer: Final Results of a Phase III Randomized Trial. J Clin Oncol. 2017;35(17):1891-7. 
11. 
Bayman NA, Wylie JP. When should the seminal vesicles be included in 
the target volume in prostate radiotherapy? Clin Oncol (R Coll Radiol). 2007;19(5):302-7. 
12. 
McKay AC, Odeluga N, Jiang J, Sharma S. Anatomy, abdomen and pelvis, 
seminal vesicle. StatPearls [Internet]. 2020. 
13. 
Van Der Burgt M, Bergsma L, De Vries J, Pos FJ, Kalisvaart R, 
Heemsbergen W, et al. Impact of tumour invasion on seminal vesicles mobility in 
radiotherapy of prostate cancer. Radiother Oncol. 2015;117(2):283-7. 
14. 
Hollander A, Both S, Vapiwala N, Kirk M, Christodouleas J, Bekelman J, et 
al. Interfraction motion of the full seminal vesicles in prostate radiation therapy using a daily 
endorectal balloon. Int J Radiat Oncol Biol Phys. 2012;84(3):S388. 
15. 
Smitsmans MHP, De Bois J, Sonke JJ, Catton CN, Jaffray DA, Lebesque 
JV, et al. Residual seminal vesicle displacement in marker-based image-guided radiotherapy 
for prostate cancer and the impact on margin design. Int J Radiat Oncol Biol Phys. 
2011;80(2):590-6. 
16. 
Oksuz DC, Dincbas FO, Ergen SA, Iktueren B, Bakir A, Koca S. Seminal 
vesicle interfraction displacement and dose variations throughout the CBCT-guided radiation 
therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014;90(1):S429-S30. 
17. 
Mak D, Gill S, Paul R, Stillie A, Haworth A, Kron T, et al. Seminal vesicle 
interfraction displacement and margins in image guided radiotherapy for prostate cancer. 
Radiat Oncol. 2012;7(1). 
18. 
Chin S, McWilliam A, Brand D, Barton S, Song YP, Van Herk M, et al. Does 
the use of an endorectal balloon improve seminal vesicle stability for prostate radiotherapy? 
Radiother Oncol. 2019;133:S1107. 

 
 
 
 
 
UPRATE 
 
23-12-2021 
 
30 of 32 
19. 
Kershaw L, van Zadelhoff L, Heemsbergen W, Pos F, van Herk M. Image 
Guided Radiation Therapy Strategies for Pelvic Lymph Node Irradiation in High-Risk Prostate 
Cancer: Motion and Margins. Int J Radiat Oncol Biol Phys. 2018;100(1):68-77. 
20. 
Li T, Sheng Y, Lee W, Wu Q. Sbrt for prostate + seminal vesicles: Fixed 
margin or online adaptation. Int J Radiat Oncol Biol Phys. 2014;90(1):S18. 
21. 
Liang J, Wu Q, Yan D. The Role of Seminal Vesicle Motion in Target 
Margin Assessment for Online Image-Guided Radiotherapy for Prostate Cancer. Int J Radiat 
Oncol Biol Phys. 2009;73(3):935-43. 
22. 
Sheng Y, Li T, Lee WR, Yin FF, Wu QJ. Exploring the Margin Recipe for 
Online Adaptive Radiation Therapy for Intermediate-Risk Prostate Cancer: An Intrafractional 
Seminal Vesicles Motion Analysis. Int J Radiat Oncol Biol Phys. 2017;98(2):473-80. 
23. 
Mercuri AL, Joon DL, Khoo V, Rolfo A, Daly K, McNamara J, et al. The 
impact of prostate and seminal vesicle motion during prostate cancer radiotherapy on 
planning margins. International Journal of Radiation Oncology Biology Physics. 
2008;72(1):S312-S. 
24. 
Van Herk M. Errors and margins in radiotherapy. Seminars in Radiation 
Oncology. 2004;14(1):52-64. 
25. 
Meijer GJ, de Klerk J, Bzdusek K, van den Berg HA, Janssen R, Kaus MR, 
et al. What CTV-to-PTV Margins Should Be Applied for Prostate Irradiation? Four-
Dimensional Quantitative Assessment Using Model-Based Deformable Image Registration 
Techniques. Int J Radiat Oncol Biol Phys. 2008;72(5):1416-25. 
26. 
Mutanga TF, Boer HCJd, Wielen GJvd. Margin evaluation in the presence 
of deformation, rotation, and translation in prostate and entire seminal vesicle irradiation with 
daily marker-based setup …: Elsevier; 2011. 
27. 
Stenmark MH, Vineberg K, Ten Haken RK, Hamstra DA, Feng M. 
Dosimetric implications of residual seminal vesicle motion in fiducial-guided intensity-
modulated radiotherapy for prostate cancer. Med Dosim. 2012;37(3):240-4. 
28. 
Thörnqvist S, Hysing LB, Zolnay AG, Söhn M, Hoogeman MS, Muren LP, 
et al. Treatment simulations with a statistical deformable motion model to evaluate margins 
for multiple targets in radiotherapy for high-risk prostate cancer. Radiother Oncol. 
2013;109(3):344-9. 
29. 
Gill SK, Reddy K, Campbell N, Chen C, Pearson D. Determination of 
optimal PTV margin for patients receiving CBCT-guided prostate IMRT: comparative analysis 
based on CBCT dose calculation with four different margins. J Appl Clin Med Phys. 
2015;16(6):252–62. 
30. 
Utsunomiya S, Yamamoto J, Tanabe S, Oishi M, Satsuma A, Kaidu M, et 
al. Complementary Relation Between the Improvement of Dose Delivery Technique and PTV 
Margin Reduction in Dose-Escalated Radiation Therapy for Prostate Cancer. Practical 
Radiation Oncology. 2019;9(3):172-8. 
31. 
Yan D, Vicini F, Wong J, Martinez A. Adaptive radiation therapy. Physics in 
Medicine and Biology. 1997;42(1):123-32. 
32. 
Ghilezan M, Yan D, Martinez A. Adaptive radiation therapy for prostate 
cancer: Elsevier; 2010. 
33. 
Lei Y, Wu Q. A hybrid strategy of offline adaptive planning and online 
image guidance for prostate cancer radiotherapy. Phys Med Biol. 2010;55(8):2221-34. 
34. 
Wu QJ, Thongphiew D, Wang Z, Mathayomchan B, Chankong V, Yoo S, et 
al. On-line re-optimization of prostate IMRT plans for adaptive radiation therapy. Phys Med 
Biol. 2008;53(3):673-91. 
35. 
Li T, Thongphiew D, Zhu X, Lee WR, Vujaskovic Z, Yin F-F, et al. Adaptive 
prostate IGRT combining online re-optimization and re-positioning: a feasibility study. 
Physics in Medicine & Biology. 2011;56(5):1243. 
36. 
Qin A, Sun Y, Liang J, Yan D. Evaluation of online/offline image 
guidance/adaptation approaches for prostate cancer radiation therapy. Int J Radiat Oncol 
Biol Phys. 2015;91(5):1026-33. 
37. 
Stanley K, Eade T, Kneebone A, Booth JT. Investigation of an adaptive 
treatment regime for prostate radiation therapy. Practical Radiation Oncology. 2015;5(1):e23-
e9. 

 
 
 
 
 
UPRATE 
 
23-12-2021 
 
31 of 32 
38. 
Li X, Quan EM, Li Y, Pan X, Zhou Y, Wang X, et al. A fully automated 
method for CT-on-rails-guided online adaptive planning for prostate cancer intensity 
modulated radiation therapy. International Journal of Radiation Oncology* Biology* Physics. 
2013;86(5):835-41. 
39. 
Tetar SU, Bruynzeel AME, Lagerwaard FJ, Slotman BJ, Bohoudi O, 
Palacios MA. Clinical implementation of magnetic resonance imaging guided adaptive 
radiotherapy for localized prostate cancer. Physics and Imaging in Radiation Oncology. 
2019;9:69-76. 
40. 
Kontaxis C, Bol GH, Kerkmeijer LGW, Lagendijk JJW, Raaymakers BW. 
Fast online replanning for interfraction rotation correction in prostate radiotherapy. Med Phys. 
2017;44(10):5034-42. 
41. 
Tong X, Chen X, Li J, Xu Q, Lin MH, Chen L, et al. Intrafractional prostate 
motion during external beam radiotherapy monitored by a real-time target localization 
system. J Appl Clin Med Phys. 2015;16(2):5013. 
42. 
King CR, Lehmann J, Adler JR, Hai J. CyberKnife radiotherapy for localized 
prostate cancer: rationale and technical feasibility. Technology in cancer research & 
treatment. 2003;2(1):25-9. 
43. 
Antico M, Prinsen P, Cellini F, Fracassi A, Isola AA, Cobben D, et al. Real-
time adaptive planning method for radiotherapy treatment delivery for prostate cancer 
patients, based on a library of plans accounting for possible anatomy configuration changes. 
PLoS ONE. 2019;14(2). 
44. 
Alongi F, Rigo M, Figlia V, Cuccia F, Giaj-Levra N, Nicosia L, et al. 1.5 T 
MR-guided and daily adapted SBRT for prostate cancer: feasibility, preliminary clinical 
tolerability, quality of life and patient-reported outcomes during treatment. Radiation 
Oncology. 2020;15(1):69. 
45. 
Telkhade T, Murthy V, Kanala TS, Mathew JM, Phurailatpam R, Mokal S, et 
al. Safety and Efficacy of Ultra-hypofractionation in Node-positive Prostate Cancer. Clin 
Oncol (R Coll Radiol). 2021;33(3):172-80. 
46. 
Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, et al. 
Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer 
(STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-66. 
47. 
Sveistrup J, af Rosenschöld PM, Deasy JO, Oh JH, Pommer T, Petersen 
PM, et al. Improvement in toxicity in high risk prostate cancer patients treated with image-
guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without 
daily image guidance. Radiation Oncology. 2014;9(1):44. 
48. 
van de Water S, Valli L, Aluwini S, Lanconelli N, Heijmen B, Hoogeman M. 
Intrafraction Prostate Translations and Rotations During Hypofractionated Robotic Radiation 
Surgery: Dosimetric Impact of Correction Strategies and Margins. International Journal of 
Radiation Oncology*Biology*Physics. 2014;88(5):1154-60. 
49. 
Muinck Keizer DM, Willigenburg T, der Voort van Zyp JRN, Raaymakers 
BW, Lagendijk JJW, Boer JCJ. Seminal vesicle intrafraction motion during the delivery of 
radiotherapy sessions on a 1.5 T MR-Linac. Radiotherapy and Oncology. 2021;162:162-9. 
 

 
 
 
 
 
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Appendix A: Acute RTOG scoring 
 
CTCAE version 5.0,  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quic
k_reference_5x7.pdf 
 
Items 
 
Gastrointestinal (GI) 
Genitourinary (GU) 
Diarrhea 
Cystitis (non-infectious) 
Fecal incontinence 
Urinary frequency 
Proctitis 
Urinary incontinence 
Gastrointestinal pain 
Urinary urgency 
Rectal Hemorrhage 
Urinary tract obstruction 
Rectal Mucositis 
Dysuria 
 
Hematuria 
 
Acute RTOG 
 
Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group 
(RTOG) and the European Organization for Research and Treatment of Cancer 
(EORTC). Int J Radiat Oncol Biol Phys. 1995 Mar 30;31(5):1341-6. And slightly modified 
according to Peeters et al. Int J Radiat Oncol Biol Phys. 2005 Mar 15;61(4):1019-34.