Palliative Radiotherapy to Dominant Symptomatic Lesion in Patients With Hormone Refractory Prostate Cancer
Phase: NA
Conditions: Hormone-refractory Prostate Cancer
Sponsor: Zealand University Hospital

PRADO V04_01.02.2018 
 
 
Palliative radiotherapy to dominant symptomatic lesion 
in patients with hormone refractory prostate cancer 
 
PRADO 
An international multicenter prospective feasibility study 
Sponsor:  
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
 
Primary Investigators:  
Jesper Carl, Phd 
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
 
Confidential: This protocol contains confidential information, which may not be communicated to 
third parties without permission of the coordinating investigator 
 

PRADO V04_01.02.2018 
 
Table of Content: 
1 
General information ............................................................................................................................. 4 
2 
Synopsis ............................................................................................................................................... 5 
3 
Background and rationale .................................................................................................................... 7 
4 
Objective ............................................................................................................................................. 8 
5 
Study design and participating centers ................................................................................................. 8 
6 
Inclusion and exclusion criteria ............................................................................................................ 9 
7 
Risks and toxicities ............................................................................................................................... 9 
8 
Registration ......................................................................................................................................... 9 
9 
Systemic therapy.................................................................................................................................10 
10 
Radiation therapy ............................................................................................................................10 
10.1 
General remarks ..........................................................................................................................10 
10.2 
Treatment planning .....................................................................................................................10 
10.3 
Target volumes ............................................................................................................................11 
10.4 
Dose specification .......................................................................................................................11 
10.5 
Organs at risk ..............................................................................................................................11 
10.6 
Start of radiotherapy ...................................................................................................................12 
11 
Trial Procedures and Assessment ....................................................................................................12 
11.1 
Specific diagnostic procedures .....................................................................................................12 
11.2 
Baseline examination ..................................................................................................................12 
11.3 
End of radiotherapy .....................................................................................................................13 
11.4 
Follow-up visits............................................................................................................................13 
11.5 
Follow-up diagnostics ..................................................................................................................13 
12 
Safety management ........................................................................................................................14 
12.1 
Adverse events ............................................................................................................................14 
13 
Data and Safety Monitoring Board ..................................................................................................14 
14 
Endpoint Adjudication Committee...................................................................................................15 
15 
Quality Assurance ...........................................................................................................................15 
16 
Statistical aspects ............................................................................................................................15 
16.1 
Case number ...............................................................................................................................15 
16.2 
Recruitment period and study duration .......................................................................................15 
16.3 
Analysis .......................................................................................................................................15 
17 
Early termination ............................................................................................................................16 

PRADO V04_01.02.2018 
 
17.1 
Early termination and close of recruitment ..................................................................................16 
17.2 
Study termination in individual patients ......................................................................................16 
18 
Ethical and legal aspects ..................................................................................................................16 
19 
Appendix 1 – Calculation of median survival ....................................................................................17 
20 
Appendix 2 – Diagnostic MR Protocol sequences .............................................................................18 
21 
Appendix 3 - Target outline procedure ............................................................................................19 
22 
Appendix 4 – Flowchart for the study ..............................................................................................20 
23 
References: .....................................................................................................................................21 
 
 
 

PRADO V04_01.02.2018 
 
 
1 General information 
Sponsor: 
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
Rådmandsengen 5, DK-4700 Næstved 
Primary Investigator 
Jesper Carl, PhD 
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
Rådmandsengen 5, DK-4700 Næstved 
Phone: +45 56 51 39 12 
E-mail: jhac@regionsjaelland.dk 
Coordinating Investigator Denmark 
Redas Trepiakas. MD 
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
Rådmandsengen 5, DK-4700 Næstved 
Phone: +45  56 51 3231 
E-mail: rtr@regionsjaelland.dk 
Coordinating Investigator in Germany 
Prof. Dr. Juergen Dunst 
Christian-Albrechts-University Kiel/  
University Hospital Schleswig-Holstein, Campus Kiel 
Department of Radiation Oncology 
Arnold-Heller-Str. 3, 24105 Kiel 
Phone: + 49 (0) 431 500-26500 
E-Mail: juergen.dunst@uksh.de 
Co-Investigator in Lubeck, Germany 
Prof. Dr. Dirk Rades 
Department of Radiation Oncology, University of Lübeck &  
Department of Radiation Oncology, University Hospital Schleswig-Holstein 
Ratzeburger Allee 160, 23538 Lübeck, Germany 
Tel.: +49 (0)451-500-45400 
Email: dirk.rades@uksh.de 
Clinical Study Center  
KFE 
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
Rådmandsengen 5, DK-4700 Næstved 
Phone:  
E-mail:  
 
 
 
 

PRADO V04_01.02.2018 
 
2 Synopsis 
  
Study title 
Palliative radiotherapy to dominant symptomatic lesion 
Short title 
PRADO 
Study type 
Multicenter feasibility study 
Patient cohort 
Patients with hormone refractory prostate cancer (HRPC) presenting a 
dominant symptomatic lesions 
Sponsor 
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
Primary Investigator 
Jesper Carl, Phd 
Sjællands Universitetshospital Næstved 
Klinisk Onkologisk Afdeling og Palliative Enheder 
Objective 
Feasibility and Safety of local hypo-fractionated radiotherapy of MR 
outlined lesion for the patient’s dominant symptom. 
Inclusion criteria 
(all criteria must be fulfilled) 
 
Patients with hormone refractory biopsy proven prostate cancer 
 
Presenting with a dominating debilitating symptom 
 
Expected median survival of 3 – 12 months 
 
Focal irradiation of lesion is feasible 
 
Systemic therapy according to guidelines   
 
age ≥18 years 
 
Legal capacity, patient is able to understand the nature, 
significance and consequences of the trial 
 
Written informed consent 
Exclusion criteria 
(recruitment is not possible if any -at 
least one- criterion is met) 
 Relevant comorbidity (with limitations to administer radiotherapy 
according to protocol)  
 Prior radiotherapy which results in limitations to administer 
radiotherapy according to protocol 
 No large metal implants in vicinity of lesion 
 Department dose constraints for normal tissue can’t be met 
 Large bony lesions with extensive osseous destruction 
 Patients symptoms do not correlate with MR findings 
Study therapy 
 
Image guided radiotherapy (IGRT) with hypo-fractionated 
simultaneous integrated boost (IMRT) 
 
GTV1 = MR T2w lesion and ADC <= 1200 * 10-3 mm^2/s 
 
GTV2 = MR T2w lesion and ADC <= median ADC in GTV1 
 
Each lesion is a CTV, CTV = GTV 
 
PTV=CTV+ margin according to department standards 
 
Dose-fractionation 
 
CTV1: 4 x 5 Gy 
 
CTV2: 4 x 7 Gy  
Primary endpoint 
Feasibility: Proportion of study participants that complete 
radiotherapy with ≥ 90% of prescribed dose 
Secondary endpoints 
 Dominant symptom (VAS) 
 Progression-free survival >6 months 
 Overall survival 

PRADO V04_01.02.2018 
 
 Acute toxicity 
 Quality of life 
 Change in ADC from before to end of treatment 
 Change in ADC from before to 6 month post treatment 
Sample size 
34 patients has to be included in the study 
Study sites 
University Hospital Sjaelland, Naestved 
UKSH Campus Kiel 
UKSH Campus Luebeck 
Time table 
Recruitment period: 12 months 
Start of study: March 2018 
End of study: March 2019 
Follow-up: minimum ≥ 6 months  
Financing 
Interreg (InnoCan) 
 
 
 
 

PRADO V04_01.02.2018 
 
3 Background and rationale 
Prostate cancer is the major cause of cancer death in men living in developed countries. Large autopsy 
studies found that patients that presented prostate cancer demonstrated metastatic disease in 35% of 
cases. Prostate cancer metastases were 90% bone metastases, with 90% of the bone metastases involved 
the spinal cord, followed by lung (46%), liver (25%) and pleura (21%). Another important pathway is the 
lymphatic system, which is involved in 9 to 16% of cases, especially at the level of obturator, pre-sacral, 
internal, and common iliac arteries, and sometimes even the extra-regional para-aortic chains (1). 
Metastatic or locally advanced prostate cancer (PC) responds well initially to hormonal manipulation by 
androgen withdrawal and peripheral androgen blockade. However, such patients have high risk of 
progression to a hormone-refractory prostate cancer (HRPC). Once the tumor has achieved a castration-
refractory metastatic stage, treatment options are limited and the average survival of patients ranging from 
two to three years only (2). Furthermore, HRPC patients will typically be frail old men.  
Skeletal metastases account for most of the morbidity in surviving HRPC patients, but patients may also 
present with dominating disabling symptoms from local pelvic disease progression with an incidence 
estimated to be about 10%-18% (3, 4), or even higher in node-positive patients treated with anti-androgen 
therapy alone (5).  
In patients with a reasonable expected median survival (6), pelvic radiotherapy (RT) may provide an 
effective palliation. Studies have demonstrated, radiotherapy contributes to relief of hematuria, pain and 
other pelvic symptoms, with acceptable toxicity in the majority of patients with HRPC (7-9).  
A recent systematic literature search demonstrated good overall symptom response rates despite large 
variations in radiotherapy dose and fractionation (10), which consequently warrants new prospective 
studies in this field. 
Radiotherapy, dependent on radiation dose-volume, however may lead to increase in radiation-induced 
toxicities (11). Both GI and GU toxicities do increase with dose and volume of respectively rectum and 
bladder irradiated (12) (13) (14). Technological advancements in radiotherapy such as image-guided 
radiotherapy (GRT), intensity modulated radiotherapy (IMRT / VMAT), stereotactic body radiation therapy 
(SBRT) or stereotactic radiosurgery (SRS) have allowed for significant treatment volume reduction, less 
normal tissue toxicity and whole-organ dose escalation. A recent review list several retrospective studies 
showing the effectiveness of SBRT and SRS in prostate cancer metastases (15) 
Even further improvement may obtained using more accurate imaging diagnostics for treatment planning, 
such as advanced MRI (16, 17). Using diffusion weighted imaging (DWI) quantitative measures such as the 
apparent diffusion coefficient (ADC) has been shown to be the most important imaging modality for 
predicting tumor location (18) (19) and local tumor recurrence larger than 0.4 ml (20).  

PRADO V04_01.02.2018 
 
The aim of the present study will be to conduct a feasibility study of a new short palliative radiotherapy 
regime that apply to patients with metastatic HRPC patients presenting with a dominating debilitating 
symptom and an expected reasonable survival. The dominant symptom can be such as pain, urinary 
retention, chronic rectal obstruction, bleeding etc., caused by localized progression of the patient’s 
metastatic prostate cancer. This new approach will apply magnetic resonance imaging (MRI) to verify 
correspondence between the progressing HRPC lesion (DSL =the dominant symptomatic lesion) and the 
patients corresponding dominant symptom. Diffusion weighted MR imaging (DWI) will apply to identify 
both the lesion and the most aggressive part of the lesion. The symptomatic lesions will be treated using 
precision radiotherapy (IGRT+IMRT/VMAT or SBRT/SRS if available) with a dose of 4 x 5 Gy, while for the 
most aggressive part of the lesion the dose will be escalated to 4 x 7 Gy using a simultaneous integrated 
boost (SIB) technique. 
4 Objective 
This prospective study will evaluate the feasibility as the primary endpoint. Secondary endpoints are visual 
analog score (VAS) of the dominating symptom, symptom progression free survival, evaluation of radiation 
induced acute toxicity, the influence on quality of life, the progression free survival and change in volume 
and ADC statistics from baseline as surrogate marker of local response to radiotherapy. The study will analyze 
patient characteristics, relevant comorbidities and tumor related factors correlation to outcomes. Based on 
the results of this study, a prospective randomized phase II/III dose escalation study may suggested. 
5 Study design and participating centers 
This is an international, multi-center single arm prospective feasibility study. Participating sites are: 
1. University Hospital Sjaelland, Naestved, Department of Oncology 
2. UKSH Campus Kiel, Department of Radiation Oncology 
3. UKSH Campus Luebeck, Department of Radiation Oncology 
  
 
 

PRADO V04_01.02.2018 
 
6 Inclusion and exclusion criteria  
Patients can be included in the study if they fulfill all of the following inclusion criteria and none of the 
following exclusion criteria. 
Inclusion criteria: 
 
Patients with hormone refractory biopsy proven prostate cancer (HRPC) 
 
Presenting with a dominating debilitating symptom 
 
Expected median survival of 3-12 months (6) 
 
Focal irradiation of lesion is feasible 
 
Systemic therapy according to guidelines   
 
age ≥18 years 
 
Legal capacity, patient is able to understand the nature, significance and consequences of the trial 
 
Written informed consent 
Exclusion criteria: 
 
Relevant comorbidity (with limitations to administer radiotherapy according to protocol)  
 
Prior radiotherapy which results in limitations to administer radiotherapy according to protocol 
 
No large metal implants in vicinity of lesion 
 
Department dose constraints for normal tissue can’t be met 
 
Large bony lesions with extensive osseous destruction (e.g. vertebral body) 
 
Patients symptoms do not correlate with MR findings 
7 Risks and toxicities 
Patients participating in this study will have standard radiotherapy. Consequently, the participating patients 
face known risks and toxicities following high dose radiotherapy. Patients participating in this study are 
offered a higher than normal radiation dose to their dominant lesion, but treatment plans will adhere to 
department standard dose constraints for all organs at risk in order to avoid excessive risks and toxicities.  
8 Registration 
The consecutive cohort of HRPC patients will be screened for eligibility according to the inclusion criteria’s in 
this protocol. Estimated median survival for patients to be included should preferably be based on the 
updated model in (6) (see appendix 1).  Before inclusion, patient clinical routine blood lab and radiology 
results should be reviewed. Available clinical routine diagnostic imaging and lab results may be used to 
calculate the expected median survival for patients using the model in (6) (see appendix 1). (6)Eligible 
patients will be informed about the study. After given informed consent, patients may be included in the 

PRADO V04_01.02.2018 
 
study. All patients included in the study receive a patient identification number (PID). The PID is composed 
of the site number and the running patient number (starting with P01, P02,.. ect.).  
Site 
SiteID 
Naestved, Denmark 
C1 
Kiel, Germany 
C2 
Lübeck, Germany 
C3 
 
For pseudonymous registration and recording of all protocol data, the department of oncology, Naestved, 
will be make an electronic web interface (Easytrial) available for participating sites.  
9 Systemic therapy 
Systemic therapy will be administered according to department standard guidelines. Systemic therapy may 
be chemotherapy, anti-hormonal therapy, targeted therapies, bisphosphonates or a combination. The type 
of therapy will be documented. Interruptions of systemic therapy, delays or changes of drugs due to 
radiotherapy should be avoided.  
10 Radiation therapy 
10.1 General remarks 
The primary endpoint is feasibility. The secondary endpoints are duration of relief from local symptoms, i.e. 
local symptom progression free survival (LPFS),  overall survival, treatment toxicity (RTOG/CTCAE 4.0), 
Quality of life (EORTC-QLQ-C30 and EPIC26), and change in ADC as surrogate marker of response (21-25). 
Patients are scheduled for protocol specific follow-up visits at 1, 3, 6 months after end of radiotherapy. 
Additional MRI (T2w and DWI) will be performed at 1 and 6 months after end of radiotherapy or in case of 
progression of the dominant symptom. 
Preferred technique is hypo-fractionated with high precision radiotherapy (radiosurgery or stereotactic 
radiotherapy) with few (1 to 5) fractions and ablative total dose. Daily IGRT is mandatory for hypo-
fractionated regimens. For the treatment of thoracic lesions and metastases in the upper abdomen, 
techniques for motion compensation (e.g. breath-hold- or gating techniques) should be used, if available. In 
specific situations (e.g. spinal metastases with involvement of the spinal canal or cord compression or 
metastases with infiltration of hollow organs), however, lower doses of radiotherapy may be necessary for 
adherence of dose constraints or to avoid radiation-induced complications such as perforation. In these 
cases, moderately hypo-fractionated or even conventionally fractionated regimens should be used. The total 
dose should exceed at least a dose equivalent to 50Gy in conventional fractionation.  
10.2 Treatment planning 

PRADO V04_01.02.2018 
 
3D planning is mandatory. Type of treatment technique (e.g. 3D-IMRT, VMAT or SBRT) is the decision of the 
radiation oncologist. The reference MR scan (se appendix 2) must be co-registered to the planning CT and 
the target volumes defined on MR transferred to the planning CT for dose planning. 
10.3 Target volumes  
Patients included in the study will be subjected to a protocol-specific MRI examination (see MR sequence 
and example of target delineation in appendix 19-20). A radiologist will read the MRI scan to validate 
correspondence between MR lesion and the patients dominating symptoms. In case of more than one 
lesion, decision on priority of target volumes will be made by the radiation oncologist based on clinical 
expertise. An ADC map will be calculated for the lesion using the DWI sequences. A cutoff ADC value of less 
than 1200 x 10-6 mm2/s in combination with a T2w image will be used to predict the MR lesion (GTV1) (26). 
The most aggressive part of the lesion (GTV2) will be defined using ADC of less than or equal to a cutoff 
value calculated as the median ADC value for the GTV1 (25). Notice that GTV2 need not to be one coherent 
volume, but may consist of several sub-volumes. 
For the definition of target volumes, the following aspects should be considered: The clinical target volume 
(CTV) is the visible macroscopic tumor (GTV). The safety margin for the planning target volume (PTV) should 
be according to the department standard, and depending on the radiation technique used. The margin for 
the PTV2 for CTV2 may be chosen to be smaller than for PTV1 as this volume is enclosed in the CTV1, which 
receives a dose of 4 x 5Gy already.. For the treatment of breathing-dependent lesions (upper abdomen), 
treatment techniques with motion compensation (e.g. breath-hold or gating) should be used. All four 
fractions of the treatment should be given within two weeks of starting the radiotherapy. 
10.4 Dose specification 
The dose will be prescribed as 95%-PTV-coverage. The favorite technique is ablative radiosurgery or hypo-
fractionated stereotactic radiotherapy if available, otherwise VMAT or IMRT is allowed. Recommended 
treatment regime 
Technique 
Dose and fractionation regimens 
Hypo-fractionated regime 
PTV1: 4F x 5Gy, total dose 20Gy 
PTV2: 4F x 7Gy, total dose 28Gy 
 
10.5 Organs at risk 
Organs at risk will be contoured if they are (at least partially) visible on transversal CT-slices on which the PTV 
is contoured or if the distance to PTVs is less 1 cm than cranio-caudal direction. Organs at risk are: 
 
Spinal cord, brain stem 
 
Optic nerves and optic chiasm 

PRADO V04_01.02.2018 
 
 
eyes 
 
parotid glands 
 
lungs 
 
heart 
 
esophagus 
 
liver 
 
kidneys 
 
bladder 
 
rectum 
Dose constraints to OARs can be used according to the institutional standard. Doses to OARs (sum plan of all 
relevant PTVs) will be documented.   
Quality assurance procedures will be performed according to the institutional standard. Each participating 
institution will provide a SOP for quality assurance. 
10.6 Start of radiotherapy 
Radiotherapy should be started within three weeks after inclusion of the patient in the study.  
11 Trial Procedures and Assessment 
11.1 Specific diagnostic procedures 
A complete staging according to current guidelines with adequate imaging is required. . The available data 
should give sufficient information about: 
 
Number of visible metastatic lesions 
 
location of each lesion (e.g. lung metastasis in left lower lobe, osseous metastases in os sacrum) 
 
Size of each lesion 
Additional specific work-up is not required.  
11.2 Baseline examination 
A baseline diagnostic MR examination corresponding to dominant symptom must be performed according 
to trial specifications in appendix 2. The MR images must be co-registered to imaging necessary for 
radiotherapy planning (CT).   
Baseline examination includes:  
 
Review of medical history inclusive previous anti-cancer treatment 
 
Review of clinical routine blood and radiology results 
 
Review of concomitant medication, analgesia, opioids, current systemic anti-cancer treatment  
 
Tumor staging, grading, classification, localizations, sizes 

PRADO V04_01.02.2018 
 
 
Physical examination (incl. height, weight) 
 
ECOG performance status  
 
Baseline dominant symptom (VAS score) 
 
Baseline acute toxicity RTOG/CTCAE v.4.03 scores  
 
Quality of life (EORTC-QLQ C30) 
11.3 End of radiotherapy 
At end of radiotherapy, the following must be documented: 
 
Review of concomitant medication, analgesia, opioids, current systemic anti-cancer treatment 
 
Review of clinical routine blood results and radiology 
 
Dominant symptom score (VAS score) 
 
Acute toxicity (NCI-CTCAE v4.03 score)  
 
Performance status (ECOG) 
 
Assessment of AE/SAEs 
Details of actually applied treatment are to be documented throughout and to be entered into the CRF at the 
end of treatment: 
 
Radiotherapy techniques uses 
 
Volumes, fractions, doses applied, dose constraint compliance for all organs at risk 
 
Cumulative doses to target volumes, any boosts 
11.4 Follow-up visits  
Protocol visits are required at registration for the trial and at end of radiotherapy and at 1,3 and 6 months 
after end of treatment (see flowchart in appendix 3). At this time, the following examination will be 
performed: 
 
Review of concomitant medication, analgesia, opioids, current systemic anti-cancer treatment 
 
Review of clinical routine blood and radiology results 
 
Dominant symptom score (VAS) 
 
Acute toxicities of radiotherapy , RTOG/NCI score 
 
Quality of life (EORTC-QLQ C30) (only at 6 months) 
 
ECOG performance status 
 
Assessment of AE/SAE 
All later visits are scheduled according to standard guidelines and institutional procedures.  
11.5 Follow-up diagnostics 

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Protocol specific follow-up MR diagnostic scan is required for patient visit at one and six months after end of 
radiotherapy or at progression of the dominant symptom. The MR diagnostics should be performed 
according to the specifications in appendix 2. Remission status evaluated at 6 month based on available 
clinical data. Follow-up MR Scans will be co-registered to the baseline MR scan. Comparative volume and 
ADC statistics will be calculated as surrogate markers of response to radiotherapy.  
12  Safety management 
12.1 Adverse events 
An adverse event (AE) is defined as any event experienced by a patient or subject of a clinical trial, which 
does not necessarily have a causal relationship to the study treatment. 
The severity of AEs should be assessed by using the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE version 4.03). If an AE occurs, which is not described in the CTCAE version 4.03, 
the following five-point scale should be used for assessment: grade 1 = mild, grade 2 = moderate, grade 3 = 
severe, grade 4 = life-threatening and grade 5 = fatal. 
The investigator must also systematically assess the causal relationship of the AEs to the trial treatment. The 
AEs should therefore be classified as reasonably related or not reasonably related (unrelated) to trial 
treatment. 
 
All AEs experienced will be documented in the appropriate section of the CRF. 
 
Any clinical AE with severity of grade 4 or 5 must also be reported as an SAE. 
Severe adverse events (SAE)  
A severe adverse event (SAE) is any untoward medical occurrence that meets the following criteria: 
 
Results in death. 
 
Is life-threatening 
 
Requires hospitalization or prolongs an existing hospitalization. 
 
Results in persistent or significant disability  
 
Is a congenital anomaly or birth defect. 
 
Is otherwise considered medically important. 
All SAEs must be documented and reported to the sponsor within 24 hours after awareness of the event 
using the online web interface for Easytrial.  
13 Data and Safety Monitoring Board 
Data will be entered pseudonymously into an online web based electronic database, Easytrial, and data 
stored on servers in Denmark. Access to the web interface is by invitation via email to staff participating in 
the study only. The Data and Safety Monitoring Board (DSMB) reviews safety after the first ten and after the 

PRADO V04_01.02.2018 
 
last patient have been treated and the respective data validated and tabulated. It may recommend 
restrictions to treatment regimens and patient eligibility.  
14 Endpoint Adjudication Committee 
The Endpoint Adjudication Committee (EAC) receives pseudonymized MRI scans and the Radiotherapy 
treatment plan for all patients up to end of trial. The EAC will assess when progression free survival ended. 
15 Quality Assurance 
The Monitoring at the German sites according to GCP is performed by ZKS Kiel/Luebeck. 
The Danish sites will be monitored according to the Danish regulations in their own responsibility. 
16 Statistical aspects 
16.1 Case number 
The objective of this study is to investigate the feasibility of applying hypo-fractionated radiotherapy to treat 
a dominant symptomatic lesion in patients with HRPC. The hypothesis is that at least 90% of the recruited 
patients complete combined systemic and local treatment with at least 90% of scheduled radiation dose 
administered. We use a two-sided one-sample proportion score test to compare the proportion of feasible 
cases to a reference value of 90%. We want to detect any difference with statistical significance of 5% and a 
power of 80% for not overlooking a true proportion non-feasible of 70%. The necessary sample size is 
estimated to 24 cases. Drop-out may happen either due to exclusion, or because patients withdraw their 
consent for participation. For patients with poor prognosis a realistic drop-out rate is estimated to be 30%, 
which implicated that 34 patients must be included in the study to reach significance. 
16.2 Recruitment period and study duration 
The recruitment period is scheduled to start in March 2018 and will last 12 months. The primary endpoint 
(feasibility) will be reached maximum 6 months after inclusion of the last patient. Documentation and data 
evaluation will take about 3 months. The primary result of the study will probably be available in end 2019.  
16.3 Analysis 
Patient and tumor characteristics are given as absolute and relative frequencies. Doses, volumes, fractions 
are listed by technique, by localization of metastasis, and by size. Maximum and median doses applied to 
organs at risk are described as median, inter-quartile range, and maximum. Summary compliance measures 
use the worst observation. Further parameter estimation, confidence intervals and tests using data at the 
metastasis level account for correlation by using GEE methods.  
Toxicities are tabulated by grade and time and shown as time profiles of cumulated grades. Adverse events 
are listed by system organ class (MedDRA), intensity and causality. Progression free survival is estimated 
using the Kaplan-Meier method.   

PRADO V04_01.02.2018 
 
17 Early termination 
17.1 Early termination and close of recruitment 
The study has to be terminated immediately, if a SAE with probable association to the study therapy occurs 
in more the 2 out of the first six patients or more than four out of the first 10 patients or in more than 40% 
of all recruited patients thereafter. The study may be terminated on the decision of the principal 
investigator in case of the following events: 
 
Insufficient recruitment 
 
new scientific data which either definitively answer the scientific question or require major changes 
of the protocol which cannot be included in an amendment  
17.2 Study termination in individual patients 
Participation in the study and study specific therapy must be stopped at any time during the study in 
individual patients for any of the following reasons 
 
withdrawal of informed consent by the patient 
 
severe toxicity with limitations or unacceptable risks to administer further study therapy 
 
inter current disease with limitations to administer protocol therapy  
 
progression of disease 
18 Ethical and legal aspects 
The study will be conducted according to the declaration of Helsinki. Approval by the ethical committees of 
the participating institution is required prior to initiation of the study. Patients must be fully informed about 
the study and give informed consent prior to inclusion. National rules for data protection must be obeyed.  
The study concept has been evaluated by the expert panel of DEGRO (German Association of Radiation 
Oncology). Approval by the German Radiation Protection Authority (BfS) is not required. A patient insurance 
will be taken out before the start of the trial for all patients, if necessary according to national rules. The trial 
will be registered in a primary study register before the start of the study. 
This study receive financial support from EU via the Interreg project.   
 
 
 

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19  Appendix 1 – Calculation of median survival 
 
 
 
 

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20 Appendix 2 – Diagnostic MR Protocol sequences 
MR protocols are modified/adapted from (24) and (27) to cover the lesion that explains the dominant 
symptom.  
The MR sequence protocol must contain an anatomical (T2w) axial sequence (reference scan see table 
below), that can be co-registered to the planning CT, ie. the reference scan must include enough rigid 
anatomical structures for a co-registration with good accuracy. The remaining MR sequences must cover 
the dominant lesion with adequate margin (typically 50 mm) that will allow for outline of the lesion in 3D.  
All MR sequences must be acquired with the same dicom origo, ie neither, the patient nor, the dicom origo 
may be moved between sequence acquisitions. This will allow all MR images to be co-registered to the 
planning CT. 
 
Sequence 
Directions 
Slice 
TR 
TE 
Avg 
  
  
mm 
msec msec 
  
T2-weighted fast SE  
Ax* / Cor / Sag 
 3/ 5/ 5 
2850 
80 
4 
T1-weighted GRE SPIR** 
Ax 
5 
1000 
3.7 
4 
Proton density–weighted fast SE   
Ax 
5 
2850 
4.7 
4 
DW imaging*** with free-breathing SE EPI SPIR* 
Ax 
5 
4687 
64 
8 
Avg = number of sample averages 
  
  
  
  
  
* Reference scan = T2w axial images 
  
  
  
  
  
** SPIR = Spectral Presaturation with Inversion Recovery 
  
  
  
  
*** b0 images and three b-values: b=50, 500 og 900 sec^2/mm 
  
  
  
  
Fat suppression should be preferably be done with a selective method as SPIR if possible. If not the STIR 
method, less specific, alternative method to use. Some post processing of MR images may be necessary to 
suppress noise in the images before automatically outlining the GTV. The ADC map should be calculated 
using all three b-values and mono-exponential fitting. 
 
 
 
 
 

PRADO V04_01.02.2018 
 
21 Appendix 3 - Target outline procedure 
The following example demonstrate the target outline procedure on the MR images. This example is a 
reconstruction based on images from (28)  
 
The target is outline on the T2W image. This image I co-registered to the ADC map and the outline is 
transferred to the ADC map. 
 
The outline transferred to the ADC map is subsequently corrected using a threshold for the ADC < 1200 
mm^2/s for the target. This target is named GTV1 
 
The median ADC value for the GTV1 target. The median value is used as threshold to obtain the most 
aggressive part of the target. This subvolume is named GTV2. 
 
 

PRADO V04_01.02.2018 
 
22 Appendix 4 – Flowchart for the study 
 
  
Inclusion 
Visit 1 
Baseline 
before RT 
After 
RT 
Visit 2 
1 month 
Visit 3 
3 month 
Visit 4 
6 month 
Screening / 
Inclusion 
X 
 
  
  
  
  
Informed Consent 
X 
 
  
  
  
  
Medical history 
X 
 
 
 
 
 
MR scanning 
 
X 
  
X 
  
X 
Anamnesis 
 
X 
  
  
  
  
Medical 
examination 
 
X 
X 
X 
X 
X 
Local Symptoms 
 
X 
X 
X 
X 
X 
Quality of Life 
 
X 
  
 
  
X 
Toxicity 
 
X 
X 
X 
X 
X 
LPFS 
 
  
X 
X 
X 
X 
ADC Response 
 
  
X 
 
  
X 
Survival 
 
  
X 
X 
X 
X 
AE/SAE 
 
 
X 
X 
X 
X 
Concomitant 
medication 
 
X 
X 
X 
X 
X 
VAS 
 
X 
X 
X 
X 
X 
ECOG 
 
X 
X 
X 
X 
X 
 
 
 

PRADO V04_01.02.2018 
 
 
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