A Single Arm Phase II Trial of Ultrahypofractionated Focal Salvage Radiotherapy for Isolated Prostate Bed Recurrence After Radical Prostatectomy
Phase: NA
Conditions: Recurrent Prostate Cancer
Sponsor: Insel Gruppe AG, University Hospital Bern

 
HypoFocal SRT Trial  
V5.0, 24.01.2025 
 
 
 
 
A single arm phase II trial of ultrahypofractionated focal salvage 
radiotherapy for isolated prostate bed recurrence after radical 
prostatectomy 
 
(HypoFocal SRT Trial) 
 
 
 
Study Type: 
 Other Clinical Trial according to ClinO, Chapter 4 
 
Risk Categorisation:  
Risk category A according to ClinO, Art. 61 
 
Study Registration: 
Clinicaltrials.gov: NCT05746806 
Cantonal Ethics Committee Number: KEK-BE 2202-01026 
 
 
Sponsor-Investigator  
Mohamed Shelan, MD  
 
Department of Radiation Oncology, Inselspital, 
Bern University Hospital and University of Bern, Bern, 
Switzerland. 
Phone: +41 31 632 24 31 
Fax: +41 31 632 85 67 
E-mail: mohamed.shelan@insel.ch 
 
Investigated Intervention: 
treating isolated prostate bed macroscopic recurrence after radical 
prostatectomy using ultrahypofractionated radiotherapy.  
 
Protocol ID 
 
 
 
Version and Date: 
 
Version 5.0 (24.01.2025) 
 
 
Change history 
Version 
Nr 
Version date 
Modified 
without version 
change 
Description, comments 
Control 
1.0 
30.05.2022 
 
Initial version 
2.0 
11.09.2022 
no 
Amended upon request of the ethics committee 
 MS 
3.0 
11.11.2022 
no 
Amended upon request of the ethics committee 
MS 
4.0 
29.02.2024 
no 
Addition of new recruiting center and investigators 
Amendment  of SAEs reporting 
Amendment of trial schedule  
Adaption max. dose 
MS 
5.0 
25.01.2025 
no 
Adaption ADT 
MS 
 
 
 
 

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CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of the sponsor 
investigator. The information may not - in full or in part - be transmitted, reproduced, published, 
or disclosed to others than the applicable competent ethics committees and regulatory authorities 
without prior written authorization from the sponsor except to the extent necessary to obtain 
informed consent from those who will participate in the study.  
 
PROTOCOL SIGNATURE FORM    
 
 
Study Title 
 
A single arm phase II trial of ultrahypofractionated focal salvage 
radiotherapy for isolated prostate bed recurrence after radical 
prostatectomy 
 
 
 
The Sponsor-Investigator has approved the protocol version 5.0 (24/01/2025) and confirm hereby 
to conduct the study according to the protocol, current version of the World Medical Association 
Declaration of Helsinki, and ICH-GCP guidelines as well as the local legally applicable 
requirements. 
 
Sponsor Investigator: 
 
 
Name: Dr. med. Mohamed Shelan  
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
 
 
 

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PROTOCOL SIGNATURE FORM FOR LOCAL INVESTIGATOR:  
 
The local Investigator has approved the protocol version 5.0 (24/01/2025) and confirm hereby to 
conduct the study according to the protocol, current version of the World Medical Association 
Declaration of Helsinki, and ICH-GCP guidelines as well as the local legally applicable 
requirements 
   
Local Principal Investigator at study site: 
 
 
 
 
Site:  
Principal Investigator:  
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS 
3 
GLOSSARY OF ABBREVATIONS 
4 
1 STUDY SYNOPSIS 
6 
2 BACKGROUND AND RATIONALE 
11 
3 STUDY OBJECTIVES AND DESIGN 
15 
3.1 Hypothesis and primary objective 
15 
3.2 Primary and secondary endpoints 
16 
3.3 Study design 
16 
3.4. Study intervention 
16 
3.4.1 Pre-registration imaging 
16 
3.4.2 Radiation treatment (SBRT) 
16 
3.4.3 Androgen deprivation therapy 
18 
4 STUDY POPULATION AND STUDY PROCEDURES 
19 
4.1 Inclusion and exclusion criteria, justification of study population 
19 
Schedule of assessments 
20 
4.4 Withdrawal and discontinuation 
21 
5 STATISTICS AND METHODOLOGY 
21 
5.1. Statistical analysis plan and sample size calculation 
21 
5.2. Definition of endpoints 
22 
5.3. Handling of missing data and drop-outs 
23 
6 Regulatory Aspects AND SAFETY 
23 
6.1 Local regulations / Declaration of Helsinki 
23 
6.2 (Serious) Adverse Events and notification of safety and protective measures 
24 
6.3 (Periodic) safety reporting 
25 
6.4 Radiation 
25 
6.5 Pregnancy 
25 
6.6 Amendments 
25 
6.7 (Premature) termination of study 
26 
6.8 Insurance 
26 
7 FURTHER ASPECTS 
27 
7.1 Overall ethical considerations 
27 
7.1.1 Patient protection 
27 
7.1.2 
Subject identification 
27 
7.1.3 
Informed consent 
27 
7.2 Risk-benefit assessment 
27 
8 QUALITY CONTROL AND DATA PROTECTION 
28 
8.1 Quality measures 
28 
8.2 Data recording and source data 
28 
8.3 Confidentiality and coding 
28 
8.4 Retention and destruction of study data 
29 
9  MONITORING AND REGISTRATION 
29 
10. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
29 
11 REFERENCES 
29 

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GLOSSARY OF ABBREVATIONS 
 
AE 
Adverse Event 
ADC 
Apparent diffusion coefficient 
ADT 
Aandrogen deprivation therapy 
ASR/DSUR 
Annual Safety Repot / Development Safety Report 
ASTRO/ 
American societies of radiation oncology, medical oncology and urology 
ASCO/AUA 
 
BASEC 
Business Administration System for Ethical Committees 
bRFS 
Biochemical relapse free survival 
CA 
Clinical approval 
CBCT 
Cone Beam CT 
CEC 
Clinical ethics committee  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: 
OClin, in Italian: OSRUm) 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTU 
Clinical trials unit 
CTV 
Clinical target volume 
DCE 
Dynamic contrast enhancement 
DEGRO 
German society of radiation oncology 
DFS 
Disease free survival 
DRE 
Digital rectal examination 
DVH 
Dose volume histogram 
DWI 
Diffusion-weighted imaging 
EAU 
European association of urology 
EORTC 
European organisation for research and treatment of cancer 
18F 
Fluorine-18 
FADP 
Federal Act on Data Protection (in German: DSG, in French: LPD, in Italian: LPD) 
FOPH 
Federal Office of Public Health 
18F- DCFPYL  Pylarify - piflufolastat Fluorine-18 
eCRF 
Electronic Case Report Form 
68Ga 
Gallium-68 
GCP 
Good Clinical Practice 
GTV 
Gross tumor volume 
GI 
Gastrointestinal 
GU 
Genitourinary  
HR 
Hazard ratio 
HRA 
Human Research Act (in German: HFG, in French: LRH, in Italian: LRUm) 
ICH 
International Conference on Harmonisation  
IGRT 
Image guided radiotherapy 
IMRT 
Intensity modulated radiotherapy 

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LHRH 
Luteinizing hormone releasing hormone 
LHRHa 
Luteinizing hormone releasing hormone agonist 
MFS 
Metastasis free survival 
mpMRI 
Multiparametric magnetic resonance imaging 
MRI 
Magnetic resonance imaging 
NCI 
National cancer institute 
NTCP 
Normal tissue complication probability 
NTD 
Normalized total dose 
NCCN 
National comprehensive cancer network 
OAR 
Organs at risk 
OS 
Overall survival 
OSEM 
Ordered subset expectation maximization 
PET/CT 
Positron electron computed tomography 
PFS 
Progression-free survival 
PI 
Principal Investigator  
PRV 
Planning organ at risk volume 
PSA 
Prostate specific antigen 
PSF 
Point-spread-function 
PSMA 
Prostate-specific membrane antigen 
PTV 
Planning target volume 
RP 
Radical prostatectomy 
RT 
Radiotherapy 
RTOG 
Radiation therapy oncology group 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic body radiotherapy 
SI 
Signal intensity 
SRT 
Salvage radiotherapy 
TLC 
Thin layer chromatography 
TMF 
Trial master file 
TNM 
Tumor Nodes Metastases 
TOF 
Time of flight 
UICC 
Union internationale contre le cancer 
UPN 
Unique Patient Number 
VUA 
Vesicourethral anastomosis 
WHO 
World health organization 
QLQ 
Quality of life questionnaire  
QoL 
 
Quality of life 
 

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1 
STUDY SYNOPSIS 
Sponsor / Sponsor-
Investigator 
 
Mohamed Shelan, MD 
Study Title: 
A single arm phase II trial of ultrahypofractionated focal salvage 
radiotherapy for isolated prostate bed recurrence after radical 
prostatectomy  
Short Title / Study ID: 
HypoFocal-SRT 
Protocol Version and 
Date: 
Ver. 5.0 date 24.01.2025   
Trial registration: 
NCT05746806 
Study category and 
Rationale 
Category A  
 
Ultrahypofractionated radiotherapy is not a standard of care in patients 
with local recurrence after radical prostatectomy. However, based on 
published data from retrospective series and phase I trial using a similar 
or higher fractionation scheme to the one used in this trial, toxicity is not 
expected to be higher than in case of normofractionated salvage 
radiotherapy. In terms of tumor control outcome, a benefit of 
hypofractionation can be expected due to the low α/β value of prostate 
cancer.  
 
Clinical Phase: 
Phase II 
Background 
and 
Rationale: 
Radical prostatectomy and radiotherapy (RT) are the considered as 
backbones for treating localized disease1. However radical prostatectomy, 
30 – 60% of patients will develop recurrent disease2,3. Several large 
randomized controlled trials have shown a benefit of postoperative 
radiation therapy in patients with a high risk of local recurrence after RPE, 
e.g. pT3 disease or positive resection margins4–8. In the era of high 
sensitivity PSA and PSMA-PET/CT, there has been additional evidence 
suggesting a similar oncological outcome if patients are treated with early 
salvage radiotherapy in case of a rising PSA after RPE instead of 
immediate adjuvant radiotherapy9–12. However, the above mentioned 
studies as well as the studies including patients receiving salvage 
radiotherapy in case of a macroscopic tumor recurrence in the prostate 
bed were done with conventionally fractionated radiotherapy, usually in 2 
Gy per fraction4–12. 
 
In the setting of definite radiotherapy to the prostate, ultrahypofractionated 
radiotherapy has been used as a treatment option in patients with low or 
intermediate risk for a long time and there are published data with a 
reasonable follow up that shows excellent biochemical control with low 
high grade toxicity rates13–20. In addition, data on ultrahypofractionated in 
high-risk patients are emerging with several large trials being published 
with encouraging results21–26. The rationale for using ultrahypofractionated 
in patients treated for prostate cancer is the estimated low α/β value of 
around 1.5 Gy27,28. Therefore, using a larger fraction dose is expected to 
improve the therapeutic ratio and consequently the probability of tumor 
control. 
 
Although Data on moderate hypofractionation in the setting of 
postoperative radiotherapy with a fraction dose of up to 3 Gy per fraction 
does not seem to support this concern, given the low toxicity rates that 
were reported in several analyses29–38. However, data on postoperative 
ultrahypofractionated radiotherapy to the prostate bed remains immature. 

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The rates of acute and late toxicities following ultrahypofractionated 
radiotherapy to the prostate bed were reported in retrospective and phase 
I studies are within the above mentioned ranges. The rate of acute ≥ G2 
GI and GU toxicities range from 0 – 50 % and 0 – 33.3 % and for late ≥ 
G2 GI and GU toxicities from 0 – 11.5 % and 0 – 38.5 %39–48. This data 
suggests that SBRT to the prostate bed can be applied with toxicity rates 
similar to that of normofractionated or mildly hypofractionated radiotherapy
 
Further improvement in the oncological outcomes can be expected 
through technological developments in radiotherapy delivery and precise 
targeting of the local relapses in the prostate bed. A SRT using a 
ultrahypofractionated schedule delivered precisely in 5 fractions and 
limited only to the site of isolated macroscopic recurrence in the prostate 
bed as defined by PSMA-PET and multiparametric MRI (mpMRI) may 
represent a valid treatment strategy to improve the therapeutic ratio in 
these patients (short overall treatment time, better sparing of surrounding 
heathy tissues, increased dose to the target volume). 
 
Rationale for combining ADT to SRT 
- 
The benefit of ADT to salvage radiation has been demonstrated in two 
randomized phase III trials, RTOG 9601 and GETUG 16, which 
provided evidence of improved metastasis-free and overall survival 
and durable biochemical disease control with bicalutamide for 24 mo 
and ADT using LHRH agonists for 6 months, respectively.  
- 
These studies support the current National Comprehensive Cancer 
Network (NCCN) guidelines to consider combination of 6–24 months 
of hormonal therapy with SRT in this setting.  
Objective(s): 
The main objective of the trial is to explore the efficacy and safety of 
combining short-term ADT over 6 months to focal ultrahypofractionated 
SRT delivered in 5 fractions to the site of local recurrence within the 
prostate bed after radical prostatectomy where mpMRI and PSMA 
PET/CT are used to precisely identify the local recurrence and compare it 
to previously published literature. 
 
Outcome(s): 
Primary endpoints:  
- 
Biochemical relapsefree survival at 2 years 
Secondary endpoints:  
- 
Acute side effects (till 90 days after end of radiation) of grade 3 or 
higher based on CTCAE v5 
- 
Clinical progression-free survival 
- 
Metastasis-free survival 
- 
Late side effects  
- 
Quality of life (based on EORTC QLQ-C30, QLQ-PR25) 
Study design: 
This a single arm, prospective, phase II multicenter study  
Inclusion / Exclusion 
criteria: 
Inclusion criteria:
1. Written informed consent according to ICH/GCP regulations 
before registration and prior to any trial specific procedures  
2. Age ≥ 18 years at time of registration  
3. WHO performance status 0-1 
4. Lymph node negative adenocarcinoma of the prostate treated 
with radical prostatectomy (RP) at least 6 months before trial 

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registration. Tumor stage pT2a-3b, R0-1, pN0 or cN0 according 
to the UICC TNM 2009. 
5. Evidence of measurable local recurrence at the prostate bed 
detected by PSMA PET/CT and mpMRI within the last 3 months. 
In case of unclear local recurrence, a biopsy confirmation is 
recommended. 
6. Patient must have non-metastatic (N0, M0) disease, as defined by 
a lack of nodal or distant metastases seen on PSMA PET/CT scan 
7. Patients must have non-castrate levels of serum testosterone 
(≥50 ng/dL). 
8. Patients must not have previously received hormonal therapy 
(LHRH agonists, antiandrogen, or both, or bilateral orchiectomy). 
9. Absence 
of 
any 
psychological, 
familial, 
sociological 
or 
geographical condition potentially hampering compliance with the 
study protocol and follow-up schedule; those conditions should be 
discussed with the patient before registration in the trial 
Exclusion criteria: 
1. Persistent PSA (> 0.4 ng/mL) 4 to 20 weeks after RP  
2. Previous hematologic or primary solid malignancy within 3 years 
prior registration with the exception of curatively treated localized 
non-melanoma skin cancer  
3. Usage of products known to affect PSA levels within 4 weeks prior 
to start of trial treatment phase including any form of androgen 
suppression agents and androgen deprivation therapy  
4. Bilateral hip prosthesis  
5. Severe or active co-morbidity likely to impact on the advisability of 
SRT  
6. Treatment with any experimental drug or participation within a 
clinical trial within 30 days prior to registration (exception: 
concurrent participation in the biobank studies is allowed)  
Measurements 
and 
procedures: 
Investigations  to be performed within 12 weeks prior to 
registration: 
 
- 
Physical examinations including Digital rectal examination (DRE) 
- 
Multi-parametric MRI  
- 
PSMA PET/CT. 
 
Investigations during trial treatment phase  
- 
Planning CT 
- 
Multi-parametric MRI if not yet performed 
- 
Serum PSA  
- 
Total testosterone,  
- 
Assessment of recurrences in case of suspected progression 
 
During follow-up: 
- 
Physical examinations  
- 
Digital rectal examination (if suspected clinical progression),  
- 
serum PSA  
- 
Total testosterone 
- 
Assessment of recurrences with PSMA PET/CT imaging (local, 
regional, distant)  
 

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Treatment related adverse events are collected throughout the 
trial.  
Control Intervention (if 
applicable): 
This is a single arm study. Control intervention is not applicable.  
Number 
of 
Participants 
with 
Rationale: 
It is planned to enrol a total of 36 patients in the trial (see statistical 
considerations for rationale). 
Study Duration: 
Expected accrual time: 36 Months 
Study Schedule: 
First-Participant-In: Q4 2022  
Last-Participant-Out: Q1 2028 
 
Investigator(s): 
Dr. med. Mohamed Shelan 
Department of Radiation Oncology  
Inselspital, Bern University Hospital 
Bern, Switzerland. 
Phone: 031 632 29 70 
E-Mail:mohamed.shelan@insel.ch 
 
Prof. Dr. med. Daniel M. Aebersold 
Department of Radiation Oncology  
Inselspital, Bern University Hospital 
Bern, Switzerland. 
Phone: 031 632 24 31  
E-Mail:daniel.aebersold@insel.ch 
 
Jens Lustenberger  
Department of Radiation Oncology 
Unispital Basel 
E-Mail: jens.lustenberger@usb.ch 
 
Prof. Dr. Daniel R. Zwahlen  
Department of Radiation Oncology 
Kantonsspital Winterthur 
Phone: 079 553 25 63 
E-Mail:daniel.zwahlen@ksw.ch 
 
Prof. Dr. med. Thomas Zilli 
Clinica di Radio-Oncologia 
Istituto Oncologico della Svizzera Italiana-Ente Ospedaliero Cantonale 
(IOSI-EOC) 
Phone: 091/811 96 35 
E-Mail: Thomas.Zilli@eoc.ch 
 
Prof. Dr. med. Matthias Guckenberger 
Department of radiation oncology  
University Hospital of Zurich  
Mathias.guckenberger@usz.ch 
Phone:+41 44 255 29 30 
 
Dr. med. Alexander Althaus  
Department of Radiation Oncology  
Inselspital, Bern University Hospital 
Bern, Switzerland. 
Phone: 031 632 29 70 
Email: alexander.althaus@insel.ch  
 
 

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Study Centre(s): 
Multi-centre study with 5 recruiting centers in Switzerland. 
Statistical 
Considerations: 
According to the published prospective trials and retrospective series 
reporting the outcome of the normofractionated SRT, we define 
biochemical relapse free survival at 2 years of 60% as poor and of 80% 
as promising outcome that would justify further investigation. We will 
therefore test the null hypothesis that the biochemical relapse free survival 
at 2 years is lower than 60% against the alternative that it is at least 80%. 
Based on a one-sample binomial exact test with a one-sided alpha of 5%, 
36 patients are required to reach a power of 80%. The null hypothesis will 
be rejected if at least 27 patients show biochemical relapse free survival 
at 2 years. 
 
We will control the safety of the intervention during the trial by assessing 
acute side effects (grade 3 or higher) at 90 days after 12 and 24 patients. 
The trial will be stopped if there is evidence that the proportion of patients 
with acute side effects is larger than 27%, the proportion observed that will 
be tested using one-sample binomial exact tests with a one-sided alpha of 
5%. 
 
Time-to-event outcomes will be analyzed using Kaplan-Meier-curves, the 
proportion of responders at 1 and 2 years, and the restricted mean survival 
time at 1 and 2 years with 95% confidence interval. Binary outcomes will 
be reported using absolute and relative frequencies with 95% confidence 
intervals.
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as 
far as applicable) as well as all national legal and regulatory requirements.
  
 
 

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2 
BACKGROUND AND RATIONALE  
2.1 Disease background 
Prostate cancer is the most common non-cutaneous malignancy in men. An estimated 1.1 million patients 
per year worldwide were diagnosed with prostate cancer, accounting for 15% of the cancers diagnosed in 
men, with almost 70% of the cases occurring in more developed regions. Prostate cancer is the fifth leading 
cause of cancer death in men, representing 6.6% of the total male cancer mortality 49.  
The most common curative therapeutic modalities for localized prostate cancers include radical 
prostatectomy (RP) and radiotherapy with or without androgen deprivation therapy. Although there is a 
wide variability between treatment site and risk groups, approximately 50% of all men with localized 
prostate cancer undergo RP 50. After RP, between 30-60% of men can develop a biochemical relapse within 
5 years 51–54. The site of relapse in prostate cancer patients after RP is predominantly local, with a low 
incidence of distant failures 55. Within patients with biochemical relapse the actuarial rate of bone metastasis 
is 37% and 65% at 5 years and 10 years, respectively. The median time to development of bone metastasis 
after biochemical relapse is 8 years and the median time between development of bone metastasis and 
death is 5 years 56.  
 
2.2 Therapy background 
2.2.1 The use of adjuvant and salvage radiotherapy after radical prostatectomy  
Adverse pathological factors after prostatectomy, such as positive surgical margins, extracapsular 
extension, or seminal vesicle invasion, increase the likelihood of disease recurrence. Three randomized 
clinical trials have demonstrated the benefits of adjuvant radiotherapy after RP for patients with adverse 
pathological features 5,8,57. The most consistent findings were an improvement in biochemical relapse free 
survival across all three trials and improvements in loco-regional and clinical relapse free survival in the 
two trials that reported these outcomes. Although there was an improvement in overall survival in one of 
the studies 57, the use of adjuvant radiotherapy is not unanimously accepted 58. Two of these studies have 
included patients with a detectable prostate-specific antigen (PSA) at the time of adjuvant treatment; 
therefore, these patients received salvage treatment by definition. As such, many clinicians offer salvage 
radiotherapy (SRT) to patients with biochemical progression instead of adjuvant radiotherapy. The main 
advantage of salvage versus adjuvant radiotherapy is the avoidance of a potential overtreatment in cases 
that would never relapse after surgery, even in the presence of high-risk pathological features 59. Recently, 
prospective randomized trials, systematic review, and meta-analysis suggest that adjuvant radiotherapy 
does not improve event-free survival in men with localized or locally advanced prostate cancer. Until data 
on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy 
as it offers the opportunity to spare many men radiotherapy and its associated side-effects 9,10,12.  
Predictors of response to salvage radiotherapy were examined by Stephenson et al. 60 and they found that 
high Gleason score, high pre-radiotherapy PSA, negative RP surgical margins, short PSA doubling time, 
and seminal vesicle involvement were independently associated with adverse outcomes. A contemporary 
update of the original Stephenson predictive nomogram including patients treated with early SRT (at a PSA 
≤ 0.2 ng/mL) showed that early SRT at low PSA levels after RP is associated with improved freedom from 
biochemical relapse and distant metastases rates 61. 
 
2.2.2 Optimizing salvage radiotherapy with androgen deprivation therapy  
Prospective studies have shown that androgen deprivation therapy (ADT) combined with primary 
radiotherapy for intermediate- and high-risk prostate cancers improves overall survival 62. The combination 
of ADT to radiation in the postoperative setting was for long time a matter of debate. Recently the results 
of prospective phase III randomized were published demonstrating a benefit of the combined treatment63,64. 
In the RTOG 9601, 771 men with an elevated serum PSA following radical prostatectomy were randomly 
assigned to radiation plus the anti-androgen bicalutamide for two years or radiation alone. The first interim 
results at a median follow up of 7 years were negative for the primary endpoint, overall survival; however, 
the latest report at a median follow-up of 12.6 years showed an actuarial 10-year overall survival of 82% 
for salvage radiation plus ADT and 78% for salvage radiation plus placebo (HR: 0.75; 95% CI: 0.58-0.98) 
63.  

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The GETUG-AFU 16 is a phase III study that randomized men with biochemical failure after surgery to 
salvage radiation alone versus salvage radiation combined with 6 months of LHRH agonists. The 10 years 
results showed that SRT combined with short-term androgen suppression significantly reduced risk of 
biochemical or clinical progression and death compared with salvage radiotherapy alone. The results of the 
GETUG-AFU 16 trial confirm the efficacy of androgen suppression plus radiotherapy as salvage treatment 
in patients with increasing PSA concentration after RP for prostate cancer 64.  
Finally, it is worth to mention that, the current National Comprehensive Cancer Network (NCCN) guidelines 
recommend a duration of 6–24 months of ADT combined SRT. 
 
2.3. Role of new imaging modalities in identifying local recurrence after RP 
 
2.3.1 The role for MRI in the identification of prostate cancer recurrence after RP 
In men with biochemical recurrence following local treatment with curative intent for prostate cancer, it is 
important to identify those who will likely benefit from local salvage therapy. Imaging should provide a step-
by-step multimodal approach that facilitates both local and systemic staging. Clinical guidelines recommend 
the use of both nuclear medicine imaging (positron emission tomography [PET] / computed tomography 
[CT] scans) and magnetic resonance imaging (MRI) to assess local recurrence and distant metastases 65,66 
Multiparametric MRI (mpMRI) is accurate in early detection of prostate cancer local recurrence after RT 
and RP 66. T2w sequences very accurately represent the postsurgical anatomy. In most cases, a local 
recurrence differs from normal postoperative inflammation and fibrosis. Fibrotic tissue has a lower signal 
intensity (SI) than recurrent tissue 67. Recurrent tissue can have various forms, including curly, semi-
circular, nodular, and plaque-like masses. In the case of asymmetric perianastomotic soft-tissue thickening 
with an SI in between the SIs for pelvic muscle and the surrounding adipose tissue, a local recurrence is 
likely to be present 68. Functional criteria are based on diffusion-weighted imaging (DWI) and dynamic 
contrast enhancement (DCE), which represent the cellularity and vascularity of the tissue, respectively. 
DWI has good diagnostic accuracy in detecting local recurrence after RP when combined with other 
sequences68. Quite often, there is geometric distortion caused by susceptibility artefacts due to surgical 
clips. Local recurrence after RP, like primary tumours, shows high SI on high b-value DWI and low ADC 
values. In the case of artefact-altered DWI, DCE MRI is of particular importance69. DCE imaging plays the 
dominant role in the detection of RP recurrence. This technique has high sensitivity 70–72; even tiny 
recurrence “foci” that may not be visible on T2WI tend to show significant enhancement in the early arterial 
phase, often with contrast wash-out 66. In addition, post-RP recurrences enhance sooner and faster than 
normal postoperative changes 73. 
 
2.3.2 Role of PSMA PET CT in Identification of local recurrence 
 
In case of PSA recurrence, SRT is the only curative option, resulting in approximately 60% of the patients 
re-achieving an undetectable PSA. After 5 years, 80% of these men are free from progression74. The pre-
SRT PSA level is a significant factor of progression, with more favorable results for patients with low PSA 
levels (0.5 ng/mL or less)61,75. Accordingly, European guidelines (EAU) recommend early SRT at a PSA 
<0.5 ng/mL. At the same time, use of restaging PSMA PET/CT is recommended by the 2021 EAU 
guidelines for patients with a relapsing PSA > 0.2 ng/mL. However, for clinical and imaging purposes, it is 
important to distinguish between two types of local recurrence and relapse outside tumor bed. 
At PSA levels <1 ng/mL, most imaging methods are not suitable to detect the correlate for disease 
progression. Therefore, up to 20% of patients with SRT to the prostate bed (with or without including original 
seminal vesicle) without morphological correlate will be treated locally without actual local recurrence 
74Prostate-specific membrane antigen (PSMA) is a cell surface protein with high expression in majority of 
prostate cancer 76. 68Ga-PSMA has been used since 2012 as PSMA-ligand in recurrent prostate cancer 
77–79. Especially at low PSA levels, the detection rate of 68Ga-PSMA-11-PET/CT is significantly higher in 
comparison to other imaging methods. In a retrospective analysis for patients with biochemical progression 
after RP, Afshar-Oromieh et al. found that 69% of the patients had at least one positive lesion indicating 
prostate cancer recurrence. The detection rates were 43% for PSA levels ≤0.2 ng/mL, 58% for PSA >0.2 
to ≤0.5 ng/mL and 72% for PSA >0.5 to ≤1.0 ng/mL. Tumor detection was clearly associated with PSA level 
and higher Gleason scores 78. Bluemel et al. analyzed the impact of 68Ga-PSMA-11-PET/CT in patients 
with PSA failure and negative F-18-choline-PET/CT. Of 125 patients, 32 patients with negative F-18-
choline-PET/CT received an additional 68Ga-PSMA-11-PET/CT, which detected sites of recurrence in 
43.8% 80. 

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The most common site of postoperative local recurrence, accounting for 57%–62% of relapse cases, is the 
vesicourethral anastomosis (VUA), which comprises the membranous urethra, bladder neck, and 
surrounding soft tissue 81. Other typical local relapse sites are the lateral surgical margins (seminal vesicle 
bed) or remnant deferens, accounting for 25%–27% of cases 82, and the retrovesical region (topography of 
rectoprostatic/Denonvilliers fascia) in 8%–21% of cases 81At PSMA PET/CT, local recurrence appears 
more often as focal ill-defined hypo-attenuating soft tissue with moderate PSMA uptake but can also simply 
appear as focal unilateral radiotracer uptake within the fibrotic tissue. It is important to point out that in most 
cases, postoperative local recurrence relies only on the PET component of the hybrid imaging because of 
the known lack of soft-tissue contrast in the pelvic region at CT 77. 
 
 
2.4 Investigational treatment  
 
2.4.1 Hypofractionated stereotactic body radiotherapy to the site of recurrence 
 
External beam radiation therapy is one of the standard treatments for organ-confined prostate cancer, with 
cure rates similar to those of RP. Hypofractionation uses a higher dose-per-fraction of radiation, which 
reduces the number of fractions and the total duration of treatment, allowing greater comfort for the patient 
and lower costs, in addition to providing a therapeutic advantage in terms of tumor control and toxicity, as 
the α/β of prostate cancer is lower than that of adjacent healthy tissues83. In 2018, a group of experts from 
the American Societies of Radiation Oncology, Medical Oncology, and Urology (ASTRO/ASCO/AUA) 
concluded that there is sufficiently robust evidence to justify using moderate hypofractionation in prostate 
cancer as common clinical practice84. A recent Cochrane review indicated that moderate prostate cancer 
hypofractionation (with fractions up to 3.4 Gy) provides oncological outcomes in terms of overall survival 
(OS), disease-free survival (DFS), and metastasis-free survival (MFS) similar to conventional fractionation, 
without a significant increase in acute or late toxicity 85.  
In addition, technical advances in the field of radiotherapy in recent years, such as intensity-modulated 
radiotherapy (IMRT), image-guided radiotherapy (IGRT), and stereotactic radiotherapy (SBRT), have 
enabled the progressive implementation of extreme hypofractionation (defined by fractions of at least 6 Gy) 
in various scenarios of localized prostate cancer treatment. The use of SBRT in prostate cancer has 
provided sufficient evidence in terms of tumor control results, quality of life reported by the patient, and low 
toxicity 25,86,87 to back its implementation in daily clinical practice. Moreover, the prostate cancer working 
group of the German Society of Oncology (DEGRO) but also the NCCN endorses the use of SBRT in the 
treatment of localized low and intermediate-risk prostate cancer, recommending its use in clinical trials in 
patients with the localized high-risk disease88-48.  
The recent publication of two randomized trials comparing the use of extreme hypofractionation versus 
conventional fractionation (HYPO-RT-PC 25, PACE-B trial87) has been crucial in supporting its use, although 
only the Scandinavian study (HYPO-RT-PC) reported results of long-term tumor and toxicity control. In 
2020, a randomized systematic review and meta-analysis of phase III trials were published comparing 
SBRT with normofractionated and hypofractioned regimens. It concluded that the ultra-hypofractionated 
regimens obtained similar 5-year disease-free survival results, with late gastrointestinal and genitourinary 
toxicity of <15% and <21%, respectively, when compared to hypofractionated regimens and conventional 
radiotherapy 47.  
 
Use of moderate hypofractionation is becoming a standard even in the postoperative setting. Retrospective 
and prospective single arm studies support a safe toxicity profile and a promising biochemical control rates 
with hypofractionation (PMID: 29178983). The recently reported results of the phase III clinical trial NRG-
GU003 comparing hypofractionated post-operative prostate bed radiotherapy (HYPORT) to the 
conventional post-prostatectomy radiotherapy  for men with prostate cancer determined that treatment with 
HYPORT yielded no increase in patient-reported genitourinary (GU) or gastrointestinal (GI) toxicity for trial 
participants, with a similar biochemical disease control at the 2 year follow-up. 
To demonstrate the viability and safety of the use of SBRT in this clinical scenario, Repka et al 50conducted 
a theoretical feasibility study of SBRT after RP based on the NTCP (Normal Tissue Complication 
Probability) model, using patients who had previously been treated by conventional EBRT for biochemical 
recurrence after prostatectomy. Using the presimulation CT, RTOG recommendations were applied to 
define postprostatectomy volumes, and a dose of 30 Gy was prescribed to the PTV in five fractions, 
corresponding to an equivalent dose in 2 Gy fractions (EQD2) of 64.3 Gy, assuming an α/β value of 1.5 

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Gy. The NTCP model was applied to estimate the risk of late rectal and/or bladder toxicity. According to 
the NTCP model, the mean of grade≥2 late rectal toxicity was estimated at 0.28% and of late grade 2 
toxicity on the bladder neck at 0.00013%, while the calculated average for the exacerbation of late urinary 
symptoms was 4.81%. The conclusion by the authors, considering the limitations of the NTCP model, is 
that using SBRT after surgery seems feasible and may offer a safe, convenient treatment option for patients 
in both the adjuvant and salvage after biochemical failure.  
A prospective phase I study by Sampath et al. tested the usage of stereotactic dose-escalated radiotherapy 
on prostate bed in and showed a crude rate of biochemical control of 42% in the overall population 90. 
Patients were treated with dose fractionation schedules of 35, 40 and 45 Gy in five fractions. Authors 
underlined that dose escalation to 45 Gy was feasible without increasing the rate of adverse events, but no 
improvement in PSA control was reported if compared to 40 Gy in 5 fractions. Furthermore, a recent 
propensity score analysis comparing focal stereotactic SRT and conventional radiotherapy for macroscopic 
prostate bed recurrence showed comparable bRFS and PFS rates between the two modalities. On the 
other hands, a lower rate of toxicity was confirmed for patients undergoing focal stereotactic SRT compared 
to conventional fractionated SRT, with acute GI and GU adverse events reported in 4.4% versus 44.4% 
(p< 0.001) and 28.9% versus 46.7% (p= 0.08) of patients, and late GI and GU adverse events reported in 
0% versus 13.3% (p = 0.04) and 6.7% versus 22.2% (p = 0.03) of patients, respectively 91. Considering the 
favorable therapeutic ratio of this approach and the lower number of fractions needed, the authors 
suggested stereotactic is an attractive alternative to conventional SRT in this setting 
 
2.5 Rationale for performing the trial  
 
Radical prostatectomy and radiotherapy (RT) are the considered as backbones for treating localized 
disease1. However radical prostatectomy, 30 – 60% of patients will develop recurrent disease2,3. Several 
large randomized controlled trials have shown a benefit of postoperative radiation therapy in patients with 
a high risk of local recurrence after RPE, e.g. pT3 disease or positive resection margins4–8. In the era of 
high sensitivity PSA and PSMA-PET/CT, there has been additional evidence suggesting a similar 
oncological outcome if patients are treated with early salvage radiotherapy in case of a rising PSA after 
RPE instead of immediate adjuvant radiotherapy9–12. However, the above mentioned studies as well as the 
studies including patients receiving salvage radiotherapy in case of a macroscopic tumor recurrence in the 
prostate bed were done with conventionally fractionated radiotherapy, usually in 2 Gy per fraction4–12. 
 
In the setting of definite radiotherapy to the prostate, ultrahypofractionated radiotherapy has been used as 
a treatment option in patients with low or intermediate risk for a long time and there are published data with 
a reasonable follow up that shows excellent biochemical control with low high grade toxicity rates13–20. In 
addition, data on ultrahypofractionated in high-risk patients are emerging with several large trials being 
published with encouraging results21–26. The rationale for using ultrahypofractionated in patients treated for 
prostate cancer is the estimated low α/β value of around 1.5 Gy27,28. Therefore, using a larger fraction dose 
is expected to improve the therapeutic ratio and consequently the probability of tumor control. 
 
Although Data on moderate hypofractionation in the setting of postoperative radiotherapy with a fraction 
dose of up to 3 Gy per fraction does not seem to support this concern, given the low toxicity rates that were 
reported in several analyses29–38. However, data on postoperative ultrahypofractionated radiotherapy to the 
prostate bed remains immature. The rates of acute and late toxicities following ultrahypofractionated 
radiotherapy to the prostate bed were reported in retrospective and phase I studies are within the above 
mentioned ranges. The rate of acute ≥ G2 GI and GU toxicities range from 0 – 50 % and 0 – 33.3 % and 
for late ≥ G2 GI and GU toxicities from 0 – 11.5 % and 0 – 38.5 %39–48. This data suggests that SBRT to 
the prostate bed can be applied with toxicity rates similar to that of normofractionated or mildly 
hypofractionated radiotherapy 
 
Further improvement in the oncological outcomes can be expected through technological developments in 
radiotherapy delivery and precise targeting of the local relapses in the prostate bed. A SRT using a 
ultrahypofractionated schedule delivered precisely in 5 fractions and limited only to the site of isolated 
macroscopic recurrence in the prostate bed as defined by PSMA-PET and multiparametric MRI (mpMRI) 
may represent a valid treatment strategy to improve the therapeutic ratio in these patients (short overall 
treatment time, better sparing of surrounding heathy tissues, increased dose to the target volume). 
 

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Rationale for combining ADT to SRT 
- 
The benefit of ADT to salvage radiation has been demonstrated in two randomized phase III trials, 
RTOG 9601 and GETUG 16, which provided evidence of improved metastasis-free and overall survival 
and durable biochemical disease control with bicalutamide for 24 mo and ADT using LHRH agonists 
for 6 months, respectively.  
- 
These studies support the current National Comprehensive Cancer Network (NCCN) guidelines to 
consider combination of 6–24 months of hormonal therapy with SRT in this setting.  
 
3 
STUDY OBJECTIVES AND DESIGN  
3.1 Hypothesis and primary objective 
We hypothesize that focal SRT in combination with short-term ADT may further prolong or prevent 
progression, and improve the success of SRT for relapsing patients with a macroscopic relapse after RP. 
Through better definition and optimization of the target volumes sparing adjacent normal tissue, an 
improvement in the toxicity profile can be expected. 
 
The main objective of the trial is to explore the efficacy and safety of combining 6 months short-term ADT 
to focal hypofractionated SRT delivered in 5 fractions where mpMRI and PSMA-PET CT are used to 
precisely identify the local recurrence and compare it to the published literature. 
 
 

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3.2 Primary and secondary endpoints 
Primary endpoints:  
- 
Biochemical relapse free survival at 2 years 
Secondary endpoints:  
- 
Acute side effects (until 90 days after end of radiation) of grade 3 or higher based on CTCAE v5 
- 
Progression-free survival  
- 
Metastasis-free survival 
- 
Late side effects 
- 
Quality of life (based on EORTC QLQ-C30, QLQ-PR25) 
3.3 Study design  
This is a single arm, prospective phase II multicenter study.  
 
   
3.4. Study intervention 
 
3.4.1 Pre-registration imaging 
Within 3 months prior to registration either, PSMA PET/CT is mandatory to exclude regional or distant 
metastasis. Both 18F- and 68G-PSMA tracers are allowed. A mpMRI of the prostate bed acquired within 3 
months before registration is mandatory to define the extension of local recurrence. 
3.4.2 Radiation treatment (SBRT) 
3.4.2.1 Patient’s positioning, immobilization, data acquisition and simulation: 
A treatment planning CT scan, with the patient in the same position as during treatment, is required to 
define the clinical target volume (GTV), the planning target volume (PTV) and the critical structures. 
Patients will be positioned in supine position. Leg and knee support is highly recommended. Each patient 
will be positioned in an individualized immobilization device in the treatment position on a flat table. It is 
recommended that patients are scanned/simulated and treated with comfortably full bladder. An empty 
rectum is recommended for prostate bed radiotherapy. An example of a bladder and rectal protocol: An 

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empty rectum is provided by using a rectal enema +/- 60 minutes before planning CT. After emptying rectum 
and bladder the patient is asked to drink the amount of 500-750 ml of water. The planning CT is then 
performed after ca. 40 minutes. The patient repeats the bladder filling procedure during the entire treatment 
courses. An endorectal ballon can be used for repositioning purposes as per local institutional standards. 
Radiopaque fiducial markers (mandatory for robotic-based treatments) may be implanted in the prostate 
bed 1 week before the planning CT scan at the discretion of the treating center.  
 
The position of the patient will be reproduced using skin marks and orthogonal laser beams during 
treatment preparation and execution. The treatment planning CT scan should include at least the pelvis 
from the lower part of the second lumbar vertebra (L2) to the lower part of the ischial tuberosities. The entire 
target volume and all organs at risk (OAR) must be included in CT scan. CT slice thickness should be ≤ 2 
mm. The GTV, PTV and OAR must be outlined on all CT slices in which these structures are visible. 
 
Morphological and topographical information given by clinical examination, mpMRI and PET/CT, must be 
integrated to delineate the target volumes. Rigid or deformable co-registration is allowed. 
 
3.4.2.2 Volumes 
 
3.4.2.2.1 Definition of target volumes (refer to appendix 2 & 3): 
o 
The Gross Tumor Volume of the suspicious local recurrence (GTV) is defined by the physician as all 
known gross disease before any treatment as defined by the CT/MRI images and PET scan using rigid 
or deformable fusion) and/or clinical information. 
  
o 
The Planning Target Volumes (PTV) will provide margin around the GTV to compensate for variability 
in daily treatment set-up and internal motion due to breathing or motion during treatment. The PTV 
should encompass the GTV with a margin of 5 mm in all directions.  
 
3.4.2.2.2 Organs at Risk (OAR) 
o 
Delineation: 
The OAR should be delineated according to the RTOG guidelines. For more details please see RTOG/NRG 
Oncology web site to view the normal pelvis atlas for examples of normal tissue contours  
(http://www.rtog.org/CoreLab/ContouringAtlases/MaleRTOGNormalPelvisAtlas.aspx). 
 
Bladder: this organ is defined by the external wall (5-mm thickness), delineated on each slide, from the 
dome to the bladder neck and the start of the VUA. 
VUA and distal urethra: from the bladder neck to the distal urethra inside the penile bulb using the mpMRI 
sequences. A 2-mm isotropic margin is added around these structures to create a PRV volume.  
Rectum: defined by the external wall from the recto-sigmoid junction to ischial tuberosities (5-mm 
thickness). 
Femoral heads: delineated from the top of the hip joint to the small trochanter. 
Bowel bag: from the most inferior small or large bowel loop to 1 cm at minimum above PTV for coplanar 
beam plans, or more if non-coplanar beams or tomotherapy plans are used. 
 
o 
Dose constraints to OAR: 
 It is strongly recommended that dose constraints are not exceeded. If a dose constraint cannot be achieved 
due to overlap of the target with an OAR or PRV, the dose per fraction can be lowered or the target coverage 
compromised in order to meet the constraint. 
 
Organ at risk 
Dose constraint 
Aim 
Rectal wall 
V18.1 Gy 
V29 Gy 
V36 Gy 
<50% 
<20% 
<1cc 

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Bladder wall 
V18.1 Gy 
V37 Gy 
<40% 
<10cc 
PRV_VUA and distal 
urethra 
V41 Gy 
<1cc 
Femoral heads 
V14.5 Gy 
<5% 
Penile bulb 
V29.5 Gy 
<50% 
Bowel 
V18.1 Gy 
V30 Gy 
<5cc 
<1cc 
 
3.4.2.3 Treatment technique. 
Intensity modulated radiotherapy (IMRT) or use of rotational techniques is mandatory. By definition only 
dosimetry obtained by inversed treatment planning is considered as IMRT. IMRT may be performed by 
using Step-and-Shoot-Technique, Sliding-Window-Technique or Volumetric Modulated Arc Therapy 
(VMAT), including MRI-guided radiation therapy systems (MRIdian® or Elekta Unity®). Treatment with 
Cyberknife® is allowed (implant of radiopaque ﬁducial markers 1 week before the planning CT scan is 
mandatory). 
 
3.4.2.4 Dose computation. 
o 
Any treatment planning system, capable of 3D-dose computation using a convolution algorithm, 
will be used. The PTV may be treated with any combination of coplanar or non-coplanar fields 
shaped to deliver the specified dose while minimizing dose to the normal tissue OAR.   Field 
arrangements will be determined by 3D planning to produce the optimal conformal plan in 
accordance with volume definitions. The treatment plan used for each patient will be based on an 
analysis of the volumetric dose including DVH analyses of the PTV and critical OAR.  Each field is 
to be treated daily. 
 
o 
The PTVs should be outlined in all relevant planes. The dose distribution should be shown at least 
in the plane through the beam axes.  
 
o 
Dose distribution is obtained in a 3-dimensional pattern with Dose Volume Histogram (DVH). DVH 
are to be used for assessing dose to the PTVs and all normal tissues at risk. 
 
3.4.2.5. Equipment and tools.  
o 
Both a linear accelerator, tomotherapy and Cyberknife is allowed. 
 
3.4.2.6 Dose prescription. 
A total dose of 34 Gy (80% of the maximal dose) will be delivered in 5 fractions and fractions every second 
day (NTD2Gy 80 Gy α/β=1.5Gy for tumor control and 66.6 Gy α/β=3Gy for late toxicity). Treatment will be 
prescribed to the periphery of the target (80% of the dose (=34Gy), should cover 90% of the PTV) covering 
the PTV. A maximal dose of 42.5 Gy is allowed to GTV. The priority will be given to the respect of dose 
constraints over PTV coverage.  
 
3.4.2.7 Treatment Verification. 
Daily patient set-up shall be performed using laser alignment to reference marks on the skin of the patient. 
Daily cone-beam CT set-up and on-line correction of patient’s position is mandatory. If multiple targets will 
be irradiated with multiple isocenters, a CBCT prior to every treatment for every isocenter is mandatory. 
Patient immobilization devices can be used according to the institutional policy. 
3.4.3 Androgen deprivation therapy 

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o 
All patients should receive an LHRH-agonist or antagonist for a duration of 6 months according 
to institutional policy. Intramuscular, subcutaneous, or oral forms are all allowed."  
o 
In case of LHRH-agonist flare prevention with an anti-androgen is recommended for at least 5 
days prior to the first injection of the agonist and should not be continued for longer than 15 
days of the 1st month duration. 
o 
ADT should start no later than the 1st SBRT fraction and no earlier than 2 weeks before the 
start of radiotherapy.  
o 
Palliative ADT should not be started for biochemical progression without documented clinical 
progression. In case of symptomatic progression, palliative ADT is mandatory. In case of 
clinical asymptomatic progression, delayed ADT until progression to a symptomatic state is 
allowed in well-informed men (EAU 2016 guidelines). In general, we would recommend to start 
ADT in asymptomatic patients only if conventional imaging would confirm clinical progression. 
So we would not recommend the start of ADT for PET-positive lesions not suspicious on 
conventional imaging (CT/MRI/bone scintigraphy).  
o 
ADT-related toxicity should be managed according to Nguyen et al. Eur Urol. 2015 
May;67(5):825-36.  
4 
STUDY POPULATION AND STUDY PROCEDURES 
4.1 Inclusion and exclusion criteria, justification of study population 
Inclusion criteria: 
1. Written informed consent according to ICH/GCP regulations before registration and prior to any 
trial specific procedures  
2. Age ≥ 18 years at time of registration  
3. WHO performance status 0-1 
4. Lymph node negative adenocarcinoma of the prostate treated with radical prostatectomy (RP) at 
least 6 months before trial registration. Tumor stage pT2a-3b, R0-1, pN0 or cN0 according to the 
UICC TNM 2009. 
5. Evidence of measurable local recurrence at the prostate bed detected by PSMA PET/CT and 
mpMRI within the last 3 months. In case of unclear local recurrence, a biopsy confirmation is 
recommended.  
6. Patient must have non-metastatic (N0, M0) disease, as defined by a lack of nodal or distant 
metastases seen on PSMA PET/CT scan  
7. Patients must have non-castrate levels of serum testosterone (≥50 ng/dL). 
8. Patients must not have previously received hormonal therapy (LHRH agonists, antiandrogen, or 
both, or bilateral orchiectomy). 
9. Absence of any psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should be discussed 
with the patient before registration in the trial 
Exclusion criteria: 
 
1. Persistent PSA (> 0.4 ng/mL) 4 to 20 weeks after RP  
2. Previous hematologic or primary solid malignancy within 3 years prior registration with the 
exception of curatively treated localized non-melanoma skin cancer  
3. Usage of products known to affect PSA levels within 4 weeks prior to start of trial treatment phase 
including any form of androgen suppression agents and androgen deprivation therapy  
4. Bilateral hip prosthesis  
5. Severe or active co-morbidity likely to impact on the advisability of salvage RT  
6. Treatment with any experimental drug or participation within a clinical trial within 30 days prior to 
registration (exception: concurrent participation in the biobank studies is allowed 
4.2 Recruitment and screening: 

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Patient registration will only be accepted from authorized investigators.  
Prior to registration, the following steps have to be taken:  
- 
 Fill in the patient screening (used for monitoring potentially eligible patients, and will be destroyed 
after the end of the accrual period. Screening list is not a part of the CRFs), enrollment and 
identification lists.  
- 
Check the eligibility criteria  
- 
Obtain signed and dated written informed consent from the patient prior to any protocol-specific 
procedure according to ICH/GCP and local guidelines.  
- 
Patients must complete the pre-treatment of quality of life assessment per protocol  
 
Only electronic case report forms (eCRF) will be used. The use of worksheets is allowed if the copies of 
the templates are documented in the trial master file (TMF). The used worksheets must be kept with the 
patient charts. 
Registration is done via Internet ‘https://secutrial.insel.ch’. SecuTrial (interActive Systems) will be used as 
database. In case of problems investigators can phone the study coordinator from Monday through Friday. 
For technical difficulties, investigators are recommended to contact data management of CTU Bern 
E-mail: datamanagement@ctu.unibe.ch 
In order to receive authorization for online registration/data entry, sites must send a copy of the completed 
staff list to the Sponsor. The accesses to SecuTrial are created individually for each person. Login details 
for the online database will be sent to authorized persons. Each PI will confirm the accuracy and 
completeness of the data at the end of the study. 
 
4.3 Study procedures 
 
Schedule of assessments (Table 1) 
 
Required investigation  
Inclusion 
Treatment
1 Months 
after RT  
3 Months   
after RT  
6 Months   
after RT 
Every 6 Months   
till end of 2nd 
year after RT 
then once per 
year till 60 
months 
Within 12
weeks prior 
registration  
Within 4 
weeks prior 
registration 
Eligibity  Check
x
Signed informed consent
x
Record prior history
x
Visits 
 
 
 
 
 
 
Physical Examination
x
x
x
x
x
x
Biochemistry (Blood 
Samples)* 
 
 
 
 
 
 
PSA 
x 
 
x
x 
x 
x 
Testosterone 
x 
 
x 
x 
x 
x 
Radiology 
 
 
 
 
 
 
PSMA PET
x
MRI 
x
Radiotherapy
Treatment planning
x
Record Planning 
results 
 
x 
 
 
 
 
Adverse Events
Baseline toxicity 
x

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Acute toxicity
x
x
x
Late toxicity
x
x
EORTC QoL questionnaire
QLQ-C30
x
x
x
x
x
QLQ-PR25
x
x
x
x
x
* Blood samples 
The obtained blood samples are used only for PSA and testosterone values. The measurement for this 
labs is conducted within the local hospital laboratory of each participating center and the rest samples will 
be disposed afterwards. No blood will be collected or stored or used for other research purposes within 
the frame of this trial. 
4.4 Withdrawal and discontinuation 
 
Patients have the right to discontinue their participation in the trial for any reason and at any time, without 
prejudice to further treatment. Patients who refuse further trial treatment will be transferred to follow-up 
phase and continue to receive the follow-up assessments as scheduled. Patients who withdraw their 
consent (i.e. refuse further data collection), will be informed that all data and samples collected until the 
time point of their withdrawal will be kept coded and used. For the patient’s security, a last examination 
should be performed. 
 
Patients may be withdrawn at any time from trial treatment at the discretion of the treating physician 
or the investigator due to a SAE, or based on any other relevant medical condition. The patient then 
will be transferred to the follow-up phase and continue to receive the follow-up assessments as 
scheduled. 
5 STATISTICS AND METHODOLOGY 
5.1. Statistical analysis plan and sample size calculation 
According to the published prospective trials and retrospective series reporting the outcome of the 
normofractionated SRT, we define biochemical relapse free survival at 2 years of 60% as poor and of 80% 
as promising outcome that would justify further investigation. We will therefore test the null hypothesis that 
the biochemical relapse free survival at 2 years is lower than 60% against the alternative that it is at least 
80%. Based on a one-sample binomial exact test with a one-sided alpha of 5%, 36 patients are required to 
reach a power of 80%, not taking into account patients lost to follow-up. The null hypothesis will be rejected 
if at least 27 patients show biochemical relapse free survival at 2 years. 
 
We will control the safety of the intervention during the trial by assessing acute side effects (grade 3 or 
higher) at 90 days after 12 and 24 patients. The trial will be stopped if there is evidence that the proportion 
of patients with acute side effects (grade 3 or higher) is larger than 27%, the proportion observed that will 
be tested using one-sample binomial exact tests with a one-sided alpha of 5%. 

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Time-to-event outcomes will be analyzed using Kaplan-Meier-curves, the proportion of responders at 1 and 
2 years, and the restricted mean survival time at 1 and 2 years with 95% confidence interval. Binary 
outcomes will be reported using absolute and relative frequencies with 95% confidence intervals. 
 
The probability of biochemical relapse free survival and metastasis-free survival will be estimated using the 
Kaplan-Meier method. Cox proportional hazards models will be fit to assess the effects of treatment and 
baseline clinical and pathologic features (such as PSA, PSA doubling time, Gleason score etc) on 
biochemical relapse free survival and metastasis free survival   
5.2. Definition of endpoints 
5.2.1 Biochemical relapse free survival (primary endpoint) 
 
The initial PSA at time of registration will be the starting point. Freedom from biochemical progression is 
counted from the day of registration to the day of either first recorded biochemical progression as defined 
below, clinical progression or death due to clinical progression. Patients not experiencing a biochemical or 
clinical failure or death due to clinical progression are censored at time of last assessment.  
A biochemical recurrence is defined by any confirmed PSA rise above 0.20 ng/mL with a confirmatory rise 
at least 2 weeks later. For those patients whose PSA does not drop below 0.20 ng/mL at time of first 
response assessment at 3 months are considered as non-responders to treatment and are considered to 
have a biochemical recurrence in case a second measurement at least 2 weeks later confirms a rising PSA 
above this level. 
 
5.2.2 Metastasis-free survival:  
 
Metastasis-free survival is defined as time between registration and the appearance of a metastatic 
recurrence (any M1) as suggested by PET-CT or death due to any cause. Patients without any of the events 
of interest (including those with biochemical relapse only) are censored at the date of the last follow-up. 
Second cancers are not considered events in terms of this endpoint. In case of biochemical progression, 
re-staging will be made with PET-CT imaging preferably with the same tracer used before registration. In 
case of negative PET findings at biochemical relapse, a new PET imaging should be repeated on a 6-
montly basis or earlier in case clinically indicated. 
 

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5.2.3 Clinical progression-free survival: 
 
Clinical progression-free survival is defined as time between registration and the appearance of a new 
recurrence (any N1 or M1) as suggested by PET-CT, symptoms related to progressive PC, or death due 
to any cause.   
- 
A local recurrence is defined as the appearance of evidence of a recurrence within the prostate 
bed. Confirmation of the recurrence by biopsy is recommended, whenever possible.  
- 
A regional nodal recurrence is defined as a radiographic (PET-CT) evidence of a lymphadenopathy 
in the pelvis in a patient without the diagnosis of hematologic/lymphatic disorder associated with 
lymphadenopathy or if there is histopathological evidence. Histologic confirmation is not required 
although recommended, especially in the absence of biochemical recurrence.  
- 
Distant recurrence is defined as the appearance of distant metastases (M1a, M1b, M1c) outside 
the pelvis evidenced by PET-CT.  Patients without any of the events of interest (including those 
with biochemical relapse only) are censored at the date of the last follow-up.  
- 
Second cancers are not considered events in terms of this endpoint. Detailed analysis per subsite 
of recurrence (local, regional and distant) with time-to-event analysis will be performed In case of 
biochemical progression, re-staging will be made with PET-CT imaging preferably with the same 
tracer used before registration. In case of negative PET findings at biochemical relapse, repeat 
PET imaging should be repeated on a 6-montly basis or earlier in case clinically indicated. 
 
 
5.2.4 Acute and late toxicity: 
 
Radiotherapy toxicity will be assessed according to NCI CTCAE v5.0. Special attention shall be given to 
diarrhea, fecal incontinence, proctitis, rectal hemorrhage, rectal pain, hematuria, urinary frequency, urinary 
urgency, urinary retention, urinary incontinence, cystitis non-infective and erectile dysfunction. Acute 
toxicity is defined as occurring during treatment and up to 3 months after completion of treatment. Late 
toxicity is defined as occurring later than 3 months after end of treatment. 
 
5.2.5 Quality of life: 
All patients registered into this trial are to complete QoL questionnaires at the defined timepoints (see table 
1). A longitudinal design is used. Patients are asked to complete a QoL questionnaire. 
The EORTC QoL questionnaire (QLQ) C-30 Core questionnaire (version 3) and the prostate cancer module 
EORTC QLQ PR25 will be used. The QoL questionnaire including all these instruments will be provided for 
the major languages spoken in the participating centers. 
5.3. Handling of missing data and drop-outs 
We expect that all registered patients have complete baseline data. All patients that have at least one 
outcome assessment can be considered in repeated-measures analyses. Models will implicitly correct for 
missing data based on the missing at random mechanism. If there are patients with no outcome data at all, 
we will perform multiple imputations. For the time-to-event analysis, patient drop-outs will be accounted for 
by censoring. 
6 Regulatory Aspects and Safety 
6.1 Local regulations / Declaration of Helsinki 
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, the 
Swiss Law and Swiss regulatory authority’s requirements. The CEC and regulatory authorities will receive 
annual safety and interim reports and be informed about study stop/end in agreement with local 
requirements. 

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6.2 (Serious) Adverse Events and notification of safety and protective measures 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation subject 
which does not necessarily have a causal relationship with the trial procedure. An AE can therefore be any 
unfavourable or unintended finding, symptom, or disease temporally associated with a trial procedure, 
whether or not related to it. 
In this trial only treatment (ADT and radiotherapy) related (serious) adverse events need to be collected.  
 
A Serious Adverse Event (SAE) (ClinO, Art. 63) is any untoward medical occurrence that 
- 
Results in death or is life-threatening, 
- 
Requires in-patient hospitalisation or prolongation of existing hospitalisation, 
- 
Results in persistent or significant disability or incapacity, or 
- 
Causes a congenital anomaly or birth defect  
 
Both Investigator and Sponsor-Investigator make a causality assessment of the event to the trial 
intervention, (see table below based on the terms given in ICH E2A guidelines). Any event assessed as 
possibly, probably or definitely related is classified as related to the trial intervention. 
 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Both Investigator and Sponsor-Investigator make a severity assessment of the event as mild, moderate or 
severe. Mild means the complication is tolerable, moderate means it interferes with daily activities and 
severe means it renders daily activities impossible. 
 
Reporting of SAEs (see ClinO, Art. 63) 

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All treatment related SAEs are documented and reported via SAE form and eCRF immediately and to be 
sent (within a maximum of 24 hours) to the Sponsor-Investigator of the study via Email to 
hypofocalsrt@insel.ch. 
  
If it cannot be excluded that the SAE occurring in Switzerland is attributable to the intervention under 
investigation, the Investigator reports it to the Ethics Committee via BASEC within 15 days. 
 
If the SAE occurs at one of the study sites, the coordinating Investigator reports the events to the Ethics 
Committee concerned, within 15 days. 
 
Follow up of (Serious) Adverse Events 
All subjects with SAE must be followed up for outcome. The Ethics Committee must be informed according 
regulations.  
 
Notification of safety and protective measures (see ClinO, Art 62, b) 
If immediate safety and protective measures have to be taken during the conduct of the study, the 
investigator notifies the Ethics committee of these measures, and of the circumstances necessitating them, 
within 7 days. 
6.3 (Periodic) safety reporting 
An annual safety report (ASR/DSUR) is submitted once a year to the local Ethics Committee by the 
Investigator (ClinO, Art. 43 Abs). 
6.4 Radiation 
If the permitted dose guidance value (5 mSv per year if no direct benefit is expected for the participants) is 
exceeded at any time, the local Investigator notifies the Ethics Committee via BASEC within 7 working days 
of it becoming known (see ClinO, Art. 44). 
6.5 Pregnancy 
Since this cohort only consists of male patients, pregnancy of the participant is not possible. However, 
patients are counselled regarding strict birth control for at least 6 months after treatment for themselves 
and their partners.  
 
6.6 Amendments 
Substantial changes to the study setup and study organization, the protocol and relevant study documents 
are submitted to the Ethics Committee for approval before implementation. Under emergency 
circumstances, deviations from the protocol to protect the rights, safety and well-being of human subjects 
may proceed without prior approval of the Ethics Committee. Such deviations shall be documented and 
reported to the Ethics Committee as soon as possible. 
 
Substantial amendments are changes that affect the safety, health, rights and obligations of participants, 
changes in the protocol that affect study objective(s) or central research topic, changes of study site(s) or 
of study leader and sponsor (ClinO, Art. 29). 
A list of all non-substantial amendments will be submitted once a year to the competent EC together with 

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the ASR. 
6.7 (Premature) termination of study 
The sponsor-investigator has the right to close this study (or, if applicable, individual segments thereof, 
e.g., recruitment) at any time, which may be due but not limited to the following reasons: 
 
If risk-benefit ratio becomes unacceptable owing to, for example, 
 
Safety findings from this study, e.g., SAEs, 
 
Results of parallel clinical studies, 
 
Results of parallel animal studies (e.g., toxicity, teratogenicity, carcinogenicity, or reproduction toxicity), 
 
If the study conduct, e.g., recruitment rate, drop-out rate, data quality, protocol compliance, does not 
suggest a proper completion of the trial within a reasonable time frame. 
 
The Investigator has the right to close his centre at any time. For any of the above closures, the following 
applies: 
 
Closures should occur only after consultation between involved parties, 
 
All affected institutions, e.g., IEC(s) or IRB(s), competent authority, study centre, head of study centre 
must be informed as applicable according to local law, 
 
The Investigator will retain all study materials unless notification will be given by the sponsor for 
destruction, 
 
In case of a partial study closure, ongoing patients, including those in post study follow-up, must be 
cared for in an ethical manner. 
 
Upon regular study termination, the Ethics Committee is notified via BASEC within 90 days (ClinO, Art. 38).  
Upon premature study termination or study interruption, the Ethics Committee is notified via BASEC within 
15 days (ClinO, Art. 38). 
A final report is submitted to the Ethics Committee via BASEC within a year after completion or 
discontinuation of the study, unless a longer period is specified in the protocol (ClinO, Art. 38) 
 
Essential documents will be archived safely and securely in such a way that ensures that they are readily 
available upon authorities’ request. Patient (hospital) files will be archived according to local regulations 
and in accordance with the maximum period of time permitted by the hospital.  
 
After termination of the study, all study files must be archived according to the Ordinance on Clinical Trials 
in Human Research (ClinO), Art. 45:  
“1 The sponsor must retain all data relating to the clinical trial … at least for ten years after the completion 
or discontinuation of the clinical trial.  
2 The investigator must retain all documents required for the identification and follow-up of participants, and 
all other original data, for at least ten years after the completion or discontinuation of the clinical trial. 
6.8 Insurance 
Insurance will be provided by the University Hospital of Bern, Inselspital. A copy of the certificate is filed in 
each investigator site file and the trial master file. 
 

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7 
FURTHER ASPECTS 
 
7.1 Overall ethical considerations 
7.1.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either the 
Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh amendments) or the 
laws and regulations of the country, whichever provides the greatest protection of the patient. 
The protocol has been written, and the study will be conducted according to the ICH Harmonized Tripartite 
Guideline 
for 
Good 
Clinical 
Practice 
(http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/good-clinical-practice.html). 
The protocol will be approved by the Local, Regional or National Ethics Committees. 
7.1.2 Subject identification 
Trial-related data of the patient will be provided in a coded manner to the Sponsor. The names of the 
patients will not be disclosed to the University Hospital Bern, Switzerland. A sequential UPN will be 
attributed to each patient registered into the trial. Identification of patients must be guaranteed at the center. 
In order to avoid identification errors the UPN have to be provided on the CRF. Use the patient screening, 
enrollment and identification list. Patient confidentiality will be maintained according to applicable 
legislation. Patients must be informed of, and agree to, data transfer and handling, in accordance with local 
regulations. 
7.1.3 Informed consent 
All patients will be informed of the aims of the study, the possible adverse events, the procedures and 
possible hazards to which he/she will be exposed, and the mechanism of treatment allocation. They will be 
informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed 
for trial purposes by authorized individuals other than their treating physician.  
It is the responsibility of the individual investigator to translate the enclosed informed consent document. 
The translated version should be dated and version controlled.  
It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further 
participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. 
Documented informed consent must be obtained for all patients included in the study before they are 
registered. This must be done in accordance with the national and local regulatory requirements. 
7.2 Risk-benefit assessment  
This trial investigates the use of ultrahypofractionated SRT for patients with biochemical progression after 
prostatectomy who developed isolated local recurrence with no evidence of metastasis. For this group of 
patients, conventional SRT is the standard of care. Previous studies have shown that ultrahypofractionated 
RT is safe and can be considered as standard of care in treatment of primary prostate cancer. The use of 
ultrahypofractionated SRT was reported in various retrospective series and phase I trials.   
Patients presenting disease progression with radiological evidence of disease either loco-regionally and/or 
systemically (bone and/or lymph nodes) could undergo biopsy depending on clinical judgment, i.e. if the 
risks of the biopsy procedure are clinically acceptable. This will be discussed with patients at an individual 
basis. 

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8 
QUALITY CONTROL AND DATA PROTECTION 
8.1 Quality measures  
For quality assurance the sponsor, the Ethics Committee or an independent trial monitor may visit the 
research sites. Direct access to the source data and all study related files is granted on such occasions. All 
involved parties keep the participant data strictly confidential.  
8.2 Data recording and source data 
The investigators will maintain appropriate medical and research records for this trial, in compliance with 
ICH-GCP (E6) and regulatory and institutional requirements for the protection of confidentiality of subjects. 
SecuTrial (interActive Systems) will be used as database. The principal investigator, sub-investigator, and 
clinical research nurses or coordinators will have access to the records.  
The principal investigators will permit authorized representatives of the Sponsor and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety and progress. 
 
8.2.1 Case Report Forms  
The CRFs will be electronic (eCRF). All data requested on the CRFs must be recorded and the recorded 
data should be consistent with the source documents or the discrepancies should be explained. The 
Investigator should ensure the accuracy, completeness, and timeliness of the data reported in the CRF and 
all other required reports. Generally, the CRFs should be completed within one week of completion of a 
patient visit.  
 
8.2.2 Specification of source documents  
Source documents must be available at the site to document the existence of the study participants and 
must include the original documents relating to the study, as well as the medical treatment and medical 
history of the participant. Where source documents for specific entries in the CRF are not available, this 
must be explicitly documented in a note to file. Any data recorded directly in the CRF will be considered as 
source data. Any change or correction to source data should be dated, initialed, and explained (if 
necessary) and should not obscure the original entry. The use of worksheets is allowed if the copies of the 
templates are documented in the trial master file (TMF). The used worksheets must be kept with the patient 
charts.  
For all data captured in the CRF, the location of the source should be documented on a list of source 
documents, which will be stored in the investigator site file at each study site. Only the local investigator, 
the responsible study nurse team, the study monitor and the authorities can access this document. 
 
8.2.3 Record keeping / archiving  
Essential documents (written and electronic), including images and radiotherapy plans must be retained for 
a period of at least 10 years from the completion or premature termination of the trial. The investigators 
should take measures to prevent accidental or premature destruction of these documents. 
8.3 Confidentiality and coding 

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Trial and participant data will be handled with uttermost discretion and is only accessible to authorised 
personnel who require the data to fulfil their duties within the scope of the study. On the CRFs and other 
study specific documents, participants are only identified by a unique participant number.  
 
The investigator ensures anonymity of the patients; patients will not be identified by names in any 
documents. Signed informed consent forms and patient enrollment log will be kept strictly confidential to 
enable patient identification at the site. 
8.4 Retention and destruction of study data  
All study data are archived for 10 years after study termination or premature termination of the 
study. 
9  MONITORING AND REGISTRATION 
For quality control of the study conduct and data retrieval, all study sites will be visited on-site by 
appropriately trained and qualified monitors. Any findings and comments will be documented in site visit 
reports and communicated to the local PI and to the sponsor as applicable. Investigators at the participating 
study sites will support the monitor in his/her activities. Prior to study start (first participant enrolled) a plan 
detailing all monitoring-related procedures will be developed.  
All source data and relevant documents will be accessible to monitors and questions of monitors are 
answered during site visits. 
10. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
Debiopharm AG and Berger-Janser Stiftung support financially this clinical trial. 
The results will be published in the name of the Hypo-FOCAL-SRT trial in a peer reviewed international 
journal on behalf of all collaborators. All presentations and publications, including abstracts, relating to the 
trial must be authorized by the Hypo-FOCAL-SRT trial steering committee (all co-investigators listed in the 
protocol). Participating centers should ask for the approval of the trial steering committee to use any data 
related to the patients registered in the trial. 
The investigators declare that they have no conflict of interest. 
 
 
11 REFERENCES 
 
1.  
Hamdy FC, Donovan JL, Lane JA, et al. 10-Year Outcomes after Monitoring, 
Surgery, or Radiotherapy for Localized  Prostate Cancer. N Engl J Med. 
2016;375(15):1415-1424. doi:10.1056/NEJMoa1606220 
2.  
Han M, Partin AW, Zahurak M, Piantadosi S, Epstein JI, Walsh PC. Biochemical 
(prostate specific antigen) recurrence probability following radical  prostatectomy 
for clinically localized prostate cancer. J Urol. 2003;169(2):517-523. 
doi:10.1097/01.ju.0000045749.90353.c7 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
30 / 43 
3.  
Gandaglia G, Briganti A, Clarke N, et al. Adjuvant and Salvage Radiotherapy after 
Radical Prostatectomy in Prostate Cancer  Patients. Eur Urol. 2017;72(5):689-
709. doi:10.1016/j.eururo.2017.01.039 
4.  
Bolla M, Poppel H Van, Collette L, et al. Postoperative radiotherapy after radical 
prostatectomy: a randomised controlled trial (EORTC trial 22911). 2005;366:572-
578. 
5.  
Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical 
prostatectomy for high-risk prostate  cancer: long-term results of a randomised 
controlled trial (EORTC trial 22911). Lancet (London, England). 
2012;380(9858):2018-2027. doi:10.1016/S0140-6736(12)61253-7 
6.  
Thompson IMJ, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for 
pathologically advanced prostate cancer: a randomized  clinical trial. JAMA. 
2006;296(19):2329-2335. doi:10.1001/jama.296.19.2329 
7.  
Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant Radiotherapy for 
Pathological T3N0M0 Prostate Cancer Significantly Reduces Risk of Metastases 
and Improves Survival: Long-Term Followup of a Randomized Clinical Trial. J 
Urol. 2009;181(3):956-962. doi:10.1016/j.juro.2008.11.032 
8.  
Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy 
after radical prostatectomy compared  with radical prostatectomy alone in pT3 
prostate cancer with postoperative undetectable prostate-specific antigen: ARO 
96-02/AUO AP 09/95. J Clin Oncol  Off J Am Soc Clin  Oncol. 2009;27(18):2924-
2930. doi:10.1200/JCO.2008.18.9563 
9.  
Kneebone A, Fraser-Browne C, Duchesne GM, et al. Adjuvant radiotherapy 
versus early salvage radiotherapy following radical  prostatectomy (TROG 
08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial. 
Lancet Oncol. 2020;21(10):1331-1340. doi:10.1016/S1470-2045(20)30456-3 
10.  Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical 
prostatectomy (RADICALS-RT): a randomised,  controlled phase 3 trial. Lancet 
(London, England). 2020;396(10260):1413-1421. doi:10.1016/S0140-
6736(20)31553-1 
11.  Sargos P, Chabaud S, Latorzeff I, et al. Adjuvant radiotherapy versus early 
salvage radiotherapy plus short-term androgen  deprivation therapy in men with 
localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a 
randomised, phase 3 trial. Lancet Oncol. 2020;21(10):1341-1352. 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
31 / 43 
doi:10.1016/S1470-2045(20)30454-X 
12.  Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for 
the treatment of localised and locally  advanced prostate cancer: a prospectively 
planned systematic review and meta-analysis of aggregate data. Lancet (London, 
England). 2020;396(10260):1422-1431. doi:10.1016/S0140-6736(20)31952-8 
13.  Boike TP, Lotan Y, Cho LC, et al. Phase I dose-escalation study of stereotactic 
body radiation therapy for low- and  intermediate-risk prostate cancer. J Clin 
Oncol  Off J Am Soc  Clin Oncol. 2011;29(15):2020-2026. 
doi:10.1200/JCO.2010.31.4377 
14.  Brand DH, Tree AC, Ostler P, et al. Intensity-modulated fractionated radiotherapy 
versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity 
findings from an international, randomised, open-label, phase 3, non-inferiority 
trial. Lancet Oncol. 2019;20(11):1531-1543. doi:10.1016/S1470-2045(19)30569-8 
15.  Chen LN, Suy S, Uhm S, et al. Stereotactic body radiation therapy (SBRT) for 
clinically localized prostate  cancer: the Georgetown University experience. 
Radiat Oncol. 2013;8:58. doi:10.1186/1748-717X-8-58 
16.  Jackson WC, Silva J, Hartman HE, et al. Stereotactic Body Radiation Therapy for 
Localized Prostate Cancer : A Systematic Review and Meta-Analysis of Over 6 , 
000 Patients Treated On Prospective Studies. Radiat Oncol Biol. 
2019;104(4):778-789. doi:10.1016/j.ijrobp.2019.03.051 
17.  King CR, Brooks JD, Gill H, Presti JCJ. Long-term outcomes from a prospective 
trial of stereotactic body radiotherapy for  low-risk prostate cancer. Int J Radiat 
Oncol Biol Phys. 2012;82(2):877-882. doi:10.1016/j.ijrobp.2010.11.054 
18.  Kotecha R, Djemil T, Tendulkar RD, et al. Dose-Escalated Stereotactic Body 
Radiation Therapy for Patients With  Intermediate- and High-Risk Prostate 
Cancer: Initial Dosimetry Analysis and Patient Outcomes. Int J Radiat Oncol Biol 
Phys. 2016;95(3):960-964. doi:10.1016/j.ijrobp.2016.02.009 
19.  Meier RM, Bloch DA, Cotrutz C, et al. Multicenter Trial of Stereotactic Body 
Radiation Therapy for Low- and  Intermediate-Risk Prostate Cancer: Survival and 
Toxicity Endpoints. Int J Radiat Oncol Biol Phys. 2018;102(2):296-303. 
doi:10.1016/j.ijrobp.2018.05.040 
20.  Zilli T, Franzese C, Bottero M, et al. Single fraction urethra-sparing prostate 
cancer SBRT: Phase I results of the ONE  SHOT trial. Radiother Oncol  J Eur Soc 
Ther  Radiol Oncol. 2019;139:83-86. doi:10.1016/j.radonc.2019.07.018 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
32 / 43 
21.  Bauman G, Ferguson M, Lock M, et al. A Phase 1/2 Trial of Brief Androgen 
Suppression and Stereotactic Radiation  Therapy (FASTR) for High-Risk Prostate 
Cancer. Int J Radiat Oncol Biol Phys. 2015;92(4):856-862. 
doi:10.1016/j.ijrobp.2015.02.046 
22.  Callan L, Bauman G, Chen J, et al. A Phase I/II Trial of Fairly Brief Androgen 
Suppression and Stereotactic  Radiation Therapy for High-Risk Prostate Cancer 
(FASTR-2): Preliminary Results and Toxicity Analysis. Adv Radiat Oncol. 
2019;4(4):668-673. doi:10.1016/j.adro.2019.07.007 
23.  Foerster R, Zwahlen DR, Buchali A, et al. Stereotactic Body Radiotherapy for 
High-Risk Prostate Cancer: A Systematic  Review. Cancers (Basel). 2021;13(4). 
doi:10.3390/cancers13040759 
24.  Murthy V, Gupta M, Mulye G, et al. Early Results of Extreme Hypofractionation 
Using Stereotactic Body Radiation  Therapy for High-risk, Very High-risk and 
Node-positive Prostate Cancer. Clin Oncol (R Coll Radiol). 2018;30(7):442-447. 
doi:10.1016/j.clon.2018.03.004 
25.  Widmark A, Gunnlaugsson A, Beckman L, 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 (London, 
England). 2019;394(10196):385-395. doi:10.1016/S0140-6736(19)31131-6 
26.  Zilli T, Jorcano S, Bral S, et al. Once-a-week or every-other-day urethra-sparing 
prostate cancer stereotactic body  radiotherapy, a randomized phase II trial: 18 
months follow-up results. Cancer Med. 2020;9(9):3097-3106. 
doi:10.1002/cam4.2966 
27.  Brenner DJ, Martinez AA, Edmundson GK, Mitchell C, Thames HD, Armour EP. 
Direct evidence that prostate tumors show high sensitivity to fractionation (low  
alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol 
Phys. 2002;52(1):6-13. doi:10.1016/s0360-3016(01)02664-5 
28.  Miralbell R, Roberts SA, Zubizarreta E, Hendry JH. Dose-fractionation sensitivity 
of prostate cancer deduced from radiotherapy  outcomes of 5,969 patients in 
seven international institutional datasets: α/β = 1.4 (0.9-2.2) Gy. Int J Radiat 
Oncol Biol Phys. 2012;82(1):e17-24. doi:10.1016/j.ijrobp.2010.10.075 
29.  Barra S, Belgioia L, Marcenaro M, et al. Moderate hypofractionated radiotherapy 
after prostatectomy for cancer patients:  toxicity and clinical outcome. Cancer 
Manag Res. 2018;10:473-480. doi:10.2147/CMAR.S146131 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
33 / 43 
30.  Cozzarini C, Fiorino C, Deantoni C, et al. Higher-than-expected severe (Grade 3-
4) late urinary toxicity after  postprostatectomy hypofractionated radiotherapy: a 
single-institution analysis of 1176 patients. Eur Urol. 2014;66(6):1024-1030. 
doi:10.1016/j.eururo.2014.06.012 
31.  Cozzarini C, Fiorino C, Di Muzio N, et al. Hypofractionated adjuvant radiotherapy 
with helical tomotherapy after radical  prostatectomy: planning data and toxicity 
results of a Phase I-II study. Radiother Oncol  J Eur Soc Ther  Radiol Oncol. 
2008;88(1):26-33. doi:10.1016/j.radonc.2008.03.021 
32.  Fersino S, Tebano U, Mazzola R, et al. Moderate Hypofractionated 
Postprostatectomy Volumetric Modulated Arc Therapy With  Daily Image 
Guidance (VMAT-IGRT): A Mono-institutional Report on Feasibility and Acute 
Toxicity. Clin Genitourin Cancer. 2017;15(4):e667-e673. 
doi:10.1016/j.clgc.2017.01.025 
33.  Ippolito E, Cellini N, Digesù C, et al. Postoperative intensity-modulated 
radiotherapy with simultaneous integrated boost  in prostate cancer: a dose-
escalation trial. Urol Oncol. 2013;31(1):87-92. doi:10.1016/j.urolonc.2010.10.005 
34.  Katayama S, Striecker T, Kessel K, et al. Hypofractionated IMRT of the prostate 
bed after radical prostatectomy: acute  toxicity in the PRIAMOS-1 trial. Int J 
Radiat Oncol Biol Phys. 2014;90(4):926-933. doi:10.1016/j.ijrobp.2014.07.015 
35.  Krause S, Sterzing F, Neuhof D, Edler L, Debus J, Herfarth K. Hypofractionated 
helical intensity-modulated radiotherapy of the prostate bed  after prostatectomy 
with or without the pelvic lymph nodes - the PRIAMOS trial. BMC Cancer. 
2012;12:504. doi:10.1186/1471-2407-12-504 
36.  Kruser TJ, Jarrard DF, Graf AK, et al. Early hypofractionated salvage 
radiotherapy for postprostatectomy biochemical  recurrence. Cancer. 
2011;117(12):2629-2636. doi:10.1002/cncr.25824 
37.  Lewis SL, Patel P, Song H, et al. Image Guided Hypofractionated 
Postprostatectomy Intensity Modulated Radiation  Therapy for Prostate Cancer. 
Int J Radiat Oncol Biol Phys. 2016;94(3):605-611. 
doi:10.1016/j.ijrobp.2015.11.025 
38.  Massaccesi M, Cilla S, Deodato F, et al. Hypofractionated intensity-modulated 
radiotherapy with simultaneous integrated  boost after radical prostatectomy: 
preliminary results of a phase II trial. Anticancer Res. 2013;33(6):2785-2789. 
39.  Arcangeli S, Gambardella P, Agolli L, et al. Stereotactic body radiation therapy 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
34 / 43 
salvage reirradiation of radiorecurrent  prostatic carcinoma relapsed in the 
prostatic bed. Tumori. 2015;101(2):e57-9. doi:10.5301/tj.5000251 
40.  Ballas LK, Luo C, Chung E, et al. Phase 1 Trial of SBRT to the Prostate Fossa 
After Prostatectomy. Int J Radiat Oncol Biol Phys. 2019;104(1):50-60. 
doi:10.1016/j.ijrobp.2018.12.047 
41.  Caroli P, Colangione SP, De Giorgi U, et al. (68)Ga-PSMA-11 PET/CT-Guided 
Stereotactic Body Radiation Therapy Retreatment in  Prostate Cancer Patients 
with PSA Failure after Salvage Radiotherapy. Biomedicines. 2020;8(12). 
doi:10.3390/biomedicines8120536 
42.  Detti B, Bonomo P, Masi L, et al. CyberKnife stereotactic radiotherapy for isolated 
recurrence in the prostatic  bed. World J Urol. 2016;34(3):311-317. 
doi:10.1007/s00345-015-1613-5 
43.  Francolini G, Jereczek-Fossa BA, Di Cataldo V, et al. Stereotactic radiotherapy 
for prostate bed recurrence after prostatectomy, a  multicentric series. BJU Int. 
2020;125(3):417-425. doi:10.1111/bju.14924 
44.  Jereczek-Fossa BA, Rojas DP, Zerini D, et al. Reirradiation for isolated local 
recurrence of prostate cancer:  Mono-institutional series of 64 patients treated 
with salvage stereotactic body radiotherapy (SBRT). Br J Radiol. 
2019;92(1094):20180494. doi:10.1259/bjr.20180494 
45.  Olivier J, Basson L, Puech P, et al. Stereotactic Re-irradiation for Local 
Recurrence in the Prostatic Bed After  Prostatectomy: Preliminary Results. Front 
Oncol. 2019;9:71. doi:10.3389/fonc.2019.00071 
46.  Sampath S, Frankel P, Vecchio B Del, et al. Stereotactic Body Radiation Therapy 
to the Prostate Bed: Results of a Phase 1  Dose-Escalation Trial. Int J Radiat 
Oncol Biol Phys. 2020;106(3):537-545. doi:10.1016/j.ijrobp.2019.11.005 
47.  Scher N, Bauduceau O, Bollet M, et al. Stereotactic prostate focal reirradiation 
therapy for local recurrence:  preliminary results of Hartmann Oncology 
Radiotherapy Group. BJR open. 2019;1(1):20180027. doi:10.1259/bjro.20180027 
48.  Zerini D, Jereczek-Fossa BA, Fodor C, et al. Salvage image-guided intensity 
modulated or stereotactic body reirradiation of  local recurrence of prostate 
cancer. Br J Radiol. 2015;88(1052):20150197. doi:10.1259/bjr.20150197 
49.  Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality 
worldwide: sources, methods and major patterns in  GLOBOCAN 2012. Int J 
cancer. 2015;136(5):E359-86. doi:10.1002/ijc.29210 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
35 / 43 
50.  Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in 
primary treatment of localized prostate cancer. J Clin Oncol  Off J Am Soc Clin  
Oncol. 2010;28(7):1117-1123. doi:10.1200/JCO.2009.26.0133 
51.  Han M, Partin AW, Pound CR, Epstein JI, Walsh PC. Long-term biochemical 
disease-free and cancer-specific survival following anatomic  radical retropubic 
prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am. 
2001;28(3):555-565. doi:10.1016/s0094-0143(05)70163-4 
52.  Chun FK-H, Graefen M, Zacharias M, et al. Anatomic radical retropubic 
prostatectomy-long-term recurrence-free survival rates  for localized prostate 
cancer. World J Urol. 2006;24(3):273-280. doi:10.1007/s00345-006-0058-2 
53.  Amling CL, Blute ML, Bergstralh EJ, Seay TM, Slezak J, Zincke H. Long-term 
hazard of progression after radical prostatectomy for clinically localized  prostate 
cancer: continued risk of biochemical failure after 5 years. J Urol. 
2000;164(1):101-105. 
54.  Bianco FJJ, Scardino PT, Eastham JA. Radical prostatectomy: long-term cancer 
control and recovery of sexual and urinary  function (“trifecta”). Urology. 
2005;66(5 Suppl):83-94. doi:10.1016/j.urology.2005.06.116 
55.  Swanson GP, Hussey MA, Tangen CM, et al. Predominant treatment failure in 
postprostatectomy patients is local: analysis of  patterns of treatment failure in 
SWOG 8794. J Clin Oncol  Off J Am Soc Clin  Oncol. 2007;25(16):2225-2229. 
doi:10.1200/JCO.2006.09.6495 
56.  Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. 
Natural history of progression after PSA elevation following radical prostatectomy. 
JAMA. 1999;281(17):1591-1597. doi:10.1001/jama.281.17.1591 
57.  Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for 
pathological T3N0M0 prostate cancer significantly reduces  risk of metastases 
and improves survival: long-term followup of a randomized clinical trial. J Urol. 
2009;181(3):956-962. doi:10.1016/j.juro.2008.11.032 
58.  Mahal BA, Hoffman KE, Efstathiou JA, Nguyen PL. National trends in the 
recommendation of radiotherapy after prostatectomy for  prostate cancer before 
and after the reporting of a survival benefit in March 2009. Clin Genitourin 
Cancer. 2015;13(3):e167-72. doi:10.1016/j.clgc.2014.12.005 
59.  Fossati N, Karnes RJ, Cozzarini C, et al. Assessing the Optimal Timing for Early 
Salvage Radiation Therapy in Patients with  Prostate-specific Antigen Rise After 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
36 / 43 
Radical Prostatectomy. Eur Urol. 2016;69(4):728-733. 
doi:10.1016/j.eururo.2015.10.009 
60.  Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of 
salvage radiation therapy for recurrent prostate cancer  after radical 
prostatectomy. J Clin Oncol  Off J Am Soc Clin  Oncol. 2007;25(15):2035-2041. 
doi:10.1200/JCO.2006.08.9607 
61.  Tendulkar RD, Agrawal S, Gao T, et al. Contemporary Update of a Multi-
Institutional Predictive Nomogram for Salvage  Radiotherapy After Radical 
Prostatectomy. J Clin Oncol  Off J Am Soc Clin  Oncol. 2016;34(30):3648-3654. 
doi:10.1200/JCO.2016.67.9647 
62.  Dal Pra A, Cury FL, Souhami L. Combining radiation therapy and androgen 
deprivation for localized prostate cancer-a  critical review. Curr Oncol. 
2010;17(5):28-38. doi:10.3747/co.v17i5.632 
63.  Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without 
Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 
2017;376(5):417-428. doi:10.1056/NEJMoa1607529 
64.  Carrie C, Magné N, Burban-Provost P, et al. Short-term androgen deprivation 
therapy combined with radiotherapy as salvage  treatment after radical 
prostatectomy for prostate cancer (GETUG-AFU 16): a 112-month follow-up of a 
phase 3, randomised trial. Lancet Oncol. 2019;20(12):1740-1749. 
doi:10.1016/S1470-2045(19)30486-3 
65.  Panebianco V, Villeirs G, Weinreb JC, et al. Prostate Magnetic Resonance 
Imaging for Local Recurrence Reporting (PI-RR):  International Consensus -
based Guidelines on Multiparametric Magnetic Resonance Imaging for Prostate 
Cancer Recurrence after Radiation Therapy and Radical Prostatectomy. Eur Urol 
Oncol. Published online February 2021. doi:10.1016/j.euo.2021.01.003 
66.  De Visschere PJL, Standaert C, Fütterer JJ, et al. A Systematic Review on the 
Role of Imaging in Early Recurrent Prostate Cancer. Eur Urol Oncol. 
2019;2(1):47-76. doi:10.1016/j.euo.2018.09.010 
67.  Vargas HA, Wassberg C, Akin O, Hricak H. MR imaging of treated prostate 
cancer. Radiology. 2012;262(1):26-42. doi:10.1148/radiol.11101996 
68.  Barchetti F, Panebianco V. Multiparametric MRI for recurrent prostate cancer post 
radical prostatectomy and  postradiation therapy. Biomed Res Int. 
2014;2014:316272. doi:10.1155/2014/316272 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
37 / 43 
69.  Rouvière O, Vitry T, Lyonnet D. Imaging of prostate cancer local recurrences: why 
and how? Eur Radiol. 2010;20(5):1254-1266. doi:10.1007/s00330-009-1647-4 
70.  Casciani E, Polettini E, Carmenini E, et al. Endorectal and dynamic contrast-
enhanced MRI for detection of local recurrence after  radical prostatectomy. AJR 
Am J Roentgenol. 2008;190(5):1187-1192. doi:10.2214/AJR.07.3032 
71.  Panebianco V, Barchetti F, Sciarra A, et al. Prostate cancer recurrence after 
radical prostatectomy: the role of 3-T diffusion  imaging in multi-parametric 
magnetic resonance imaging. Eur Radiol. 2013;23(6):1745-1752. 
doi:10.1007/s00330-013-2768-3 
72.  Kitajima K, Hartman RP, Froemming AT, Hagen CE, Takahashi N, Kawashima A. 
Detection of Local Recurrence of Prostate Cancer After Radical Prostatectomy 
Using  Endorectal Coil MRI at 3 T: Addition of DWI and Dynamic Contrast 
Enhancement to T2-Weighted MRI. AJR Am J Roentgenol. 2015;205(4):807-816. 
doi:10.2214/AJR.14.14275 
73.  Litwin MS, Tan H-J. The Diagnosis and Treatment of Prostate Cancer: A Review. 
JAMA. 2017;317(24):2532-2542. doi:10.1001/jama.2017.7248 
74.  Wiegel T, Lohm G, Bottke D, et al. Achieving an undetectable PSA after 
radiotherapy for biochemical progression after  radical prostatectomy is an 
independent predictor of biochemical outcome--results of a retrospective study. 
Int J Radiat Oncol Biol Phys. 2009;73(4):1009-1016. 
doi:10.1016/j.ijrobp.2008.06.1922 
75.  Bottke D, Bartkowiak D, Siegmann A, et al. Effect of early salvage radiotherapy at 
PSA < 0.5 ng/ml and impact of post-SRT PSA  nadir in post-prostatectomy 
recurrent prostate cancer. Prostate Cancer Prostatic Dis. 2019;22(2):344-349. 
doi:10.1038/s41391-018-0112-3 
76.  Ghosh A, Heston WDW. Tumor target prostate specific membrane antigen 
(PSMA) and its regulation in  prostate cancer. J Cell Biochem. 2004;91(3):528-
539. doi:10.1002/jcb.10661 
77.  Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid 68Ga-PSMA 
Ligand PET/CT in 248 Patients with Biochemical  Recurrence After Radical 
Prostatectomy. J Nucl Med. 2015;56(5):668-674. doi:10.2967/jnumed.115.154153 
78.  Afshar-Oromieh A, Holland-Letz T, Giesel FL, et al. Diagnostic performance of 
(68)Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent  prostate cancer: 
evaluation in 1007 patients. Eur J Nucl Med Mol Imaging. 2017;44(8):1258-1268. 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
38 / 43 
doi:10.1007/s00259-017-3711-7 
79.  Miksch J, Bottke D, Krohn T, et al. Interobserver variability, detection rate, and 
lesion patterns of  (68)Ga-PSMA-11-PET/CT in early-stage biochemical 
recurrence of prostate cancer after radical prostatectomy. Eur J Nucl Med Mol 
Imaging. 2020;47(10):2339-2347. doi:10.1007/s00259-020-04718-w 
80.  Bluemel C, Krebs M, Polat B, et al. 68Ga-PSMA-PET/CT in Patients With 
Biochemical Prostate Cancer Recurrence and  Negative 18F-Choline-PET/CT. 
Clin Nucl Med. 2016;41(7):515-521. doi:10.1097/RLU.0000000000001197 
81.  Cirillo S, Petracchini M, Scotti L, et al. Endorectal magnetic resonance imaging at 
1.5 Tesla to assess local recurrence  following radical prostatectomy using T2-
weighted and contrast-enhanced imaging. Eur Radiol. 2009;19(3):761-769. 
doi:10.1007/s00330-008-1174-8 
82.  Fendler WP, Eiber M, Beheshti M, et al. (68)Ga-PSMA PET/CT: Joint EANM and 
SNMMI procedure guideline for prostate cancer  imaging: version 1.0. Eur J Nucl 
Med Mol Imaging. 2017;44(6):1014-1024. doi:10.1007/s00259-017-3670-z 
83.  Fowler JF. The radiobiology of prostate cancer including new aspects of 
fractionated  radiotherapy. Acta Oncol. 2005;44(3):265-276. 
doi:10.1080/02841860410002824 
84.  Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated Radiation Therapy for 
Localized Prostate Cancer: An ASTRO, ASCO,  and AUA Evidence-Based 
Guideline. J Urol. Published online October 2018. doi:10.1016/j.juro.2018.10.001 
85.  Hickey BE, James ML, Daly T, Soh F-Y, Jeffery M. Hypofractionation for clinically 
localized prostate cancer. Cochrane database Syst Rev. 2019;9(9):CD011462. 
doi:10.1002/14651858.CD011462.pub2 
86.  Jackson WC, Silva J, Hartman HE, et al. Stereotactic Body Radiation Therapy for 
Localized Prostate Cancer: A Systematic  Review and Meta-Analysis of Over 
6,000 Patients Treated On Prospective Studies. Int J Radiat Oncol Biol Phys. 
2019;104(4):778-789. doi:10.1016/j.ijrobp.2019.03.051 
87.  Brand DH, Tree AC, Ostler P, et al. Intensity-modulated fractionated radiotherapy 
versus stereotactic body radiotherapy  for prostate cancer (PACE-B): acute 
toxicity findings from an international, randomised, open-label, phase 3, non-
inferiority trial. Lancet Oncol. 2019;20(11):1531-1543. doi:10.1016/S1470-
2045(19)30569-8 
88.  Wolf F, Sedlmayer F, Aebersold D, et al. Ultrahypofractionation of localized 

HypoFocal SRT Trial 
Version 5.0, 24.01.2025 
 
 
39 / 43 
prostate cancer : Statement from the DEGRO  working group prostate cancer. 
Strahlenther Onkol. 2021;197(2):89-96. doi:10.1007/s00066-020-01723-8 
89.  Lehrer EJ, Kishan AU, Yu JB, et al. Ultrahypofractionated versus hypofractionated 
and conventionally fractionated  radiation therapy for localized prostate cancer: A 
systematic review and meta-analysis of phase III randomized trials. Radiother 
Oncol  J Eur Soc Ther  Radiol Oncol. 2020;148:235-242. 
doi:10.1016/j.radonc.2020.04.037 
90.  Trial D, Sampath S, Frankel P, et al. Stereotactic Body Radiation Therapy to the 
Prostate Bed : Results of a Phase 1. Radiat Oncol Biol. 2020;106(3):537-545. 
doi:10.1016/j.ijrobp.2019.11.005 
91.  Francolini G, Alicja B, Fossa J, et al. Stereotactic or conventional radiotherapy for 
macroscopic prostate bed recurrence : a propensity score analysis. Radiol Med. 
2022;(0123456789). doi:10.1007/s11547-022-01465-w 
12  APPENDICES 
 
 
 
Appendix 1 TNM Classification according to UICC 2009 
 
T - Primary tumor  
pT: pathological tumor classification  
Tx Primary tumor cannot be assessed  
T0 No evidence of primary tumor  
T1 Clinically unapparent tumor not palpable or visible by imaging  
T1a Tumor incidental histological finding in 5% or less of tissue resected  
T1b Tumor incidental histological finding in more than 5% of tissue resected  
T1c Tumor identified by needle biopsy (e.g., because of elevated PSA)  
T2 Tumor confined within the prostate  
T2a Tumor involves one half of one lobe or less  
T2b Tumor involves more than one half of one lobe but not both lobes  
T2c Tumor involves both lobes  
T3 Tumor extends through the prostate capsule  
T3a Extracapsular extension (unilateral or bilateral) including microscopic bladder neck 
involvement  
T3b Tumor invades seminal vesicle(s)  
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles: external sphincter, 
rectum, levator muscles, and/or pelvic wall  
N - Regional lymph nodes  
cN: clinical regional lymph node classification  
pN: pathological regional lymph node classification  
Nx Regional lymph nodes cannot be assessed  

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N0 No regional lymph node metastasis  
N1 Regional lymph node metastasis  
M - Distant metastases  
Mx Distant metastasis cannot be assessed  
M0 No distant metastasis  
M1 Distant metastasis  
M1a Nonregional lymph node(s)  
M1b Bone(s)  
M1c Other site(s)  
 

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Appendix 2 Pre-registration imaging (PSMA PET CT): 
 
For the detection of local recurrence using hybrid imaging several, PSMA-tracers are clinically 
available, such as 68Ga-PSMA-11, 18F-PSMA-1007, and 18F-DCFPYL (Pylarify - piflufolastat F 
18). Imaging is usually performed as a whole-body PET/CT for the detection of local recurrence 
and distant metastases. 
 
Imaging protocol should contain: 
- 
The radiochemical purity of the radiotracer should be greater than or equal to 95% in 
high performance liquid chromatography (HPLC) and Thin Layer Chromatography 
(TLC)) 
- 
Free 18F-fluoride or 68Ga-eluate should be the major impurity.  
- 
i.v. application of the radiotracer is beneficial 
- 
regarding the specific tracer a tracer-individual uptake period from application to imaging 
is recommended: 
o 60 min p.i. for 68Ga-PSMA-11 
o 90-120 min p.i. for 18F-PSMA-1007 
o 60 min p.i. for 18F-DCFPYL 
- 
PET scans should be acquired in the 3D mode  
o with an acquisition time of 1.5 min/bed position 
o by continues bed movement or  
o using a whole-body PET/CT scanner.  
- 
Emission data using bed position PET/CT scanners should be corrected for scatter and 
attenuation and reconstructed iteratively with an OSEM algorithm (2 iterations and 21 
subsets) followed by a postreconstruction smoothing gaussian filter. 
- 
Whole body PET images at Inselspital Bern using the Siemens Quadra or Siemens 
Biograph Vision 600 will be reconstructed with the same reconstruction parameters for 
both systems in 3D with a zoom factor of 1.0. Emission data need to be corrected for 
randoms, scatter and decay, and reconstruction with the vendor’s time of flight (TOF) 
point-spread-function (PSF) algorithm with 4 iterations and 5 subsets. 
 
 
Image interpretation: Focal uptake of 68Ga-PSMA-11, 18F-PSMA-1007, and 18F-DCFPYL higher 
than the surrounding background and not associated with physiologic uptake is considered 
suggestive of malignancy. Typical pitfalls in PSMA ligand PET imaging need to be known (e.g., 
celiac and other ganglia for 18F-PSMA-1007, fractures and degenerative changes for all 
fluorinated radiotracers, and perfusion effects in inflammatory lymph nodes for all tracers).  
 
 

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Appendix 3 Pre-treatment imaging (mpMRI) 
 
In order to define the extension of macroscopic local recurrence, a mpMRI of the pelvis with i.v. 
Gadolinium is mandatory after biochemical progression upon RP  
 
MRI should preferably be performed on a 3T MR unit; if not available a 1.5T MR unit can also be 
accepted. There is no need for an endorectal coil. MRI should cover the entire pelvis from the 
aortic bifurcation to the inferior border of the pubic symphysis. Ideally, air in the rectum should be 
minimized by emptying the rectum by applying local guidelines. The following sequences should 
be performed:  
 
 
Coronal T2-weighted sequence with isotropic voxels (1mm) covering the entire pelvis 
allowing reconstruction in the axial and sagittal plane.  
 
Axial T2-weighted high resolution covering the former prostatic bed including seminal 
vesicles (3mm slice thickness, no gap)  
 
Dynamic axial T1-weighted sequence (Dotarem®) including prostatic bed and seminal 
vesicles with high spatial resolution and slice thickness of 3mm.  
 
A T1-weighted sequence before administration of Gadolinium has to be added.  
 
Diffusion-weighted MRI (DW-MRI) in the axial plane covering the entire pelvis with slice 
thickness of 4mm and b-values of 0, 500 and 1000 sec/mm2 in order to detect lymph 
node metastases and local recurrence.  
 
Diffusion-weighted MRI (Zoomit) with limited field of view (former prostate and seminal 
vesicle bed) and b-values of 0, 500, 1000 and 2000 sec/mm2.  
 
Axial T1-weighted fat saturated sequence covering the entire pelvis (4mm slice 
thickness).  
 
Image interpretation: Local recurrence is defined as the following: soft tissue mass on T1- and 
T2-weighted sequences with early contrast medium enhancement on DCE-MRI. DW-MRI is 
analyzed qualitatively: tumor recurrence shows a high signal intensity focal lesion on the high b-
value image corresponding to a low signal intensity lesion on the corresponding Apparent 
Diffusion Coefficient (ADC) map (impeded diffusion due to high cellularity).