Improving Therapeutic Ratio With Hypo Fractionated Stereotactic Radiotherapy for Brain Metastases
Phase: NA
Conditions: Brain Metastases
Sponsor: Haaglanden Medical Centre

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RESEARCH PROTOCOL 
 
 
 
 
 

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PROTOCOL TITLE ‘Improving therapeutic ratio with hypofractionated stereotactic 
radiotherapy for brain metastases.’ 
 
Protocol ID 
NL77876.058.21 
Short title 
SAFESTEREO 
EudraCT number  
N/A 
Version 
5.0 
Date 
 14-11-2023 
Coordinating investigator  
 
 
Jeroen Crouzen, MD, MSc 
 
Haaglanden Medisch Centrum 
Burgemeester Banninglaan 1 
2262 BA Leidschendam 
The Netherlands 
 
Phone: 088 979 23 57 
e-mail:  j.crouzen@haaglandenmc.nl 
Principal investigator (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
Jaap Zindler, MD, PhD, radiation oncologist 
 
Haaglanden Medisch Centrum 
Burgemeester Banninglaan 1 
2262 BA Leidschendam 
The Netherlands 
 
Phone: 088 979 23 57 
e-mail: j.zindler@haaglandenmc.nl 
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Jaap Zindler, MD, PhD radiation oncologist 
 
Haaglanden Medisch Centrum 
Burgemeester Banninglaan 1 
2262 BA Leidschendam 
The Netherlands 
 
Phone: 088 979 23 57 
e-mail: j.zindler@haaglandenmc.nl 

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Statistician 
Prof.dr. M. Fiocco, PhD, Professor of Applied 
Mathematics 
 
Mathematical Institute - Leiden University 
Niels Bohrweg 1 
2333 CA Leiden 
The Netherlands 
 
Phone: 071 527 71 11 
e-mail: m.fiocco@math.leidenuniv.nl 
 
Clinical physicist 
Anna Petoukhova, PhD, clinical physicist 
 
Haaglanden Medisch Centrum 
Burgemeester Banninglaan 1 
2262 BA Leidschendam 
The Netherlands 
 
Phone: 088 979 23 57 
e-mail: a.petoukhova@haaglandenmc.nl 
Research & Development team 
Ursula Fisscher, PhD, data manager 
e-mail: u.fisscher@haaglandenmc.nl 
 
Mirjam Mast, PhD, R&D 
e-mail: m.mast@haaglandenmc.nl 
 
Haaglanden Medisch Centrum 
Burgemeester Banninglaan 1 
2262 BA Leidschendam 
The Netherlands 
Phone: 088 979 23 57 
Subsidising party 
N/A 
Independent expert (s) 
Leonard Bokhorst, MD, radiation oncologist 
Haaglanden Medisch Centrum 
Burgemeester Banninglaan 1 
2262 BA Leidschendam 
The Netherlands 
 
Phone: 088 979 23 57 
e-mail:  l.bokhorts@haaglandenmc.nl 

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Laboratory sites <if applicable> 
N/A 
 
 
Pharmacy <if applicable> 
N/A 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
 
Dr. Jaap Zindler, MD, PhD, radiation 
oncologist 
 
 
 
14-11-2023 
Coordinating Investigator: 
 
Dr. Jaap Zindler, MD, PhD, radiation 
oncologist 
 
 
 
14-11-2023 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................14 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 
Population (base) ...................................................................................................15 
4.2 
Inclusion criteria .....................................................................................................15 
4.3 
Exclusion criteria ....................................................................................................15 
4.4 
Sample size calculation ..........................................................................................15 
5. 
TREATMENT OF SUBJECTS .......................................................................................17 
5.1 
Investigational product/treatment ............................................................................17 
5.2 
Use of co-intervention (if applicable) ......................................................................17 
5.3 
Escape medication (if applicable) ...........................................................................17 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................18 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................19 
8. 
METHODS ....................................................................................................................20 
8.1 
Study parameters/endpoints ...................................................................................20 
8.1.1 
Main study parameter/endpoint .......................................................................20 
8.1.2 
Secondary study parameters/endpoints ..........................................................20 
8.1.3 
Other study parameters ...................................................................................20 
8.2 
Randomization, blinding and treatment allocation ..................................................20 
8.3 
Study procedures ...................................................................................................22 
8.3.1 
MR imaging before SRT ..................................................................................24 
8.3.2 
Cessation of systemic treatments during SRT .................................................24 
8.3.3 
Fractionation schedule and radiation dose before SRT ...................................24 
8.3.4 
GTV and OARs ...............................................................................................25 
8.3.5 
SRT PTV .........................................................................................................25 
8.3.6 
SRT planning procedure .................................................................................25 
8.3.7 
SRT treatment technique ................................................................................26 
8.3.8 
Dose reporting SRT.........................................................................................26 
8.3.9 
MR imaging after SRT .....................................................................................26 
8.3.10 
Questionnaires and other measurements ........................................................26 
8.4 
Withdrawal of individual subjects ............................................................................26 
8.4.1 
Specific criteria for withdrawal (if applicable) ...................................................27 
8.5 
Replacement of individual subjects after withdrawal ...............................................27 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................27 
8.7 
Premature termination of the study .........................................................................27 
9. 
SAFETY REPORTING ..................................................................................................28 
9.1 
Temporary halt for reasons of subject safety ..........................................................28 
9.2 
AEs, SAEs and SUSARs ........................................................................................28 
9.2.1 
Adverse events (AEs) ......................................................................................28 
9.2.2 
Serious adverse events (SAEs) .......................................................................28 

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9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................29 
9.3 
Annual safety report ...............................................................................................29 
9.4 
Follow-up of adverse events ...................................................................................29 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee ....................................30 
10. 
STATISTICAL ANALYSIS ..........................................................................................31 
10.1 
Primary study parameter(s) ....................................................................................31 
10.2 
Secondary study parameter(s) ...............................................................................31 
10.3 
Other study parameters ..........................................................................................31 
10.4 
Interim analysis ......................................................................................................32 
11. 
ETHICAL CONSIDERATIONS ...................................................................................33 
11.1 
Regulation statement .............................................................................................33 
11.2 
Recruitment and consent........................................................................................33 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................34 
11.4 
Benefits and risks assessment, group relatedness .................................................34 
11.5 
Compensation for injury .........................................................................................34 
11.6 
Incentives (if applicable) .........................................................................................35 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................36 
12.1 
Handling and storage of data and documents ........................................................36 
12.2 
Monitoring and Quality Assurance ..........................................................................36 
12.3 
Amendments ..........................................................................................................36 
12.4 
Annual progress report ...........................................................................................37 
12.5 
Temporary halt and (prematurely) end of study report ............................................37 
12.6 
Public disclosure and publication policy ..................................................................37 
13. 
STRUCTURED RISK ANALYSIS...............................................................................38 
14. 
REFERENCES ..........................................................................................................39 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the 
application form that is required for submission to the accredited 
Ethics Committee; in Dutch: Algemeen Beoordelings- en 
Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AED 
Anti-epileptic drugs 
ALE 
Adverse local event 
BED 
Biologically effective dose 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical target volume 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EORTC 
European Organisation for Research and Treatment of Cancer 
EPTN 
European Particle Therapy Network 
EudraCT 
European drug regulatory affairs Clinical Trials  
Gd 
Gadolinium 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
GTV 
Gross tumor volume 
fSRT 
Hypofractionated stereotactic radiotherapy 
HRQoL 
Health-related quality of life 
IADL 
Instrumental activities of daily living 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
KPS 
Karnofsky performance status 
LINAC 
Linear accelerator 
LPRNO 
National Platform Radiotherapy and Neuro-oncology in the 
Netherlands; in Dutch: Landelijk Platform Radiotherapie en Neuro-
oncologie 

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METC  
Medical research ethics committee (MREC); in Dutch: medisch-
ethische toetsingscommissie (METC) 
MRI 
Magnetic resonance imaging 
OAR(s) 
Organ(s) at risk 
PI 
Principal investigator 
PTV 
Planning target volume 
RANO 
Response Assessment in Neuro-Oncology 
RANO-BM 
Response Assessment in Neuro-Oncology Brain Metastases 
RLIES 
Revised Liverpool Impact of Epilepsy Scale 
(S)AE 
(Serious) Adverse Event  
SRT 
Stereotactic radiotherapy 
Sponsor 
The sponsor is the party that commissions the organization or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organization or investigator. A 
party that provides funding for a study but does not commission it is 
not regarded as the sponsor, but referred to as a subsidizing party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet AVG 
V12Gy 
Tissue volume receiving a dose of at least 12Gy 
WBRT 
Whole brain radiotherapy 
WHO-PS 
World Health Organization performance status 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale:  Stereotactic radiotherapy is one of the most frequently chosen treatment options 
for brain metastases. There are an increasing number of long term survivors. Brain necrosis 
(e.g. radionecrosis) is the most important long term side effect of the treatment, occurring in 
up to 40% of patients, dependent on the size of the metastasis and delivered radiotherapy 
dose. Retrospective studies have shown that the incidence of radionecrosis, as well as local 
tumor recurrence, can be decreased with a risk difference of around 20% by administrating 
fractionated stereotactic radiotherapy (fSRT, e.g. five fractions) over single fraction 
stereotactic radiotherapy, especially in large brain metastases. 
Objective: To determine if the incidence of adverse local events (local failure or 
radionecrosis) can be reduced with more than 20% using fSRT versus SRT in one or three 
fractions. 
Study design: Prospective, multicenter, open label, randomized, phase II study with two 
cohorts.  
Study population: Patients, 18 years and older, with one or more brain metastases from 
solid primary tumors diagnosed on a high resolution contrast-enhanced MRI scan referred for 
stereotactic radiotherapy. 
Intervention (if applicable): One group is treated with SRT in one or three fractions. The 
other group is treated with fSRT in five fractions. 
Main study parameters/endpoints: The main study parameter is the incidence of adverse 
local event (either local failure or radionecrosis according to RANO) at 2 years post-
radiotherapy with respect to baseline. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The study aims to investigate a different and potentially safer treatment 
method than the current standard of care. It is unlikely that the risk of adverse events will be 
increased in the experimental cohort compared to the standard cohort. The additional burden 
as a result of study participation consists of the following: between two and four additional 
site visits for treatment in the experimental group; a total of eighteen (facultative) 
questionnaires spread throughout the follow-up period. 
 
 

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1.  INTRODUCTION AND RATIONALE 
Since publication of the QUARTZ trial, the palliative benefit and indication of whole brain 
radiotherapy (WBRT) is a matter of debate for patients with brain metastases.1 After WBRT, 
patients may suffer from alopecia, fatigue, and there is a risk of neurocognitive dysfunction 
caused by the elective brain irradiation. In phase III trials, (elective) WBRT has never shown 
benefit in survival nor health-related quality of life in large cell cancer histologies.2 
In the last decades, effective alternative treatments for brain metastases have become 
available. Targeted agents and/or immunotherapy have shown to effectively treat brain 
metastases in several subtypes of cancer. Stereotactic radiotherapy (SRT) has become 
widely available, also for multiple brain metastases.3 SRT has shown to treat brain 
metastases more effectively with a higher probability of local tumor control than WBRT. 
Moreover, elective brain irradiation is avoided and thereby side effects of WBRT. Because of 
publication of the favorable results in terms of local tumor control and median survival of 
large cohorts of patients with SRT also in patients up to ten brain metastases with low 
volume disease, several international guidelines (UK NICE guideline, American neurosurgery 
guideline) state that SRT is also a treatment option for patients with more than three brain 
metastases.4 This advice is also stated in the revised Dutch guideline for brain metastases, 
that radiosurgery is a treatment option for patients up to 10 brain metastases with a 
maximum individual volume of the brain metastases of 20 cm3 and a maximum cumulative 
volume of 30 cm3.5 In the current era of personalized medicine, the main question is how to 
integrate SRT into the multimodality treatment for brain metastases with systemic therapies 
and surgery. This is complex and decided in the multidisciplinary board.6 
As clinicians, we observe an increasing number of long term survivors over several years 
with brain metastases. Brain necrosis or radionecrosis is a long term side effect of SRT 
which occurs in +/-20% of patients and the incidence may increase up to +/-40% if SRT is 
combined with immunotherapy.7 Radionecrosis may cause neurologic symptoms, such as 
focal neurological deficits, neurocognitive dysfunction and seizures, which require treatment 
with steroids, bevacuzimab, or sometimes even surgery. SRT is mostly delivered with an 
ablative high radiotherapy dose in a single fraction. In the first millimeters close to the brain 
metastasis, the healthy brain tissue receives a high dose as well. 
In radiotherapy literature, it is known that more fractionated radiotherapy, e.g. 
hypofractionated radiotherapy (fSRT), may decrease side effects. fSRT means delivering the 
ablative dose in multiple fractions (f.e. 5 fractions) over several days instead of delivering the 
ablative dose within half an hour.8 Recent retrospective studies showed that risk difference of 
local failure and radionecrosis is almost 30% in larger tumors (>2.5 cm; constituting around 

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50% of metastases), while the incidence is equivalent in smaller metastases.9,10, 22 To 
achieve a local control of more than 90% after one year, it is important to deliver a 
cumulative biologically effective dose (BED) of at least 50 Gy. 35 Gy in 5 fractions results in 
a BED of more than 50Gy.11,12 Another potential benefit of fSRT over SRT in one or three 
fractions is better induction of an abscopal effect. SRT in one or three fractions results in 
massive tumor necrosis. fSRT may result in more regulated cell death: apoptosis, with better 
antigen presentation of dying tumor cells. It is hypothesized that this may subsequently result 
in better activation of the immune cells against the cancer and better control of 
micrometastases outside the irradiation field.13 Several studies are ongoing in which SRT is 
combined with immunotherapy to increase systemic tumor control and thereby improve 
survival.14  
 

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2. OBJECTIVES 
 
Primary Objective: To determine if the percentage of adverse local events (either local failure 
or radionecrosis) can be reduced by using fSRT versus SRT in one or three fractions 2 years 
post-SRT. 
Secondary Objective(s): To investigate if fSRT provides better quality of life and lower 
incidence of epilepsy versus SRT in one or three fractions. Additionally, to estimate overall 
survival as well as the cumulative incidence of local failure or radionecrosis with death as 
competing risk. 

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3. STUDY DESIGN 
The study is a prospective randomized cohort study with two study cohorts. Patients are 
allocated to a study cohort by randomization. The follow-up will be two years. The study will 
take place in a multicenter clinical setting. 
 
Patients from the two study cohorts will receive a different fractionation treatment schedule. 
Patients in the standard cohort will receive SRT in one or three fractions according to the 
Dutch guideline (consensus Landelijk Platform Radiotherapie en Neuro-oncologie; LPRNO), 
while patients in the experimental cohort will receive fSRT in five fractions. 
 
The planned duration is as follows: 
Data collection: March 2022-March 2027 (3 years for patient inclusion, 2 years follow-up) 
Statistical analyses: March 2027 
Writing article: April 2027-June 2027 
NB: these dates are an estimate and are dependent on several factors, such as approval 
from the ethics and research commissions. 
 
 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Patients (≥18 years old) with one or more brain metastases from solid primary tumors 
diagnosed on a high resolution contrast-enhanced MRI scan referred for SRT in Dutch 
hospitals. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
Age ≥ 18 years 
 
At least one brain metastasis of large cell cancer suitable for SRT 
 
Karnofsky Performance Status ≥ 70 
 
Ability to provide written informed consent 
 
Previous systemic therapy for brain metastases allowed 
 
New brain metastases during follow-up after surgery allowed (outside resection 
cavity) 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
Contra-indication for MRI scan 
 
Primary tumor of small cell lung cancer, germinoma or lymphoma 
 
Prior whole brain radiotherapy or SRT on the current target brain metastases (BM) 
(in field re-irradiation; salvage SRT of non-irradiated BM allowed if radiation dose 
from previous irradiation in current target field is <1.0 Gy) 
 
Presence of leptomeningeal metastases 
 
Previous inclusion in the SAFESTEREO study 
 
4.4 Sample size calculation 
Standard cohort: Mean risk of local failure or radionecrosis 1 year = 30% 
Experimental cohort: Mean risk of local failure or radionecrosis experimental arm @ 1 year = 
10% 
Enrollment ratio standard vs experimental cohort 1:1 
Alpha = 0.05 
Power=0.8 
Sample size standard arm n=59 
Sample size experimental arm n=59 
Minimum number of patients required for the study: 118 
Number of patients including additional 10% to account for missing data: 130 
 
These number were based on the following power analysis and were calculated with PASS® 
software (NCSS Statistical Software): 
 

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The results are based on the exact binomial test: 
Numeric results of tests based on the difference: P1 - P2 
H0: P1 - P2 = 0. H1: P1 - P2 = D1≠0. Test Statistic: Z test with pooled variance. 
 
Power 
Sample 
size 
group 1 
(N1) 
Sample 
size 
group 2 
(N2) 
Prop|H1 
Group 1 
(P1) 
Prop 
Group 2 
(P2) 
Diff if 
H0 (D0) 
Diff if 
H1 (D1) 
Target 
alpha 
Actual 
alpha 
Beta 
0.8051 
59 
59 
0.3000 
0.1000 
0.000 
0.200 
0.0500 
0.0507 
0.1949 
 
Note: exact results based on the binomial were only calculated when both N1 and N2 were 
less than 100. 
 
The total number of patients with brain metastases treated at the department of radiotherapy 
in our hospital in 2019 was around 150, of whom an estimated 135 would have been eligible 
for inclusion. Therefore, a 3-year period (as mentioned in paragraph 3) should be sufficient to 
include enough patients. 
 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
The investigational treatment is SRT delivered in five fractions. This treatment is 
described in more detail in paragraphs 8.3.1-8.3.9. The standard treatment of stereotactic 
radiotherapy delivered in one or three fractions is also described in those paragraphs. 
 
5.2 Use of co-intervention (if applicable) 
N/A 
5.3 Escape medication (if applicable) 
N/A 
 
 

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6. INVESTIGATIONAL PRODUCT  
The study does not include use of a medicinal product, food product, medical device or other 
product. Therefore, this chapter is not applicable. 

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7. NON-INVESTIGATIONAL PRODUCT 
No challenge agents or products used to assess endpoints are used in the trial. Therefore, 
this chapter is not applicable. 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 
Main study parameter/endpoint 
Incidence of adverse local event (ALE) at 2 years post-radiotherapy with respect to baseline. 
 
Definition of ALE = either radionecrosis or local failure according to Response Assessment in 
Neuro-Oncology Brain Metastases (RANO-BM).15, 22 
 
Definition of radionecrosis = increasing size and low perfusion MR by interpretation of a 
dedicated radiologist (multidisciplinary board). 
 
Definition of local failure is ≥20% increase in sum longest distance relative to nadir in target 
lesion. 
 
8.1.2 
Secondary study parameters/endpoints 
 
Survival time/survival at 2 years post-SRT 
 
Incidence of symptomatic radionecrosis 
 
Incidence of symptomatic local failure 
 
Incidence of salvage treatments at 2 years post-SRT 
 
Distant brain recurrences at 2 years post-SRT 
 
Dose dexamethasone at baseline, 3 months after radiotherapy and 
thereafter every three months until 2 years  
 
Anti-epileptic drug (AED) use  
 
Bevacizumab use 
 
Grade 2 or more toxicity (CTCAE v5.0) 
o Alopecia, cognitive symptoms, fatigue, dysphasia, hearing loss, 
visual impairment, generalized muscle weakness 
 
8.1.3 
Other study parameters 
 
 
Facultative endpoints: 
 
HRQoL (measured with EORTC QLQ-C30 and QLQ-BN20)  at baseline, 3, 
6, 12, 18 and 24 months after radiotherapy 
 
IADL (measured with EQ-5D 5L)  at baseline, 3, 6, 12, 18 and 24 months 
after radiotherapy 
 
 
 
8.2 Randomization, blinding and treatment allocation 
Patients who meet the inclusion criteria (see paragraph 4.2) can be included in the 
study after consultation with the radiation oncologist and after they have signed 
informed consent. They will be randomized into either of the two cohorts. 
 
 

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Blinding of the groups cannot be performed, because the planning system needs to 
calculate the treatment time based on the fractionation schedule, which is determined 
by randomization. The involved employees of the radiation department need to 
process the data in the radiation therapy software and they need to carry out QA 
checks on the radiation treatment plans. The latter can only be performed if all 
information is available. 
 
Patients who are randomized into the standard treatment group will receive the 
treatment as currently advised by the LPRNO guidelines. Patients will receive 1 
fraction of SRT, unless it concerns a large tumor in proximity to the brainstem or a 
large tumor in proximity to other metastases, see paragraph 8.3.3. Based on previous 
literature, local progression or survival outcome are comparable for SRT in 1 or 3 
fractions.16  
 
Randomization to either SRS (1 or 3 fractions, see paragraph 8.3.3) or fSRT (5x7Gy 
or 5x6 Gy if in brainstem, see paragraph 8.3.3) will be 1:1, stratified by institute with 
block sizes 4 and 6. 
 
 
 

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Day -7 (or earlier)  
   0 
 
   week 1 
 
week 2  
3 months after RT and thereafter 
 
 
 
 
 
 
 
 
 
 
every 3 months until 2 years 
8.3 Study procedures 
Procedures which are part of the standard medical treatment are summarized in paragraphs 
8.3.1-8.3.9. Measurements which are specifically measured for this study are listed in 
paragraph 8.3.10. A study flow chart is shown in figure 1. A treatment summary table, 
including an overview of what is and is not part of standard of care, is shown in table 1. 
 
Figure 1: Study flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Referral for SRT 
 
Inclusion criteria 
met 
No exclusion criteria 
Follow-up MRI + consult with 
radiation oncologist (toxicity 
scored) 
 
Facultative: 
Only 3, 6, 12, 18 and 24 months 
after RT:  
Questionnaire HRQoL and IADL 
Mask 
 
Planning CT 
 SRT in one, three 
or five fractions 
Planning MRI 
 
Signing of consent 
form 
 
Randomization 
 
Facultative: 
Questionnaire 
HRQoL, IADL,  

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Table 1 Study parameter summary table 
 
 
 
 
Months post (f)SRT 
 
Baseline 
End of RT 
3M 
6M 
9M 
12M 
15M 
18M 
21M 
24M 
Standard clinical care: 
 
 
 
 
 
 
 
 
 
 
Clinical characteristics: year of birth, gender, 
primary tumor type, presence of extracranial 
visceral metastases, primary tumor control, date 
diagnosis primary tumor, type of systemic 
therapy 
 
Coded data (see paragraph 12.1): patient 
number in electronic patient dossier 
 
X 
 
 
 
 
 
 
 
 
 
Planning MRI & CT: number of brain 
metastases, total volume of brain metastases, 
volume of largest brain metastases 
 
X 
 
 
 
 
 
 
 
 
 
Treatment characteristics: GTV largest 
metastasis, PTV largest metastasis, total volume 
GTV of all metastases, and total volume PTV of 
all metastases. Maximum dose in the PTV in 
anymetastasis. Maximum dose brain stem, 
chiasm, and optic nerves 
 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
WHO-PS and/or KPS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard follow-up: 
 
 
 
 
 
 
 
 
 
 
Follow-up MRI: adverse local event (either 
radionecrosis or local failure according to 
RANO), distant brain recurrences 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity (CTCAE v5.0) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Not part of standard follow-up: 
 
 
 
 
 
 
 
 
 
 
HRQoL (EORTC QLQ-C30, QLQ-BN20) 
X 
 
X 
X 
 
X 
 
X 
 
X 
IADL ( EQ-5D 5L) 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Other follow-up: 
 
 
 
 
 
 
 
 
 
 
Use of dexamethasone or bevacizumab 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Use of AED 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Salvage treatment, type of salvage treatment, 
date of salvage treatment 
 
 
 
 
 
X 
 
 
 
X 
Alive/dead 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Symptomatic radionecrosis or local failure  
 
 
X 
X 
X 
X 
X 
X 
X 
X 

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8.3.1 
MR imaging before SRT 
The definitive number of brain metastases and the definitive maximum lesion diameter any 
direction of the largest brain metastasis is determined on contrast-enhanced (single - triple 
dose Gd is allowed) T1-sequences, maximum slice thickness 1.5 mm, field strength (1.0-3.0 
Tesla with a 3D-distortion correction protocol. 
8.3.2 
Cessation of systemic treatments during SRT 
The combination of SRT with several systemic cancer treatments, namely gemcitabine, 
erlotinib, vemurafenib and trastuzumab-emtansine, has been reported to increase the risk of 
radionecrosis. Therefore, these systemic treatments are halted at least one week before the 
first fraction until at least one week after the last fraction. Immunotherapy can be continued 
during SRT. All other systemic treatments are halted at least three days before the first 
fraction until at least three days after the last fraction. All the above is in accordance with the 
Dutch guidelines for treatment of brain metastases 
(https://richtlijnendatabase.nl/richtlijn/hersenmetastasen/startpagina_-
_hersenmetastasen.html). 
8.3.3 
Fractionation schedule and radiation dose before SRT 
Patients randomized into the experimental fSRT cohort receive a fractionation schedule 
based on “Working Agreement for uniform dose prescription stereotactic (LINAC) irradiation 
of brain metastases, Dutch Platform of Neuro Oncology”. This is 35 Gy in five fractions, or 30 
Gy in five fractions if the metastasis is situated in the brainstem.  
 
Patients randomized into the standard cohort will receive a fractionation schedule based on 
“Working Agreement for uniform dose prescription stereotactic (LINAC) irradiation of brain 
metastases, Dutch Platform of Neuro Oncology”. This is in the range of 15 Gy in a single 
fraction up to a 24 Gy in three fractions. 
 
The dose gradient outside the PTV will be as steep as possible to spare healthy brain tissue. 
Within the PTV there will be considerable dose inhomogeneity 
Dose prescription to brain metastases 
PTV of brain 
metastases 
 
Dose  
1 fraction 
BM in brainstem 
(GTV=PTV) 
 Dose 5 
fractions (Gy) 
 BM in 
brainstem 
(GTV=PTV) 
<1 cm3 
24 
 16 
 35 
30 
1-10 cm3 
21 
 16 
 35 
30 
10-20 cm3 
18 
 16 
 35 
30 
20-65 cm3 
15 or 3X8Gy 
 No SRS 
 35 
30 
 

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Organ at risk constraints 
 
 
 1 
fraction 
(Gy) 
Optimal 
1 fraction 
(Gy) 
Mandatory 
 Dmax 3 
fractions 
(Gy) 
Optimal 
Dmax 3 
fractions 
(Gy) 
Mandatory 
 Dmax 5 
fractions 
(Gy) 
Optimal 
Dmax 5 
fractions 
(Gy) 
Mandatory 
Brainstem Dmax 
10 
18 
24 
27 
23 
30 
Cochlea Dmean 
4 
9 
17 
20 
22 
25 
Chiasm Dmax 
8 
10 
15 
23 
20 
25 
Lens Dmax 
1 
3 
2 
4 
3 
5 
Optic nerves Dmax 
8 
10 
15 
23 
22 
25 
Pituary gland Dmean 
8 
10 
15 
23 
22 
25 
 
Acceptable and unacceptable variation in dose 
Volume 
Per protocol 
D (Gy) 
Acceptable 
variation 
Unacceptable 
variation 
PTV  
V100% = 99% 
98%<V100%<99% 
V100%<98% 
Dmax OAR if volume of 
OAR<2cm3 
0.035 cm3  
D0.035cm3≤Dmax 
D0.035cc>Dmax 
Dmax OAR if volume of 
OAR≥2cm3 
2% 
D2%≤Dmax 
D2%>Dmax 
 
 
8.3.4 
GTV and OARs 
The GTV is defined by contouring the outer contrast-enhancing border of the brain 
metastasis on a T1 Gd weighted MRI scan. Brain metastases are named GTV1, GTV2, 
GTV3, etc. from cranial to caudal. OARs (brainstem, optic nerves, chiasm, pituitary gland, 
etc.) are contoured according to EPTN consensus.17  
8.3.5 
SRT PTV 
The PTV is defined by a 0-2 mm isotropic expansion of the GTV, according to institutional 
standards for SRT. If a brain metastasis is within or adjacent to the brainstem, the PTV 
margin will be 0 mm. If in an institution a smaller GTV to PTV margin is used when lesions 
are treated using multiple isocenters, then this technique is to be considered to reduce the 
V12Gy of the largest brain metastasis if it would otherwise be more than 10 cm3.  
8.3.6 
SRT planning procedure 
Patients will be immobilized in supine position wearing a thermoplastic mask or stereotactic 
non-invasive frame, with or without bite block and/or other fixation, according to institutional 
standards for SRT. The accuracy of the stereotactic fixation system should be sufficient to 
justify the CTV to PTV margin used. This means the intrafraction motion should at least be 
within the CTV-PTV margin used. If a margin of 0 mm is used, the maximum intrafraction 
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≤2 mm thick contiguous slices (preferable CT slice thickness = 1mm) will be fused to a 
contrast-enhanced stereotactic MRI scan. The interval between the planning-MRI and actual 
SRT treatment is a maximum of 3 weeks. 
8.3.7 
SRT treatment technique 
Single or multiple isocenters are allowed for delivering SRT according to the treating 
center preference. Tissue density inhomogeneity correction will be used. Positional 
verification and correction prior to (and/or during) radiation should be executed 
according to the institutional protocol for stereotactic radiotherapy and should be in 
accordance with the CTV-PTV margin used. All techniques that result in the dose 
requirements being met are allowed. Participating institutes will have to define their 
radiation delivery treatment prior to the initiation of the study. Techniques that have a 
shorter treatment time duration are preferred as this is more comfortable for the patient 
and might prevent an increase of the intrafraction displacement over the treatment time. 
8.3.8 
Dose reporting SRT 
Tumor volume and treatment plan characteristics are reported (maximum dose, prescribed 
dose, and dose in critical organs at risk). 
8.3.9 
MR imaging after SRT 
Tumor response evaluation as well as presence of distant brain recurrences are monitored 
every three months after SRT on contrast-enhanced (single - triple dose Gd is allowed) T1-
sequences, maximum slice thickness 3 mm, field strength (1.0-3.0 Tesla with a 3D-distortion 
correction protocol including perfusion MR). 
8.3.10 Questionnaires and other measurements 
The following facultative questionnaires will be assessed at baseline, 3 months, 6 months, 
and 12 months, 18 months and 24 months after SRT: HRQoL (measured with EORTC QLQ-
C30 and QLQ-BN20) and IADL (measured with EQ-5D 5L). 
Toxicity (according to CTCAE v5.0) and use of AED,  dexamethasone and bevacizumab is 
evaluated at baseline, 3 months after SRT and thereafter every three months until 2 years 
via telephone or during scheduled outpatient clinic visits. Need for salvage treatments, or 
symptomatic radionecrosis, and survival are all evaluated 2 years after SRT. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
 

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If a subject becomes incapacitated during the study period, and if it will no longer be 
possible to make MRI scans, to send questionnaires, to evaluate toxicity, etc. In 
such a case, the same guidelines are followed as described for subjects who 
withdraw from the study for any reason (see 8.5 and 8.6). 
8.4.1 
Specific criteria for withdrawal (if applicable) 
 
 
N/A 
8.5 Replacement of individual subjects after withdrawal 
With respect to patients applicable for this study willing to participate, and who have signed 
informed consent (paragraph 11.2): before randomization any patient will be replaced if the 
patient withdraws for any reason. These patients are not included in the statistical analysis. 
After the randomization, patients withdrawing for any reason will not be substituted by 
additional patients and these patients are analyzed by intention to treat. 
8.6 Follow-up of subjects withdrawn from treatment 
Patients who withdraw after randomization will not be requested to participate for follow-up 
questionnaires. Patients are asked if it is allowed to consult their medical chart for treatment 
characteristics and survival length. 
8.7  Premature termination of the study 
The aim of the study is to investigate a different and possibly safer treatment method than 
the current standard of care. The study is based on the radiotherapy concept of fractionating 
the treatment. When the total dose of radiation is divided into several, smaller doses over a 
period of several days, there are fewer toxic effects on healthy cells. Therefore, the risk of 
adverse events in the experimental cohort is unlikely to be greater than in the standard 
cohort and premature termination of the study is not likely. 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardize subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the experimental intervention. 
All adverse events reported spontaneously by the subject or observed by the 
investigator or his staff will be recorded in the medical record of the patient. 
 
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator shall report serious adverse events to safestereo@haaglandenmc.nl 
without undue delay after obtaining knowledge of the events, unless, for certain 
serious adverse events, the protocol provides that no immediate reporting is required. 
 
Adverse experiences of a serious and unexpected nature, whether or not related to 
the cerebral radiotherapy, must be reported immediately. Adverse events that are 

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unexpected, should be reported if there is a possibility that it could be related to the 
administration of the radiotherapy. 
 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events, except for the following SAEs: epilepsy, 
deterioration of existing neurologic impairment after the radiotherapy, alopecia, 
fatigue, headache, and taste disorders. 
 
The sponsor will report the unexpected SAEs through the web portal ToetsingOnline 
to the accredited METC that approved the protocol, within 7 days of first knowledge 
for SAEs that result in death or are life threatening followed by a period of maximum 
of 8 days to complete the initial preliminary report. All other unexpected SAEs will be 
reported within a period of maximum 15 days after the sponsor has first knowledge of 
the serious adverse events. 
 
Patients with brain metastases generally have a poor life expectancy of around 3-12 
months. Therefore, a significant proportion of patients is expected to die within the 
study duration of 1 year after SRT. 
 
Expected SAEs are hospitalization or death by progression of both extracranial and 
intracranial cancer. Moreover, patients are treated with systemic therapy, and may be 
hospitalized or die because of complications of the systemic therapy, such as 
secondary infections. Furthermore, a proportion of patient will have severe neurologic 
impairment and epilepsy, because of intracranial cancer progression despite 
radiotherapy. These expected SAEs will be reported every half year in a line listing. 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
N/A 
9.3 Annual safety report 
 
N/A 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported until end of study within the Netherlands, as defined in the 
protocol. 
 

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9.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
The establishment of a Data Safety Monitoring Board or Safety Committee is not deemed 
necessary for this study. The study aims to investigate a potentially safer treatment 
method than the current standard of care. It is unlikely that the risk of adverse events will 
be increased in the experimental cohort compared to the standard cohort. The only 
difference between the two cohorts is the fractionation schedule. The only difference is 
expected in the rate of local control and radionecrosis, which constitutes the primary study 
endpoint. 
 
 
 

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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter(s) 
Differences in the composite endpoint (either radionecrosis or local failure) at 2 years post-
radiotherapy are calculated as a percentage in each cohort. The binomial test will be used to 
compare the percentage between the two cohorts. 
Summary tables for continuous variables will include the following statistics: mean, standard 
deviation. Summary tables for categorical variables will include: N, proportion.  
If the data is normally distributed, the means will be compared using independent samples 
Student’s T-Tests. In case of violation of the normality assumptions, non-parametric tests will 
be used. Proportions will be compared by using Chi-square testing. Unless otherwise 
indicated, tests will be 2-sided. 
 
10.2 Secondary study parameter(s)  
Secondary study parameters (as listed in paragraph 8.1.2, including facultative endpoints 
such as HRQoL and neurocognition) will be presented per cohort. Due to the presence of 
repeated measurements mixed modelling will be used to analyze use of anti-epileptica, 
dexamethasone and bevacizumab, IADL and to investigate the effect of fSRT on quality of 
life. 
 
Overall survival (from date of first radiotherapy until death) will be estimated by using Kaplan-
Meier methodology. To assess whether there is difference between survival in the groups, 
the Log-rank test will be used. To investigate the effect of prognostic factors on survival, a 
Cox regression model will be used. To estimate the cumulative incidence of adverse local 
events (ALE), a competing risk model with death as a competing risk will be estimated.18 Fine 
and Gray’s test will be employed to assess the difference between cumulative incidence in 
the two cohorts.19 Cause specific hazard Cox model will be employed to investigate the effect 
of prognostic factors on the cumulative incidence of ALE. 
Care will be taken to minimize missing data and to continue to follow up those who withdraw 
from the study. To account for non-compliance and protocol deviation the analysis will be 
performed based on the intention to treat concept. 
All analyses concerning the competing risk model will be performed in R environment by 
using the library mstate and cprisk.20,21 All other analyses will be performed in SPSS version 
26.0 (IBM Corp, Armonk, NY). 
 
10.3 Other study parameters 
N/A 
 

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10.4 Interim analysis 
See paragraph 8.7. 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The responsible investigator will ensure that this study is conducted in agreement with the 
Declaration of Helsinki (Brazil, October 2013) and in accordance with the Medical 
Research Involving Human Subjects Act (WMO), as well as the Algemene verordering 
gegevensbescherming (AVG). 
The protocol has been written, and the study will be conducted according to the ICH 
Harmonized Tripartite Guideline for Good Clinical Practice (GCP). 
The protocol will be approved by the Local, Regional or National Ethics Committees. The 
treating physician asks the patient to participate. If a patient is interested in the study, the 
researcher of the participating hospital or physician assistant supplies more detailed 
information about the study. 
 
11.2 Recruitment and consent 
Eligible patients will receive information about this study from the physician on intake, i.e. 
the radiation oncologist, and will at that time also receive a written patient information and 
informed consent forms. All patients will be informed about the aims of the study, the 
possible adverse events, the procedures and possible hazards to which they will be 
exposed. They will be informed about the strict confidentiality of their data, and that their 
medical records may be reviewed for trial purposes by authorized individuals other than 
their treating physician. Information will be given both spoken and written as in the Patient 
Information Form. The Patient Informed Consent Statement and the Patient Information 
text are given as separate documents along with this protocol. 
 
It will be emphasized that the participation is completely voluntary and the patient does 
not need to give any further explanation for not participating. The patient is allowed to 
refuse further participation in the protocol whenever they want. 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 in the study. 
 
Patients will have at least 2 days or more  to consider participation in the study. After 2 
days the radiation oncologist will contact the patient and if needed will give the patient 
more time to reconsider participating in the study. They can contact a physician who is 
not involved in the study for further independent information about the study protocol. 
When the patient decides to participate in the study, he will date and sign the informed 
consent form, sometimes after orally consenting to participation. After the patient has 

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signed, the physician/researcher or their representative also dates and signs this 
informed consent. These signing dates are not necessarily on the same day, due to 
logistical reasons. Planning of treatment can start when oral consent is given. Before any 
study-related actions take place, the written informed consent must be given to the 
treating physician. Written informed consent form should be signed and personally dated 
by the patient as well as the local investigator. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Minors are not allowed to participate in this study. Incapacitated subjects are not suited for 
radiotherapy treatment for brain metastases. 
 
11.4 Benefits and risks assessment, group relatedness 
This study is performed on both male and female subjects who are to be treated for brain 
metastases with radiotherapy. The aim of this study is to assess whether or not fSRT can 
reduce the incidence of adverse local events compared to SRT in one or three fractions. 
fSRT and SRT in one or three fractions are globally accepted treatment options for brain 
metastases, and both treatments will be delivered according to current state of the art. One 
difference between the two treatment options is that patients receiving fSRT will have to go 
to the hospital five times to receive the treatment as opposed to once. No side effects are 
expected in addition to side effects common in daily clinical practice. 
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO.  
  
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 
 
1. € 750.000,-- (i.e. seven hundred and fifty thousand Euro) for death or injury for each 
subject who participates in the research; 
2. € 5.000.000,-- (i.e. five million Euro) for death or injury for all subjects who 
participate in the research;  
3. € 7.500.000,-- (i.e. seven million five hundred thousand Euro) for the total damage 
incurred by the organization for all damage disclosed by scientific research for the 

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sponsor as ‘verrichter’ in the meaning of said Act in each year of insurance 
coverage. 
 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives (if applicable) 
Subjects will not receive any type of special or financial incentives for participating in this 
study. 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
All anonymized data will be entered into Castor Electronic Data Capture (EDC) system. A 
code will be attributed to each patient registered in the trial consisting of sequential 
inclusion number. This code will identify the patient number in the electronic patient 
dossier. This data needs to be anonymized, because it can be traced back to the 
individual patient. 
 
The code number must be included on all case report forms. The code will be attributed 
by the data manager of the radiotherapy department of Haaglanden MC and linked to the 
non-anonymized data in a list kept by the data manager only. This list is kept in a digitally 
secure environment of the Haaglanden MC, to which no-one except the data manager 
and the R&D associate have access. 
 
The non-coded data may only be viewed by the data manager, the responsible 
physicians and, if necessary, the (national) regulatory authorities. The coded data in 
Castor EDC can only be viewed by the data manager, the coordinating investigator and 
principal investigator, as well as by the regulatory institutions. 
 
The duration of the storage of the study data is 15 years. The IGJ (Inspectie 
Gezondheidszorg en Jeugd) and monitors have permission to check all data and 
documents. 
 
12.2 Monitoring and Quality Assurance  
  
In accordance with Haaglanden Medical Center guidelines, monitoring is mandatory for all 
research that is subject to the Medical Research Involving Human Subjects Act (WMO). 
This will take place 1-2 times a year. And will be arranged by the sponsor. 
 
12.3 Amendments  
Amendments are changes made to the research after a favorable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favorable opinion.  
 

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All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit. 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC. 
12.6 Public disclosure and publication policy 
 
First author on papers with results of the study will be JC (Jeroen Crouzen) and last 
author JZ (Jaap Zindler). The same policy will be applied to side results. Everyone who 
contributed as well, such as investigators or participating centers, will be considered as 
co-author. The sequence of co-authorship of participating investigators will be determined 
by the number of patients included in the study. Persons who contributed in a minor way 
to a study may be considered for the acknowledgments section. Conflicts will be resolved 
by the PI and his co-PIs. Results will be published unreservedly regardless of their nature 
in accordance with the CCMO statement on publication policy. 

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13. STRUCTURED RISK ANALYSIS  
As mentioned in chapter 6 and 7, no medicinal product, food product, medical device or other 
product is tested in this study. Therefore, this chapter is not applicable. 
 
 

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14. REFERENCES 
 
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Dexamethasone and supportive care with or without whole brain radiotherapy in 
treating patients with non-small cell lung cancer with brain metastases unsuitable for 
resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-
inferiority, . Lancet [Internet]. 2016;388(10055):2004–14. 
2. Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, et al. A 
European Organisation for Research and Treatment of Cancer phase III trial of 
adjuvant whole-brain radiotherapy versus observation in patients with one to three 
brain metastases from solid tumors after surgical resection or radiosurgery: Quality-
of-life. J Clin Oncol. 2013;31(1):65–72. 
3. Hartgerink D, Swinnen A, Roberge D, Nichol A, Zygmanski P, Yin FF, et al. LINAC 
based stereotactic radiosurgery for multiple brain metastases: guidance for clinical 
implementation. Acta Oncol (Madr) [Internet]. 2019;58(9):1275–82. 
4. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, Kawagishi J, et al. 
Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): A 
multi-institutional prospective observational study. Lancet Oncol [Internet]. 
2014;15(4):387–95. 
5. Hilkens NA, Enting RH, Hendriks LEL, Lagerwaard FJ, de Vos FYFL, Gijtenbeek 
JMM. Herziene richtlijn ‘Hersenmetastasen.’ Ned Tijdschr Geneeskd. 2020;164:1–4. 
6. Hartgerink D, van der Heijden B, De Ruysscher D, Postma A, Ackermans L, Hoeben 
A, et al. Stereotactic radiosurgery in the management of patients with brain 
metastases of non-small cell lung cancer: Indications, decision tools and future 
directions. Front Oncol. 2018;8(MAY):1–12. 
7. Martin AM, Cagney DN, Catalano PJ, Alexander BM, Redig AJ, Schoenfeld JD, et al. 
Immunotherapy and symptomatic radiation necrosis in patients with brain metastases 
treated with stereotactic radiation. JAMA Oncol. 2018;4(8):1123–4. 
8. Zindler JD, Schiffelers J, Lambin P, Hoffmann AL. Improved effectiveness of 
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