Prospective Phase II Trial to Assess Feasibility of Individualized, Model-guided Optimization of Proton Beam Treatment Planning in Patients With Low Grade Glioma Multicentric, Prospective Interventional, Randomized, Observer Blind Two Arm (Active Control), Parallel Group Investigator-initiated Phase II Trial
Phase: PHASE2
Conditions: Low Grade Glioma
Sponsor: University Hospital Heidelberg

 
 
 
 
 
 
 
 
 
 
 
Clinical trial protocol 
version 1.1 / 21.10.2022 
 
 
Version 1.0 
Erstellt 
Version 1.1 
 
 
 
Am 
17.03.2022 
21.10.2022 
 
 
 
Von 
Harrabi 
Harrabi 
 
 
 
 
clinical trial protocol 
– INDIGO – 
prospective phase II trial to assess feasibility of 
individualized, model-guided optimization of proton beam 
treatment planning in patients with low grade glioma 
 
multicentric, prospective interventional, randomized, observer blind two arm (active control), parallel 
group investigator-initiated phase II trial 
Version 1.1 / 21.10.2022 
Reg.-Nr.: TBA 
principal investigator 
Dr. Semi Harrabi 
University Hospital Heidelberg 
Im Neuenheimer Feld 400 
69120 Heidelberg 
 
CONFIDENTIAL: This protocol contains confidential information and is intended solely for the guidance of the 
clinical investigation. This protocol may not be disclosed to parties not associated with the clinical 
investigation or used for any purpose without the prior written consent of the Principal Investigator/ 
Coordinating Investigator. 
Financial support for this trial is applied for at the clinical trials program of the Deutsche 
Forschungsgemeinschaft (DFG). 
 

 
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Table of content 
Table of content ........................................................................................................................... 2 
Abbreviations .............................................................................................................................. 5 
Responsibilities ........................................................................................................................... 6 
Flowchart .................................................................................................................................... 13 
1 
Introduction ................................................................................................................ 15 
 
Scientific background .................................................................................................. 15 
 
Trial rationale .............................................................................................................. 15 
 
Benefit / risk assessment ............................................................................................16 
 
Risk/Benefit Consideration with reagard to SARS-CoV-2 pandemic .............................. 17 
2 
Trial objectives ............................................................................................................ 17 
 
Primary objectives ....................................................................................................... 17 
 
Secondary objectives ..................................................................................................18 
3 
Trial design and schedule ............................................................................................18 
 
Trial design .................................................................................................................18 
 
Trial duration and schedule .........................................................................................18 
 
Participating centers ...................................................................................................18 
3.3.1 
Requirements for participating centers ................................................................... 19 
4 
Trial population ........................................................................................................... 19 
 
Inclusion criteria ......................................................................................................... 19 
 
Exclusion criteria ........................................................................................................ 20 
 
Patient registration ..................................................................................................... 20 
 
Withdrawal of patients ............................................................................................... 20 
 
Specification of safety parameters .............................................................................. 21 
5 
Radiation therapy ....................................................................................................... 22 
 
Treatment planning .................................................................................................... 22 
 
Target volume definition ............................................................................................. 23 
 
Organs at risk ............................................................................................................. 23 
 
 
Assessment of toxicity ................................................................................................ 24 

 
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5.4.1 
Patient reported outcome ...................................................................................... 24 
 
Assessment of quality of life....................................................................................... 25 
 
Plan for treatment or care after the trial ...................................................................... 25 
6 
Clinical examinations (trial visits) ............................................................................... 26 
 
Overview .................................................................................................................... 26 
 
Base line examination ................................................................................................ 27 
 
Weekly examination during radiotherapy ................................................................... 27 
 
End of radiotherapy .................................................................................................... 27 
 
Follow-up ................................................................................................................... 27 
7 
Assessment of efficacy parameters ............................................................................ 28 
 
Assessment of efficacy parameters ............................................................................ 28 
7.1.1 
Radiation induced contrast enhancement .............................................................. 28 
7.1.2 
Progression free survival ........................................................................................ 28 
7.1.3 
Overall survival ...................................................................................................... 29 
8 
Assessment of safety parameters ............................................................................... 29 
 
Adverse events ........................................................................................................... 29 
 
Serious adverse events ............................................................................................... 31 
 
Expectedness ............................................................................................................. 32 
 
Coherency between AEs and trial treatment ................................................................ 32 
 
Outcome of AEs .......................................................................................................... 33 
9 
Quality assurance ...................................................................................................... 34 
 
Central review of treatment plans ............................................................................... 34 
 
Dummy run................................................................................................................. 34 
10 
Documentation .......................................................................................................... 34 
 
Data management ...................................................................................................... 34 
 
Patient Identification Log............................................................................................ 35 
 
Data Acquisition/ Case Report Forms ......................................................................... 35 
 
Archiving of Study Documents .................................................................................... 36 
 
Confidentiality ............................................................................................................ 36 
11 
Sample Size ............................................................................................................... 37 
12 
Statistical Analyses .................................................................................................... 38 

 
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Primary objective and study design ............................................................................ 38 
 
Hypothesis ................................................................................................................. 39 
 
Analysis ..................................................................................................................... 39 
12.3.1 
Analysis sets ...................................................................................................... 39 
12.3.2 
Confirmatory analysis of the primary endpoint ................................................... 39 
12.3.3 
Analysis of the secondary endpoints .................................................................. 40 
12.3.4 
Safety analysis ................................................................................................... 41 
12.3.5 
Homogeneity of the intervention groups ............................................................. 41 
 
Interim analysis .......................................................................................................... 42 
12.4.1 
Randomisation .................................................................................................. 43 
13 
Ethical, legal and administrative aspects ................................................................... 43 
 
Good clinical practice/ declaration of Helsinki ........................................................... 43 
 
Subject information and informed consent ................................................................. 43 
 
Responsibilities of investigator .................................................................................. 44 
 
Approval of trial protocol and amendments ................................................................ 45 
 
Registration of the trial ............................................................................................... 45 
14 
Agreements ................................................................................................................ 45 
 
Financing ................................................................................................................... 45 
 
Reports ...................................................................................................................... 46 
 
Publication ................................................................................................................. 46 
15 
Signatures .................................................................................................................. 47 
16 
References ................................................................................................................. 48 
 

 
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Abbreviations 
 
AE 
Adverse Event 
 
 
 
NCT 
national center for tumor diseases 
CEBL 
contrast enhancing brain lesion 
 
NTCP 
normal tissue complication probability 
CNS 
central nervous system 
 
 
OS 
overall survival 
CR 
complete response  
 
 
PD 
progressive disease 
CT 
computer tomography 
 
 
PFS 
progression free survival  
CTCAE 
Common Terminology Criteria for Adverse Events 
 
PP 
per protocol 
EC 
ethics committee 
 
 
 
PR 
partial response 
eCRF 
electronic Case Report Form  
 
PRO- 
patient reported outcome 
FAS 
full analysis set 
 
 
 
PRT 
Proton Beam Therapy 
FSI 
First subject in 
 
 
 
PTV 
Planning Target Volume 
FU 
follow up 
 
 
 
 
QoL 
quality of life 
GCP 
good clinical practice 
 
 
RBE 
relative biological effectiveness 
Gy 
Gray 
 
 
 
 
RT 
Radiotherapy 
HIT 
Heidelberg Ion-Beam Therapy Center 
SAE 
Serious Adverse Event 
IMPT 
Intensity Modulated Proton Therapy  
SOP 
Standard Operating Procedure 
ISF 
Investigator Site File 
 
 
TMF 
Trial Master File 
ITT 
intention to treat 
 
 
 
WHO 
world health organization 
LGG 
low-grade glioma 
LSI 
Last subject in 
LSO 
Last subject out 
MoCA 
Montreal neurocognitive assessment 
MRI 
magnetic resonance imaging 
NCI 
national cancer institute 
 

 
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Responsibilities 
Coordinating center: 
University Hospital Heidelberg 
 
 
Prof. Dr. Dr. Jürgen Debus 
 
 
-Head of the Department- 
 
 
Dept. of Radiation Oncology 
 
 
Heidelberg Ion Beam Therapy Center (HIT) 
 
 
Im Neuenheimer Feld 400 
 
 
69120 Heidelberg 
 
 
Principal investigator: 
Dr. Semi Harrabi 
 
 
Dept. of Radiation Oncology 
 
 
University Hospital Heidelberg 
 
 
Im Neuenheimer Feld 400 
 
 
69120 Heidelberg 
 
 
 
 
 
 
 
 
Co-investigator: 
Prof. Dr. Mechthild Krause 
 
 
-head of the department- 
 
 
Oncoray 
 
 
University Hospital Dresden 
 
 
Fetscherstraße 47 
 
 
01307 Dresden 
 
 
 
  
Participating centers: 
University Hospital Dresden 
 
 
Oncoray 
 
 
Fetscherstraße 47 
 
 
01307 Dresden 
 
 
 
 
Clinical Trial Office: 
Dr. Adriane Hommertgen 
 
 
Dept. of Radiation Oncology 
 
 
University Hospital Heidelberg 
 
 
Im Neuenheimer Feld 400 
 
 
69120 Heidelberg 
 
 
 
 
Study nurse & documentation: 
Study Nurse Team  
 
 
Dept. of Radiation Oncology 
 
 
University Hospital Heidelberg 
 
 
Im Neuenheimer Feld 400 
 
 
69120 Heidelberg  
 
 
IT: 
 
Andreas Kudak 
 
 
Dept. of Radiation Oncology 
 
 
University Hospital Heidelberg 
 
 
Im Neuenheimer Feld 400 
 
 
69120 Heidelberg 
 
 
 
Trial Statistician: 
M.Sc. Christopher Büsch 
 
 
Institute of Medical Biometry 
 
 
University Hospital Heidelberg 
 
 
Im Neuenheimer Feld 130.3 

 
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69120 Heidelberg 
 
 
 
Responsible Statistician: 
Dr. Johannes Krisam 
 
 
Institute of Medical Biometry 
 
 
University Hospital Heidelberg 
 
 
Im Neuenheimer Feld 130.3 
 
 
69120 Heidelberg  
 
 
Data-Safety-Monitoring-Board: 
Dr. David Krug 
 
 
Dept. of Radiation Oncology 
 
 
University Hospital Schleswig-Holstein 
 
 
Arnold-Heller-Straße 3 
 
 
24105 Kiel 
 
 
 
Prof. Dr. Marc Münter 
 
 
Dept. of Radiation Oncology 
 
 
Katharinenhospital 
 
 
Kriegsbergstraße 60 
 
 
70174 Stuttgart 
 
 
 
Dr. Claudia Schmoor 
 
 
Head of Biometry and Data Management 
 
 
Clinicical Trials Unit 
 
 
University Hospital Freiburg 
 
 
Stefan-Meier-Straße 26 
 
 
79104 Freiburg 
 

 
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Summary 
 
Title 
INDIGO - prospective phase II trial to assess feasibility of model-guided 
optimization of proton beam treatment planning in patients with low grade 
glioma 
Summary 
Radiotherapy can be considered as standard treatment option for patients 
with low grade glioma. Typically, a dose of 45-54 Gy in conventional 
fractionation of 1.8-2 Gy is applied. Age of the patient, size and localization 
of the tumor as well as neurologic status can affect the choice of the 
appropriate irradiation modality. Irradiation with photons is still the 
predominantly used modality. Considering that the prognosis is typically 
favorable the prevention of late sequelae is of particular importance. 
Proton beam therapy (PRT) and its advantageous physical properties has 
the potential to further reduce the burden of treatment related side effects. 
However, in about 20 % of all patients, late contrast-enhancing brain 
lesions (CEBL) appear on follow-up MR images 6 – 24 months after 
treatment. At HIT in Heidelberg and at OncoRay in Dresden, CEBLs have 
been observed to occur at very distinct locations in the brain and treatment 
field. Retrospective analysis has elucidated potential key factors that lead 
to CEBL occurrence. However, avoidance of CEBLs is hardly feasible using 
conventional treatment planning strategies. 
Model-aided risk avoidance denotes the use of model-based CEBL risk 
calculations as an auxiliary tool for clinical treatment planning: Model-
based risk calculations and risk reduction via software-based optimization 
help the clinician to minimize risk of CEBL occurrence during treatment 
planning. 
In a randomized-controlled trial, patients with low-grade glioma will be 
treated based on treatment plans that rely on either conventional planning 
strategies (control arm), or planning with model-aided risk avoidance 
(interventional arm). Through regular follow-up examinations during a 
period of at least 24 months post treatment, occurrence of CEBLs will be 
examined by MR imaging in all patients. The hypothesis will be tested that 
model-aided risk avoidance reduces the overall incidence of CEBLs. 
Principal 
investigator 
/ 
Trial Coordinator 
Dr. Semi Harrabi 
Clinical Trial Office 
Dr. Adriane Hommertgen 

 
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Trial population 
inclusion criteria: 
 
Age > 18 years 
 
histologically proven low-grade glioma 
 
indication for definitive or adjuvant radiotherapy 
 
ability to understand character and personal consequences of 
the clinical trial 
 
written informed consent 
 
exclusion criteria:  
 
previous cerebral irradiation 
 
contraindication for contrast-enhanced MRI  
 
neurofibromatosis 
 
participation in another clinical trial with competing objectives 
Trial design 
Multicentric prospective interventional, randomized, observer blind two 
arm (active control), parallel group investigator-initiated phase II trial with 
interim analysis to assess feasibility of model-aided optimization of proton 
beam treatment planning 
Sample size 
To be assessed for eligibility: n = 150 
To be allocated to trial: n = 120 
To be analyzed: n = 100 
Trial treatment 
Patients will be randomized to either conventional or model-aided 
treatment planning arm stratified by center. Both arms receive standard 
radiotherapy for patients with low grade glioma up to 54 Gy RBE. 
Treatment technique 
Protons, active raster-scanning, SBO/IMPT, model-guided re-planning 
Trial hypotheses 
Model-guided risk avoidance reduces the risk of contrast-enhancing brain 
lesions in low-grade glioma patients treated with proton-beam therapy. 
To formalize the statistical approach, the following notation will be used: 
𝑝𝑐𝑜𝑛𝑣/𝑝𝑎𝑖𝑑𝑒𝑑: cumulative incidence CEBL negative binomial rate within 24 
months in the conventional / model-aided experimental group. The 
following test problem is defined: 
𝐻0: 𝑝aided  ≥𝑝𝑐𝑜𝑛𝑣 
vs.     𝐻1: 𝑝aided  < 𝑝𝑐𝑜𝑛𝑣, 
which will be assessed at a one-sided significance level of 2.5 %. 
Outcome(s) 
 
Primary endpoint: cumulative incidence of contrast-enhancing brain 
lesions within 2 years. Contrast-enhancing brain lesions are defined as 
focal spots diagnosed by contrast-enhanced MRI within or adjacent to the 
irradiated high dose volume, but outside the initial tumor volume 
(independently diagnosed by two radiologists). 
Key secondary endpoint(s): Incidence of radiation-induced brain injuries > 
CTC°II, progression-free survival, overall survival, safety. 

 
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Assessment of safety: Safety will be assessed by the type, incidence, 
severity (graded by the NCT CTCAE Version 5.0) and relatedness of AEs to 
treatment. 
Sample size calculation  
Sample size calculation is based on the primary endpoint “cumulative 
incidence of contrast enhancing brain lesions (CEBL) observed within 24 
months after PRT”.  
Analyses based on own retrospective data showed that the primary 
endpoint is negative binomial distributed and that an 86% cumulative 
incidence CBL rate (of greater or equal than one), 𝑝conv , as well as 
dispersion parameter of Φ=0.2597 can be assumed in the conventional 
group. On the bases of additional experiments, a 60% reduction of 𝑝conv 
in 
the 
model-aided 
experimental 
group 
is 
assumed, 
hence 
𝑝𝑎𝑖𝑑𝑒𝑑=0.6∗𝑝conv, when assuming the same dispersion parameter in 
both groups.  
For a fixed sample size design, the sample size required to achieve a power 
of 1−𝛽 of 80% for the one-sided negative binomial regression at a 
significance level of 𝛼=0.025 assuming the same dispersion-parameter in 
conventional and experimental group and a randomization allocation ratio 
of 1:1 as well as the above-mentioned assumptions, amounts to 2∗46=92 
. It can be expected that including covariates of prognostic importance in 
the negative binomial regression model as defined for the confirmatory 
analysis (see Section 9) will increase the power as compared to no 
included covariates.  
A group-sequential design with interim analysis allowing to prematurely 
stop the trial for efficacy or futility (using O’Brien-Fleming- type alpha and 
beta spending functions) is performed. This will allow to prematurely 
declare the treatment as effective in case of a substantially large treatment 
effect, as well as to stop the trial in case the treatment does not prove to 
be effective. The interim analysis is conducted after half of the patients did 
reach the primary endpoint. Additionally, the study can be stopped in the 
interim analysis due to futility. These assumptions would lead to a sample 
size of 98 (49 per group) without consideration of drop-outs or premature 
death within 12 months after randomization. With an assumed 18% drop-
out rate, 120 patients (60 per group) are needed to achieve a power of 80%.  
Calculations were performed with R packages gscounts (Mütze et al. 2018) 
for sample size calculations and MASS (Venables & Ripley 2002) for 
estimation of the dispersion parameter. R version 4.1.2 was used.  
Statistical analysis 
Primary Endpoint 

 
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The primary endpoint of this clinical trial is the cumulative incidence of 
CEBLs within 24 months after PRT measured by quarterly contrast 
enhanced MRI of the brain. The null hypothesis is tested with a two-level 
negative binomial regression model including the covariates treatment, 
prescribed dose, and the random factor center at an overall one-sided 
significance level of 𝛼= 0.025 is applied. Confirmatory analysis of the 
primary endpoint will be primarily based on the Full Analysis Set. An 
evaluation of the per protocol and safety set is performed additionally. 
Also, multiple sensitivity analyses of the primary endpoint will be 
performed.  
A group-sequential design with interim analysis according to O’Brien-
Fleming type alpha and beta spending decision boundaries is performed. 
The interim analysis is conducted after n = 49 patients did reach the 
primary endpoint within 24 months, which is half of the planned total 
sample size not considering dropouts or premature deaths. No sample size 
recalculation is performed at the interim analysis. This design allows early 
stopping of the trial under control of the overall type I error rate, or, 
alternatively, a stop for futility. Results of the interim analysis will be 
presented to the Data Safety and Monitoring Board (DSMB) who will advise 
the Steering Committee of the trial to either terminate or to continue the 
trial. 
Secondary endpoints 
The secondary endpoints overall survival and progression-free survival will 
be analyzed using Kaplan-Meier-Curves. The 1-year and 2-year survival 
rates as well as the median survival rate will be provided alongside two-
sided 95%- confidence intervals. Furthermore, progression-free-survival 
and overall survival will be descriptively assessed at the interim analysis 
using Kaplan-Meier curves.  A Cox regression frailty model will be 
conducted to compare the two treatment groups. The other secondary 
endpoints and the patients’ characteristics will be displayed by descriptive 
measures grouped by treatment group. Continuous variables will be 
described using number non-missing values, mean, standard deviation, 
median, Q1, Q3, minimum and maximum. For binary or categorical 
variables absolute and relative frequencies will be provided. 
Safety analysis 
For safety analysis, laboratory parameters, all AEs and all SAEs will be 
analyzed via descriptive statistical methods in the safety population. The 

 
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safety analysis includes calculation of frequencies and rates of 
complications and serious adverse events together with corresponding 
95%-confidence intervals. In addition, tolerability and dosing will be 
described by numbers of patients in whom treatment was given as 
planned, delayed or permanently stopped. 
Detailed procedures of the interim and final analysis will be specified in 
separate Statistical Analyses Plans (SAP), which will be finalized before 
interim/final database lock. 
Trial duration 
Overall duration: 
 
 
 
 
60 months 
Minimal Follow-up: 
 
 
 
 
24 months 
FSI (first subject in):   
 
 
                  01/2023 
50% accrual:      
 
 
 
 
   09/2024 
LSI (last subject in):  
 
 
 
                  01/2026 
LSO (last subject out):  
 
 
                  01/2028 
Participating sites 
University Hospital Heidelberg - HIT 
University Hospital Dresden - OncoRay 

 
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Flowchart 
 

 
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Treatment schedule 
baseline 
visit 
weekly 
during  
RT 
end 
of 
RT 
FU 1 
6 weeks 
post RT 
FU 2 
3 months 
post RT 
FU 3 
6 
months 
post RT 
FU 4 
9 
months 
post RT 
FU 5 
12 
months 
post RT 
FU 6 
15 
months 
post RT 
FU 7 
18 
months 
post RT 
FU 8 
21 
months 
post RT 
FU 9 
24 
months 
post RT 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria  
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
 
 
 
 
 
 
 
 
 
 
 
 
Anamnesis/ 
clinical examination 
 
 
 
 
 
 
 
 
 
 
 
 
randomization 
 
 
 
 
 
 
 
 
 
 
 
 
AEs und SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms/toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
 
 
 
 
 
 
 
 
 
 
 
 
QLQ-C30 & QLQ-
BN20 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-CTCAE 
 
 
 
 
 
 
 
 
 
 
 
 
(Cognitive 
assessment) 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1 Introduction 
 Scientific background 
Low-grade glioma (LGG) represent typically slowly growing primary brain tumors with world 
health organization (WHO) grade I or II who affect young adults around their fourth decade. 
Radiological feature on MRI is a predominantly T2 hyperintense signal, LGG show typically 
no contrast uptake. Radiotherapy plays an important role in the treatment of LGG. 
However, not least because of the good prognosis with long term survivorship the timing 
of radiotherapy has been discussed controversially. In order to avoid long term sequelae 
such as neurocognitive impairment, malignant transformation or secondary neoplasms 
initiation of irradiation was often postponed as long as possible [1].  
The use of proton beam therapy (PRT) has constantly increased over the last decade. On 
account of the low entrance dose and effectively no dose distally, PRT most commonly 
utilizes just one to three radiation beams. Since this allows highly conformal treatment 
fields with very low integral dose absorbed by the surrounding healthy brain tissue, PRT 
seems to be a very promising technique to improve the clinical outcome of patients with 
LGG even further [2]. Corresponding dosimetric data have illustrated significantly 
decreased doses to various normal tissues for a variety of central nervous system (CNS) 
tumors independent of their localization within the brain [3]. 
However, there is lack of data in the literature regarding the risk of radiation induced 
contrast enhancement following PRT. Proton beam therapy is still considered as sparsely 
ionizing irradiation with a similar biological effect as photons. Currently, in clinical practice 
the physical dose of protons is multiplied with a fixed relative biological effectiveness 
(RBE) factor of 1.1 to obtain the biological effective dose in units of Gray RBE [4]. There is 
an intensifying controversial discussion whether this fixed RBE of 1.1 should further be 
used for protons or not. 
 
 Trial rationale 
Since patients with low grade glioma are expected to become long-term survivors, the 
prevention of long-term sequelae is particularly important. In addition to disease 
progression, also treatment related side effects such as decline of neurocognitive 
function, endocrine impairment or sensorineural deficits can have a negative impact on 
patient’s quality of life.  

 
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Owing to the biophysical properties of protons with an inverse depth dose profile 
compared to photons and a steep dose fall of to the normal tissue, there is a strong 
rationale for the use of PRT in the treatment of patients with low-grade glioma. Although 
data from large randomized trials are still missing there is increasing evidence from 
smaller prospective trials and retrospective analyses that the expected advantages indeed 
transform into clinical advantages [5,6].  
However, in about 20 % of all patients, late contrast-enhancing brain lesions (CEBL) 
appear on follow-up MR images 6 – 24 months after treatment [7]. At HIT in Heidelberg and 
at OncoRay in Dresden, CEBLs have been observed to occur at very distinct locations in the 
brain and relative to the treatment field. Retrospective analysis has elucidated potential 
key factors that lead to CEBL occurrence. However, avoidance of CEBLs is hardly feasible 
using conventional treatment planning strategies. Model-aided risk avoidance denotes 
the use of model-based CEBL risk calculations as an auxiliary tool for clinical treatment 
planning: Model-based risk calculations and risk reduction via software-based 
optimization help the clinician to minimize risk of CEBL occurrence during treatment 
planning. 
 Benefit / risk assessment 
Patients will be treated according to international accepted standard protocols. Target 
volume definition and dose prescription will be the same in both treatment arms. It is 
recommended that patients should receive a dose of 45 – 54 Gy in 1.8 – 2 Gy fractions [8-
10]. Proton beam therapy is an established treatment option for patients with low grade 
glioma. The possible side effects of the treatment in this study correspond to those of 
conventional photon radiotherapy. However, the frequency of asymptomatic treatment 
related changes seen on MRI follow-up is higher compared to conventional radiotherapy. 
The avoidance of CEBL occurrence has large potential benefit for the patients. In severe 
cases, they may develop into brain necrosis and lead to significant reduction in QoL and 
neurocognitive performance. The potential harm is ameliorated by the fact that CEBLs can 
often not be clearly distinguished from tumor progression. False classification may lead to 
either untreated tumor recurrence or to unnecessary treatment with radiation or 
chemotherapy of an already impaired brain tissue, causing further deterioration. 

 
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 Risk/Benefit Consideration with reagard to SARS-CoV-2 pandemic 
The specified measures and guidelines within the Covid-19 pandemic of the respective 
study centers are strictly adhered to in the INDIGO trial. Participation in the study does not 
lead to an increased risk with regard to SARS-CoV-2, since the number of fractions and 
thus the number of days on which the patient is irradiated on site is not increased. 
Therefore, despite the current overall situation, study initiation is reasonable considering 
the following aspects. The study education and the study inclusion take place under 
observance of the hygiene measures. Also, in the further course of the study, no 
additional, purely study-specific appointments are planned beyond the standard 
procedures required for patients with brain metastases. If a study patient becomes 
infected with SARS-CoV-2 during the study participation or if there is a justified suspicion, 
the health department and the principal investigator and study coordinator and the clinic 
director and local study director of the respective study center must be informed 
immediately. In this case, the regulations of the respective clinic for the handling of 
patients with evidence or reasonable suspicion of a Covid-19 infection apply. If infection 
occurs during radiotherapy, early discontinuation of therapy is usually required until 
complete and proven recovery of the patient. If infection occurs during the follow-up 
interval, the follow-up appointment can be postponed until proven recovery of the patient. 
If there are changes in the study schedule due to the pandemic, the study participants will 
be informed by the principal investigator or his representative. 
 
2 Trial objectives 
 Primary objectives 
The primary endpoint of this clinical trial is the cumulative incidence of contrast enhancing 
brain lesions observed within 24 months after PRT measured by quarterly contrast 
enhanced MRI of the brain. In case patients are not followed up for 24 months, e.g. due to 
death, loss to follow-up or withdrawal of informed consent, but are observed for at least 
12 months after randomization, their primary endpoint will be set to the number of lesions 
observed until last date of follow-up. Otherwise, e.g. if the follow-up of a patient is less 
than 12 months, the primary endpoint will be set to missing. 

 
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 Secondary objectives 
• incidence of radiation-induced brain injuries > CTC°II 
• progression-free survival 
• overall survival 
• safety 
• patient reported outcome (PRO-CTCAE) 
• quality of life (QLQ-C30 and QLQ-BN20) 
 
3 Trial design and schedule 
 Trial design 
Multicentric, prospective interventional, randomized, observer blind two arm (active 
control), parallel group, investigator-initiated phase II trial with interim analysis to assess 
feasibility of model-guided optimization of proton beam treatment planning.  
 
 Trial duration and schedule 
Overall duration 
 
 
 
 
 
 
 
 
60 months 
Minimal Follow-up:  
 
 
 
 
 
 
 
24 months 
FSI (first subject in):   
 
 
 
 
 
 
 
01/2023 
50% accrual:      
 
 
 
 
 
 
 
 
06/2024 
LSI (last subject in):  
 
 
 
 
 
 
 
01/2026 
LSO (last subject out): 
 
 
 
 
 
 
 
01/2028 
Recruitment period  
 
 
    
 
 
      01/2023 – 01/2026 
 
 Participating centers 
coordinating center: 
Prof. Dr. Dr. Jürgen Debus 
University Hospital Heidelberg 
Heidelberg Ion Beam Therapy Center (HIT) 
Im Neuenheimer Feld 400 
69120 Heidelberg 
 

 
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Principal investigator and responsible coordinator for this trial is Dr. Semi Harrabi, 
department radiation oncology at Heidelberg University Hospital. Administrative trial 
coordinator is Dr. Adriane Hommertgen, Head of the Clinical Trial Office, department 
radiation oncology at Heidelberg University Hospital.  Trial documentation is performed by 
the department’s Study Nurse Team, clinical trial office department radiation oncology at 
Heidelberg University Hospital.  Biometrical planning and statistical analysis are 
conducted by Christopher Büsch M.Sc., institute for medical biometry and informatics, 
Heidelberg University Hospital. Responsible statistician is Dr. Johannes Krisam, institute 
for medical biometry and informatics, Heidelberg University Hospital. 
 
Further participating centers are: 
University Hospital Dresden 
Oncoray 
Fetscherstraße 47 
01307 Dresden 
 
3.3.1 Requirements for participating centers 
Participating centers are required to successfully perform a dummy run for model-aided 
optimized re-planning before initiation of the trial.  
 
4 Trial population 
The predictive model used in this study is based on retrospective data from low-grade 
glioma patients. Predictions from the model were used in the design of the trial to calculate 
e.g. sample size. Therefore, a restriction to the same, homogeneous population seems 
necessary. Patients with the diagnosis of low-grade glioma and the indication for 
radiotherapy will be evaluated and screened for the protocol. All patients fulfilling the 
inclusion and exclusion criteria will be informed about the study. 
 Inclusion criteria 
✓ Age > 18 years 
✓ histologically proven low-grade glioma  

 
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✓ indication for definitive or adjuvant radiotherapy 
✓ ability to understand character and personal consequences of the clinical trial 
✓ written informed consent 
 Exclusion criteria 
− previous cerebral irradiation 
− contraindication for contrast-enhanced MRI  
− neurofibromatosis 
− participation in another clinical trial with competing objectives 
 Patient registration 
The study center keeps a logbook in which all patients who meet the selection criteria are 
recorded consecutively and documented in a registration form. If not included in the study, 
the reason is documented. All patients who fulfill the selection criteria, who have been 
informed and have given their consent to participate in the study, are registered as 
recruited at the study center. For this purpose, the registration form and the signed 
informed consent are handed over or faxed to the study center. In the study center, the 
registration form is checked for completeness and the patient is recorded in the logbook. 
The informed consent of each patient takes place through a conversation between the 
study physician and the patient before inclusion in the study. The physician has to give 
the patient sufficient time for reflection and opportunity for further inquiries and must be 
convinced that the informed consent was understood by the patient. All questions of the 
patient must be answered and any ambiguities eliminated. The consent of the patient 
must explicitly refer to the collection and processing of personal data. Therefore, patients 
are explicitly informed about the purpose and scope of the survey and the use of this data, 
in particular health data. The storage of full names, dates of birth, addresses, and 
telephone numbers in the study center will be recorded in writing. 
The patient may withdraw consent at any time and without giving any reason and 
discontinue the study. In such a case, he should be asked to give the reason for the 
termination, but pointed out that he does not have to do this. 
 Withdrawal of patients  
A subject may voluntarily discontinue participation in this study at any time at their own 
request. The investigator may also, at his/her discretion, withdraw the subject from the 

 
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study at any time. In addition, study treatment will be discontinued if unmanageable 
toxicity is documented, or if the Principal Investigator decides to terminate the trial. A 
subject will be withdrawn from the protocol if, in the investigator’s opinion, continuation 
of the trial would be detrimental to the subject’s well-being.  
If the subject withdraws from the trial and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should 
be collected.  
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject’s 
medical records. In case of withdrawal of a subject at his/ her own request, the reason 
should be asked for as extensively as possible and documented. All efforts will be made 
to follow up the subjects and, all examinations scheduled for the final trial day will be 
performed as far as possible on all patients and documented.  
All ongoing Adverse Events (AEs)/ Serious Adverse Events (SAEs) of withdrawn patients 
have to be followed up until no more signs and symptoms are verifiable or the subject is 
on stable condition. 
 
 Specification of safety parameters 
Reasons for a preliminary discontinuation of the trial might be: 
• Principal investigators decision due to unacceptable risks or toxicity after 
careful benefit-risk-consideration 
• Consideration to discontinue after any grade 5 toxicity, after 2 consecutive 
grade 4 toxicities, after 5 consecutive grade 3 toxicities  
• New scientific findings during trial period 
• Major delay in recruitment 
• Major problems with quality of acquired data that cannot be resolved 
• Timely recognition of a significant superiority or inferiority of one of the 
treatment arms as defined by the terms of the interim analysis 
• Neglecting legal or ethical regulations 
 

 
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5 Radiation therapy 
Patients will be treated with proton beam therapy up to 54 Gy RBE. The prescribed dose 
will be delivered in active scanning technique at one of the participating centers using a 
fractionation of either 30 x 1.8 Gy RBE or 27 x 2 Gy RBE with five fractions per week. Patients 
in the control arm are treated according to the current clinical standard in the respective 
facilities. 
 Treatment planning 
For treatment planning, patients will be immobilized using an individually manufactured 
head mask. Both CT as well as contrast enhanced MR-imaging will be performed for 
optimal target definition. CT slice thickness should be 1 mm. Treatment planning MRI 
should be performed with 3T not earlier than 4 weeks prior to radiotherapy. Minimum 
required sequences are: 
• T1 MPRAGE with and without contrast enhancement, slice thickness ~ 1mm 
• 3D FLAIR / dark fluid TIRM, slice thickness ~ 1mm 
Treatment planning in the control arm is performed with the available treatment planning 
system at each participating center (e.g. Siemens Syngo TPS, Raysearch Raystation) using 
a fixed RBE of 1.1. Each plan should aim for a dose distribution as homogenous and as 
conformal as possible. The number and directions of beams are adapted to the patient 
anatomy. Single beam plans must be avoided whenever possible. The optimization 
strategy in the conventional treatment planning arm is not determined by the protocol. In 
principal both Single Beam Optimization/Single Field Uniform Dose or IMPT could be used. 
Model-based NTCP is calculated after plan approval, however, no further adjustments are 
to be made to the approved treatment plan.  
Re-planning in the experimental arm is performed with Raysearch Raystation, a 
commercially available treatment planning software with CE certification as medical 
medical product, using identical beam directions and normal tissue constraints as the 
initial treatment plan. Compared to the initial treatment plan, the following optimization 
objectives are modified and added, respectively: 

 
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1. the optimization objectives that control the maximum dose in the target volume employ 
a variable, LETd-dependent model for RBE that allows us to include the RBE-variations 
predicted by the NTCP model 
2. the periventricular volume, defined as the volume closer than 4 mm to the ventricular 
wall, is included into the optimization with a constraint on its Equivalent Uniform Dose 
(EUD) and with the variable RBE model described above. Thereby, the combined effect of 
the RBE variation and increased sensitivity of the periventricular volume, as predicted by 
the NTCP model, is included. 
The effectiveness of the re-planning is verified by a second NTCP computation. 
 Target volume definition 
Target volume definition is based on international consensus guidelines. The following 
target volumes must be delineated: 
− GTV: gross tumor volume is defined as the hyperintense area on T2/FLAIR/TIRM 
sequences at the time of treatment planning.  
− GTV_initial: in case of postoperative radiotherapy gross tumor volume is defined as the 
hyperintense area on T2/FLAIR/TIRM sequences before surgery. 
− Tumorbett: in case of postoperative radiotherapy the tumor bed is defined as overlap 
of resection cavity and initial GTV. 
− CTV: the clinical target volume is defined as GTV plus an isotropic margin of 1 cm. 
− PTV: the planning target volume is defined as CTV plus a margin of 3 mm. 
− Overlap: defined as the overlap of Ventrikelsaum and PTV outside the GTV 
 Organs at risk 
The following organs at risk should be defined according to international accepted 
standards 
(see 
EPTN 
International 
Neurological 
Contouring 
atlas 
at 
https://www.cancerdata.org/. To facilitate future comparison of the structures, enable 
template based planning or automated plan evaluation and dose-volume-histogram 
analysis the proposed uniform nomenclature is to be used: 
− Auge li. 
− Auge re. 
− Chiasma 
− Hippocamous li. 
− Hippocampus re. 

 
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− Hirn 
− Hirnstamm 
− Hypophyse 
− Hypothalamus li. 
− Hypothalamus re. 
− InnenOhr li. 
− InnenOhr re. 
− Linse li. 
− Linse re. 
− Rueckenmark 
− Sehnerv li. 
− Sehnerv re. 
− Traenendruese li. 
− Traenendruese re. 
− Ventrikel 
− Ventrikelsaum (=Ventrikel + 6 mm) 
 
To avoid inacceptable radiation induced toxicity the maximum dose to organs at risk must 
not exceed the TD 5/5 (toxic dose causing 5% severe complications in 5 years). For further 
details 
see 
detailed 
results 
of 
QUNATEC 
analysis 
(https://www.redjournal.org/issue/S0360-3016(10)X0002-5). 
 
 Assessment of toxicity 
This study will use the International Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for toxicity and adverse event reporting. A copy or the CTCAE can be 
accessed 
from 
the 
CTEP 
home 
page 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5
_Quick_Reference_8.5x11.pdf). 
Safety and toxicity of the study treatment will be evaluated by clinical neurological 
examination as well as neuro-imaging studies (MRI or CT). 
 
5.4.1 Patient reported outcome 
This trial will assess patient reported outcomes of the common terminology criteria for 
adverse events (PRO-CTCAE). PRO-CTCAE is a patient-reported outcome measurement 

 
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system developed by the National Cancer Institute to capture symptomatic adverse events 
in patients on cancer clinical trials. 
 
 Assessment of quality of life 
Quality of life will be assessed prior to radiation, at the end of treatment and during follow-
up. Quality of life will be assessed using EORTCs (brain specific) questionnaires for quality 
of life of cancer patients (QLQ-C30 and QLQ-BN20). 
 
 
 Plan for treatment or care after the trial 
After completion of trial treatment, no further adjuvant treatment is scheduled or 
recommended. Any systemic treatment or chemotherapy or any other treatment applied is 
not part of the clinical trial.  
For tumor progression, treatment alternatives will be evaluated and discussed in the 
interdisciplinary setting considering options of neurosurgical resection, systemic 
treatment such as chemotherapy, a second course of radiation therapy, or other.

 
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6 Clinical examinations (trial visits) 
 Overview 
Treatment schedule 
baseline 
visit 
weekly 
during  
RT 
end 
of 
RT 
FU 1 
6 
weeks 
post RT 
FU 2 
3 months 
post RT 
FU 3 
6 
months 
post RT 
FU 4 
9 
months 
post RT 
FU 5 
12 
months 
post RT 
FU 6 
15 
months 
post RT 
FU 7 
18 
months 
post RT 
FU 8 
21 
months 
post RT 
FU 9 
24 
months 
post RT 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion 
criteria  
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
 
 
 
 
 
 
 
 
 
 
 
 
Anamnesis/ 
clinical examination 
 
 
 
 
 
 
 
 
 
 
 
 
randomization 
 
 
 
 
 
 
 
 
 
 
 
 
AEs und SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms/toxicity 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
 
 
 
 
 
 
 
 
 
 
 
 
QLQ-C30 
& 
QLQ-
BN20 
 
 
 
 
 
 
 
 
 
 
 
 
PRO-CTCAE 
 
 
 
 
 
 
 
 
 
 
 
 
(Cognitive 
assessment) 
 
 
 
 
 
 
 
 
 
 
 
 

 
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The number of trial visits and the extent of their examinations is equivalent to standard 
care. Trial related additional expense is a result of the neurocognitive testing. The MoCA 
test is designed to take less than 15 min. Completing the PRO-CTCAE form takes less than 
5 min. Additional time is needed for completing the quality of life questionnaires which 
takes approx. additional 20 min per visit. In total, the additional time expense for the 
patient sums up to 40 min on five trial visits and 5 min at the remaining visits. 
 Base line examination 
− Anamnesis and clinical examination 
− Assessment of QoL 
− Assessment of toxicity (CTCAE) 
− Assessment of patient reported outcome (PRO-CTCAE) 
 Weekly examination during radiotherapy 
− Assessment of toxicity (CTCAE) 
− Assessment of patient reported outcome (PRO-CTCAE) 
 End of radiotherapy 
− Assessment of QoL 
− Assessment of toxicity (CTCAE) 
− Assessment of patient reported outcome (PRO-CTCAE) 
 Follow-up 
Trial follow-up starts six weeks after completion of radiotherapy. Further follow-up exams 
are scheduled every three months for a period of two years. The following parameters will 
be assessed: 
− Contrast-enhanced MRI of the brain 
− Clinical status 
− Toxicity (according to CTCAE 5.0) 
− Patient reported outcome of CTCAE (PRO-CTCAE) 
− Quality of life (only after 6, 12 and 24 months) 
 

 
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7 Assessment of efficacy parameters 
 Assessment of efficacy parameters 
7.1.1 
Radiation induced contrast enhancement 
All MRI scans will be evaluated by two independent radiologists. Any new contrast 
enhancement seen outside the GTV but inside the treated high-dose volume (defined as 
the 80% isodose) is classified as potentially radiation induced. In case of detection of new 
contrast enhancing lesions, the corresponding series will be imported into the treatment 
planning system, merged with the initial treatment planning CT and delineated as new 
volume of interest. The dose distribution will be updated by re-calculating dose volume 
histograms enabling an in-depth dosimetric and volumetric analysis and correlation with 
beam parameters. Furthermore, the localization will be checked against the prediction of 
the NTCP-model. 
7.1.2 Progression free survival 
Progression-free survival (PFS) is one of the secondary endpoints of the trial. Progression-
free survival will be counted from the first day of radiotherapy treatment until the date of 
the first event of either progression or death due to any cause. Patients alive without 
progressive disease at the time of data analysis will be censored at the time of the most 
recent follow-up visit. Radiological responses will be classified as follows: 
 
Complete remission (CR): Remission of all solid tumor lesions on CT or MRI without 
worsening of neurologic status  
Partial remission (PR): at least 50% remission of the solid tumor lesion on CT or MRI 
without increase in steroid medication and without worsening of the neurologic status  
Stable disease (SD): Remission of the solid tumor on CT or MRI of less than 50% or 
progression of the solid tumor on CT or MRI of less than 25%, without increase in steroid 
medication of worsening of the neurologic status  
Progressive disease (PD): Increase in solid tumor of 25% or more or development of a new 
lesion  
 
Progression-free survival and its distinction from radiation induced contrast enhancement 
will be assessed as defined hereunder:  

 
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Follow-up assessments (including MRI or CT) will be performed as described until disease 
progression (even after the end of the study). Special attention should be given so as to 
avoid tissue reaction to radiation treatment to be classified as tumor or disease 
progression. Such variations in post-radiotherapy imaging may continue for months, and 
may be accompanied by clinical signs and symptoms. In addition, surgical procedures may 
cause increased contrast uptake which should be differentiated from tumor progression. 
The clinical follow-up must dictate how the initial progression of the lesion should be 
labeled. If the course of events shows that true progression indeed occurred, the date of 
the first increased is to be considered as the date of progression. The principal investigator 
may be contacted for further discussion on a case by case basis. 
7.1.3 Overall survival 
Overall survival (OS)is one of the secondary endpoints of the trial. The duration of survival 
is the time interval between initial diagnosis (date of the neuropathology report) and the 
date of death due to any cause. Patients not reported dead or lost to follow-up will be 
censored at the date of the last follow-up examination. 
8 Assessment of safety parameters 
 Adverse events 
According to GCP, an adverse event (AE) is defined as follows: Any untoward medical 
occurrence in a subject administered a pharmaceutical product or treatment and which 
does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product or treatment, whether or not related to the medicinal (investigational) product.  
 
 
An AE may be:  
− New symptoms/ medical conditions  
− New diagnosis  
− Changes of laboratory parameters  
− Intercurrent diseases and accidents  
− Worsening of medical conditions/ diseases existing before clinical trial start 

 
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− Recurrence of disease  
− Increase of frequency or intensity of episodical diseases.  
A pre-existing disease or symptom will not be considered an adverse event unless there 
will be an untoward change in its intensity, frequency or quality. This change will be 
documented by an investigator. Each AE developing during study treatment or within 30 
days after completion of study treatment should be documented up to 6 months after 
completion of study treatment. The investigator is responsible to perform and consider all 
required therapeutic measures and methods to follow-up this condition. An event, which 
occurs in conjunction or association with tumor progression will not be considered an AE 
or subsequently as an SAE unless more severe than expected.  
 
Following examples will also not be considered as an AE:  
− A medical or surgical procedure (the condition that led to the procedures is an AE)  
− Situations in which an untoward medical occurrence did not occur (e.g. social 
and/or convenience admission to a hospital) 
− Anticipated day-to-day fluctuations of pre-existing disease(s) or conditions(s) 
present or detected at the start of the study that do not worsen 
− The disease/disorder being studied or expected progression, signs or symptoms of 
the disease/disorder being studied, unless they are more severe than expected for 
the subject’s condition  
 
The grading of AEs in this trial will be carried out on the basis of the 5-grade scale as 
defined in CTCAE v5.0: 
Grade 1 
 
mild AE 
Grade 2 
 
moderate AE 
Grade 3 
 
severe AE 
Grade 4 
 
life-threatening AE or AE causing disablement 
Grade 5 
 
death related to AE 
The grading of all AEs listed in the CTCAE v5.0 will be based on the information therein. 
The grading of all other AEs, i.e. those who are not listed will be performed by a responsible 
investigator, based on the definition given above. 
 

 
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Surgical procedures themselves are not AEs; they are therapeutic measures for conditions 
that require surgery. The condition for which the surgery is required may be an AE. Planned 
surgical measures permitted by the clinical trial protocol and the condition(s) leading to 
these measures are not AEs, if the condition leading to the measure was present prior to 
inclusion into the trial.  
− AEs are classified as "non-serious" or "serious". 
 Serious adverse events  
A serious adverse event (SAE) is one that at any dose:  
− Results in death  
− Is life-threatening (the term life-threatening refers to an event in which the subject 
was at risk of death at the time of event and not to an event which hypothetically 
might have caused death if it was more severe)  
− Requires subject hospitalization or prolongation of existing hospitalization  
− Results in persistent or significant disability/ incapacity  
 
Examples of SAEs that do not need to be reported:  
− Medical or surgical procedures (i.e. endoscopy, appendectomy); the condition that 
leads to the procedure may be an AE 
− Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to the hospital)  
− Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen  
− The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
subject’s condition 
− A hospitalization which was planned before the patient consented for study 
participation and where admission did not take longer than anticipated  
 
Any SAE that occurs outside the SAE detection period (after the 30-day period) considered 
to be reasonably related to the investigational treatment or study participation have to be 
documented and reported.  

 
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This must be done within 24 hours of the initial observation of the event. The principal 
investigator will decide if these events are related to the protocol treatment (i.e. unrelated, 
likely related, and not assessable) and the decision will be recorded on the Serious 
Adverse Event form, if necessary with the reasoning of the principal investigator. The 
investigator is obligated to assess the relationship between investigational product and 
the occurrence of each AE/SAE. A “reasonable possibility” is meant to convey that there 
are facts/evidence or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out. The investigator will use clinical judgement to determine 
the relationships. Alternative causes, such as natural history of the underlying diseases, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
investigational treatment will be considered and investigated. 
 Expectedness 
An ‘unexpected’ adverse event is one the nature or severity of which is not consistent with 
the known common side effects after radiation therapy according to the CTCAE criteria. 
Furthermore, reports which add significant information on specificity or severity of a known 
adverse reaction constitute ‘unexpected’ events. 
 
 Coherency between AEs and trial treatment 
The investigator will evaluate each AE that occurred after administration of investigational 
medicinal product regarding the coherency with the administration of the investigational 
medicinal product possibly: 
 
Related 
There is a reasonable possibility that the event may have been 
caused by the trial treatment. A certain event has a strong temporal 
relationship and an alternative cause is unlikely 
Probable 
An AE that has a reasonable possibility that the event is likely to have 
been caused by the trial treatment. The AE has a timely relationship 
and follows a known pattern of response, but a potential alternative 
cause may be present.  
Possible 
An AE that has a reasonable possibility that the event may have been 
caused by the trial treatment. The AE has a timely relationship to the 

 
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trial treatment; however, the pattern of response is untypical, and an 
alternative cause seems more likely, or there is significant 
uncertainty about the cause of the event  
Unlikely 
Only a remote connection exists between the trial treatment and the 
reported adverse event. Other conditions including concurrent 
illness, progression or expression of the disease state or reaction of 
the concomitant medication appear to explain the reported adverse 
event  
Not related 
An AE that does not follow a reasonable temporal sequence related 
to the trial treatment and is likely to have been produced by the 
subject’s clinical state, other modes of therapy or other known 
etiology  
 Outcome of AEs 
The outcome of an AE at the time of the last observation will be classified as: 
 
Recovered/resolved: 
all signs and symptoms of an AE disappeared without 
any sequels at the time of the last interrogation  
Recovering/resolving: 
the intensity of signs and symptoms has been 
diminishing and/ or their clinical pattern has been 
changing up to the time of the last interrogation in a 
way typical for its resolution  
Not recovered/not resolved 
signs and symptoms of an AE are mostly unchanged at 
the time of the last interrogation  
Recovered/resolved with sequel 
actual signs and symptoms of an AE disappeared but 
there are sequels related to the AE  
Fatal 
resulting in death. If there are more than one adverse 
event only the adverse event leading to death (possibly 
related) will be characterized as ‘fatal’ 
Unknown 
the outcome is unknown or implausible and the 
information cannot be supplemented or verified  
 

 
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9 Quality assurance 
 Central review of treatment plans 
To ensure consistent quality of the treatment plans a central review of the first three 
treatment plans in the control arm and of every treatment plan in the experimental arm will 
be performed prior to first irradiation. Data will be exchanged using the HIRO research data 
base. 
The plans will be assessed by the coordinating investigators of the participating centers. 
At least the following criteria will be evaluated: 
• definition of target volumes 
• definition of OARs 
• dose prescription 
• target coverage for CTV and PTV 
• dose constraints for OARs 
• beam arrangement 
 
 Dummy run 
The Dummy Run will ensure that the contouring and treatment planning is consistent with 
the protocol requirements. The Dummy Run will include a submission of contouring, dose 
planning, and optimised re-planning for evaluation. Based on this, the study coordinators 
will evaluate if the centre is ready to participate and at least the above-mentioned quality 
criteria are met. In case of deviations from the specifications of the protocol the 
coordinating investigators will discuss the results and the dummy run might be repeated. 
 
10 Documentation 
 Data management 
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to 
a paper form or an electronic data record or both, depending on the data collection method 
used at each participating center. All findings including clinical and laboratory data will be 
documented by the investigator or an authorized member of the study team in the 

 
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subject's medical record and in the CRF. The investigator is responsible for ensuring that 
all sections of the CRF are completed correctly and that entries can be verified against 
source data. 
 Patient Identification Log 
All patient-related data are recorded in a pseudonymized form. Each patient is uniquely 
identified by a patient identification number. The investigator maintains a patient 
identification list in which the patient identification numbers are associated with the full 
patient name. This list must be kept absolutely confidential and must not leave the testing 
center. The patient identification list must be archived for at least 30 years after the end of 
the study. 
All clinical data entered in the HIRO database in the eCRFs, treatment plans and imaging 
will be sent exclusively pseudonymized. 
 
 Data Acquisition/ Case Report Forms 
The data is collected, managed and processed electronically in the in-house HIRO research 
database. In the case of revocation of the consent, the data may continue to be used, as 
long as there is no request for complete deletion of the data. 
It is the responsibility of the principal investigator to conduct the study in accordance with 
applicable legal provisions and the study protocol, and that the data is entered correctly 
and completely in the eCRFs. 
All data collected in this study must be documented by authorized persons in the eCRFs. 
Access to the database must be authorized in writing by the principal (Signature Log). Only 
authorized persons are granted access to the database. Access authorization may not be 
passed to third parties. 
Data in the HIRO database will be checked by programmed value ranges, validity and 
consistency checks. If necessary, queries may arise that are made using the HIRO 
database and authorized persons. Based on the queries, the study physician / study nurse 
can review and answer or correct the resulting discrepancies. 
The eCRFs must be completed promptly and then checked by the investigator. 

 
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After completion of the study and after entry of all relevant data and clarification of the 
queries, the data base will be closed. 
 Archiving of Study Documents 
The originals of all central study documents, including documentation sheets, are kept at 
the Study Center for at least 30 years after the final report has been prepared. 
The principal investigator of the study center keeps the administrative documents 
(correspondence with the ethics committee, study administration, study center), the 
patient identification list, the signed declarations of consent, copies of the CRFs and the 
general study documentation (protocol, amendments) for the above-mentioned time. 
Original data of the patients (medical records) must be kept for the required archiving 
period of the study center, but not less than 30 years. 
 
 Confidentiality 
The data obtained in the course of the trial will be treated pursuant to the Federal Data 
Protection Law (Bundesdatenschutz- bzw. Landesdatenschutzgesetz, BDSG-neu, LDSG 
and the General Data Protection Regulation (DSGVO).  
During the clinical trial, patients will be identified solely by means of their year of birth, 
and an individual identification code (Subject ID). Trial findings stored on a computer will 
be stored in accordance with local data protection law and will be handled in strictest 
confidence. For protection of these data, organizational procedures are implemented to 
prevent distribution of data to unauthorized persons. The appropriate regulations of local 
data legislation will be fulfilled in its entirety.  
The subject consents in writing to relieve the investigator from his/her professional 
discretion in so far as to allow inspection of original data for monitoring purposes by health 
authorities and authorized persons (inspectors, monitors, auditors). Authorized persons 
(clinical monitors, auditors, inspectors) may inspect the subject-related data collected 
during the trial ensuring the data protection law.  
The investigator will maintain a subject identification list (subject IDs with the 
corresponding subject names) to enable records to be identified.  
Patients who did not consent to circulate their pseudonymized data will not be included 
into the trial. 

 
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11 Sample Size 
Sample size calculation is based on the primary endpoint “cumulative incidence of 
contrast enhancing brain lesions (CEBL) observed within 24 months after PRT”.  
Our previous analysis showed that the primary endpoint is negative binomial distributed 
and that an 86 % cumulative incidence CBL negative binomial event rate, 𝑝𝑐𝑜𝑛𝑣, as well as 
dispersion parameter of Φ = 0.2597 can be assumed in the conventional group. On the 
bases of additional experiments, a 60 % reduction of the probability for at least one lesion 
in the model-aided experimental group is assumed, corresponding to a negative binomial 
event rate 𝑝𝑎𝑖𝑑𝑒𝑑= 0.18 when assuming the same dispersion parameter in both groups. 
For a fixed sample size design, the sample size required to achieve a power of 1 −𝛽 of 
80% for the one-sided negative binomial regression at a significance level of 𝛼= 0.025  
in conventional and experimental group and a randomization allocation ratio of 1 as well 
as the above-mentioned assumptions, amounts to 2 ∗46 = 92 . It can be expected that 
including covariates of prognostic importance in the negative binomial regression model as 
defined for the confirmatory analysis (see section 13.3) will increase the power as compared 
to no included covariates. 
As the individual results for the primary endpoint are collected within 24 months, there is 
a possibility of some patients not surviving the observation period, becoming lost to 
follow-up or withdrawing their informed consent. If a patient discontinues from the study 
prematurely without having a full observation time (e.g. due to death, loss to follow, or 
withdrawal of informed consent) but was observed for at least one year after randomization, 
the primary outcome variable will be set to the number of lesions observed until the last 
available follow-up visit. If a patient has a follow-up less than one year after randomization, 
the primary endpoint will be set to missing. In order to take this potential loss of information 
into account, a premature death rate of 8% and a drop-out rate of 10% (loss to follow or 
withdrawal of informed consent) after 12 months is assumed. Thus, an overall “drop-out” 
rate of 18% after 12 months is assumed, and therefore the total sample size required for a 
fixed design amounts to 𝑛= 92 + 22 = 114 patients (57 per group). 
A group-sequential design with interim analysis allowing to prematurely stop the trial for 
efficacy or futility, using O´Brien-Fleming-type alpha and beta spending functions, is 

 
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performed. This will allow to prematurely declare the treatment as effective in case of a 
substantially large treatment effect, as well as to stop the trial in case the treatment does 
not prove to be effective. The interim analysis is conducted after half of the patients did 
reach the primary endpoint (see the detailed description of the procedure applied for the 
interim analysis in section 13.3 below). Additionally, the study can be stopped in the 
interim analysis due to futility (boundaries for interim and final analysis are given in 
section 13.4). These assumptions would lead to a sample size of 98 (49 per group) without 
consideration of drop-outs. With an assumed 18% drop-out rate 120 patients (60 per 
group) are needed to achieve a power of 80%.  
It should be noted that the interim analysis will likely take place after the total number of 
120 patients have been enrolled. While in such a case, it is not possible to reduce the total 
number of enrolled patients, the follow-up time of the trial might be reduced, thus allowing 
to save resources and costs. 
Calculations were performed with R packages gscounts for sample size calculations and 
MASS for estimation of the dispersion parameter. R version 3.6.3 was used. 
 
12 Statistical Analyses 
 Primary objective and study design 
The primary endpoint of this clinical trial is the cumulative incidence of CEBLs within 24 
months after PRT measured by quarterly contrast enhanced MRI of the brain.  
A group-sequential design with interim analysis according to O’Brien-Fleming type alpha 
and beta spending decision boundaries is performed to not withhold a possible effective 
treatment to the control group as well as the general trial population in case of a large 
beneficial treatment effect, and to prevent harm for the patients in case the experimental 
treatment should prove to be ineffective at interim. The interim analysis is conducted after 
n = 49 patients did reach the primary endpoint within 24 months, which is half of the 
planned total sample size not considering dropouts or premature deaths. No sample size 
recalculation is performed at the interim analysis. Furthermore, descriptive statistics for 
progression-free-survival and overall survival will be given at the interim analysis. This 
design allows early stopping of the trial under control of the overall type I error rate, or, 

 
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alternatively, a stop for futility. Results of the interim analysis will be presented to the Data 
Safety and Monitoring Board (DSMB) who will advise the Steering Committee of the trial to 
either terminate or to continue the trial. 
 
 Hypothesis 
To formalize the statistical approach, the following notation will be used: 
𝑝𝑐𝑜𝑛𝑣/𝑝𝑎𝑖𝑑𝑒𝑑: cumulative incidence CEBL negative binomial rate within 24 months in the 
conventional / model-aided experimental group. The following test problem is defined: 
𝐻0: 𝑝aided  ≥𝑝𝑐𝑜𝑛𝑣 vs.     𝐻1: 𝑝aided  < 𝑝𝑐𝑜𝑛𝑣, 
which will be assessed at a one-sided significance level of 2.5 %. 
 Analysis 
12.3.1 
Analysis sets 
The allocation of each patient to the different analysis populations will be defined and 
explained in further detail in the statistical analysis plan (SAP) prior to the analysis.  
Full Analysis Set (FAS): All patients who fulfilled the inclusion and exclusion criteria and 
hence were included into the trial. The term “ITT-analysis” is used for an analysis applying 
ITT principles to all patients of the FAS.  
Per Protocol Set (PP): All patients from the FAS, excluding patients with major protocol 
violations. During the interim analysis, deviations from the protocol will be assessed as 
„minor” or „major”.  „Major” protocol violations will be discussed with the coordinating 
investigator.   
Safety Set: All patients from the FAS who received at least one fraction of radiotherapy. 
Patients will be allocated to the treatment they actually received.  
12.3.2 Confirmatory analysis of the primary endpoint 
The null-hypothesis is tested with a two-level negative binomial regression model 
including the covariates treatment, prescribed dose, and the random factor center. An 
overall one-sided significance level of 𝛼= 0.025 is applied. Confirmatory analysis of the 
primary endpoint will be primarily based on the FAS which is consistent with the intention-
to-treat (ITT)-principle by including all patients who were randomized to one of the study 

 
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groups. If a patient discontinues from the study prematurely without having a full 
observation time (e.g. due to death, loss to follow, or withdrawal of informed consent) but 
was observed for at least one year after randomization, the primary outcome variable will 
be set to the number of lesions observed until the last available follow-up visit. If a patient 
has a follow-up less than one year after randomization, the primary endpoint will be set to 
missing. An evaluation of the PP and safety set is performed additionally and the results 
are compared with those of the ITT analysis. Additionally, multiple sensitivity analyses of 
the primary endpoint will be performed by applying alternative methods dealing with 
missing data such as:  
- 
Complete-case analysis, which means that the primary outcome of all patients with 
an incomplete 24 month follow up will be set to missing and neglected for the 
primary analysis.  
- 
Analysis based on the FAS. If a patient discontinues from the study prematurely 
without having a full observation time, missing data for the primary outcome 
variable will be replaced by using multiple imputation by means of fully conditional 
specification method (van Buuren, 2006). The variables treatment, dose, center, 
lesions observed until censoring, and observation time will be included in the 
imputation model, which will use predictive mean matching to impute missing 
primary outcome data.   
- 
Analysis based on the FAS of the primary endpoint using the non-parametric van 
Elteren test stratified by center, where the number of CEBLs is set to infinity for all 
deceased patients. If a patient discontinues from the study prematurely without 
having a full observation time due to loss to follow-up, missing data for the primary 
outcome variable will be replaced by using multiple imputation by means of fully 
conditional specification method (van Buuren, 2006).  The variables treatment, 
dose, center, lesions observed until censoring, and observation time will be 
included in the imputation model, which will use predictive mean matching to 
impute missing primary outcome data.   
12.3.3 Analysis of the secondary endpoints 
The secondary endpoints overall survival and progression-free survival will be analyzed 
using Kaplan-Meier-Curves. The 1-year and 2-year survival rates as well as the median 
survival rate will be provided alongside two-sided 95%- confidence intervals.   A Cox 

 
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regression frailty model adjusting for the fixed factors treatment and dose, and the frailty 
factor center will be conducted to compare the two treatment groups.  
Missing values in the items of PRO-CTCAE, QLQ-C30 and QLQ-BN20 will be handled as 
described in the scoring manuals of the QoL measures. Further missing values will be 
documented and frequencies will be described with descriptive methods. 
The secondary endpoint neurocognition (MoCA) will be analyzed using a non-parametric 
Van Elteren Test stratified for center. 
The other secondary endpoints and the patients` characteristics will be displayed by 
descriptive measures grouped by treatment group. Continuous variables will be described 
using number non-missing values, mean, standard deviation, median, Q1, Q3, minimum 
and maximum. In addition, t-test between treatment groups will be performed. 
For binary or categorical variables absolute and relative frequencies will be provided. 
Furthermore, two-sided 95%- confidence intervals will be calculated and chi-square tests 
between treatment groups. 
12.3.4 Safety analysis 
For safety analysis, laboratory parameters, all AEs and all SAEs will be analyzed via 
descriptive statistical methods in the safety population. The safety analysis includes 
calculation of frequencies and rates of complications and serious adverse events together 
with corresponding 95%-confidence intervals. In addition, tolerability and dosing will be 
described by numbers of patients in whom treatment was given as planned, delayed or 
permanently stopped. 
Further details of the analysis will be specified in the statistical analysis plan (SAP) which 
will be finalized before database closure. All analyses will be done using R version 3.6.3 
or higher.  
12.3.5 Homogeneity of the intervention groups 
The homogeneity of the treatment groups will be described by comparison of the 
demographic data and the baseline values. 
 

 
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  Interim analysis 
A group-sequential design with interim analysis containing decision boundaries without 
sample size recalculation will be performed after availability of the results for the primary 
endpoint for a total of 49 randomized patients (i.e., 50% of the sample size).  
The following type I error rates, decision boundaries for the interim and the final analysis 
are specified: 
• Global one-sided type I error rate: 𝛼= 0.025 
• Boundary for the one-sided p-value for accepting the null-hypothesis within the interim 
analysis: 𝛼0 = 0.2879 (according to an O’Brien-Fleming type beta-spending 
approach). This rule is considered as a non-binding stopping rule for futility. 
• One-sided local type I error rate for testing the null-hypothesis within the interim 
analysis: 𝛼1 = 0.0015 (according to an O’Brien-Fleming type alpha-spending 
approach) 
• Boundary for the one-sided p-value for testing the null-hypothesis within the final 
analysis: 𝛼2 = 0.0235 (according to an O’Brien-Fleming type alpha-spending 
approach) 
The trial will only be continued as planned after the interim analysis, if for the one-sided 
p-value 𝑝1 of the interim analysis 𝑝1 ∈]0.0015, 0.2879[ holds true. Furthermore, 
descriptive progression-free-survival and overall survival will be analyzed at the interim 
analysis using Kaplan-Meier-Curves. The 1-year and 2-year survival rates as well as the 
median survival rate will be provided alongside two-sided 95%- confidence intervals.    
In case the trial is prematurely stopped due to efficacy or futility, patients who are still 
under observation but were not yet included in the interim analysis will not be followed up 
as planned.  
It should be noted that the interim analysis will likely take place after the total number of 
120 patients have been enrolled. While in such a case, it is not possible to reduce the total 
number of enrolled patients, the follow-up time of the trial might be reduced, thus allowing 
to save resources and costs. 
Results of the interim analysis will be presented to the Data Safety and Monitoring Board 
(DSMB) who will advise the Steering Committee of the trial to either terminate or to 
continue the trial.  

 
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Detailed procedures of the interim analysis will be specified in a separate interim 
Statistical Analyses Plan (SAP), which will be finalized before interim database lock. 
12.4.1 
Randomisation 
Screened and eligible patients will be included into the trial once the study has been 
initiated. The patients will be randomized with the help of the web-based software 
randomizer.at (provided by the Institute for Medical Informatics, Statistics and 
Documentation; Medical University of Graz; https://www.randomizer.at). Block 
randomization stratified by center will be performed to ensure approximately equal sample 
sizes within the treatment groups. 
 
13 Ethical, legal and administrative aspects 
 Good clinical practice/ declaration of Helsinki 
The procedures set out in this trial protocol, pertaining to the conduct, evaluation, and 
documentation of this trial, are designed to ensure that all persons involved in the trial by 
Good Clinical Practice (GCP) and the ethical principles described in the applicable version 
of the Declaration of Helsinki (2013 Version of the Declaration of Helsinki, adopted at the 
64th WMA General Assembly, Fortaleza, Brazil, October 2013).  
The trial will be carried out in keeping with local legal and regulatory requirements. The 
study plan will be submitted to the Institutional Review Board (IRB)/independent Ethics 
Committee (EC) of the Medical Faculty Heidelberg for approval. Patient recruitment will not 
start before the written approval by the ethics committee has been obtained. 
 
 Subject information and informed consent 
Participation in this trial is voluntary for all patients – and only for those patients – who 
conform to the inclusion and exclusion criteria put down in this protocol. A study subject 
may at any point withdraw his/her consent and thus terminate his/her participation in the 
study without the need to specify reasons for doing so. 
Participation in the clinical trial is voluntary for subjects. Before inclusion in the study, a 
potential subject will be thoroughly and in detail informed about the nature, the aims, the 
risks and benefits of the study before informed consent can be given. Detailed information 
shall be provided in a fashion and language understood by the patient. An informational 

 
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handout as well as an informed consent form – both documents conforming to ICH-GCP 
standards – will be provided to the patient before inclusion. Informed consent must be 
given only after an appropriate amount of time for consideration and then must be in 
writing and complemented with information about date and time of signature in the 
patient’s own handwriting. Informed consent must be countersigned by the treating 
physician. If a patient is incapable of signing the informed consent form himself, the oral 
informed consent must be confirmed by the signature of a witness.  
The personally signed and dated Informed Consent Form must be kept on file by the 
investigator(s), and documented in the case report form.  
A copy of the signed informed consent document must be given to the subject. The 
documents must be in a language understandable to the subject and must include the 
name of the investigator who informed the subject. The Informed Consent Form must be 
signed by the subject as well as the investigator giving informed consent.  
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information and must give their 
written informed consent to continue the study. Clinical subjects are completely free to 
refuse to enter the study or to withdraw from it at any time for any reason without incurring 
any penalty or withholding of treatment on the part of the investigator. This study includes 
no additional invasive or otherwise harmful or burdening procedures. 
Upon withdrawal, patients will be asked if they agree with the use of the data obtained 
so far. The information about the withdrawal must be documented in the patient file as 
well as on the participant's informed consent form. 
 Responsibilities of investigator 
The Principal Investigator should ensure that all persons assisting with the trial are 
adequately informed about the protocol, any amendments to the protocol, the trial 
treatments, and their trial-related duties and functions. The Principal Investigator should 
maintain a list of investigators and other appropriately qualified persons to whom he or 
she has delegated significant trial-related duties. 
The current trial is neither a clinical investigation of a drug according to the German 
Medicinal Products Act (Arzneimittelgesetz) nor a clinical investigation of a medical device 
according the Medical Device Regulation. The treatment planning software Raystation is a 

 
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commercially available software with CE label and currently used as standard treatment 
planning software in the clinical routine as well.  
 Approval of trial protocol and amendments 
Before the start of the trial, the trial protocol, informed consent document, and any other 
appropriate documents will be submitted to the independent Ethics Committee (EC). 
written favorable vote of the EC is a prerequisite for initiation of this clinical trial. The 
statement of EC should contain the title of the trial, the trial code, the trial site, and a list 
of reviewed documents. It must mention the date on which the decision was made and 
must be officially signed by a committee member.  
Before the first subject is enrolled in the trial, all ethical and legal requirements must be 
met. All planned substantial changes (see §10, (1) of German GCP-Regulation) will be 
submitted and must be approved by the EC.  
The investigator and the Clinical Trial Center at the Department of Radiation Oncology, 
University Hospital of Heidelberg, Heidelberg, Germany, will keep a record of all 
communication with the EC and the regulatory authorities. 
 
 Registration of the trial 
Prior to the beginning of the clinical phase (FSI) the coordinating/principal investigator will 
register the trial at Current Controlled Trials (http://www.controlled-trials.com/) or 
http://www.clinicaltrials.gov. Thus, the trial will be given a unique registration code (e.g. 
ISRCTN), which is a prerequisite for a publication in many peer-reviewed journals. 
 
14 Agreements 
 Financing 
An application for funding has been made for this clinical trial (clinical trials programme, 
DFG). Funding was requested for human resources such as treating physicians, medical 
physicists, study nurses, data management, biostatistics and project management. 
Furthermore funding for print costs, travel costs, monitoring, hardware and fees was 
applied for. 

 
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The Department of Radiation Oncology, University Hospital Heidelberg, INF 400, 69120 
Heidelberg, and the Department of Radiation Oncology, university Hospital Dresden, 
Fetscherstr. 47, 01307 Dresden, will cover the additional costs of the clinical study.  
Participation in this trial will cause no additional costs for the patient (compared to 
standard treatment). 
All persons involved (including the principal investigator and coordinator) declare that 
there is no conflict of interest in connection with the implementation and evaluation of the 
study. 
 Reports  
A report summarizing the results of the trial will be prepared within one years after closure 
of the data base by the Study Center of the Department of Radiation Oncology, University 
Hospital of Heidelberg, Germany. 
 
 Publication 
All information concerning the trial is confidential before publication. Publication will be 
prepared under the lead of the study coordinator of the study. The first and last authorship 
are reserved for the principal investigator and the study coordinator of the study if both do 
not wish to transfer their authorship to a third person. All data will be published 
independently of the results of the trial.  

 
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15 Signatures 
The present trial protocol was subject to critical review and has been approved in the 
present version by the persons undersigned. The information contained is consistent with:  
- the current risk-benefit assessment of the investigational treatment  
- the moral, ethical, and scientific principles governing clinical research as set out the 
principles of GCP and in the applicable version of Declaration of Helsinki.  
The investigator will be supplied with details of any significant or new finding including 
AEs relating to treatment with the investigational treatment. 
 
Principal investigator 
 
 
 
28.10.2022 
____________________________ 
___________________ 
Dr. Semi Harrabi 
date  
 
 
Statistician 
 
 
____________________________ 
___________________ 
M.Sc. Christopher Büsch 
date  
 
 
 
 
 
 

 
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Harrabi, S.B., et al., Dosimetric advantages of proton therapy over conventional radiotherapy with 
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192(11): p. 759-769. 
3. 
Adeberg, S., et al., Dosimetric Comparison of Proton Radiation Therapy, Volumetric Modulated Arc 
Therapy, and Three-Dimensional Conformal Radiotherapy Based on Intracranial Tumor Location. 
Cancers, 2018. 10(11): p. 401. 
4 
Mohan, R. and D. Grosshans, Proton therapy – Present and future. Advanced Drug Delivery Reviews, 
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5 
Pulsifer, M.B., et al., Cognitive and Adaptive Outcomes After Proton Radiation for Pediatric Patients 
With Brain Tumors. International Journal of Radiation Oncology*Biology*Physics, 2018. 102(2): p. 
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Shih, H.A., et al., Proton therapy for low-grade gliomas: Results from a prospective trial. Cancer, 
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Bahn, E., et al., Late contrast enhancing brain lesions in proton treated low-grade glioma patients: 
clinical evidence for increased periventricular sensitivity and variable RBE. International Journal of 
Radiation Oncology • Biology •Physics, 2020. doi: https://doi.org/10.1016/j.ijrobp.2020.03.013. 
8 
Karim, A.B.M.F., et al., Randomized trial on the efficacy of radiotherapy for cerebral low-grade 
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with the Medical Research Council study BRO4: an interim analysis. International Journal of 
Radiation Oncology*Biology*Physics, 2002. 52(2): p. 316-324. 
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Shaw, E.G., et al., Randomized Trial of Radiation Therapy Plus Procarbazine, Lomustine, and 
Vincristine Chemotherapy for Supratentorial Adult Low-Grade Glioma: Initial Results of RTOG 9802. 
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van den Bent, M.J., et al., Long-term efficacy of early versus delayed radiotherapy for low-grade 
astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. The Lancet, 
2005. 366(9490): p. 985-990