Safety of Intensity-modulated Radiotherapy Treatment With Inhomogeneous Dose Distribution in Patients With Relapsed High-grade Gliomas.
Phase: NA
Conditions: Glioblastoma Multiforme, Glioblastoma, Glioblastoma, Adult
Sponsor: Azienda USL Reggio Emilia - IRCCS

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 1 a 35 
Title 
Safety of intensity-modulated radiotherapy treatment 
with inhomogeneous dose distribution in patients with 
relapsed high-grade gliomas 
 
Identification code (GLIORAD_15-18) 
 
Version 6r.1 dated: 04/16/2019 
 
 
Promoter: 
ASMN-IRCCS, Services of Medical Physics and Oncological 
Radiotherapy, RE 
 
Proposer: 
 
Medical Physics Service (PI)  
Participants: 
 
Oncological Radiotherapy Service 
Medical Physics Service 
Neuroradiology Unit 
Neurology Service 
Neurosurgery Unit 
Pathological Anatomy Service 
Molecular Biology Service 
 
Statistical Officer 
 
Clinical Studies and Statistics Group of the Research and 
Statistics Infrastructure, AO ASMN- IRCCS RE 
 
Data management and monitoring  
 
Clinical Studies and Statistics Group of the Research and 
Statistics Infrastructure, AO ASMN- IRCCS RE 
 
 
 
 
KEYWORDS 
Relapsed glioblastoma 
Intensity modulated radiotherapy 
Dose painting

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 2 a 35 
INDICES 
SYNOPSIS ................................................................................................................................... 3 
1. INTRODUCTION ...................................................................................................................... 4 
2. RATIONAL OF THE STUDY ..................................................................................................... 12 
3. STUDY POPULATION ............................................................................................................. 12 
3.1 Inclusion criteria ....................................................................................................................... 12 
3.2 Exclusion criteria ...................................................................................................................... 13 
3.3 Methods of recruitment .......................................................................................................... 13 
4. OBJECTIVES .......................................................................................................................... 13 
4.1 Primary objective ..................................................................................................................... 13 
4.2 Secondary objectives ............................................................................................................... 13 
5. DESIGN OF THE STUDY .......................................................................................................... 14 
5.1 Duration of the study ............................................................................................................... 14 
5.2 Early termination of the study ................................................................................................. 14 
6. TREATMENT PLAN ................................................................................................................ 14 
6.1 Radiotherapy treatment .......................................................................................................... 14 
6.2 Irradiation technique ............................................................................................................... 15 
6.3 Positioning and immobilization of the patient ........................................................................ 15 
6.4 Planning CT and MRI ................................................................................................................ 15 
6.5 Target volume and organs at risk (OAR) .................................................................................. 15 
6.6 Dose prescription ..................................................................................................................... 16 
6.6.1 Target dose .................................................................................................................... 16 
6.6.2 Dose limits for primary risk organs ............................................................................... 16 
6.6.3 Dose limits for secondary risk organs............................................................................ 17 
6.7 Changes or suspension of treatment ....................................................................................... 17 
6.8 Recommended concomitant therapies and permitted drugs ................................................. 17 
6.9 Concomitant Therapies Prohibited .......................................................................................... 17 
7. EXIT FROM THE STUDY AND SUSPENSION OF THE TREATMENT ............................................. 17 
7.1 Exit from the study ................................................................................................................... 18 
7.2 Suspension of treatment.......................................................................................................... 18 
7.3 Evaluations in case of suspension of treatment ...................................................................... 18 
8. EVALUATION PROGRAM ....................................................................................................... 18 
8.1 Baseline assessment before the start of radiotherapy treatment .......................................... 18 
8.1.1 Mandatory assessments: .............................................................................................. 18 
8.1.2 Optional assessments based on tumor site: .................................................................. 18 
8.2 Evaluation at the end of the radiotherapy treatment ............................................................. 19 
Clinical visit at the end of radiotherapy: ................................................................................ 19 
8.3 Follow-up evaluation ............................................................................................................... 19 
8.3.1 Mandatory assessments: .............................................................................................. 19 
8.3.2 Optional assessments based on tumor site or patient's particular condition: ............. 19 
9. OUTCOMES EVALUATION PLAN ............................................................................................ 19 
10. SAFETY ASSESSMENTS OF RADIOTHERAPY .......................................................................... 20 
10.1 Evaluation of adverse events from radiotherapy .................................................................. 21 
10.1.1 Severity / Severity of an event ..................................................................................... 21 
10.1.2 Causation of an event.................................................................................................. 22 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 3 a 35 
10.1.3 Outcome ...................................................................................................................... 22 
10.2 Recording an Adverse Event .................................................................................................. 22 
10.3 Intermediate safety reports ................................................................................................... 23 
11. SURVEILLANCE ON MEDICAL DEVICES ................................................................................. 23 
11.1 Security Definitions ................................................................................................................ 23 
11.2 Timing for reporting an Incident ............................................................................................ 24 
11.3 Forwarding of the report to the Competent Authority and to the Ethics Committee .......... 25 
11.4 Urgent security measures ...................................................................................................... 25 
12. STATISTICAL ASPECTS ......................................................................................................... 25 
12.1 The champion ......................................................................................................................... 25 
12.2 Analysis plan ........................................................................................................................... 26 
12.3 Data management ................................................................................................................. 26 
13. ETHICAL AND AUTHORIZATION ASPECTS ............................................................................. 27 
13.1 General aspects ...................................................................................................................... 27 
13.2 Insurance aspects ................................................................................................................... 27 
13.3 Monitoring and Quality Control (QC) ..................................................................................... 28 
13.4 Responsibility and publication policy..................................................................................... 28 
14. BIBLIOGRAPHY ................................................................................................................... 28 
 
SYNOPSIS 
Title of the study 
• 
Safety of intensity-modulated radiotherapy treatment with 
inhomogeneous dose distribution in patients with relapsed high-
grade gliomas 
Study design 
• 
Exploratory, prospective, experimental and monocentric study. 
Primary goal 
• 
Assessment of acute and subacute toxicity of radiotherapy 
treatment. 
Secondary objectives 
• 
Evaluation of the response rate according to the RANO criteria: local 
control of the disease. 
• 
Incidence of treatment-related radionecrosis. 
• 
Evaluation (descriptive) of the Quality of Life assessed through 
EORTC QLQ-C30 questionnaires. 
• 
Evaluation (descriptive) of neuro cognitive functions as indicated 
below. 
• 
Overall survival (OS) assessment. 
• 
Assessment of progression-free survival (PFS). 
Inclusion criteria 
• 
GBM 
relapsed 
after 
standard 
surgery-radio-chemotherapy 
treatment or other therapeutic lines, or GBM secondary to 
anaplastic 
astrocytoma 
previously 
treated 
with 
radio 
and 
chemotherapy, or relapses of anaplastic astrocytoma with clear 
radiological signs of change. 
• 
Age ≥ 18 years. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 4 a 35 
• 
ECOG Performance Status 0-2, Performance Karnofsky Score> 60. 
• 
Written informed consent. 
• 
Life expectancy> 3 months. 
• 
Availability of the patient to be followed for all phases of 
chemotherapy treatment and for the subsequent follow-up. 
Exclusion criteria 
• 
Patients with KPS <70%. 
• 
Participation in other studies that involve the administration of 
experimental drugs or explicitly exclude the possibility of 
participating in other studies in general or in studies whose 
characteristics include aspects of this study. 
• 
Any concomitant medical or psychological conditions that could 
prevent participation in the study or that compromise the ability to 
provide informed consent. 
• 
Pregnant and breast-feeding patients. 
Treatment 
• 
The treatment provided for in the protocol involves the planning and 
execution 
of 
a 
hypofractionated 
radiotherapy 
treatment, 
administered in 5 daily sessions, with modulated intensity technique 
and uneven distribution of the dose guided by diffusion magnetic 
resonance images (MRI). 
Sample of the study 
• 
12 patients 
Expected date of start 
and end of the study 
• 
25 months: 22 months of enrolment + 3 months of follow-up 
1. INTRODUCTION 
The standard therapy for glioblastoma multiforme (GBM) patients has been surgery and 
radiotherapy for many years. In 2005, the results of a major multicenter Phase III study conducted 
by the EORTC and the NCIC were published which demonstrated that the addition of 
Temozolomide chemotherapy to surgery and postoperative radiotherapy can lead to an increase 
in overall (OS) and progression-free (PFS) [1] survival. However, the prognosis of these patients 
remains very severe: the recent update of the EORTC / NCIC trial data demonstrated a median 
survival of 14.6 months (range, 15-18 months) [2], with a local relapse rate of over 90%. Less than 
10% of patients are alive at 5 years [3]. More than 90% of all GBMs recur in the vicinity of the 
surgical cavity and in any case within the radiotherapy volume [4]. 
To date, many salvage therapeutic approaches are available for relapsed GBMs after surgery-
radio-chemotherapy (Stupp protocol), such as re-intervention, chemotherapy or re-irradiation, 
although an optimal standard does not yet exist. Systemic therapy is the most frequent option for 
GBM relapses, but the literature data report an overall survival with chemotherapy alone of 4-6 
months from relapse [5]. Recent series report encouraging results with TMZ monotherapy with 
traditional or intensification schedules (dose-dense schedules) with a PFS of 30% [6,7,8,9]. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 5 a 35 
Unfortunately, considering the small number of patients enrolled in these studies and the large 
variability of therapeutic regimens, there is no evidence today that one regimen is more beneficial 
than another, and despite an increase in PFS, there does not appear to be any increase in OS with 
none of the systemic approaches tested. Bevacizumab was recently approved by the US Food and 
Drug Administration for the treatment of relapsed GBM with phase II studies that reported an 
increase in PFS and OS at 6 months [10]. 
In the context of relapsed GBMs, re-irradiation has always been a controversial topic due to the 
risk of toxicity. The tolerance of healthy brain tissue to possible re-irradiation depends on many 
factors, such as the daily dose, the total dose, the total treatment time, the interval since the 
previous radiotherapy, the volume of healthy tissue already irradiated, the additional therapies 
and many other factors [11, 12]. But recently some studies have been published which, in the face 
of limited radio-induced toxicity, have reported good results in terms of local control with re-
irradiation of relapsed GBMs [13-15]. Furthermore, the technological innovation of recent years in 
the field of radiotherapy, with the advent of more sophisticated delivery techniques such as 
intensity modulation radiotherapy (IMRT) or stereotaxic radiotherapy (SRT), allows us today to 
affirm that re-irradiation of malignant brain neoplasms is effective and safe in terms of both acute 
and subacute toxicity. The most used radiotherapy approach is undoubtedly stereotaxic 
radiotherapy and many data are now present in the literature with a median survival of 6 to 10 
months from the diagnosis of relapse, with low rates of toxicity [13-21]. Some more recent series 
have also evaluated the association of re-irradiation with systemic therapies, reporting a median 
OS of 8-13 months and a PFS of 5-8 months [22-26]. 
Table 1 summarizes all the studies published to date on the re-irradiation of GBMs with various 
techniques and radiation doses. 
Table 1 – Clinical studies analised 
Re-irradiation with external beam radiotherapy with or without chemotherapy 
Authors 
Patients (n) 
Total dose/fractions 
Outcomes from the re-irradiation
Bauman et al.  
10 
18-74 Gy 
1,8-2 Gy x fraction 
median OS 8.3 months 
median PFS 3.3 months 
Kim et al.  
14 
36 
median OS 7 months 
Hayat et al.  
11 
30/2.5 Gy 
median OS 13 months 
Arcicasa et al.  
24 
34.5 
median OS 13.7 months 
Nieder et al.  
31 
45.4 bid 
median OS 8.5 months 
median PFS 5 months 
Verninga et al.  
22 
46 
median OS 6.1 months GBM 
8.2 months HGG 
Henke et al.  
21 
20 
median OS 10.2 months 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 6 a 35 
Osman et al.  
29 
(20 GBM, 
9 HGG) 
30-40 Gy/ 1.8 Gy/ fraction
median OS 11 months 
median PFS 10 months 
Re-irradiation with fractionated stereotactic radiotherapy with or without chemotherapy 
Cho et al. 
20 (15 GBM) 
Median dose of 37.5 Gy 
(range,  20-45 Gy) /2.5 Gy 
fractions (range,  1.8-3 Gy)
Median survival 12 months 
Combs et al.  
40 
36 Gy/2 Gy fractions 
Median OS 16 months 
Median PFS 8 months 
Combs et al.  
50 
36 Gy/2 Gy fractions 
Median OS 8 months 
Median PFS 5 months 
Vordermark et al. 
19 (14 GBM) 
Median total dose 30 Gy 
(range, 20–30 Gy) /5 Gy 
fractions (range, 4–10 Gy) 
Median OS 9.3 months 
Median PFS 4.9 months 
GBM 7.9 months 
HGG 15.4 months 
Grosu et al.  
44 (33 GBM) 
30 Gy 
Median OS 8 months 
Laing et al.  
19 (12 GBM) 
40 Gy 
Median OS 9.8 months 
Selch et al.  
21 (14 GBM) 
25 Gy 
Median OS 6.7 months 
Median PFS 4 months 
Wurm et al.  
25 (20 GBM) 
25-30 Gy 
Median OS 14.5 months 
Median PFS 10.5 months 
Kolshi et al.  
25 (11 GBM) 
28.1-68.2 Gy 
Median OS GBM 11 months 
Median OS HGG 19 months 
Ciammella et al.  
15 
25 Gy/5 fx 
Median OS 9.5 months 
Ernst-Stecken et al.  
15 (11 GBM) 
35 Gy/7 Gy fractions 
6 months PFS 75% 
12 months PFS 53% 
Fokas et al. 
53 
Median dose 54 Gy (range 
20-60 Gy)/ 3 Gy fractions 
(range 2-5 Gy) 
Median OS 9 months 
1-year PFS 22% 
2-year PFS 5% 
Schwer et al.  
15 (11 GBM) 
18-36 Gy 
Median OS 10 months 
Median PFS 7 months 
6 months PFS 63% 
Coombs et al.  
25 
36 Gy 
Median OS 8 months 
Median PFS 5 months 
6 months PFS 48% 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 7 a 35 
Henke et al.  
31  
(2 grade III,  
29 grade IV) 
Median total dose 20Gy 
(range, 20–25)/ 5 Gy 
fractions 
Median OS 10.2 months 
Patel et al.  
10 
36 Gy 
Median OS 7.4 months 
Gutin et al.  
25 (20 GBM) 
30 Gy 
Median OS 12.5 months 
Median PFS 7.5 months 
6 months PFS 64% 
Fogh et al.  
147  
(42 grade III, 
105 grade IV)
Median dose 35 Gy in 3.5-
Gy fractions 
Median OS   11 months for grade 
III and  8 months for grade IV 
Hauff et al.  
59 
30 Gy + thermotherapy 
Median OS 13.4 months 
Villaceincio et al.  
26 
20 
Median OS 7 months 
Torcuator et al.  
16 
36 Gy 
Median OS 7.2 months 
Median PFS 2.6 months 
Minniti et al.  
36 
37.5 Gy 
Median OS 9.7 months 
Median PFS 3 months 
6 months PFS 42% 
Shepherd et al.  
29 
Median dose 35 Gy (range, 
20–50 Gy)/ 5 Gy fractions 
Median OS  10.7 months 
Glass et al.  
20  
(7 grade III,  
13 grade IV) 
Median dose 38 Gy  (range, 
35–42 Gy)/ 3.5–6 Gy 
fractions 
Median OS  12.7 months 
Hudes et al.  
20 
 (19 GBM) 
Median dose 30 Gy  (range, 
24–35 Gy)/ 3–3.5 Gy 
fractions 
Median OS  10.5 months 
Lederman et al.  
88 
Total dose 18–36/ 4–9 Gy 
(weekly) 
Median OS  7 months 
Voynov et al.  
10  
(6 grade III,  
4 grade IV) 
30 Gy /5 Gy fractions 
Median OS  10.1 months 
Wuthrick E.J et al.  
11 
36 Gy (range, 30-42 Gy in 
2.5 – to 3.75 Gy fractions) 
6 months PFS 45% 
Greenspoon et al.  
32 
25-30 Gy 
Median OS 9 months 
Median PFS 7 months 
6 months PFS 60% 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 8 a 35 
Re-irradiation with radiosurgery 
Alexander et al.  
25 (16 GMB) 
13 Gy to 79% isodose 
Median OS 9 months 
Chamberlain et al.  
13 (5 GBM) 
Mean 12 Gy for GBM 
Mean 14 Gy for HGG 
Median OS 8 months 
Median PFS 4 months 
Shrieve et al.  
86 
13 Gy to med. 80% isodose
Median OS 10.2 months 
Larson et al. 
63 (46 GBM) 
Med. Min. 16 Gy to med. 
50% isodose 
Median OS 14 months 
Kondziolka et al.  
42 (19 GBM) 
Mean 15.5 Gy for GBM 
Mean 15.2 Gy for HGG 
to 50% isodose 
Median OS 30 months for GBM 
Median OS 31 months for HGG 
Cho et al.  
46 (27 GBM) 
17 Gy to med. 
50% isodose 
Median OS 11 months 
Park et al.  
23 
15 Gy to 60% isodose 
Median OS 10.3 months 
Median PFS 4.7 months 
Larson et al.  
26 (14 GBM) 
Med. Min. 15 for GBM 
16.5 Gy for HGG 
For GBM: Median OS 9.5 months
Median  PFS 3.7 months 
For HGG: Median OS 17 months
Median PFS 7 months 
Combs et al.  
32 
15 Gy to 80% isodose 
Median OS 10 months 
Median PFS 5 months 
Hsieh et al.   
26 
12 Gy to 50% isodose 
Median OS 10 months 
Mahajan et al.  
41 
n.r. 
Median OS 11 months 
Kong et al.  
114 (65 GBM)
16 Gy to 50% or 80% 
isodose 
For GBM: Median OS 13 months
Median PFS 4.6 months 
For HGG: median OS 26 months
Median PFS 8.6 months 
Biswas et al.  
18 
15 Gy to the isocenter 
Median OS 5.3 months 
Median PFS 3.4 months 
Patel et al.  
26 
18 Gy to 90% isodose 
Median OS 8.4 months 
Maranzano et al.  
13 
17 Gy to the isocenter 
Median OS 11 months 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 9 a 35 
Martínez-Carrillo et al. 
87 
(46 GBM, 41 
AA) 
18 Gy to the isocenter 
Median OS 10 months 
7.5 months for GBM 
17 months for AA 
Dodoo et al.  
55 
(35 GBM, 20 
AA) 
Median prescription dose 
20 Gy (14-22 Gy) 
Median OS 11.3 months for GBM
Median OS 24.2 months for AA 
Pouratian et al. 
26 
 
Median dose of 17 Gy to 
70%  isodose 
Median OS 9.4 months 
Cabrera et al. 
15 
24 or 18 Gy in a single 
fraction 
25 Gy total in 5 consecutive 
daily 5- Gy fractions. 
Median OS  14.4 months 
Median PFS 3.9 months 
6-months  PFS of 20% 
Most of these studies are mono-institutional retrospective series conducted in past years with less 
sophisticated treatment delivery techniques than those available today, and above all with 
predominantly morphological imaging. Furthermore, many of these studies do not report how the 
site of recurrence was identified and with which imaging methods, but it is easy to assume that CT 
and NMR scans were used for the definition of gross tumor volume (GTV). On the latter, for years 
the only contrast point in T1-weighted sequences was identified as GTV without taking into 
account the surrounding edema and the functional characteristics of the area to be irradiated. 
With modern high-field Magnetic Resonance (MRI) equipment, equipped with suitable hardware 
elements (high intensity gradients and broadband RF amplifiers), sophisticated in vivo analyzes 
and characterizations of the anatomical-functional structure of the human brain are possible. 
Advanced NMR techniques allow to perform measurements on microscopic scales by measuring 
effects not only ascribable in classical terms to direct measurements of relaxation times (T1, T2) 
and proton density, but also linked to more complex mechanisms of biochemical and biophysical 
cell interaction same. 
In particular: the study of the energy distribution of nuclear spin levels, which makes it possible to 
measure the concentration and spatial distribution of metabolic complexes (Magnetic Resonance 
Spectroscopy, MRS); the study of the dynamics of the capillary flow which allows to obtain non-
invasive tissue perfusion measurements (PWI) previously obtainable only with nuclear techniques 
(PET, SPECT); the study of the Brownian motion of water molecules in tissues through the 
estimation of the apparent diffusion coefficient (DWI) and / or the characterization of the 
Diffusion Tensor (DTI). 
The introduction of dedicated contrast media, distinct in relation to their pharmacokinetics 
(interstitial contrast media and organ-specific contrast media) and their magnetic [paramagnetic 
(gadolinium chelates) and super-paramagnetic] characteristics, enhance the offered characteristics 
by the method and considerably increased its diagnostic power in clinical practice. The high levels 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 10 a 35 
of spatial and temporal resolution that can be obtained and the absence of ionizing radiation also 
represent a further strength of the method. 
These potentials are extremely effective in the study of brain tumors and in particular in the study 
of brain re-irradiations, where they can be applied in order to obtain a more correct 
characterization and definition of the target volume. 
The integration between this advanced imaging modality and the new planning and delivery 
techniques of radiotherapy treatment can allow selective irradiation (dose painting) of 
pathological areas at different risk of progression through the identification of pathological sub-
volumes. The new frontier of dispensing inhomogeneous dose within the target volume and 
adapting "the necessary dose levels" to the "true volume" is a more adequate approach in terms 
of tumor control probability than the more classic concept of distribution homogeneous dose. 
However, such a treatment modality requires sophisticated imaging sequences and new 
processing tools to be able to carry out an integrated and accurate evaluation of the pattern to be 
treated (creation of multi-parametric maps [79] that describe the different characteristics and / or 
properties of the tissues under examination), ad hoc software (see the Technical Annex) to create 
an appropriate segmentation of the tumor and an accurate dose planning, as well as a hi-tech 
linear accelerator (Varian TrueBeam STx), that allows a rapid delivery of the dose with 
submillimetric precision and continuous verification of the patient's correct set-up [75-78]. 
The segmentation of the different volumes to be treated is achieved by integrating the different 
NMR imaging sequences in multi-parametric maps, thanks to which it will be easier to proceed to 
a better definition of the GTV, CTV and PTV [80, 81]. The imaging that will be used will use 
conventional imaging sequences such as those weighed in T1 (T1w), T2 (T2w) and FLAIR, with 
(T1wGd) and without gadolinium contrast, but these data will be integrated with the information 
provided by the sequences more advanced than NMR: MRS [82], PWI [83] and DWI [84] or DTI [83, 
84]. 
Brain spectroscopic imaging (MRS) provides information on neuronal integrity, cell proliferation 
and degradation, energy metabolism (concentration of metabolites), necrotic transformation of 
the brain or tumor tissue. Its use will provide valuable help in assessing the degree of cellular 
anaplasia of tumors, the anatomical extent of peri-tumor edema glioblastoma. 
It will also represent a valuable tool in monitoring the evolution of neoplastic disease, especially 
after surgical and / or radiotherapy treatment, that is, in the differentiation of damage from 
radionecrosis - from residual or tumor recurrence. 
Brain perfusion imaging (PWI) [84, 85], thanks to the close relationship between physiological 
function, metabolism and local blood supply, provides an in vivo measure of the regional cerebral 
hemodynamic of the area under examination. To evaluate the flow, the response of the system to 
an intravascular tracer is recorded over time, which can be both exogenous (gadolinium chelates) 
and endogenous (H2O molecules present in the blood). Limiting ourselves to the first case (DSC-
MRI technique), by applying mathematical models on the properties of blood transport and on the 
mechanisms of exchange with the tissue, we go back to the measurement of hemodynamic 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 11 a 35 
parameters, such as cerebral blood flow (CBF), blood volume (CBV) and the Average Transit Time 
(MTT). The method provides information on the identification of areas of high angiogenesis and 
permeability, allowing to follow the evolution of the tumor residue and / or to discriminate 
between the areas of recurrence and / or radionecrosis, as well as being linked, albeit with a 
certain approximation, to the presence of oxygen in a tissue and therefore to its level of toxicity or 
hypoxia. 
Diffusion Weighted Imaging (DWI) [84] provides a measure of water mobility which is a valid tool 
for describing tissue structure at microscopic scales, as water diffusion plays a fundamental role in 
transport processes enzymes, metabolic substrates and metabolites. Human tissues can only 
survive within a narrow temperature range in which most of the tissue components are in a liquid 
state and exhibit a highly inhomogeneous structure at the microscopic level (cell membranes and 
various organelles hinder the free movement of water and of other molecules). Neoplasm, 
characterized by uncontrolled cell reproduction, is characterized by an increase in tissue cellularity 
(cell density) in which the extra-cellular volume fraction (ECVF) decreases compared to the 
equivalent healthy tissue [86]. 
The signal intensity variation map can provide useful information such as mean diffusivity and 
diffusion anisotropy index (DTI), computational tracing of white matter fiber bundles (Fiber 
Tracking) or apparent diffusion coefficient ( ADC) [86]. 
Thanks to the estimation of the ADC of the molecules it is possible to study the conformation of 
the tissues, their integrity and to classify the normal and pathological tissue using the respective 
ADC values: the high cellularity of the tumors determines a restriction of the diffusivity that 
produces low ADC values conversely, necrosis, which consists in a rupture of the membranes with 
cell death, causing an increase in the diffusivity of the water generates high ADC values [86, 87]. 
Although the complex interactions between water and tissue microstructures have not yet been 
fully understood, the scientific literature highlights the existence of an inverse proportionality 
between the cellularity of tissues and the ADC value [86 - 90]. This type of correlation makes it 
possible to propose, after having 'correctly' segmented the different areas of the tumor, the use of 
ADC values as a guide for dose redistribution (dose painting) with photon beams. Considering 
these values as a surrogate of cellularity, it is reasonable to hypothesize that low ADC values are 
correlated to high values of cell density and therefore to a high number of clonogens (which are a 
small fraction, ≤ 1%, of the number of cells that make up the whole neoplastic tissue) [91].  
The higher dose values would therefore be focused on these values, while the higher ADC values 
would correspond to the lower dose values. 
Recently the literature has shown that diffusion maps also seem to provide an early assessment of 
the tumor response to treatment [86 - 90], showing a variation in their distribution with respect to 
the response to treatment. Similar data were also found in the ADC pattern of some patients 
irradiated by us with conventional treatment (STUPP) and for which the trend of the parameters 
of such distribution was retrospectively monitored using indicators calculated with the Texture 
Analysis (TA). The TA [92, 93] is an analysis method that allows to study and evaluate the 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 12 a 35 
distribution of the pixels (the punctual signal of each image) that make up the images, in our case 
the values of the NMR images, expressed in the form of indicators that describe the shape and the 
trend: mean, standard deviation, entropy, kurtosis, etc. The post-therapy reproduction of the pre-
treatment ADC values, relative to the regions where the relapse has re-manifested and / or has 
not succeeded to control the neoplasm, is indicative of a non-response to treatment and therefore 
seems to confirm the guidance of ADC values as a sensitive marker of radio-resistance. 
2. RATIONAL OF THE STUDY 
Relapsed GBMs have a life expectancy of a few months and reirradiation has been shown to be 
safe in terms of toxicity and effective in increasing OS. Our recent study Ciammella P. et al [94] 
reported a median survival of 9.5 months in patients affected by recurrent GBM and treated with 
stereotaxic radiotherapy with a total dose of 25 Gy in 5 consecutive sessions, in which the dose 
was prescribed at isodose of 70% with a homogeneous gradient towards the center of the target 
volume. The identification with functional imaging of specific areas with higher tumor cell density, 
and the possibility of accurately delivering, thanks to the most advanced therapy units, different 
doses to the different sub-volumes, can lead to an increase in the maximum deliverable dose. in 
the most aggressive areas (with a greater tumour killing effect), compared to lower doses in the 
areas with the lowest signal alteration. This dose selectivity should allow an increase in the 
efficacy of the therapy and therefore a hypothesized increase in local control, in the face of a 
radio-induced toxicity on surrounding healthy tissues almost comparable to that achieved with 
previous hypofractionated treatments [94]. In fact, delivering very high doses to the entire volume 
would lead to an excess of radio-induced necrosis within the regions irradiated with high doses, as 
well as the impossibility of minimizing the doses on healthy areas and / or on non-neoplastic 
critical areas, keeping them at internal dose range associated with minimum and acceptable 
toxicity levels. Since there are no studies that provide clear indications on the acute and late 
toxicity of irradiated healthy tissues, that have already been the subject of a first course of 
radiotherapy (STUPP), the choice of safety is the primary objective of the study.  
3. STUDY POPULATION 
Patients suffering from: 
• 
GBM relapsed after standard treatment surgery-radio-chemotherapy or other therapeutic 
lines; 
or 
• 
relapses of anaplastic astrocytoma with clear radiological signs of change. 
3.1 Inclusion criteria 
All patients who meet the following criteria will be eligible: 
• 
GBM relapsed after standard surgery-radio-chemotherapy treatment, or other 
therapeutic lines, or GBM secondary to anaplastic astrocytoma previously treated with 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 13 a 35 
radio and chemotherapy or relapses of anaplastic astrocytoma with clear radiological 
signs of change. 
• 
Age ≥ 18 years. 
• 
ECOG Performance Status 0-2, Performance Karnofsky Score> 60. 
• 
Written informed consent. 
• 
Life expectancy> 3 months. 
• 
Availability of the patient to be followed for all phases of radiotherapy treatment and for 
the subsequent follow-up. 
3.2 Exclusion criteria 
• 
Patients with KPS <70%. 
• 
Participation in other studies involving the administration of experimental drugs. 
• 
Any concomitant medical or psychological conditions that could prevent participation in 
the study or that compromise the ability to provide informed consent. 
• 
Pregnant or breastfeeding patients. 
3.3 Methods of recruitment 
• 
Patients belonging to the U.O. of Oncological Radiotherapy, Neurology and Oncology of 
the ASMN-IRCCS of Reggio Emilia are eligible for participation in the study. After 
evaluation of eligibility and acquisition of informed consent from the patient, each will be 
assigned a progressive number which will be used to identify the subject during all phases 
of the study. 
4. OBJECTIVES 
4.1 Primary objective 
The study proposes the evaluation of the side effects of the proposed experimental radiotherapy 
treatment and the acceptability of the risk / benefit ratio. 
Acute / subacute toxicity will be analysed with recording of adverse events (related or unrelated) 
reported during the entire treatment and within 3 months of its end. 
4.2 Secondary objectives 
• 
Evaluation of the response rate according to the RANO criteria. 
• 
Incidence of treatment-related radionecrosis measured with advanced MRI sequences. 
More information on the methods followed in the study to make a correct discrimination 
between radionecrosis and tumor relapses are given in a specific Technical Annex. 
• 
Evaluation (descriptive) of the Quality of Life assessed through EORTC QLQ-C30 and BN20 
questionnaires. 
• 
Evaluation (descriptive) of neuro-cognitive functions as indicated in the rest of the 
protocol. 
• 
Overall survival (OS) assessment. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 14 a 35 
• 
Assessment of progression-free survival (PFS). 
5. DESIGN OF THE STUDY 
It is an exploratory, prospective, experimental, monocentric study. 
Having identified a main safety endpoint (toxicity of radiotherapy treatment), and in the absence 
of data currently available from previous studies and useful for sample sizing, the sample is 
defined according to criteria of expediency and feasibility, (12 cases), with a design (3 cases + 3 
cases + 6 cases) which provides for two intermediate safety assessment steps, one month after 
the end of treatment for the third and sixth patient. The study will be continued only in the event 
of a positive evaluation of both steps. 
5.1 Duration of the study 
54 months of which 51 for patient enrolment and 3 months for completion of treatment and 
evaluation of the response of the last patient enrolled. 
For each individual patient, the treatment is considered completed if: 
a) 
the experimental radiotherapy treatment was completed; 
b) 
the first follow-up radiological evaluation (NMR) was performed; 
c) 
study treatment was prematurely discontinued due to lack of efficacy (documented 
disease progression) or unacceptable toxicity. 
5.2 Early termination of the study 
An internal board will evaluate according to the analysis plan defined in section 12.1 the 
continuation / interruption of the study in the protection of patients' interests, based on 
information on the safety of the cases already treated. 
The study can be concluded early: 
• 
if the nature and frequency of the events and / or any urgent safety measures are such 
that the risk and benefit ratio is not acceptable; 
• 
if the number of patients who drop out of the study is such that it is difficult to complete 
the study. 
6. TREATMENT PLAN 
6.1 Radiotherapy treatment 
The treatment envisaged by the protocol involves the planning and execution of a 
hypofractionated radiotherapy (RT) treatment, administered in 5 daily sessions, with modulated 
intensity technique and inhomogeneous distribution of the dose guided by diffusion images 
obtained with magnetic resonance imaging (MRI). 
The radiotherapy treatment must begin within 7 days from the date of execution of the centering 
MRI which will include both the classic morphological sequences with administration of contrast 
medium and functional. In this regard, for more details see the Technical Annex. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 15 a 35 
In selected cases and according to clinical judgment, it will be possible to request a review of the 
anatomo-pathological and radiological findings. 
6.2 Irradiation technique 
For each patient, a radiotherapy treatment plan will be carried out with conformed techniques 
such as intensity modulated radiotherapy (IMRT) with dose redistribution: dose-painting [95 - 97]. 
More details are described in the Technical Annex. 
6.3 Positioning and immobilization of the patient 
The patient should be treated in the supine position. The arms should be placed along the body. 
The use of a knee support is recommended. The head will be immobilized with a thermoplastic 
mask and corresponding neck rest supports. 
6.4 Planning CT and MRI 
The planning CT should possibly be acquired with reduced layer thickness that contains the entire 
volume of the skull and the upper part of the shoulders. This is done to allow for the possibility of 
planning non-coplanar treatments. 
The last follow-up MRI or radiotherapy centering is used for planning, consisting of standard and 
functional sequences, in addition to those that the neuroradiologist will have considered useful to 
better characterize the clinical case in question. More details in this regard are described in the 
Technical Annex. 
6.5 Target volume and organs at risk (OAR) 
The following target volumes should be identified [98]: 
• 
Gross tumor volume (GTV): is defined using and combining conventional and advanced 
MR imaging sequences. 
• 
Planning target volume (PTV). It is represented by the GTV with three-dimensional 
expansion between 0 and 5 mm according to the problems highlighted during the 
segmentation phase of the tumor. In this regard, for more details see the Technical 
Annex. 
The following primary risk organs (OARs) must be identified: 
• 
Optic nerves. The definition of the related planning risk volume is also suggested (PRV: 
organ at risk with three-dimensional expansion; this margin must be chosen taking into 
consideration the acquisition thickness of the centering CT and the chosen GTV-PTV 
expansion margin) 
• 
Chiasma. The definition of the relative PRV is also suggested (organ at risk with three-
dimensional expansion; this margin must be chosen taking into consideration the 
acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin) 
• 
Retinas. The definition of the relative PRV is also suggested (organ at risk with three-
dimensional expansion; this margin must be chosen taking into consideration the 
acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin). 
Alternatively, the eyeballs can be outlined. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 16 a 35 
• 
Brain stem. 
• 
The following secondary OARs must be identified: 
• 
Lenses / Crystalline. The definition of the relative PRV is also suggested (organ at risk with 
three-dimensional expansion; this margin must be chosen taking into consideration the 
acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin) 
• 
Healthy brain tissue. It is represented by the volume of the brain minus the PTV. 
• 
Ear cochlea. The definition of the relative PRV is also suggested (organ at risk with three-
dimensional expansion; this margin must be chosen taking into consideration the 
acquisition thickness of the centering CT and the chosen GTV-PTV expansion margin). 
6.6 Dose prescription 
6.6.1 Target dose 
The prescription dose provides for a minimum dose of 30 Gy (6 Gy per session) for the areas with 
the highest ADC, with a gradual increase in the dose for the areas with the lowest ADC. The 
maximum hypothesized dose is 50 Gy, with a dose of 10 Gy per session at no more than 1cc of 
irradiated brain tissue. For more details see the Technical Annex. 
The treatment plan, however, will be developed according to the following order of priority: 
1. Compliance with dose limits for primary OAR. 
2. PTV coverage. 
3. Compliance with dose limits for secondary OARs. 
6.6.2 Dose limits for primary organs at risk 
In the scientific literature there are various studies that indicate the dose limits of the organs at 
risk for cerebral radiotherapy treatments. However, these limitations concern therapies in which 
conventional fractionations and deliveries to non-irradiated brain tissue are used [bibliography of 
the studies proposed in Table 1, 98]. The few reports relating to retreatments [99, 100] are mainly 
addressed to other anatomical areas with poor indications for brain treatments (only the spinal 
cord and brainstem is mentioned), especially when it comes to hypofractionated techniques as in 
our case. In retreatments with hypo-fractionation the references refer exclusively to healthy brain 
tissue. Not being able to use well-coded literature indications, it was decided to refer to the few 
literature data as well as to the clinical history of our radiotherapy center.  
In the work of Ciammella [94] the outcomes of conventional hypofractionated retreatments (5Gy x 
5 sessions) on glioblastomas performed at the Reggio Emilia radiotherapy are described both in 
terms of efficacy and acute toxicity. Therefore the radiotherapist, in the evaluation phase of the 
dose-painting plans envisaged in this study, will be able to use as an indication and reference of 
the doses on critical organs estimated for a conventional hypofractionated plan. Since these doses 
are a function of the anatomical configuration of the patient, as well as of the conformation and 
position of the tumor recurrence, it is necessary to carry out planning for each individual patient 
belonging to the study. The final word regarding the clinical approval of the plan to be provided 
will still be up to the radiotherapist who will clinically evaluate the treatment plan. For more 
details see the Technical Annex. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 17 a 35 
6.6.3 Dose limits for secondary risk organs 
Also for secondary risk organs, what has been indicated in the previous point (6.6.2) regarding the 
relative dose limits is valid. 
6.7 Changes or suspension of treatment 
During the treatment program, neurological toxicities will be evaluated according to criteria of the 
National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), version 4.0. 
The patient will be monitored for the appearance of adverse events for the entire duration of the 
study, including the follow-up period. 
Events 
Actions 
a) Neurological toxicity ≤ grade 2 responsive to supportive 
care 
b) Grade ≤ 3 non-neurological toxicity 
The RadioTherapy treatment continue
c) grade> 3 neurological and non-neurological toxicity; 
d) grade ≤ 2 neurological toxicity unresponsive to 
supportive care; 
e) disease progression during treatment; 
f) second medical opinion, for safety reasons; 
g) refusal of the patient to continue the treatment; 
h) need to start antineoplastic therapy. 
The presence of at least one of the 
events determines the definitive 
suspension of the treatment. It also 
involves leaving the study in cases (e) 
and (h) 
In case of grade ≤ 2 neurological toxicity with response to adequate supportive therapy (steroids, 
mannitol, anticomitials) the radiotherapy treatment will continue. 
6.8 Recommended concomitant therapies and permitted drugs 
The use of anticomitial drugs will be allowed, as prophylaxis, if patients are already on 
antiepileptic therapy, as well as the continuation of steroid therapy if already in place. The 
following drugs and / or supportive therapies can be used, if clinically indicated: 
• 
steroids; 
• 
antiemetics; 
• 
mannitol i.v .; 
• 
anticomitial drugs. 
6.9 Concomitant Therapies Prohibited 
During the entire duration of the treatment it will not be allowed to use: 
• 
antineoplastic drugs; 
• 
other experimental drugs. 
7. EXIT FROM THE STUDY AND SUSPENSION OF THE TREATMENT 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 18 a 35 
7.1 Exit from the study 
Should one of the following conditions occur, the patient should be considered off-study and will 
not be included in the study's end point analysis: 
a.  refusal of the patient to continue the treatment (withdrawal of informed consent); 
b. violation of the inclusion / exclusion criteria. 
7.2 Suspension of treatment 
Treatment must be permanently suspended if one or more of the following situations occur: 
• 
grade> 3 neurological and non-neurological toxicity; 
• 
grade ≤ 2 neurological toxicity unresponsive to supportive care; 
• 
disease progression during treatment; 
• 
second medical opinion, for safety reasons; 
• 
refusal of the patient to continue the treatment; 
• 
need to start antineoplastic therapy. 
Permanent discontinuation of treatment, in case of disease progression or unacceptable toxicity, 
will be considered as a therapy failure, therefore patients will be included in the study's end-point 
analysis. 
7.3 Evaluations in case of suspension of treatment 
Patients who discontinue treatment for reasons other than death and withdrawal of consent will 
be evaluated with a follow-up visit within 7 days of discontinuing treatment. Patients who suspend 
the treatment, envisaged by the protocol, will receive medical treatment as required by the 
clinical practice of the center. 
8. EVALUATION PROGRAM 
8.1 Baseline assessment before the start of radiotherapy treatment 
8.1.1 Mandatory assessments: 
• 
general and neurological examination. A palliative doctor will be supported by the 
radiotherapist. 
• 
Detection of vital parameters and anthropometric indices. 
• 
Definition of the ECOG and Karnofsky indices. 
• 
Quality of life assessment through EORTC QLQ-C30 and BN20 questionnaires. 
8.1.2 Optional assessments based on tumor site: 
• 
neurological visit. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 19 a 35 
• 
Endocrinological examination with hormonal profile (FT3, FT4, TSH, FSH, LH, Estradiol (E2) 
if female, testosterone if male, prolactin, cortisol, ACTH, GH). 
• 
Otolaryngological examination with complete audiometric examination (tonal and vocal). 
• 
Eye examination with neuro-ophthalmological evaluation. 
• 
PET with labeled amino acids or with membrane metabolism tracers. 
• 
Other examinations and / or specialist visits depending on the particular conditions of the 
patient. 
8.2 Evaluation at the end of the radiotherapy treatment 
Clinical visit at the end of radiotherapy: 
• 
General and neurological examination. A palliative doctor will be assisted by the 
radiotherapist. 
• 
Detection of vital parameters and anthropometric indices. 
• 
Definition of the ECOG and Karnofsky indices. 
• 
Detection of acute toxicity via CTCAE version 4.0 scale. 
8.3 Follow-up evaluation 
Clinical visits at 7 days, 15 days, 30 days, 60 days and 90 days from the end of radiotherapy (RT). 
8.3.1 Mandatory assessments: 
• 
General and neurological examination. A palliative doctor will be supported by the 
radiotherapist. 
• 
Detection of vital parameters and anthropometric indices. 
• 
Definition of the ECOG and Karnofsky indices. 
• 
Detection of acute / subacute / late toxicity by CTCAE version 4.0 scale. 
• 
Quality of life assessment through EORTC QLQ-C30 and BN20 questionnaires (at 1 and 3 
months). 
• 
MRI of the brain before and after m.d.c. paramagnetic (1 month and 3 months from the 
end of RT). 
8.3.2 Optional assessments based on tumor site or patient's particular condition: 
• 
Additional specialist visits (endocrinology, ophthalmology, etc.) according to medical 
indications. 
9. OUTCOMES EVALUATION PLAN 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 20 a 35 
The response to radiotherapy treatment will be evaluated according to the RANO criteria 
(Technical Annex) with morphological and functional (multiparametric) brain MRI performed at 1 
month after the end of radiotherapy and then after 3 months. 
The toxicity assessment will be made with reference to the International Common Toxicity Criteria 
for Adverse Event (CTCAE) - version 4.0 (The complete document is available on the website of the 
National Institute of Health 
The response to radiotherapy treatment will be evaluated according to the RANO criteria (Annex) 
with morphological and functional (multiparametric) brain MRI performed at 1 month after the 
end of radiotherapy and after 3 months. 
The toxicity assessment will be made with reference to the International Common Toxicity Criteria 
for Adverse Event (CTCAE) - version 4.0 (The complete document is available on the National 
Institute 
of 
Health 
(NIH) 
website 
at 
the 
following 
address: 
http: 
//ctep. 
cancer.gov/reporting/ctc.html), excluding neurological adverse events of grade ≤ 2 that responded 
adequately to supportive care. 
Safety and tolerability will be defined for: 
• 
type, frequency, severity and relationship of adverse events to treatment; 
• 
number of subjects who prematurely discontinued treatment due to any adverse event; 
• 
frequency of clinically significant changes and / or laboratory tests. 
All patients who have started radiation treatment will be considered for analysis, until the 
completion of the study (i.e. until the final visit at the end of the entire program for patients who 
complete the treatment) or until the scheduled follow-up visit in case of premature suspension of 
the study. Patients will be instructed by the Investigator on the need to report any adverse events 
that may occur during the study. 
10. SAFETY ASSESSMENTS OF RADIOTHERAPY 
The investigator will report all adverse events, serious and non-serious, related and unrelated 
within the CRF, with the exception of: 
1. Any medical conditions of the patient present at baseline before the start of study 
treatment. Worsening of these conditions during the study will instead be recorded as an 
adverse event. 
2. Abnormal laboratory values, unless they lead to exit from the study, a specific treatment, 
modification or interruption of study treatment, other therapeutic interventions or 
clinically important in the opinion of the Investigator. If the laboratory parameter is part of 
a pathological state, only the diagnosis of the same must be reported as AE within the CRF. 
If possible, the laboratory abnormality should be recorded as a diagnosis and not simply as 
an abnormal laboratory result. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 21 a 35 
10.1 Evaluation of adverse events from radiotherapy 
An adverse event (AE) is any adverse clinical event that occurs in a patient or clinical trial subject 
receiving treatment and which does not necessarily have a causal relationship to that treatment. 
An adverse event can occur in the treatment period and in the follow-up period. 
An adverse event is defined as SERIOUS (SAE) if it has: 
• 
lethal outcome; 
• 
endangers the patient's life (it means that in the Investigator's opinion the patient is at 
immediate risk of death); 
• 
imposes a hospitalization or extends the hospitalization in progress following the 
procedures provided for in the protocol; 
• 
involves severe or prolonged disability or incapacity, a congenital anomaly or 
malformation or a birth defect; 
• 
may endanger the subject or require intervention to prevent one of the above situations. 
Within the protocol, hospitalizations already planned before the start of the protocol or as parts of 
the protocol, hospitalizations lasting less than 24 hours or occurring in the absence of an adverse 
event will not be considered serious adverse events. 
For each adverse event (AE), the Investigator will provide information on the nature of the event, 
severity, start and end date, actions taken, causation with the treatment, seriousness and 
outcome. 
10.1.1 Severity / Severity of an event 
The Investigator will have to evaluate the severity of the event on the International Common 
Toxicity Criteria for Adverse Event (CTCAE) classification - version 4.0, graduated on a scale from 1 
to 5. In case of an event not included in the International Common Toxicity Criteria for Adverse 
toxicity scale Event (CTCAE) - version 4.0, the following scale will be used to indicate the severity of 
an event. 
The severity of adverse events not listed in this classification will be assessed on the basis of the 
following levels: 
• 
mild: the adverse event is easily tolerated by the subject, causing minimal discomfort and 
no interference with daily activities and does not require specific treatments; 
• 
moderate: the adverse event interferes with normal daily activities but improves 
following therapeutic intervention; 
• 
severe: the adverse event prevents normal daily activities and requires specific 
therapeutic intervention; 
• 
life risk: immediate risk that requires hospitalization and clinical intervention; 
• 
death. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 22 a 35 
10.1.2 Causation of an event 
The Investigator is responsible for evaluating a causal link between the adverse event and the 
treatment, regardless of the doses administered, according to the following definitions and with 
respect to the information contained in the study documentation: 
• 
not related: when the event is not considered related to the treatment (if the event is 
easily explained by the clinical situation, underlying diseases, concomitant therapies, 
specific procedures or if there is no temporal correlation); 
• 
correlated (or possible correlation): when there are facts (evidence) or arguments that 
indicate or suggest a causal link (temporal relationship, nature of the event, dependence 
of the nature of the event on the suspension / resumption of treatment, unlikely 
relationship with concomitants, underlying pathologies or any procedures) between the 
event and the treatment. 
10.1.3 Outcome 
The Investigator must indicate the action taken due to an adverse event in terms of: 
• 
continuation of treatment; 
• 
interruption of treatment; 
indicating whether additional interventions not provided for in the protocol were necessary for the 
management of the event. All adverse events that did not lead to the interruption of the subject's 
participation in the study must be monitored until resolution of the event, partial resolution, 
aggravation or death (due to the event itself). 
The Investigator is responsible for an adequate clinical follow-up of the event until resolution, 
stabilization of the event, patient death or loss of the patient at follow-up. This may mean that in 
some circumstances the follow-up continues even after the end of the study. 
10.2 Recording an Adverse Event 
The Investigator must record any adverse events that occur during the treatment period and 
thereafter, up to the study closing visit in the CRF and in the relevant health records. 
A completely resolved AE that recurs or increases in severity will have to be recorded as a new 
event within the CRF. 
A description of the event will be reported with medical terms, date of presentation and 
resolution, severity, causation with respect to the treatment, actions taken, seriousness of the 
event. All the measures required for the management of the adverse event must be recorded in 
the reference health documentation. 
If an AE is considered serious, the AE section within the CRF must be completed. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 23 a 35 
10.3 Intermediate safety reports 
The investigator will produce a safety report as per the analysis plan defined in paragraph 12.1 and 
upon request to be submitted to the internal board and / or the Ethics Committee. 
11. SURVEILLANCE ON MEDICAL DEVICES 
Since the medical devices under study are CE marked and used in accordance with the intended 
use indicated by the Manufacturer, the surveillance will be carried out in accordance with the 
provisions for post-market investigations (MEDDEV 2.12.1 - Guidelines on a medical devices 
vigilance system): the specific definitions of adverse event and reporting obligations will therefore 
be applied and in compliance with the company Procedure "Supervision of medical devices, active 
implantable medical devices, in vitro diagnostic devices" (PRDMVIG01 of 12/01/2015). 
In accordance with the provisions of the Meddev 2.7-3 guideline (Guidelines on medical devices 
clinical investigations: serious adverse event reporting), any safety reports will be notified to the 
Ethics Committee. 
11.1 Security Definitions 
Accident definition:  an accident / near miss is any malfunction or deterioration of the 
characteristics and / or performance as well as any deficiency in the labeling or in the instructions 
for use of a device which, directly or indirectly, may cause or have caused death or serious injury. 
worsening of the state of health of the patient or of a user or other people. 
Any event that meets all three of the basic detection criteria listed below is considered an accident 
and must be reported to the National Competent Authority. 
• 
An event happened 
This also includes situations in which, following tests performed on the device or following the 
analysis of the information provided with the device or any other scientific information, factors 
emerge that could lead or have led to an event. Typical events include, but are not limited to: 
a. a malfunction or deterioration in characteristics or performance (a malfunction or 
deterioration must be interpreted as an inability of the device to operate in accordance 
with its intended use, even if the device is used according to the manufacturer's 
instructions ); 
b. false positive or false negative test results that are outside the stated performance limits of 
the test; 
c. unexpected adverse reactions or unexpected side effects; 
d. interactions with other substances or products; 
e. degradation / destruction of the device; 
f. inappropriate therapy; 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 24 a 35 
g. lack of accuracy in labeling, instructions for use and / or promotional material. Lack of 
accuracy includes omissions and deficiencies. Omissions do not include the absence of 
information that should be well known to the intended user. 
• 
It is suspected that the manufacturer's medical device is a contributing cause of the 
accident 
In assessing the link between the device and the accident / missed accident, the Investigator or 
other healthcare professional must take into account: 
a. the opinion, based on available evidence, of health professionals;  
b. evidence of similar incidents that occurred previously; 
c. the results of the manufacturer's preliminary assessment; 
d. other evidence held by the manufacturer; 
e. if the judgment is difficult and in complex circumstances it must be assumed that the 
device may have caused or contributed to causing the accident and that the manufacturers 
have not paid due caution. 
• 
The event caused, or could have caused the death or serious deterioration of the state 
of health (of the patient, user or other person) 
Severe deterioration in health can mean: 
a. a serious illness;  
b. permanent impairment of a bodily function or permanent damage to a bodily structure; 
c. a condition that requires medical or surgical intervention to prevent cases (a) or (b); 
d. any indirect damage resulting from the onset of incorrect diagnostic results or IVD tests, 
when used in compliance with the manufacturer's instructions for use; 
e. fetus distress, fetus death, or any congenital anomalies or birth defects. 
PLEASE NOTE: It should be noted that not all accidents involve a risk and / or cause death or 
serious deterioration of the state of health (of the patient, user or other person). The non-
occurrence of this outcome may be due to other circumstances or the intervention of the 
healthcare professional. It is therefore sufficient that an accident associated with a device has 
occurred, and that the accident was such that, if it recurs, it could lead to death or serious 
deterioration of health (of the patient, user or other person). 
11.2 Timing for reporting an Incident 
The reporting of an accident by the Investigator or other health professionals must take place 
immediately after the occurrence of the accident / missed accident, to allow compliance with the 
transmission times to the Ministry, or within a maximum of 10 days. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 25 a 35 
The report must be sent signed by the Investigator to the contact person for the surveillance 
device (RAV) of Active Medical Devices and Health Equipment of CND Y and Z class, completing the 
report form (Attachment), available on the company intranet in a complete and legible way 
following the path: Portal Home> Medical Devices Company Commission> MEDICAL DEVICES 
SURVEILLANCE. 
Contact person for the supervision of the 
Active Medical Devices and health equipment of CND Y and Z class 
Ing. Paolo Bottazzi 
Tel 0522/296149 
Fax 0522/377891 
E-mail: paolo.bottazzi@asmn.re.it 
For 10 days following the submission of the report, the medical device must remain available to 
the competent authority. After this deadline, the medical device subject to reporting must be 
entrusted to the RAV subject to agreements with the same for the times and methods of delivery. 
11.3 Forwarding of the report to the Competent Authority and to the Ethics 
Committee 
The RAV provides for the transmission of the complete Accident Form signed by the Investigator, 
together with a cover letter, to the Ministry of Health at Office V of the General Directorate of 
Medical Devices and Pharmaceutical Service (DGDMF). This documentation will also be sent to the 
local Ethics Committee. 
The RAV will transmit the appropriate feedback information to the reporter, the PI of the study and 
the Local Ethics Committee. 
11.4 Urgent security measures 
Any communications relating to safety notices and / or recall on medical devices in use within the 
study, communicated by the Manufacturer and / or Competent Authority and received by the RAV, 
will be sent to the IP of the study and to the provincial Ethics Committee and to the internal board 
(for safety assessment). 
12. STATISTICAL ASPECTS 
12.1 The champion 
The study is proposed as an exploratory, prospective, experimental and monocentric study. 
Regarding the main endpoint (toxicity of the proposed radiotherapy treatment), there are no data 
currently available from previous studies. In the absence of criteria useful for the sizing of the 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 26 a 35 
sample in formal terms, the sample (12 cases) is defined according to criteria of opportunity and 
feasibility, with two steps of evaluation of the outcome as follows: 
• 
after the first 3 patients enrolled and treated with the proposed radiotherapy scheme, 
there will be a 1 month stop in the enrollment of subsequent patients, in which tolerance 
and the occurrence of serious adverse events will be analyzed. 
• 
At the end of the month, if none of the patients treated shows toxicity attributable to 
radiation treatment> 3, the enrollment of the next 3 patients will continue with a further 
stop in enrollment for another month. 
• 
If these patients, together with the 3 previously treated, do not have serious adverse 
events induced by radiation treatment, the enrollment of the last 6 patients will continue. 
All patients in the study will be followed, for the primary endpoint of the study, for at least 3 
months from enrollment, or until disease progression or death from another cause. 
At the end of each intermediate step, the investigator will produce a report on the safety of the 
cases already treated which will be subjected to the evaluation of an internal board, composed of 
the Health Director, the Scientific Director and the Legal Doctor of the ASMN-IRCCS of Reggio 
Emilia, who will will express on the continuation / interruption of the study and subsequently 
notified to the EC. 
The internal board will also evaluate any urgent safety measures (as defined in paragraph 11.4) 
transmitted by the RAV, expressing its opinion on the continuation / interruption of the study and 
subsequently notifying the EC of this opinion. 
12.2 Analysis plan 
By virtue of the exploratory nature of the study and the limited number of subjects, the data will 
be presented mainly through tables and lists. Confidence intervals for percentages will be 
calculated following the Clopper-Pearson method to properly take into account the limited number 
of subjects. OS and PFS will be graphed using the Kaplan-Meier method and briefly described in 
percentile terms. The analyses will be conducted with R, SAS System, or SPSS software on the basis 
of availability at the time of the analyzes and in the versions in use in that period 
12.3 Data management 
For the management of the study, a data collection form on the web platform (e-CRF) with 
personalized access credentials will be requested from the Company's IT Service (STIT), which 
meets regulatory requirements and guarantees privacy criteria in accordance with the law 
(Authorization of the Privacy Guarantor n.72 of 26 March 2012). All data will be collected and 
processed in codified form. 
A paper draft of the CRF will be provided to the Ethics Committee, which is being prepared. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 27 a 35 
Patients will be registered in the CRF, registration form, at the time of entry into the study 
(Signature of informed consent). All signed consents and patient screening and enrolment 
procedures must be kept in the study's Trial Master File. 
13. ETHICAL AND AUTHORIZATION ASPECTS 
13.1 General aspects 
The study will be activated only after approval by the Local Ethics Committee / competent 
Authorities, and any communications to the Ministry of Health and will be conducted in 
accordance with this protocol and any amendments introduced. 
The protocol has been written and the study will be conducted in accordance with the ethical 
principles of the Declaration of Helsinki (http://www.wma.net/e/policy/b3.htm) and ICH 
Harmonized 
Tripartite 
Guideline 
for 
Good 
Clinical 
Practice 
(http: 
//www.ifpma.org/pdfifpma/e6.pdf) and UNI ISO 14155 (2012) (Clinical investigation of medical 
devices fior human subject-GCP) and following the guidelines on the medical device vigilance 
system Meddev 2.12-1. 
The study documentation will be collected and stored at the participating centers and in its 
entirety by the coordinating center of the study (Medical Physics Service, ASMN-IRCCS of Reggio 
Emilia) and will be stored according to regulatory indications. 
All documentation must be made available for any inspections required by regulatory authorities, 
during or after the conclusion of the study, and for planned monitoring activities. 
Each patient eligible for treatment will be adequately informed by the specialist on the purposes of 
the study, the expectations of the proposed experimental intervention, the objectives and 
methods of conducting the study and must sign a specific consent for the study and data 
processing. 
Each patient has the right to withdraw their membership at any time without having to justify the 
choice; from that moment on his data will no longer contribute to the study dataset and 
documented in the patient's medical record. 
13.2 Insurance aspects 
The study in question is defined as a non-profit study, aimed at improving clinical practice as an 
integral part of health care; no medicine is envisaged and the study has no industrial purpose. In 
these cases, the legislation decrees that as a guarantee for any damage caused to the patient to 
cover the risks associated with the experimental treatment not already documented, it is possible 
to take advantage of the coverage already provided for the assistance activity which is also 
extended to the experimentation activities. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 28 a 35 
The information on the risks known to the treatment and on the company insurance policy 
covering the study must be specifically provided to the patient in the information documentation, 
before signing the consent. 
13.3 Monitoring and Quality Control (QC) 
Through an electronic e-CRF set up on a web platform by the IT Service of the ASMN-IRCCS 
company, of Reggio Emilia (promoter of the study), the registration of patients entering the study 
and the availability of clinical data will be guaranteed with continuity. 
The Clinical Studies and Statistics Office will propose a monitoring program suitable for the type of 
study in accordance with the company SOPs with centralized monitoring actions, off site and on 
site, managed by adequately trained staff. 
In the event of early termination of treatment, patients will still be monitored for the entire 
duration of the study or for any documented disease progression, death or exit from follow-up. 
13.4 Responsibility and publication policy 
The study is independent and promoted by the IRCCS-ASMN Hospital which will manage the 
conduct of the study, the collection and analysis of data and its dissemination. 
The submission of articles to scientific journals and / or the presentation of papers at national / 
international scientific conferences will be attended by the experimenters interested in the study 
and those who participated in the development and drafting of the project. 
The results will be published and / or presented at scientific conferences even in the event of an 
early interruption of the study. 
14. BIBLIOGRAPHY 
1.  Stupp R, Mason WP, van den Bent MJ, et al. Rdaiotherapy plus concomitant and adjuvant 
temozolomide for gliobalstoma. N Engl J Med. 2005; 352 (10): 987-96. 
2. Stupp R, Heigi ME, Mason WP et al. Effects of radiotherapy with concomitant and adjuvant 
temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III 
study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncolol. 2009. Mar 6 
3. Central Brain Tumor Registry of the United States. CBTRUS statistical report: primary brain 
and central nervous system tumors diagnosed in the United States in 2004-2007. 
www.cbtrus.org. Accessed June 28, 2012 
4. Nieder C, Grosu AL, Molls M. A comparison of treatment results for recurrent malignant 
gliomas. Cancer Treatment Reviews 2000; 26:397-409 
5. Ammirati M, Galicich JH, Arbit E, Liao Y. Reoperation in the treatment of recurrent intracranial 
malignant gliomas. Neurosurgery 1987; 21:607-14  
6. Manikandan A, Sarkar B, Holla R, Vivek TR, Sujatha N. Quality assurance of dynamic 
parameters in volumetric modulated arc therapy. Br J Radiol 2012; 85: 1002-1010. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 29 a 35 
7. Richmond ND, Pilling KE, Peedell C, Shakespeare D, Walker CP. Positioning accuracy for lung 
stereotactic body radiotherapy patients determined by on-treatment cone-beam CT imaging. 
Br J Radiol 2012; 85: 819-823. 
8. Brandes AA, Tosoni A, Cavallo G, et al. Temozolomide 3 weeks on and 1 week off as first-line 
therapy for recurrent glioblastoma: phase II study from Gruppo Italiano Cooperativo di Neuro-
oncologia (GICNO). Br J Cancer. 2006;95(9):1155-1160 
9. Hammond A, Norden AD, Lesser GJ, et al. Phase II study of  dose-intense temozolomide in 
recurrent gliblastoma. J Clin Oncol. 2011:29:2038 
10. Brandes AA, Franceschi E, Tosoni A, Bartolini S, Bacci A, Agati R, et al. O(6)-methylguanine 
DNA-methyltransferase methyleation status can change between first surgery for newly 
diagnosed glioblastoma and second surgery fro recurrence: clinical implications. Neuro-
Oncology 2010; 12: 283-8 
11. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the central nervous system. Int J 
Radiat Oncol Biol Phys 1995; 31:1093-112 
12. Veninga T, Langendijk HA, Slotman BJ, et al. Reirradiation of primary brain tumors: survival, 
clinical response and prognostic factors. Rdaiother Oncol 2001;59:127-37 
13. Barbagallo GM, Jenkinson MD, Brodbelt AR. Recurrent Gliobastoma multiforme- when should 
we reoperate? Br J Neurosurg. 2008;22(3):452-455 
14. Young B, Oldfield EH, Markesbery WR, Haack D, Tibbs Pa, McCoombs P, et al. Reoperation for 
glioblastoma. Journal of Neurosurgery 1981; 55:917-21 
15. Barker 2nd FG, Chang SM, Gutin PH, Malec MK, McDermott MW, Prados MD, et al. Survival 
and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 
1998; 42:709-20 
16. Barker 2nd FG, Chang SM, Gutin PH, Malec MK, McDermott MW, Prados MD, et al. Survival 
and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery 
1998; 42:709-20 
17. Coombs SE, Debus J, Shulz-Ertner D. Radiotherapeutic alternatives for previously irradiated 
recurrent gliomas. BMC Cancer. 2007;7:167 
18. Hall WA, Djalilian HR, Sperduto PW, et al. Stereotactic radiosurgery for recurrent malignant 
gliomas. J Clin Oncol. 1995; 13:1642-1648 
19. Cho KH, Hall WA, Gerbi BJ, Higgins PD, et al. Single dose versus fractionated stereotactic 
radiotherapy for recurrent high-grade gliomas. Int J Radiat Oncol Biol Phys.1999; 45: 1133-
1141 
20. Combs SE, Gutwein S, Thilman CH, et al. Stereotactically guided fractionated reirradiation in 
recurrent glioblastoma multiforme. J Neurooncol. 2005; 74:167-171 
21. Combs SE,  Thilman CH, Edler L, et al. Efficacy of fractionated stereotactic reiraddiation in 
recurrent gliomas: long-term result in 172 patients treated in a single institution. J Clin Oncol. 
2005; 23:8863-8869 
22. Vordermark D, Kolbl O, Ruprecht K, et al. Hypofractionated stereotactic  re-irradiarion: 
treatment option in recurrent malignant glioma. BMC Cancer. 2005; 5:55 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 30 a 35 
23. Lederman G, Wronski M, Arbit E, et al. Treatment of recurrent glioblastoma multiforme using 
fractionated stereotactic radiosurgery and concurrent paclitaxel. Am J Clin Oncol. 2000; 
23:155-159 
24. Arcicasa M, Roncadin M, Bidoli E, et al. Reirradiation and lomustine in patients with relapsed 
high-grade gliomas. Int J Radiat Oncol Biol Phys. 1999; 43:789-793 
25. Combs SE, Bischof M, Welzel T, et al. Radiochemotherapy with temozolomide as re-irradiation 
using high precision fractionated stereotactic radiotherapy (FSRT) in patients with recurrent 
gliomas. J Neurooncol. 2008; 89:205-210 
26. Minniti G, Armosini V, Salvati M, et al. Fractionated stereotactic reirradiation and concurrent 
temozolomide in patients with recurrent glioblastoma. J Neurooncol. 2011 Jul;103(3):683-91. 
27. Bauman G.S., Sneed P.K., Wara W.M. et al. Reirradiation of primary CNS tumors. Int. J. Radiat. 
Oncol. Bbiol. Phys. 1996, 36,433-441 
28. Kim H.K., Thorton A.F., Greenberg H.S., et al. Results of re-irradiation of primary intracranial 
neoplasms with three-dimensional conformal therapy. Am. J. Clin. Oncol. 1997, 20, 358-363. 
29. Hayat K., Jones B., Bisbrown G. Et al. Retreatment of patients with intracranial gliomas by 
external beam radiotherapy and cytotoxic chemotherapy. Clin. Oncol. (R. Coll. Radiol.) 1997, 
9, 158-163. 
30. Nieder C., Nestle U., Ketter R. et al. Hyperfractionated and accelerated-hyperfractionated 
radiotherapy for glioblastoma multiforme. Radiat. Oncol. Investig. 1999, 7, 36-41. 
31. Henke G., Paulsen F., Steinbach J.P. et al. Hypofractionated reirradiation for recurrent 
malignant glioma. Strahlenther. Onkol. 2009, 185, 113-119.  
32. Osman M.A.,    et al. Phase II trial of temozolomide and reirradiation using conformal 3D-
radiotherapy in recurrent brain gliomas. Ann. Transl. Med. 2014, 2(5):44 
33. Grosu A.L., Weber W.A., Franz M. et al. Reirradiation of recurrent high-grade gliomas using 
amino acid PET (SPECT)/CT/MRI image fusion to determine gross tumor volume for 
stereotactic fractionated radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2005, 63, 511-519. 
34. Laing R.W., Warrington A.P., Graham J. et al. Efficacy and toxicity of fractionated stereotactic 
radiotherapy in the treatment of recurrent gliomas (phase I/II study). Radiother. Oncol. 1993, 
27, 22-29. 
35. Selch M.T., DeSalles A.A.F., Solberg T.D., Wallace R.E. et al. Hypofractionated stereotactic 
radiotherapy for Recurrent Malignant Gliomas. J. Radiosurg. 2000, 3, 3-12. 
36. Wurm R.E., Kuczer D.A., Schlenger L. et al. Hypofractionated stereotactic radiosurgery 
combined with topotecan in recurrent malignant glioma. Int. J. Radiat. Oncol. Biol. Phys. 2006, 
66, S26-S32. 
37. Kohshi K, Yamamoto H, Nakahara A, et al. Fractionated stereotactic radiotherapy using 
gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas. J Neurooncol 
2007;82:297–303. 
38. Ciammella P, Podgornii A., Galeandro M., et al. Hypofractionated stereotactic radiation 
therapy for recurrent glioblastoma: single institutional experience. Radiat Oncol. 2013, 25: 
8:222. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 31 a 35 
39. Ernst-Stecken A, Ganslandt O, Lambrecht U, Sauer R, Grabenbauer G. Survival and quality of 
life after hypofractionated stereotactic radiotherapy for recurrent malignant glioma. J 
Neurooncol, 2007; 81:287-294 
40. Fokas E, Wacker U, Gross MW, Henzel M, Encheva E, Engenhart-Cabillic R. Hypofractionated 
stereotactic reirradiation of recurrent glioblastomas: a beneficial treatment option after high-
dose radiotherapy? Strahlenther Onkol. 2009; 185:235-240 
41. Schwer A.L., Damek D.M., Kavanagh B.D. et al. A phase I dose-escalation study of fractionated 
stereotactic radiosurgery in combination with gefitinib in patients with recurrent malignant 
gliomas. Int. J. Radiat. Oncol. Biol. Phys. 2008, 70, 993-1001. 
42. Patel M., Siddiqui F., Jin J.Y. et al. Salvage reirradiation for recurrent glioblastoma with 
radiosurgery: radiographic response and improved survival. J. Neurooncol. 2009, 92, 185-191.  
43. Gutin P.H., Iwamoto F.M., Beal K. et al. Safety and efficacy of bevacizumab with 
hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int. J. Radiat. Oncol. 
Biol. Phys. 2008, 75, 156-163. 
44. Fogh SE, Anrews DW, Glass J, Curran W, Glass C, Champ C, Evans JJ, Hyslop T, Pequignot E, 
Downes B, Comber E, Maltenfort M, Dicker AP, Werner-Wasik M. Hypofractionated 
stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin 
Oncol, 2010; 28:3048-3053 
45. Maier-Hauff K., Ulrich F., Nestler D., et al. Efficacy and safety of intratumoral thermotherapy 
using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on 
patients with recurrent glioblastoma multiforme. J. Neurooncol. 2011, 103, 317-324. 
46. Villavicencio A.T., Burneikiene S., Romanelli P. et al. Survival following stereotactic 
radiosurgery for newly diagnosed and recurrent glioblastoma multiforme: A multi center 
experience. Neurosurg. Rev. 2009, 32, 417-424. 
47. Torcuator R.G., Thind R., Patel M. et al. The role of salvage reirradiation for malignant gliomas 
that progress on bevacizumab. J.Neurooncol. 2010, 97, 401-407. 
48. Shepherd SF, Laing RW, Cosgrove VP, Warrington AP, Hines F, Ashley SE, Brada M: 
Hypofractionated stereotactic radiotherapy in the management of recurrent glioma. Int J 
Radiat Oncol Biol Phys 1997, 37:393-398. 
49. Glass J, Silverman CL, Axelrod R, Corn BW, Andrews DW: Fractionated stereotactic 
radiotherapy with cis-platinum radiosensitization in the treatment of recurrent, progressive or 
persistent malignant astrocytoma. Am J Clin Oncol 1997, 20:226-229. 
50. Hudes RS, Corn BW, Werner-Wasik M, Andrews D, Rosenstock J, Thoron L, Downes B, Curran 
WJ: A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage 
therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys 1999, 
43:291-298 
51. Voynov G, Kaufman S, Hong T, Pinkerton A, Simon R, Dowsett R: Treatment of recurrent 
malignant gliomas with stereotactic intensity modulated radiation therapy. Am J Clin Oncol 
2002, 25:606-611. 
52. Wuthrick EJ., Curran WJ., Camphausen K.. et al. A pilot study of hupofractionated stereotactic 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 32 a 35 
radiation therapy and sunitinib in previously irradiated patients with recurrent high-grade 
glioma. Int. J. Radiat. Oncol. Biol. Phys. 2014, 90(2):369-75. 
53. Alexander E., Loffler J.S. Radiosurgery using a modified linear accelerator. Neurosurg. Clin. N. 
Am. 1992, 3, 167-190. 
54. Chamberlain M.C., Barba D., Kormanik R.N., et al. Stereotactic radiosurgery for recurrent 
gliomas. Cancer 1994, 74, 1342-1347. 
55. Shrieve D.C., Alexander E., Wen P.Y., et al. Comparison of stereotactic radiosurgery and 
brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 1995, 36, 
275-284. 
56. Greenspoon JN, Sharieff W, Hirte H et al. Fractionated stereotactic radiosurgery with 
concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a 
prospective cohort study. Onco Targets Ther. 2014 Mar 24;7:485-90. 
57. Shrieve D.C., Alexander E., Wen P.Y., et al. Comparison of stereotactic radiosurgery and 
brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 1995, 36, 
275-284. 
58. Larson D.A., Gutin P.H., McDermott M. et al. Gamma knife for glioma: Selection factors and 
survival. Int. J. Radiat. Oncol. Biol. Phys. 1996, 36, 1045-1053. 
59. Kondziolka D., Flickinger J., Jonh C. et al. Survival benefit of stereotactic radiosurgery for 
patients with malignant glial neoplasm.  Neurosurgery 1997, 41, 776-785. 
60. Park J.L., Suh J.H., Barnett G.H., Reddy C.S. et al. Survival after stereotactic radiosurgery for 
recurrent glioblastoma multiforme. J. Radiosurg. 2000, 3, 169-175. 
61. Larson D.A., Prodos M., Lamborn K.R., et al. Phase II study of high central dose gamma knife 
radiosurgery and marimastat in patients with recurrent malignant glioma. Int. J. Radiat. Oncol. 
Biol. Phys. 2002, 54, 1397-1304. 
62. Coombs S.E., Widmer V., Thilmann C. et al. Stereotactic radiosurgery (SRS). Treatment option 
for recurrent glioblastoma multiforme (GBM). Cancer 2005, 104, 2168-2173. 
63. Hsieh P.C., Chandler J.P., Bhangoo S. et al. Adjuvant gamma knife stereotactic radiosurgery at 
the time of tumor progression potentially improves survival for patients with glioblastoma 
multiforme. Neurosurgery 2005, 57, 684-691. 
64. Mahajan A., McCutcheon I.E., Suki D. et al. Case-control study of stereotactic radiosurgery for 
recurrent glioblastoma multiforme. J. Neurosurg. 2005, 103, 210-217. 
65. Kong D.S., Lee J.I., Park K. et al. Efficacy of stereotactic radiosurgery as a salvage treatment for 
recurrent malignant gliomas. Cancer 2008, 112, 2046-2051. 
66. Biswas T., Okunieff P., Schell M.C. et al. Stereotactic radiosurgery for glioblastoma: 
Retrospective analysis. Radiat. Oncol. 2009, 4, 11.  
67. Maranzano E., Anselmo P. Casale M. et al. Treatment of recurrent glioblastomawith 
stereotactic radiotherapy: Long-term results of a mono-institutional trial. Tumori 2011, 97, 56-
61. 
68. Greenspoon JN, Sharieff W, Hirte H et al. Fractionated stereotactic radiosurgery with 
concurrent temozolomide chemotherapy for locally recurrent glioblastoma multiforme: a 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 33 a 35 
prospective cohort study. Onco Targets Ther. 2014 Mar 24;7:485-90. 
69. Martínez-Carrillo M, Tovar-Martín I, Zurita-Herrera M et al. Salvage radiosurgery for selected 
patients with recurrent malignant gliomas. Biomed Res Int. 2014;2014:657953. 
70. Souhami L. Seiferheld D., Brachman D. et al. Randomized comparisno of stereotactic 
radiosurgery followed by conventional radiotherapy with carmustine to conventional 
radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation 
Therapy Oncology Group 93-05 protocol. Int. J. Radiat. Oncol. Biol. Phys. 2004, 60, 3: 853-860. 
71. Dodoo E, Huffmann B, Peredo I et al. Increased survival using delayed gamma knife 
radiosurgery for recurrent high-grade glioma: a feasibility study. World Neurosurg. 2014 
Nov;82(5):e623-32. 
72. Pourtian N, Crowley W., Sherman J.H. Et al. Gamma Knife radiosurgery after radiation therapy 
as an adjunctive treatment for glioblastoma. J Neuro-Oncol. 2009, 94, 409-418. 
73. Masui K., Cloughesy T.F., Mischel P.S. Et al. Review: molecular pathology in adult high-grade 
gliomas: from molecular diagnostics to target therapies. Neuropathology and applied 
neurobiology. 2012, 38,3: 271-291. 
74. Cabrera AR, Cuneo KC, Desjardins A, et al. Concurrent stereotactic radiosurgery and 
bevacizumab in recurrent malignant gliomas: a prospective trial.Int J Radiat Oncol Biol Phys. 
2013 Aug 1;86(5):873-9 
75. Isambert A, Dhermain F, Bidault F, et al. Evaluation of an atlas based automatic segmentation 
software for the delineation of brain organs at risk in a radiation therapy clinical context. 
Radiother nOncol, 2008,87:93-99. 
76. Metcalfe P, Liney GP, Holloway L, et al. The potential for an enhanced role for MRI in 
radiation-therapy treatment planning. Technol Cancer Res Treat, 2013,12:429-446. 
77. Holdsworth CH, Corwin D, Stewart RD, et al. Adaptive IMRT using a multiobjective 
evolutionary algorithm integrated with a diffusion invasion model of glioblastoma. Phys Med 
Biol, 2012,57:8271- 
78. Neal ML, Trister AD, Ahn S, et al. Response classification based on a minimal model of 
glioblastoma growth is prognostic for clinical outcomes and distinguishes progression from 
pseudoprogression. Cancer Res, 2013,73:2976-2986. 
79. McMillan KM, Rogers BP, Koay CG, Laird AR, Price RR, Meyerand ME.  An objective method for 
combining multi-parametric MRI datasets to characterize malignant tumors. Med Phys. 2007 
Mar;34(3):1053-61. 
80. Mabray MC, Barajas RF Jr, Cha S. Modern brain tumor imaging. Brain Tumor Res Treat. 2015 
Apr;3(1):8-23. 
81. Bruzzone MG, D'Incerti L, Farina LL, Cuccarini V, Finocchiaro G. CT and MRI of brain tumors. Q 
J Nucl Med Mol Imaging. 2012 Apr;56(2):112-37. 
82. Horská A, Barker PB. Imaging of brain tumors: MR spectroscopy and metabolic imaging. 
Neuroimaging Clin N Am. 2010 Aug;20(3):293-310. 
83. Lee SK. Diffusion tensor and perfusion imaging of brain tumors in high-field MR imaging. 
Neuroimaging Clin N Am. 2012 May;22(2):123-34. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 34 a 35 
84. Gerstner ER, Sorensen AG. Diffusion and diffusion tensor imaging in brain cancer. Semin 
Radiat Oncol. 2011 Apr;21(2):141-6. 
85. Ginat DT, Mangla R, Yeaney G, Wang HZ. Correlation of diffusion and perfusion MRI with Ki-67 
in high-grade meningiomas. AJR Am J Roentgenol. 2010 Dec;195(6):1391-5. 
86. Chen L, Zhang J, Chen Y, Wang W, Zhou X, Yan X, Wang J. Relationship between apparent 
diffusion coefficient and tumour cellularity in lung cancer. PLoS One. 2014 Jun 11; 
9(6):e99865. 
87. Schnapauff D, Zeile M, Niederhagen MB, Fleige B, Tunn PU, Hamm B, Dudeck O. Diffusion-
weighted echo-planar magnetic resonance imaging for the assessment of tumor cellularity in 
patients with soft-tissue sarcomas. J Magn Reson Imaging. 2009 Jun;29(6):1355-9. 
88. Chen L, Liu M, Bao J, Xia Y, Zhang J, Zhang L, Huang X, Wang J. The correlation between 
apparent diffusion coefficient and tumor cellularity in patients: a meta-analysis. PLoS One. 
2013 Nov 11;8(11):e79008. 
89. Matsumoto Y, Kuroda M, Matsuya R, Kato H, Shibuya K, Oita M, Kawabe A, Matsuzaki H, 
Asaumi J, Murakami J, Katashima K, Ashida M, Sasaki T, Sei T, Kanazawa S, Mimura S, Oono S, 
Kitayama T, Tahara S, Inamura K. In vitro experimental study of the relationship between the 
apparent diffusion coefficient and changes in cellularity and cell morphology. Oncol Rep. 2009 
Sep;22(3):641-8. 
90. Alexiou GA, Zikou A, Tsiouris S, Goussia A, Kosta P, Papadopoulos A, Voulgaris S, Kyritsis AP, 
Fotopoulos AD, Argyropoulou MI. Correlation of diffusion tensor, dynamic susceptibility 
contrast MRI and (99m)Tc-Tetrofosmin brain SPECT with tumour grade and Ki-67 
immunohistochemistry in glioma. Clin Neurol Neurosurg. 2014 Jan;116:41-5. doi: 10.1016. 
91. Baker F1, Sanger L. The density of clonogenic cells in human solid tumors. Int J Cell Cloning. 
1991 Mar;9(2):155-65. 
92. Maani R, Yang YH, Kalra S. Voxel-based texture analysis of the brain. PLoS One. 2015 Mar 
10;10(3): e0117759. 
93. Alobaidli S, McQuaid S, South C, Prakash V, Evans P, Nisbet A. The role of texture analysis in 
imaging as an outcome predictor and potential tool in radiotherapy treatment planning. Br J 
Radiol. 2014 Oct;87(1042):20140369. 
94. Ciammella P, Podgornii A, Galeandro M, D'Abbiero N, Pisanello A, Botti A, Cagni E, Iori M, Iotti 
C. Hypofractionated stereotactic radiation therapy for recurrent glioblastoma: single 
institutional experience. Radiat Oncol. 2013 Sep 25;8:222 
95. Supiot S, Lisbona A, Paris F, Azria D, Fenoglietto P.  ["Dose-painting": myth or reality?]. Cancer 
Radiother. 2010 Oct;14(6-7):554-62. 
96. Ken S, Vieillevigne L, Franceries X, Simon L, Supper C, Lotterie JA, Filleron T, Lubrano V, Berry I, 
Cassol E, Delannes M, Celsis P, Cohen-Jonathan EM, Laprie A. Integration method of 3D MR 
spectroscopy into treatment planning system for glioblastoma IMRT dose painting with 
integrated simultaneous boost. Radiat Oncol. 2013 Jan 2;8:1. 
97. Rickhey M, Koelbl O, Eilles C, Bogner L. A biologically adapted dose-escalation approach, 
demonstrated for 18F-FET-PET in brain tumors. Strahlenther Onkol. 2008 Oct;184(10):536-42. 

GLIORAD_15-18 
Versione 6r.1 del 16/04/2019 
 
Pag. 35 a 35 
98. Nguyen D, Rwigema JC, Yu VY, Kaprealian T, Kupelian P, Selch M, Lee P, Low DA, Sheng K. 
Feasibility of extreme dose escalation for glioblastoma multiforme using 4π radiotherapy. 
Radiat Oncol. 2014 Nov 7;9:239. 
99. Chojnacka M, Skowrońska-Gardas A, Pędziwiatr K, Morawska-Kaczyńska M, Perek M, Perek D. 
Reirradiation of relapsed brain tumors in children. Rep Pract Oncol Radiother. 2011 Nov 
13;17(1):32-7. 
100. Sminia P, Mayer R. External beam radiotherapy of recurrent glioma: radiation tolerance of 
the human brain. Cancers (Basel). 2012 Apr 5;4(2):379-99.