Phase III Trial on Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q Deleted Anaplastic Glioma. The CATNON Intergroup Trial.
Phase: PHASE3
Conditions: Brain and Central Nervous System Tumors
Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

EORTC 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België – Belgique 
Tel: +32 2 774 16 11  
e-mail: eortc@eortc.org
www.eortc.org
Intergroup Study (EORTC 26053-22054) 
(EudraCT number 2006-001533-17) 
(NCT00626990) 
Phase III trial on Concurrent and Adjuvant Temozolomide chemotherapy in non-1p/19q deleted 
anaplastic glioma. The CATNON Intergroup trial. 
Collaborative Groups/Co-Chairs: 
EORTC Brain Tumor Group/W. Wick, A. Omuro, R. Soffietti 
EORTC Radiation Oncology Group/ B. Baumert 
NCI-C/ J.G. Cairncross, W. Mason 
RTOG/M. Metha, M. Vogelbaum 
MRC/NCRI Brain tumor Clinical Studies Group/S. Erridge 
COGNO CTC/A. Nowak 
Study Chairman: Martin van den Bent 
Warning: 
This is an Intergroup study coordinated by the EORTC. The present protocol is written according to the EORTC template and is 
fully applicable to all collaborative groups (with the exception of EORTC specific chapters or other collaborative group(s) 
specific appendix and unless otherwise specified). 
The chapters 18 to 21 and the PIS/IC (Appendix F, Appendix G, Appendix H,) are fully applicable to EORTC investigators only. 
Corresponding items and contact addresses for non EORTC investigators are provided in their Group specific appendix that 
supersedes the contents of chapters 18-21 (unless otherwise specified). 
March 07, 2006 
PRC outline approval 
September 27, 2006 
Full protocol approval 
Version 1.0 
October 25, 2006 
First Amendment (non-substantial) 
Version 1.1 
January 22, 2007 
Second Amendment (substantial) 
Version 2.0 
February 09, 2007 
Third Amendment (non-substantial) 
Version 2.1 
November 30, 2007 
Fourth Amendment (non-substantial) 
Version 2.2 
February 05, 2009 
Fifth Amendment (non-substantial) 
Version 2.2 (Full protocol not recompiled) 
July 14, 2009 
Sixth Amendment (administrative) 
Version 2.2 (Full protocol not recompiled) 
June 18, 2010 
Seventh Amendment (administrative) 
Version 2.2 (Full protocol not recompiled) 
June 27, 2011 
Eighth Amendment (scientific) 
Version 3.0 
January 10, 2014 
Tenth Amendment (scientific) 
Version 4.0 
June 28, 2017 
Thirteenth Amendment (scientific) 
Version 5.0 
September 07, 2020 
Fourteenth Amendment (scientific) 
Version 6.0 
Version 6.0 / September 07, 2020 
Copyright EORTC 2020 

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Contact addresses 
Study coordinators: 
 
 
EORTC (coordinating 
group):  
M. van den Bent 
 
 
Steering Committee: 
Study Coordinators from each participating group and 
representative person from the coordinating group Data 
Center 
Writing Committee: 
B. Baumert, Maastro - Maastricht Radiation Oncology, 
Maastricht, The Netherlands 
A. Bottomley, EORTC Headquarters, Brussels, Belgium. 
M. Brada, Royal Marsden Hospital, Sutton (Surrey), United 
Kingdom. 
T. Gorlia, EORTC Headquarters, Brussels, Belgium. 
M. Hegi, Centre Hospitalier Universitaire Vaudois, Lausanne, 
Switzerland. 
M. Klein, VU Medisch Centrum, Amsterdam, The 
Netherlands. 
D. Lacombe, EORTC Headquarters, Brussels, Belgium. 
A. Omuro, CHU Pitié-Salpêtrière, Paris, France. 
R. Rampling, Western Infirmary, Glasgow, United Kingdom 
R. Soffietti, Azienda Ospedaliera San Giovanni Battista Di 
Torino-Universita Di Torino, Torino, Italy. 
M.J.B. Taphoorn, Medisch Centrum Haaglanden – 
Westeinde, Den Haag, The Netherlands. 
M.J. van den Bent, Erasmus University Medical Center, 
Rotterdam, The Netherlands. 
W. Wick, Universitaetsklinikum Heidelberg, Heidelberg, 
Germany. 
 
 
 
 

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Contact addresses for EORTC  
 
 
Study Coordinator: 
Martin van den Bent 
Phone: +31 10 704 14 15 
e-mail: m.vandenbent@erasmusmc.nl 
Clinical Research 
Physician: 
Vassilis Golfinopoulos 
Phone: +32 2 774 16 65 
e-mail: vassilis.golfinopoulos@eortc.org  
Data Manager: 
Christine Olungu 
Phone: +32 2 774 10 97 
e-mail: christine.olungu@eortc.org  
Statistician: 
Thierry Gorlia 
Phone: +32 2 774 16 52 
e-mail: thierry.gorlia@eortc.org  
Clinical Operations 
Manager 
Kin Jip Cheung 
Phone: +32 2 774 16 07 
e-mail: kin-jip.cheung@eortc.org  
Pharmacovigilance: 
Phone: +32 2 774 16 76 
Fax: 
+32 2 772 80 27 
e-mail: Pharmacovigilance@eortc.org  
 
 
Contact addresses for other groups: see group specific appendices 
 
 
 

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Sponsor signatory page 
 
Protocol 26053-22054 
 
Sponsor: 
 
___________________________________________________ 
__________________ 
Vassilis Golfinopoulos  
 
 
 
 
 
(Date) 
Director, EORTC Headquarters 
EORTC 
European Organisation for Research and Treatment of Cancer 
AISBL-IVZW 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
Phone: +32 (0)2 774 16 65 
E-mail:  vassilis.golfinopoulos@eortc.org 
Website: http://www.eortc.org 
 
Study Coordinator: 
 
___________________________________________________ 
__________________ 
Martin J. van den Bent 
 
 
 
 
 
(Date) 
Erasmus University Medical Center 
Postbus 5201 (Groene Hilledijk 301) 
NL 3008 AE Rotterdam 
The Netherlands 
Phone: +31 10 704 14 15 
Fax: 
+31 10 704 10 31 
E-mail: m.vandenbent@erasmusmc.nl 
 
Investigator: (if applicable) 
 
___________________________________________________ 
__________________ 
Investigator’s name (printed clearly)  
 
 
 
(Date) 
 
09 September 2020 | 00:23:28 PDT
08 September 2020 | 16:35:38 CEST

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Table of contents: 
Protocol summary ......................................................................................................................................... 11 
Trial organization ........................................................................................................................................... 15 
1 
Background and introduction ............................................................................................................... 16 
1.1 
Anaplastic glioma .......................................................................................................................... 16 
1.1.1 Molecular classification of anaplastic glioma ........................................................................... 16 
1.1.2 Concomitant and adjuvant temozolomide in anaplastic glioma .............................................. 16 
1.1.3 The relevance of progression free survival ............................................................................... 17 
1.1.4 Further considerations for anaplastic glioma ........................................................................... 17 
1.2 
Study outline ................................................................................................................................. 17 
2 
Objectives of the trial ............................................................................................................................ 18 
2.1 
Primary objectives ......................................................................................................................... 18 
2.2 
Secondary objectives ..................................................................................................................... 18 
2.3 
End-points ..................................................................................................................................... 18 
2.3.1 Primary endpoint....................................................................................................................... 18 
2.3.2 Secondary endpoints ................................................................................................................. 18 
3 
Patient selection criteria ....................................................................................................................... 18 
3.1 
At the time of registration ............................................................................................................. 19 
3.2 
Randomization step....................................................................................................................... 19 
4 
Trial Design ............................................................................................................................................ 20 
5 
Therapeutic regimens, expected toxicity, dose modifications ............................................................. 21 
5.1 
Drug information ........................................................................................................................... 21 
5.1.1 Temozolomide ........................................................................................................................... 21 
5.1.1.1 
General information .......................................................................................................... 21 
5.1.1.2 
Packaging, dispensing and storage ................................................................................... 21 
5.1.1.3 
Temozolomide accountability ........................................................................................... 21 
5.2 
Initial dose and schedule ............................................................................................................... 22 
5.2.1 Radiotherapy ............................................................................................................................. 22 
5.2.1.1 
Gross Tumor Volume ......................................................................................................... 22 
5.2.1.2 
Clinical Target Volume ...................................................................................................... 22 
5.2.1.3 
Planning Target Volume .................................................................................................... 23 
5.2.1.4 
Planning procedure ........................................................................................................... 23 
5.2.1.5 
Treatment technique ........................................................................................................ 23 
5.2.1.6 
Acute toxicity and treatment interruption ....................................................................... 23 
5.2.1.7 
Dose prescription, fractionation ....................................................................................... 24 

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5.2.1.8 
Dose Limitation to Critical Structures ............................................................................... 24 
5.2.1.9 
Dose reporting ................................................................................................................... 24 
5.2.1.10 
Potential Late Complications ........................................................................................ 24 
5.2.2 Temozolomide ........................................................................................................................... 24 
5.2.2.1 
Temozolomide randomization possibilities ...................................................................... 24 
5.2.2.2 
Concomitant temozolomide dosing during radiotherapy treatment ............................... 25 
5.2.2.3 
Resting period following radiotherapy treatment ............................................................ 25 
5.2.2.4 
Temozolomide dosing during adjuvant treatment ........................................................... 25 
5.2.3 Summary of initial dosages and schedules ............................................................................... 25 
5.3 
Treatment duration ....................................................................................................................... 25 
5.4 
Withdrawal criteria ....................................................................................................................... 26 
5.5 
Dose and schedule modifications ................................................................................................. 26 
5.5.1 General ...................................................................................................................................... 26 
5.5.2 Radiotherapy ............................................................................................................................. 26 
5.5.3 Temozolomide ........................................................................................................................... 27 
5.5.3.1 
Dose modifications of temozolomide during concomitant treatment ............................. 27 
5.5.3.2 
Dose modification of temozolomide during the adjuvant treatment .............................. 27 
5.6 
Concomitant medications ............................................................................................................. 29 
5.7 
Prohibited medications ................................................................................................................. 29 
6 
Clinical evaluation, laboratory tests and follow-up .............................................................................. 30 
6.1 
Immediately post-surgery: registration step ................................................................................ 30 
6.2 
Before treatment start: randomization step ................................................................................ 30 
6.3 
During radiotherapy treatment ..................................................................................................... 30 
6.3.1 During radiotherapy with or without concomitant temozolomide treatment ........................ 30 
6.3.1.1 
Weekly visits ...................................................................................................................... 31 
6.3.1.2 
Evaluation at week 4 and 6 ............................................................................................... 31 
6.3.1.3 
Evaluation 4 weeks after the end of radiotherapy ........................................................... 31 
6.4 
After the end of radiotherapy ....................................................................................................... 31 
6.4.1 Six monthly disease evaluation after the end of radiotherapy ................................................ 31 
6.4.2 During adjuvant temozolomide treatment ............................................................................... 31 
6.4.2.1 
Prior to each cycle of adjuvant therapy ............................................................................ 32 
6.4.2.2 
Day 21 (+/- 48 hours) of each cycle of adjuvant therapy .................................................. 32 
6.5 
After the documentation of first progression ............................................................................... 32 
6.6 
Summary table .............................................................................................................................. 33 
7 
Criteria of evaluation ............................................................................................................................. 34 

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7.1 
Progression free survival ............................................................................................................... 34 
7.1.1 Schedule of disease evaluation ................................................................................................. 34 
7.1.2 Definition of progression........................................................................................................... 34 
7.1.2.1 
Radiological progression ................................................................................................... 34 
7.1.2.2 
Clinical /neurological progression ..................................................................................... 35 
7.1.2.3 
Considerations in the diagnosis of clinical/neurological progression............................... 35 
7.2 
Neurological deterioration free survival ....................................................................................... 35 
7.3 
Evaluation of cognitive function ................................................................................................... 35 
7.4 
Overall survival .............................................................................................................................. 36 
7.5 
Evaluation of toxicity ..................................................................................................................... 36 
7.5.1 Adverse events and side effects ................................................................................................ 36 
7.5.2 General evaluation of side-effects ............................................................................................ 36 
7.5.3 Serious adverse events .............................................................................................................. 36 
7.5.4 Toxic deaths ............................................................................................................................... 36 
7.5.5 Evaluability of toxicity ............................................................................................................... 36 
8 
Statistical considerations ...................................................................................................................... 37 
8.1 
Statistical design ............................................................................................................................ 37 
8.1.1 Sample size ................................................................................................................................ 37 
8.1.2 Randomization and stratifications ............................................................................................ 38 
8.2 
Statistical analysis plan .................................................................................................................. 38 
8.2.1 Primary and secondary endpoints ............................................................................................ 38 
8.2.1.1 
Overall survival (primary endpoint) .................................................................................. 38 
8.2.1.2 
Progression-free Survival (secondary endpoint) ............................................................... 38 
8.2.1.3 
Neurological deterioration-free survival (secondary endpoint) ....................................... 38 
8.2.1.4 
Toxicity (secondary endpoint) ........................................................................................... 38 
8.2.1.5 
Mini Mental State Examination (MMSE) (secondary endpoint) ....................................... 38 
8.2.2 Analysis populations .................................................................................................................. 39 
8.2.3 Statistical methods .................................................................................................................... 39 
8.2.3.1 
Analyses populations......................................................................................................... 39 
8.2.3.2 
Analyses methods for efficacy endpoints ......................................................................... 39 
8.2.3.3 
Analyses methods for safety endpoints ............................................................................ 39 
8.2.3.3.1 Hematological parameters 
40 
8.2.3.3.2 Biochemical parameters 
40 
8.2.3.3.3 All AEs 
40 
8.2.3.3.4 Related AEs 
40 

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8.2.3.4 
Analysis of MMSE .............................................................................................................. 40 
8.2.3.5 
Quality of Life analysis ....................................................................................................... 40 
8.2.4 Pre-planned sensitivity or exploratory analyses ....................................................................... 41 
8.2.4.1 
Pre-planned sensitivity analyses ....................................................................................... 41 
8.2.4.2 
Pre-planned exploratory analyses ..................................................................................... 41 
8.2.5 Prognostic factor analyses ........................................................................................................ 41 
8.2.6 Data recording and display........................................................................................................ 42 
8.3 
Interim analyses ............................................................................................................................ 42 
8.3.1 Original plan .............................................................................................................................. 42 
8.3.2 New plan.................................................................................................................................... 43 
8.4 
End of study ................................................................................................................................... 44 
9 
Trial Governance and Data Monitoring................................................................................................. 44 
9.1 
Study committees ......................................................................................................................... 44 
9.1.1 Study Management Group (SMG) ............................................................................................. 44 
9.1.2 Study Steering committee (SSC)................................................................................................ 44 
9.1.3 Independent data monitoring committee (IDMC) .................................................................... 44 
9.2 
Data Monitoring ............................................................................................................................ 44 
9.2.1 Monitoring during medical review meetings ............................................................................ 44 
9.2.2 Monitoring by the IDMC............................................................................................................ 45 
10 Quality of life assessment ..................................................................................................................... 45 
10.1 
Rationale / objectives and hypothesis (background literature) ................................................... 45 
10.2 
QL measures .................................................................................................................................. 46 
10.3 
Study design .................................................................................................................................. 46 
10.3.1 
QoL data collection - Timing and where and how ................................................................ 46 
10.3.2 
Compliance ............................................................................................................................ 47 
10.4 
Statistical considerations .............................................................................................................. 47 
10.5 
Additional analysis of the QOL scales as possible prognostic factors ........................................... 48 
11 Translational research ........................................................................................................................... 48 
11.1 
Generalities ................................................................................................................................... 48 
11.2 
Rational.......................................................................................................................................... 49 
11.3 
Goals .............................................................................................................................................. 49 
11.4 
Approaches .................................................................................................................................... 49 
11.5 
Collection of patient material ....................................................................................................... 50 
11.6 
Routing and banking of biologic al patient material ..................................................................... 50 
11.7 
IDH mutations analysis .................................................................................................................. 50 

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12 Result dissemination policy ................................................................................................................... 51 
12.1 
Study disclosure ............................................................................................................................ 51 
12.1.1 
Trial Registration ................................................................................................................... 51 
12.1.2 
Final Analysis Report ............................................................................................................. 51 
12.2 
Publication policy .......................................................................................................................... 51 
12.3 
Data sharing................................................................................................................................... 52 
13 Investigator authorization procedure ................................................................................................... 52 
14 Patient registration and randomization procedure .............................................................................. 53 
14.1 
Registration before molecular testing (step 1) ............................................................................. 53 
14.2 
Blinded MGMT methylation status (Step 2) ................................................................................. 54 
14.3 
Randomization (Step 3) ................................................................................................................. 54 
15 Forms and procedures for collecting data ............................................................................................ 55 
15.1 
Case report forms and schedule for completion .......................................................................... 55 
15.2 
Data flow ....................................................................................................................................... 56 
16 Reporting of Serious Adverse Events .................................................................................................... 56 
16.1 
Definitions ..................................................................................................................................... 56 
16.2 
Exceptions ..................................................................................................................................... 57 
16.3 
Severity assessment ...................................................................................................................... 58 
16.4 
Causality assessment ..................................................................................................................... 58 
16.5 
Expectedness assessment ............................................................................................................. 58 
16.6 
Reporting procedure for investigators .......................................................................................... 59 
16.7 
Reporting to investigators and competent authorities ................................................................ 59 
16.8 
Pregnancy reporting ...................................................................................................................... 60 
17 Quality assurance .................................................................................................................................. 60 
17.1 
Control of data consistency ........................................................................................................... 60 
17.2 
Audits ............................................................................................................................................. 60 
17.3 
External review of histology and molecular diagnosis .................................................................. 61 
17.3.1 
Central review of histology ................................................................................................... 61 
17.3.2 
Central review of molecular diagnosis .................................................................................. 61 
17.3.2.1 
Centers without local 1p/19q testing ........................................................................... 62 
17.3.2.2 
Centers with local 1p/19q testing facilities ................................................................... 62 
17.3.2.3 
Central review for MGMT ............................................................................................. 62 
17.3.3 
Sample requirements and routing ........................................................................................ 62 
17.3.4 
Post randomization tissue studies ........................................................................................ 63 
17.4 
Other central review procedures .................................................................................................. 63 

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17.4.1 
Central review for Imaging .................................................................................................... 63 
17.4.2 
Central review for Quality Assurance in Radiotherapy ......................................................... 63 
17.4.2.1 
Facility Questionnaire ................................................................................................... 63 
17.4.2.2 
Case Review ................................................................................................................... 63 
17.4.2.3 
Complex Dosimetry Check for IMRT ............................................................................. 63 
18 Ethical considerations ........................................................................................................................... 65 
18.1 
Patient protection ......................................................................................................................... 65 
18.2 
Subject identification .................................................................................................................... 65 
18.3 
Informed consent .......................................................................................................................... 65 
19 Administrative responsibilities .............................................................................................................. 66 
19.1 
The study coordinator ................................................................................................................... 66 
19.2 
The EORTC Headquarters .............................................................................................................. 67 
19.3 
The EORTC group ........................................................................................................................... 67 
20 Trial sponsorship and financing ............................................................................................................ 68 
21 Trial insurance ....................................................................................................................................... 68 
  
Table of appendices: 
Appendix A: References ................................................................................................................................ 70 
Appendix B: WHO performance status scale ................................................................................................ 73 
Appendix C: Common Terminology Criteria for Adverse Events .................................................................. 74 
Appendix D: EORTC Quality of Life evaluation: guidelines for administration of questionnaires (Revised 
June 2008) ..................................................................................................................................................... 75 
Appendix E: World Medical Association Declaration of Helsinki .................................................................. 79 
Appendix F: Patient information sheet and Informed consent document for registration in the clinical 
trials including mandatory research on biological material ......................................................................... 83 
Appendix G: Patient information sheet and informed consent document for randomization in the clinical 
trial ................................................................................................................................................................ 84 
Appendix H: Patient information sheet and informed consent document for future and optional research 
on biological material .................................................................................................................................... 85 
Appendix I: Neurocognitive testing for dedicated centers – Side study ...................................................... 86 
Appendix J: Minimum requirements for local 1p/19q diagnostics ............................................................. 100 
Appendix K: Procedures and routing of tumor and blood samples prior to randomization ...................... 101 
Appendix L: Mini-Mental State Examination (MMSE) ................................................................................ 103 
Appendix M: Specific protocol instructions during the COVID-19 crisis ..................................................... 104 
 
 
 

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Protocol summary 
Title of the Study 
Phase III trial on Concurrent and Adjuvant Temozolomide chemotherapy in 
non-1p/19q deleted anaplastic glioma. The CATNON Intergroup trial. 
Objective(s) 
This trial is a follow up study of EORTC 26981 and of EORTC 26951 
addressing the overall strategy of optimizing the treatment in newly 
diagnosed anaplastic glioma patients without combined 1p/19q loss. 
Patients will be randomized immediately after surgery to one of the four 
following therapeutic options:  
Arm 1 : RT alone (and further treatment including chemotherapy at 
progression) 
Arm 2 : RT & concurrent CT 
Arm 3 : RT + adjuvant CT 
Arm 4 : RT & concurrent CT + adjuvant CT  
Twelve months of adjuvant treatment is foreseen. Patients will be 
included based on the 1p/19q status of the tumor. Centers with known 
expertise in 1p/19q testing will be allowed to include patients based on 
local testing, with central review for 1p/19q testing (and histology). For 
sites without access to 1p/19q testing a central facility will be created. 
Methylation status of the MGMT promoter gene will be a stratification 
factor.  
Primary objectives: 
To assess whether concurrent radiotherapy with daily temozolomide 
chemotherapy improves overall survival as compared to no daily 
temozolomide in non-1p/19q deleted anaplastic glioma.  
To assess whether adjuvant temozolomide chemotherapy improves 
survival as compared to no adjuvant temozolomide chemotherapy in non-
1p/19q deleted anaplastic glioma 
Methodology 
Phase III – difference 
Number of patients  
Number planed 
(Statistical design) 
Number analyzed 
This is a 2 by 2 factorial design with Overall Survival as the primary 
endpoint when comparing:  
Patients receiving RT alone or RT + adjuvant TMZ to those receiving RT & 
concurrent TMZ or RT & concurrent TMZ + adjuvant TMZ.  
[Comparison I: test for superiority of the concurrent TMZ chemotherapy] 
Patients receiving RT alone and RT & concurrent TMZ to those receiving RT 
+ adjuvant TMZ or RT & concurrent TMZ + adjuvant TMZ. 
[Comparison II: test for superiority of the adjuvant TMZ chemotherapy] 
For both comparisons, to detect a reduction of the risk of death of 22.5% 
based on a two-sided logrank test, at an overall significance level of 5% 
and a power of 83%, a total of 534 events are needed. With an estimated 
accrual rate of 150 patients per year, a total of 748 patients can be 
recruited in 5 years. A minimum follow-up of 2 ½ years will be needed to 

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observe the events. One interim analysis for efficacy only is planned when 
41% of the events have been observed (219). To perform this interim look 
11 additional events were necessary to preserve the study power.  
Diagnosis and main 
criteria for inclusion 
Histologically confirmed newly diagnosed anaplastic oligodendroglioma, 
anaplastic oligoastrocytoma or anaplastic astrocytoma by local diagnosis 
and absence of combined 1p/19q loss 
Availability of tumor material for central 1p/19q assessment, central 
MGMT promoter methylation assessment and central pathology review 
Previous surgery for a low grade tumor is allowed, provided histological 
confirmation of an anaplastic tumor is present at the time of progression  
WHO performance status 0-2 
Age ≥ 18 years  
Start of radiotherapy within 8 days from randomization 
Start of radiotherapy within 7 weeks (49 days) from surgery 
No prior chemotherapy 
No prior radiotherapy to the brain 
Treatment 
Test product, dose 
and mode of 
administration 
Radiotherapy (arms 1-4) 
Radiotherapy will consist of a conventionally fractionated regimen, 
delivering a total dose of 59.4 Gy in 6.5 weeks, in a once daily schedule of 
1.8 Gy per fraction for a total of 33 fractions. 
Concomitant temozolomide (arms 2 & 4) 
Patients randomized to concomitant temozolomide will receive 
temozolomide continuously at a daily dose of 75 mg/m² during 
radiotherapy. The drug will be administered orally 1 hour before each 
session of radiotherapy during weekdays. During weekends without 
radiotherapy, the drug will be taken in the morning. The dose 
administered will be determined using the body surface area (BSA) 
calculated at the beginning of the concomitant treatment. The daily dose 
will be rounded to the nearest 5 mg. 
Adjuvant temozolomide (arms 3 & 4) 
Patients randomized to adjuvant temozolomide will start adjuvant 
temozolomide after a 4 week resting period after the end of radiotherapy. 
Temozolomide will then be administered orally once a day for 5 
consecutive days (days 1-5). The starting dose for the first cycle will be 150 
mg/m²/day with a single dose escalation to 200mg/m²/day in subsequent 
cycles if no significant toxicity is observed in the first cycle. The dose 
administered will be determined using the BSA calculated at the beginning 
of each treatment cycle. The dose will be rounded to the nearest 5 mg. 

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Duration of 
treatment 
 
Concomitant temozolomide (arms 2 & 4) 
The concomitant temozolomide is scheduled to last for 6.5 weeks 
according to the radiotherapy schedule during which temozolomide will 
be administered on a daily basis for a maximum of 7 weeks in case of 
radiotherapy delays. 
Adjuvant temozolomide (arms 3 & 4) 
One cycle is defined as 28 days and a maximum of 12 cycles will be 
administered. 
Reference therapy, 
dose and mode of 
administration 
Radiotherapy (arm 1-4) 
Radiotherapy will consist of a conventionally fractionated regimen, 
delivering a total dose of 59.4 Gy in 6 weeks 3days, in a once daily 
schedule of 1.8 Gy per fraction for a total of 33 fractions. 
Criteria for 
evaluation 
 
Efficacy 
Overall survival (OS) 
All patients will be followed until death. The duration of survival is the 
time interval between randomization and the date of death due to any 
cause. Patients not reported dead and lost of follow up will be censored 
on the date of their last visit.  
Progression-free survival (PFS) 
Disease progression is defined as radiological or neurological/clinical 
progression (whichever occurs first); progression free survival (PFS) is the 
time interval between the date of randomization and the date of disease 
progression or death whichever occurs first. If neither event has been 
observed, the patient is censored at the date of the last follow up 
examination 
Neurological deterioration free survival 
This study will assess neurological deterioration as a secondary endpoint 
to investigate if the prolongation of progression free survival translates 
into a better preservation of neurological function. Neurological 
deterioration is defined as a decrease in WHO performance status. Quality 
of Life analysis will also be used to assess neurological deterioration free 
progression. 
Safety 
This study will use the International Common Terminology Criteria for 
Adverse Events (CTCAE), version 3.0, for toxicity and adverse event 
reporting. 

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Statistical methods 
For the primary analysis of OS and PFS, two-sided superiority logrank tests 
will be computed at an overall significance level of 5%. 
The Kaplan-Meier technique will be used to obtain estimates of the OS 
and PFS. 
The Cox proportional hazard model will be fitted with the treatment and 
the following adjustment factors: WHO performance status (PS 0 vs >0), 
Age (<=50 vs >50), Presence of 1p loss (Yes vs No), Presence of 
oligodendroglial elements (Yes vs No). The MGMT promoter methylation 
status will be used as a stratification factor. 
Changes in MMSE scores over time will be analyzed. The distributions in 
treatment arms will be compared at each evaluation point using a Chi-
square test for trend. A Bonferroni adjustment of the type I error rate will 
be used to correct for multiple tests. 
Central pathology 
Translational 
research 
Central pathology review will be performed.  
Upfront assessment of 1p/19q LOH is mandatory  
Following registration of the patient as soon as possible after surgery the 
following material must be sent:  
A paraffin embedded tumor sample (preferably a tumor block, otherwise 
30 unstained slides) 
20 ml whole blood collected in an EDTA tube  
the pathology review and 1p/19q review reports  
Following central pathology review, central 1p/19q assessment, MGMT 
promoter methylation status determination and IDH mutation analysis, 
the H&E stained slides will be entered into the EORTC virtual tumor bank.  
Quality of Life 
The main objective of QoL assessment within this clinical trial is to 
determine the impact of no adjuvant chemotherapy versus adjuvant 
therapy until progression for anaplastic glioma on overall health/QoL. 
Based on the recent EORTC study 26981, the hypothesis is that we expect 
no differences between arms using the global QOL scale during treatment, 
but there may be a later benefit to the adjuvant therapy arm if disease 
progression is achieved, thereby leading to a better global QOL. 
 
 
 

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Trial organization 
• This trial is an Intergroup Trial, jointly conducted by several national/international cancer clinical 
research groups in different countries of European Union and third countries.  
• Each participating group is the Sponsor for their participants (unless otherwise agreed). 
• In summary: 
Country 
Recruiting group(s) 
Sponsor  
Canada 
NCIC 
NCIC 
United Kingdom 
MRC 
EORTC 
United States 
RTOG 
RTOG 
Australia/New 
Zealand 
COGNO CTC 
COGNO CTC 
Other countries 
EORTC 
EORTC 
 
• The EORTC is the coordinating group in this trial and therefore centrally manages trial design and 
activation, attribution of duties and responsibilities between participating research groups, data 
collection and quality control of data, statistical analysis and publication. 
• Each participating group / Sponsor locally manages the notification/submission of all necessary 
documents to the Competent Authorities and/or Ethics Committees and gets the confirmation of the 
review by IRB/IEC following the applicable national law. 
• This protocol is to be followed by all participating groups. Chapters 1 to 17 are fully applicable to all 
groups. Chapters 18-21 are specific to the EORTC participants (members of the EORTC covered by the 
sponsorship of the EORTC). All particularities of participation of each individual group are included is 
the Group Specific Appendixes annexed at the end of the protocol.  
• The patient information sheets and informed consent templates (Appendix F, Appendix G, Appendix 
H) are applicable as such only for participants under the sponsorship of the EORTC (participants under 
a different sponsorship should refer to the corresponding Group specific appendix or to their Group). 
• The participation to this trial is only possible through one of the participating clinical cancer research 
groups. For contacts and addresses please refer to the Group Specific Appendix of the group of your 
membership or of your national group (should you have any difficulty in identifying such a group, 
please contact the EORTC Headquarters). 
• Investigators members of several groups participating to the trial should select one of these groups 
for the framework of this trial and to include all patients through this group. In some cases, because 
of the national legal framework the choice may be imposed. For EORTC members all patients will be 
accounted for the membership independently from the group they choose to participate through (see 
EORTC Policy 10). 
• The investigational drug will be supplied by Merck.  
• This is an academic trial with an educational grant support from Merck.  

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1 Background and introduction 
1.1 
Anaplastic glioma 
About 20-30% of all newly diagnosed primary brain tumors in adults are considered to be WHO grade III 
tumors or anaplastic glioma: anaplastic astrocytoma, anaplastic oligoastrocytoma and anaplastic 
oligodendroglioma. Usually, patients who are newly diagnosed with these tumors are treated similarly to 
patients with glioblastoma multiforme, the most malignant primary brain tumor in adults. It is unclear 
whether that assumption is correct. Recent studies show that anaplastic glioma differ both at the clinical 
level and at the molecular level from glioblastoma multiforme (and from grade II tumors). For example, 
an important difference exists between recurrent anaplastic oligodendroglioma, oligoastrocytoma or 
astrocytoma and recurrent glioblastoma multiforme in sensitivity to PCV or temozolomide 
chemotherapy.(Ref. 1, Ref. 2, Ref. 3, Ref. 4, Ref. 5) Genetic analysis has shown that oligodendroglioma 
are characterized by combined loss of 1p/19q which can be found in 60-70% of anaplastic 
oligodendrogliomas but which is much less frequent in anaplastic oligoastrocytoma.(Ref. 6, Ref. 7) In 
particular these 1p/19q loss tumors are now known to be very sensitive to chemotherapy, with virtually 
all tumors responding to PCV chemotherapy.(Ref. 8)  
1.1.1 
Molecular classification of anaplastic glioma 
Because of the sensitivity to chemotherapy of oligodendroglial tumors both the RTOG and EORTC have 
investigated whether these tumors benefit from adjuvant PCV chemotherapy. These studies, EORTC 
study 26951 and its North-American counterpart RTOG 9402, both showed that the addition of 
(neo)adjuvant PCV chemotherapy (consisting of procarbazine, CCNU and vincristine) to 59.4 Gy 
radiotherapy does increase progression free survival (PFS) without improving overall survival in anaplastic 
oligodendroglioma and anaplastic oligoastrocytoma.(Ref. 9, Ref. 10) A major finding of both studies is the 
large difference in prognosis of patients with and without combined 1p/19q loss. In patients with 1p/19q 
loss median survival is well over 6-7 years, but only 2-3 years for patients without 1p/19q loss. The latter 
survival in non-codeleted anaplastic glioma is in line with the survival usually observed in anaplastic 
astrocytoma. Based on these differences in survival and the clear different outcome in anaplastic 
oligodendroglioma with 1p/19q loss, it is no longer rational to treat these patients according to histology 
without taking the genotype of these tumors into account. For this and other current neuro-oncological 
studies it is therefore proposed to classify high grade glioma into glioblastoma multiforme (median 
survival 12-15 months), anaplastic glioma without 1p/19q loss (median survival 2-3 years) and anaplastic 
oligodendroglial tumors with loss of both 1p and 19q (1p/19q co-deleted; median survival more than 6-7 
years). The present study proposal considers the non-1p/19q co-deleted anaplastic glioma. 
1.1.2 
Concomitant and adjuvant temozolomide in anaplastic glioma 
The recent large randomized EORTC study 26981-22981/NCI-C CE3 showed that combined radiotherapy 
and temozolomide chemotherapy provides a superior outcome for patients with newly diagnosed 
glioblastoma as compared to adjuvant treatment with radiotherapy only.(Ref. 11) Correlative studies 
suggest that the benefit of combined alkylating agent chemotherapy and radiotherapy may be limited to 
patients whose tumors have a methylated (and thus silenced) MGMT gene promoter (Ref. 12). It is 
however far from clear that these results can be extrapolated to anaplastic glioma without 1p/19q loss.  
Both toxicity and efficacy issues may be different for anaplastic glioma as compared to glioblastoma 
multiforme. Reviews of old RTOG/ECOG studies suggested a decreased survival in more aggressively 
treated anaplastic astrocytoma patients (Ref. 13). These data were obtained from historical comparisons 
over several trials, so the conclusions should be viewed with caution. Similarly though, in contrast to the 
reported 40-50% response rates to temozolomide if given prior to irradiation in newly diagnosed 

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glioblastoma, trials of pre-irradiation chemotherapy in anaplastic glioma yielded disappointing response 
rates, with only 17% to 30% of patients responding.(Ref. 14, Ref. 15, Ref. 16, Ref. 17) Radiotherapy may 
cause delayed neurological side-effects, in particular a subacute leuko-encephalopathy with mental 
slowing, memory disturbances, gait disorder and micturation problems. It is at present not known 
whether combined modality treatment with radiotherapy and temozolomide increases delayed neuro-
toxicity in patients with longer survival. The study of combined modality treatment in glioblastoma did 
not explore whether this increased late toxicities. Other treatments in which radiotherapy to the brain 
was combined with chemotherapy (e.g., primary CNS lymphoma) do suggest however that there may be 
a real risk. This becomes an even more relevant question in patients with a better prognosis who are at 
risk of developing these toxicities over a longer period of time.  
Thus, it cannot be taken for granted that approaches leading to a better outcome in glioblastoma will 
also provide a superior outcome in anaplastic astrocytoma.  
1.1.3 
The relevance of progression free survival 
Both EORTC study 26951 and RTOG 94-02 showed an increase of progression free survival after adjuvant 
treatment. Many glioma patients deteriorate at the time of progression, and thus prolonging time to 
progression may help to keep patients in a good clinical condition for a longer period. Thus, postponing 
progression in patients with glioma (either low grade or high grade) may have a significant impact on the 
quality of life. This has not yet been investigated however with proper measures in any of the large 
randomized phase III neuro-oncological trials. 
1.1.4 
Further considerations for anaplastic glioma 
Neither the role of adjuvant chemotherapy after radiotherapy nor the role of concurrent chemo-
irradiation has been established in anaplastic glioma. Various surveys among clinicians underline the 
absence of evidence based consensus on how to treat these patients: different institutions have adopted 
various strategies, including radiotherapy only, radiotherapy followed by adjuvant chemotherapy (with a 
variety of regimens), and concurrent chemo-irradiation with or without further adjuvant treatment.  
Moreover, if indeed adjuvant treatment does not increase overall survival in this patient population (as 
suggested by both EORTC 26951 and RTOG 9402), postponing chemotherapeutic treatment until 
recurrence will avoid the continuation of an inactive treatment in unresponsive patients. This would 
shorten initial treatment considerably, and would be an argument to stop treatment at the end of 
irradiation and to withhold further treatment until progression. On the other hand, postponing 
progression by adjuvant treatment may help to keep patients in a better condition.  
Because of significant toxicity of the PCV regimen in EORTC 26951 and RTOG 9402 studies  
(Ref. 9, Ref. 10) and good tolerability of temozolomide overall and in the EORTC 26981 study (Ref. 11), 
temozolomide serves as preferred drug for future trials of radiochemotherapy. 
These considerations and the concern for late toxicities require a prospective trial to examine the role of 
adjuvant and concurrent temozolomide chemotherapy in non-1p/19q co-deleted anaplastic glioma. 
1.2 
Study outline 
The present study will establish whether concurrent and adjuvant temozolomide improves the outcome 
of patients with non-codeleted 1p/19q anaplastic gliomas. Patients will be randomized in a 2 x 2 design to 
radiotherapy (with further treatment including chemotherapy if indicated at the time of progression), 
radiotherapy with concurrent temozolomide, radiotherapy followed by adjuvant temozolomide and 
radiotherapy with concurrent temozolomide followed by adjuvant temozolomide. In view of the large 
impact of methylation of the MGMT promoter gene on the outcome in glioblastoma, patients will be 

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stratified for MGMT status. Molecular diagnostic assessment of both MGMT and 1p/19q status prior to 
the start of radiotherapy is required. Patients will be followed after progression to assess whether the 
initial treatment with temozolomide prolongs time to neurological deterioration. An abbreviated neuro-
psychological test will establish whether initial treatment with temozolomide increases the risk of 
treatment-related cognitive deterioration. 
Patients can be randomized on the basis of either local histological and 1p/19q diagnosis, or on central 
histological and 1p/19q diagnosis. The patients will first be registered to the trial. At this step, for all 
patients, tumor and blood samples must be sent for histology review, 1p/19q analysis and MGMT assay. 
If inclusion is based on central pathology and 1p/19q diagnosis the patient can be randomized into the 
trial once found eligible at central assessment. Centers must decide prior to study activation whether 
they will include patients based on local or on central diagnosis of histology and 1p/19 status. 
2 Objectives of the trial 
2.1 
Primary objectives  
• To assess whether concurrent radiotherapy with daily temozolomide chemotherapy improves overall 
survival as compared to no daily temozolomide in patients with non-1p/19q deleted anaplastic 
glioma.  
• To assess whether adjuvant temozolomide chemotherapy improves survival as compared to no 
adjuvant temozolomide chemotherapy in patients with non-1p/19q deleted anaplastic glioma  
2.2 
Secondary objectives 
• To assess whether concurrent and adjuvant temozolomide treatment prolongs progression free 
survival and neurological deterioration free survival in patients with non-1p/19q deleted anaplastic 
glioma. 
• To assess the safety of concurrent and adjuvant temozolomide in patients with non-1p/19q deleted 
anaplastic glioma, including late effects on cognition. 
• To assess the impact of concurrent and adjuvant temozolomide treatment on the quality of life in 
patients with non-1p/19q deleted anaplastic glioma. 
2.3 
End-points 
2.3.1 
Primary endpoint 
The primary endpoint of the study is overall survival, as measured from the day of randomization. 
2.3.2 
Secondary endpoints 
Secondary endpoints of the study are progression free survival, neurological deterioration free survival, 
quality of life, toxicity, and development of cognitive deterioration. 
3 Patient selection criteria 
All patients are initially registered into the trial as soon as possible after surgery. After this point, material 
must be sent for 1p/19q analysis and MGMT promoter methylation assay. This should again be done as 
soon as possible. Patients can only be randomized into the trial within 8 days from the start of 
radiotherapy; at this time, all baseline requirements for the study must have been fulfilled. 
 
 

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3.1 
At the time of registration  
• Histologically confirmed newly diagnosed anaplastic oligodendroglioma, anaplastic oligoastrocytoma 
or anaplastic astrocytoma by local diagnosis  
• Availability of tumor material for central 1p/19q assessment, central MGMT promoter methylation 
assessment and central pathology review.  
• Previous surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic 
tumor is present at the time of progression  
• WHO performance status 0-2 
• Age ≥ 18 years  
• All patients must use effective contraception if of reproductive potential. Females must not be 
pregnant or breast feeding 
• Absence of known HIV infection, chronic hepatitis B or hepatitis C infection 
• Absence of any other serious medical condition that can interfere with follow-up 
• Absence of any medical condition which could interfere with oral medication intake (e.g., frequent 
vomiting, partial bowel obstruction) 
• No previous other malignancies, except for any previous malignancy which was treated with curative 
intent more than 5 years prior to registration, and except for adequately controlled limited basal cell 
carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix. 
• Absence of any psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule; those conditions should be discussed 
with the patient before registration in the trial 
• No prior chemotherapy (including no treatment with BCNU containing wafers (Gliadel®)  
• No prior radiotherapy to the brain 
• Before patient registration, written informed consent must be obtained, according to ICH/GCP, and 
national/local regulations. 
3.2 
Randomization step 
• The combination of: 
• Histologically confirmed newly diagnosed anaplastic oligodendroglioma, anaplastic 
oligoastrocytoma or anaplastic astrocytoma by local diagnosis 
 
 
AND 
• Absence of combined 1p/19q loss  
 
both of which must have been determined by either local testing or central review  
• Availability of tumor material for central 1p/19q assessment, central MGMT promoter methylation 
assessment and central pathology review 
• WHO performance status 0-2 
• Age ≥ 18 years  
• Previous surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic 
tumor is present at the time of progression  
• Start of radiotherapy within 8 days from randomization 
• Start of radiotherapy within 7 weeks (49 days) from surgery (extra 2 days could be allowed) 
• Patients must be on a stable or decreasing dose of steroids for at least two weeks 
• No prior chemotherapy (including no treatment with BCNU containing wafers (Gliadel®) 
• No prior radiotherapy to the brain 

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• No concomitant treatment with other anti-cancer agents or with any other experimental agent 
• Adequate hematological, renal and hepatic function according to all of the following laboratory values 
(to be performed within 28 days prior to randomization):  
• neutrophils greater or equal to 1.5*109 cells/l 
• platelets greater or equal to 100*109 cells/l 
• bilirubin < 1.5 times upper limit of laboratory normal 
• alkaline phosphatase, ASAT and ALAT <2.5 times upper limit of laboratory normal 
• serum creatinine lower than 1.5 times upper limit of laboratory normal  
• All patients must use effective contraception if of reproductive potential. Females must not be 
pregnant or breast feeding 
• Absence of known HIV infection, chronic hepatitis B or hepatitis C infection 
• Absence of any other serious medical condition that could interfere with follow-up 
• Absence of any medical condition which could interfere with oral medication intake (e.g., frequent 
vomiting, partial bowel obstruction) 
• Absence of any psychological, familial, sociological or geographical condition potentially hampering 
compliance with the study protocol and follow-up schedule. 
• Before patient randomization, written informed consent must be given according to ICH/GCP, and 
national/local regulations. 
• Patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for 
biochemistry are acceptable. 
Important note: All eligibility criteria must be adhered to, in case of deviation discussion with 
Headquarters and study coordinator is mandatory. 
4 Trial Design 
This randomized phase III study investigates the optimal treatment in patients with newly diagnosed 
anaplastic glioma without combined 1p/19q loss. Patients will be randomized after surgery to one of the 
four following therapeutic options:  
Arm 1: Radiotherapy and further treatment including chemotherapy if indicated at progression  
Arm 2: Radiotherapy & concurrent temozolomide  
Arm 3: Radiotherapy + adjuvant temozolomide for 12 cycles  
Arm 4: Radiotherapy & concurrent temozolomide + adjuvant temozolomide for 12 cycles 
For patients randomized to receive adjuvant temozolomide, twelve months of adjuvant treatment is 
foreseen. Patients will be included based on the 1p/19q status of the tumor. Centers with known 
expertise in 1p/19q testing will be allowed to include patients based on their local diagnosis, with central 
review for both the histological diagnosis and 1p/19q testing. For sites without access to 1p/19q testing a 
central facility is available. Methylation status of the MGMT promoter gene will be a stratification factor. 
Clinical follow-up must be continued after the diagnosis of first progression to allow assessment of time 
to neurological deterioration and to assess Quality of Life. 

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† Institution must choose to evaluate 1p/19q LOH locally or use central facility.  
‡ After registration, all material is centrally reviewed for MGMT methylation status.  
* Investigators can’t randomize a patient: 
- If the central facility is used: before the histological diagnosis, diagnosis of no combined 1p/19q LOH has been centrally 
confirmed and the MGMT methylation status (methylated/unmethylated or indeterminate) has been communicated by the 
EORTC Data Center. The randomization is based on the central histological and 1p/19q LOH evaluation.  
- If the local assessment is used: before the MGMT methylation status (methylated/unmethylated or indeterminate) has been 
communicated by the EORTC Data Center. The randomization is based on the local histological and 1p/19q LOH evaluation.  
5 Therapeutic regimens, expected toxicity, dose 
modifications 
5.1 
Drug information 
5.1.1 
Temozolomide 
5.1.1.1 
General information 
Temozolomide is commercially available. 
5.1.1.2 
Packaging, dispensing and storage 
Temozolomide is available as hard gelatin capsules (5mg, 20mg, 100mg, 250mg). 
Temozolomide should be stored between +2°C - +30°C and protected from moisture. 
Temozolomide should be administered in a fasting state at least one hour prior to eating. 
5.1.1.3 
Temozolomide accountability  
The investigator/pharmacist must maintain an accurate record of dispensing of temozolomide in a drug 
accountability ledger, a copy of which must be given to EORTC at the end of the study. An accurate 
record of the date and amount of study drug dispensed to each patient must be available for inspection 
at any time. 
Surgery 
MRI/CT 
Eligibility 
Local 
pathology 
& 1p/19q 
 
 
 
 
 
 
R
1: RT (further trt at 
PD)
2: RT & conc TMZ 
3: RT + adjuv TMZ 
4: RT & conc TMZ  
+ adjuv TMZ 
Registration‡ 
Central facility  
 Central 
pathology  
Central 1p/19q  
l
Max 1 wk 
≈ 2 wks 
4 wks 
Stratification: 
 
Institution 
PS, Age, 1p LOH 
Oligodendroglial elements 
MGMT methylation 
Local facility 
Central MGMT 
methylation*  

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5.2 
Initial dose and schedule 
5.2.1 
Radiotherapy 
Radiotherapy will consist of a conventionally fractionated regimen, delivering a total dose of 59.4 Gy in 
6.5 weeks, in a once daily schedule of 1.8 Gy per fraction for a total of 33 fractions. 
Treatment should start within 7 weeks of surgery and 8 days from randomization 
A single phase treatment volume will be used throughout treatment – a cone-down or boost volume is 
not normally used (other than for shielding organs which have reached a tolerance limit e.g. optic chiasm 
at 55 Gy). 
Whenever possible, target volume definition should be based on magnetic resonance imaging (MRI). 
Image fusion (= co-registration) of the MRI scans and the planning CT scan should be used for target 
volume definition. Centers having the possibility of image co-registration should use this technique for all 
trial patients. The accuracy of image co-registration should remain within < 0.5 cm. Post-operative 
imaging after resection and debulking is preferable. 
CT-based 3-D treatment planning using beam’s-eye-view and the registration of Dose-Volume-
Histograms is mandatory for all centers.  
5.2.1.1 
Gross Tumor Volume 
The Gross Tumor Volume (GTV) is defined by: 
1. 
The entire region of high signal intensity on T2 weighted MRI images or FLAIR sequences 
(corresponding to the hypodense area on CT images). 
Plus 
2.  
The region of enhancement on post-operative CT/MRI if available or the region of enhancement 
on pre-operative CT/MRI if post op imaging is not available (usually contained in 1 above) 
Plus 
3. 
The tumor resection margin (usually contained in the above)  
In some tumors no area of enhancement can be seen and the GTV is defined entirely on the T2 
abnormality.  
In case of complete or subtotal removal, the position of the tumor bed can have shifted, and the GTV 
should take the new position of the abnormalities on the planning CT scan and any post-operative 
imaging into account. Postoperative imaging is not mandatory, and it is acceptable to define GTV based 
on pre-operative scans and a planning CT. 
5.2.1.2 
Clinical Target Volume 
The Clinical Target Volume (CTV) is defined by a 1.5 - 2 cm volumetric expansion of the GTV 
The CTV extends to the contralateral hemisphere only when midline structures such as the corpus 
callosum and the contralateral hemisphere are invaded by tumor. The tentorium and meninges should be 
considered as anatomical borders and therefore a margin of 7-10 mm is sufficient to encompass the 
microscopic spread at these borders.  
Volumetric expansion may also be reduced in areas adjacent to sensitive structures. 

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5.2.1.3 
Planning Target Volume 
The Planning Target Volume (PTV) will take into account uncertainties of planning and setup. This margin 
should be based upon known departmental values, but will usually be of the order of 0.5-0.7 cm. 
All margins should be added using a three-dimensional (3-D) growth algorithm where possible. 
5.2.1.4 
Planning procedure 
Patient either supine or prone depending on site of lesion, in an immobilization device (any fixation 
system with relocation accuracy < 5 mm).  
The use of a Planning CT is mandatory. The use of a contrast medium, a maximum CT slice thickness of 3 
mm in order to obtain good quality of Digitally Reconstructed Radiographs (DRR’s) and margin definition 
is recommended.  
Co-registration of CT and MRI data is strongly recommended for centers having implemented this 
function. For centers not having this possibility, a manual/visual fusion with the MRI shall be done.  
Conventional or virtual simulation is mandatory. Planning with beams-eye-views (BEV’s) of each beam is 
mandatory.  
Use of shielding blocks or a multi-leaf collimator is mandatory.  
Planning should conform to ICRU 50/62 criteria for target volume coverage, dose normalization and 
homogeneity. (Ref. 18)  
5.2.1.5 
Treatment technique 
Treatment must be delivered with a linear accelerator with a minimal nominal beam energy of 4-6 MV. 
The volume should be treated by multiple field technique, all fields treated at each fraction. 
The use of a vertex field is optional. If used it requires either a diagram or photograph of treatment 
position.  
NOTE: the use of a strict vertex field may result in increased dose to the thyroid and whole body!  
Treatment position verification is carried out by at least weekly portal imaging or portal films according 
to the institute’s standards.  
For 3DCRT: The prescription dose is specified and reported at the ICRU reference point as defined in ICRU 
Reports #50 and #62 [ICRU 1993; ICRU 1999].  
For Intensity-modulated RT (IMRT): Treatment with IMRT is allowed provided that conventional 
fractionation and dose prescription according to ICRU #50 and #62 is used. No simultaneous integrated 
boost is allowed. IMRT will be allowed providing sufficient proof of external credentialing is submitted to 
and approved by EORTC QART team. 
Stereotactic radiotherapy, implants, brachytherapy are NOT ALLOWED. 
5.2.1.6 
Acute toxicity and treatment interruption 
Expected acute toxicity of conventional radiotherapy includes headache, fatigue, hair loss, skin reaction, 
sickness sometimes, mucositis (if nasopharynx included), temporary reduced hearing (if ear canal 
included), and temporary loss of taste (if nasopharynx included). 
No dose adjustments are recommended irrespective of length of treatment interruptions. 
Maximum overall treatment time: 7 weeks (theoretical optimal treatment time: 6.5 weeks). 

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Individual reasons for treatment interruption, such as major worsening of neurological or mental status 
or any other medical condition that would preclude the continuation of radiotherapy, and conversely the 
decision to resume radiation therapy after interruption, will be taken on an individual basis by the local 
investigator. 
5.2.1.7 
Dose prescription, fractionation 
Dose prescription and recording will according to ICRU 62-criteria. Dose homogeneity requirements in 
the PTV shall be -5% + 7%. The PTV should be encompassed by the 95% isodose.  
The 90% isodose is acceptable in close proximity to organs-at-risk.  
Total dose: 59.4 Gy; dose per fraction: 1.8 Gy in 33 daily fractions  
5.2.1.8 
Dose Limitation to Critical Structures 
Organs-at-risk to be spared if possible-are: eyes, pituitary gland, optic chiasm, optic nerves, brainstem, 
ear, uninvolved brain areas. 
The optic chiasm, optic nerves and brainstem (= medulla, pons and midbrain) should not receive doses 
higher than 60 Gy. 
The eye balls including the lens and retina should not be included in any direct beam. Maximum dose for 
the lens: < 5 Gy, for the retina: ≤ 36 Gy.  
The normal brain contralateral to the tumor location may not receive > 60% of the total dose. 
5.2.1.9 
Dose reporting 
The isodose distributions will be calculated and printed for documentation in three planes (transverse, 
coronal and sagittal planes) through the isocenter.  
Isodose distributions with marked PTV and isodose lines with the maximum dose, 100%, 95%, 90%, 80%, 
60%, 50%, 40%, 20% of the prescription dose should be reported for a reviewer to judge the adequacy of 
target coverage. 
The following volumes should be calculated and documented in cm3: GTV, CTV, PTV and the total volume 
of the brain tissue (exclusive of PTV) as well as dose volume histograms of PTV and organs-at-risk. 
Weekly portal imaging or portal films will be undertaken for set-up verification 
5.2.1.10 
Potential Late Complications 
Depending on the tumor location and the region to be irradiated, several tissues or organs are potentially 
at risk for late damage, such as cortical brain, brain stem, chiasm, ear (mid or internal) and pituitary 
gland. All efforts should be made during planning to minimize the dose to critical structures. Late 
complications will be recorded according to CTC version 3.0 
5.2.2 
Temozolomide 
5.2.2.1 
Temozolomide randomization possibilities 
Patients can be randomized to a) concomitant radiotherapy and temozolomide, b) adjuvant 
temozolomide, c) both or d) neither (this latter randomization should be understood as temozolomide 
chemotherapy at the time of progression). 

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5.2.2.2 
Concomitant temozolomide dosing during radiotherapy treatment 
Patients randomized to concomitant temozolomide will receive temozolomide continuously at a daily 
dose of 75 mg/m² during radiotherapy. The drug will be administered orally 1 hour before each session of 
radiotherapy during weekdays. During weekends without radiotherapy, the drug will be taken in the 
morning. 
The dose administered will be determined using the body surface area (BSA) calculated at the beginning 
of the concomitant treatment. The daily dose will be rounded to the nearest 5 mg. In case of high value 
of BSA, an upper limit of 2.1 m² is suggested to calculate the dose. Patients should be told to swallow the 
whole capsules in rapid succession without chewing them. If vomiting occurs during the course of the 
treatment, no re-dosing of the patient is allowed before the next scheduled dose.  
5.2.2.3 
Resting period following radiotherapy treatment 
The radiotherapy treatment is followed by a four weeks resting period. 
5.2.2.4 
Temozolomide dosing during adjuvant treatment 
Patients randomized to adjuvant temozolomide will start adjuvant temozolomide after a 4 week resting 
period after the end of radiotherapy. Temozolomide will then be administered orally once a day for 5 
consecutive days (days 1-5). The starting dose for the first cycle will be 150 mg/m²/day with a single dose 
escalation to 200mg/m²/day in subsequent cycles if no significant toxicity is observed in the first cycle. 
One cycle is defined as 28 days and a maximum of 12 cycles will be administered. Treatment can be 
discontinued earlier in case of significant toxicity interfering with further treatment and not responding 
to dose reductions, or at the patient wish. 
The dose administered will be determined using the BSA calculated at the beginning of each treatment 
cycle. The dose will be rounded to the nearest 5 mg. In case of high value of BSA, an upper limit of 2.1 m² 
is suggested to calculate the dose. The exact dose administered should be recorded on the CRF. Each 
daily dose should be given with the least number of capsules. Patients should be instructed to fast 1 hour 
before and one hour after administration of temozolomide. Water is allowed during the fasting period. 
Patients should be told to swallow the whole capsules in rapid succession without chewing them. If 
vomiting occurs during the course of the treatment, no redosing of the patient is allowed before the next 
scheduled dose.  
5.2.3 
Summary of initial dosages and schedules 
 
Concomitant/RT 
Adjuvant/year 1 after RT 
RT 
59.4 Gy, 6.5 weeks, 1.8 
Gy/fractions, 33 fractions 
None 
TMZ 
75mg/m2/day, maximum 7 
weeks 
 
TMZ 
 
150-200mg/m2/day, D1-5, every 28 days 
(maximum 12 cycles) 
5.3 
Treatment duration 
The concomitant temozolomide is scheduled to last for 6.5 weeks according to the radiotherapy schedule 
during which temozolomide will be administered on a daily basis. In case of delays in the delivery of the 
radiotherapy temozolomide will be given for a maximum of 7 weeks. Adjuvant temozolomide treatment 
is planned for a maximum of 12 cycles.  

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Treatment should be administered until documented disease progression, unacceptable toxicity, patient 
refusal or further treatment not in patient’s best interest or until the maximum treatment duration as 
specified in the protocol is reached. 
5.4 
Withdrawal criteria 
Whatever the disease status, treatment will be discontinued in case of 
• Patient refusal 
• Unacceptable toxicity precluding further therapy 
• Best interest of the patient 
Patients discontinuing therapy in the absence of progression should usually not receive other cancer 
treatment before their disease progresses, unless this is clearly not in the interest of the patient. 
After progression, further treatment will be at the discretion of the treating physician. Any anti-cancer 
therapy other than the study regimen described in this protocol will not be considered as part of the 
protocol treatment. 
5.5 
Dose and schedule modifications 
5.5.1 
General 
In the general approach of the management of toxicities it is important to define to which drug the 
toxicities are related. After determination of the origin of the toxicity, the drug specific procedures have 
to be followed. For temozolomide these procedures are described in the following chapters. 
If administration of temozolomide is interrupted due to unacceptable toxicities, the patient must be 
evaluated at least once a week following demonstration of the toxicity until resolution of the toxicity 
which should occur within 14 days allowing for re-treatment according to the guidelines below. These 
evaluations include: a physical examination, vital signs, hematologic tests, serum chemistries, and 
assessment of adverse events and concomitant medications.  
5.5.2 
Radiotherapy 
With the type and site of radiotherapy foreseen in this protocol, interruption due to acute radiation 
toxicity is unlikely. Individual reasons, such as major worsening of neurological or mental status or any 
other medical condition that would preclude the continuation of radiotherapy and conversely the 
decision to resume radiation therapy after interruption will be taken on an individual basis by the local 
investigator.  
For example, cranial irradiation can be withheld for CNS toxicity or ototoxicity greater than or equal to 
grade 3 attributable to radiotherapy. The overall time of interruption and over all time of radiotherapy 
must be recorded. Radiotherapy should not be interrupted due to haematologic toxicities or other 
temozolomide related toxicities. If radiotherapy is interrupted, actions regarding dosing on concomitant 
temozolomide are described hereunder. 
• If the administration of temozolomide (see section 1.1.3) is interrupted, the radiotherapy will proceed 
normally and no catch up days of temozolomide will be given after the end of radiotherapy.  
• The concomitant treatment will last until the end of radiotherapy and may be continued up to a 
maximum of 7 weeks. In case of radiotherapy delays, the duration of the concomitant treatment part 
will never exceeds 49 days. 
• If radiotherapy is definitely stopped for toxicity, concomitant temozolomide is to be continued as per 
protocol unless progression occurs. 

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5.5.3 
Temozolomide 
5.5.3.1 
Dose modifications of temozolomide during concomitant treatment 
During the concomitant treatment, no dose reductions will be made. Delay and discontinuation will be 
decided according to toxicity criteria and the relationship to the study drug as defined hereunder. In case 
of toxicity related to temozolomide, the following actions should be taken. 
Please note that the delay may not exceed 2 weeks, if toxicity is ongoing at that time, concomitant 
treatment with temozolomide must be discontinued. 
Although most of the toxicities caused by temozolomide will be of hematological origin, according to 
previous studies non hematological events could be expected too: nausea and vomiting, fatigue, 
infections, hepatic function disturbances and rash.  
 
Averse Drug Reaction 
Value 
CTCAE Grading  
Version 3.0 
Action 
Haematological  
 
ANC 
≥ 0.5 and < 1.5 x 109/L 
2-3 
Delay TMZ1 until 
normalization  
ANC 
< 0.5 x 109/L 
4 
Stop concomitant TMZ 
Platelets 
≥ 25 and < 75 x 109/L 
2-3 
Delay TMZ until 
normalization 
 
Platelets 
< 25 x 109/L 
4 
Stop concomitant TMZ 
Non haematological 
 
Except fatigue, 
alopecia, nausea and 
vomiting* 
 
2 
Delay TMZ until 
normalization 
 
Except fatigue, nausea 
and vomiting* 
 
3-4 
Stop concomitant TMZ 
* For Nausea and vomiting; please refer to section 5.6. 
1 temozolomide 
5.5.3.2 
Dose modification of temozolomide during the adjuvant treatment 
During adjuvant treatment temozolomide dose interruptions as well as modifications are allowed. 
Dose modifications are based on toxicity observed during prior treatment cycle. If multiple toxicities are 
seen, the dose administered should be based on the dose reduction required for the most severe grade 
of any single toxicity. 
 
 

E O R T C- 2 6 0 5 3 _ 2 2 0 5 4  
PIII tri al of a n a pl astic gli o m a wit h o ut 1 p/ 1 9 q L O H  
V ersi o n 6. 0  
2 8  / 1 0 5 
S e pt e m b er 0 7, 2 0 2 0  
T h e p ossi bl e d os es of t e m oz ol o mi d e ar e as f oll o ws:  
D os e l e v el  
D os e m g/ m²/ d a y ( 1 -5)  
Acti o n  
-1  
1 0 0  
R e d ucti o n if pri or t oxicity  
0  
1 5 0  
St arti n g d os e cycl e 1  
+ 1  
2 0 0  
Esc al at e d d os e as of cycl e 2 i n 
a bs e nc e of t oxicit y  
T h e first cycl e of t e m oz ol o mi d e is a d mi nist er e d at t h e d os e of 1 5 0 m g/ m² d 1 -5. T h e d os e is esc al at e d at 
2 0 0 m g/ m² / d a y as of cycl e 2 i n a bs e nc e of t oxicity.  
•  D os e r e d ucti o n acc or di n g t o w orst a d v ers e dr u g r e acti o n d uri n g pr e vi o us cycl e  
A d v ers e dr u g r e acti o n  V al u e  
C T C A E gr a di n g  
V ersi o n 3. 0  
Acti o n  
H a e m at ol o gic al  
 
 
 
A N C  
a n d  
Pl at el ets  
≥ 1. 5 x 1 0 9/L 
 
≥ LL N  
0 -1  
 
0 
Esc al ati o n t o D os e 
L e v el + 1 ( o nl y at cycl e 
2)  ♣ or c o nti n u e at 
c urr e nt d os e 
A N C  
a n d  
Pl at el ets  
≥ 1 a n d < 1. 5 x 1 0 9/L 
 
≥ 5 0 a n d <LL N  
2  
 
1- 2 
D os e u nc h a n g e d  
A N C  
a n d/ or  
Pl at el ets  
< 1 x 1 0 9/L 
 
< 5 0 x 1 0 9/L 
3 -4  
 
3- 4 
R e d uc e b y 1 d os e l e v el  
N o n h a e m at ol o gic al 
t o xicit y 
 
 
 
E xc e pt f ati g u e, 
al o p eci a, n a us e a a n d 
v o miti n g *  
 
0 -2  
Esc al ati o n t o D os e 
L e v el + 1 ( o nl y at cycl e 
2)  ♣ or c o nti n u e at 
c urr e nt d os e 
E xc e pt f ati g u e, n a us e a 
a n d v o miti n g *  
 
3  
R e d uc e b y 1 d os e l e v el  
E xc e pt f ati g u e, n a us e a 
a n d v o miti n g *  
 
4  
St o p tr e at m e nt  
♣ t h e d os e of t e m oz ol o mi d e m a y o nl y b e i ncr e as e d fr o m 1 5 0 m g/ m²/ d a y t o 2 0 0 m g/ m²/ d a y as of cycl e 2.  
* F or n a us e a a n d v o miti n g, pl e as e s e e s ecti o n 5. 6 . 
A m a xi m u m of 2 d os e r e d ucti o ns  is p er mitt e d. H o w e v er, if t h e s a m e (i n n at ur e a n d s e v erit y) n o n 
h a e m at ol o gic al t oxicit y occ urs at 2 s u bs e q u e nt cycl es d es pit e 1 d os e r e d ucti o n, a s ec o n d d os e r e d ucti o n 
is n ot p er mitt e d a n d t h e p ati e nt s h o ul d st o p t h e tr e at m e nt. N o d os e r e d ucti o ns b el o w 1 0 0 m g/ m 2 ar e 

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allowed, if 100mg/m2 is not tolerated the patient should stop treatment. Once a dose has been reduced, 
no dose re-escalation is allowed. 
• Treatment delay according to worst adverse drug reaction during previous cycle 
Adverse Drug 
Reaction 
Value 
CTCAE Grading 
Version 3.0 
Action 
Haematological 
 
 
 
ANC 
and/or 
Platelets 
< 1.5 x 109/L 
 
< 75 x 109/L 
2-3-4 
 
2-3-4 
Delay up to 2 weeks 
until resolution to at 
least grade 1. If 
unresolved then stop 
Non haematological 
toxicity 
 
 
 
Except fatigue, 
alopecia, nausea and 
vomiting* 
 
2-3 
Delay up to 2 weeks 
until resolution to at 
least grade1. If 
unresolved then stop 
Except fatigue, nausea 
and vomiting* 
 
4 
Stop treatment 
• For nausea and vomiting, please see section 5.6. Summary of initial dose and schedule 
5.6 
Concomitant medications 
• Prophylactic antiemetics will be administered at the discretion of the treating physician. The 
prophylactic use of a 5-HT-3 antagonist is strongly recommended before the adjuvant temozolomide 
administration, especially on day 1-3 and should be taken 1 hour before temozolomide is 
administered. During radiotherapy with concomitant daily dose of temozolomide antiemetic 
prophylaxis is usually not necessary, but may be considered on the first three days. 
• Corticosteroids are administered at the treating physician’s discretion, but the dosage should be kept 
as low as possible. 
• Pneumocystis carinii prophylaxis is mandatory during radiotherapy-daily temozolomide concomitant 
treatment. Corticosteroid therapy and continuous temozolomide therapy induce lymphocytopenia. 
Patients are therefore at an increased risk of opportunistic infections. Therefore a prophylaxis against 
Pneumocystis carinii pneumonia is mandatory. It can be either pentamidine inhalations once every 4 
weeks or trimethoprim-sulfamethoxazole 960 mg 3 times a week. Prophylaxis should be continued 
during the entire concomitant treatment or until patients have recovered from lymphocytopenia to at 
least grade 1. 
5.7 
Prohibited medications 
• No other investigational treatment should be used. 
• No other anti-cancer agents. 
• No growth factors unless it is vital for the patient. 

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6 Clinical evaluation, laboratory tests and follow-up 
6.1 
Immediately post-surgery: registration step 
For the submission of tumor material for pre-randomization 1p/19q analysis (or review) and MGMT 
analysis, all patients must be registered at the EORTC Headquarters as soon as possible, and material 
must be sent as soon as possible, as follows:  
• Submission of paraffin tumor blocks or 30 unstained sections for central pathology review, for 
1p/19q LOH, and for determination of MGMT promoter methylation  
• Submission 20 ml whole blood collected in EDTA tube for assessment of LOH 1p/19q  
6.2 
Before treatment start: randomization step 
All pretreatment physical, neurological and quality of life evaluations should be performed within 2 
weeks of randomization but after the surgical procedure leading to the diagnosis of anaplastic glioma. All 
laboratory evaluations must be carried out within 4 weeks from randomization. The initial assessment of 
disease with MR or CT must be performed between the surgery and the start of radiotherapy, unless 
patients underwent a biopsy only in which case the pre-operative imaging is sufficient (and only a CT for 
radiotherapy planning is required). Radiotherapy and concomitant temozolomide should be started 
within 8 days of randomization. 
The baseline evaluations include: 
• Complete medical history 
• Physical examination including neurological evaluation and vital signs 
• Vital signs, blood pressure, height and weight 
• WHO-ECOG performance status  
• Mini mental status examination (MMSE) 
• Quality of Life C30 and BCM20  
• Corticosteroid intake 
• Complete blood counts: hemoglobin, haematocrit, white blood cells and differential, platelets. 
• Serum chemistry: sodium, potassium, calcium, creatinine, urea, glucose, ASAT, ALAT, total 
bilirubin, alkaline phosphatase, gamma-GT, total protein, LDH.  
• Toxicity according to CTCAE v.3 
• Gadolinium enhanced MRI or contrast enhanced CT scan of the brain  
• Fresh frozen tumor material for translational research (optional) 
• Cognitive exam (dedicated centers only) 
6.3 
During radiotherapy treatment 
6.3.1 
During radiotherapy with or without concomitant temozolomide 
treatment  
Patients are seen on a weekly basis. A more detailed evaluation will take place at week 4, week 6 (= end 
of radiotherapy) and 4 weeks after the end of radiotherapy. Patients treated with temozolomide during 
radiotherapy require monitoring for side-effects, particularly hematotoxicity. 
 
 

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6.3.1.1 
Weekly visits 
• Physical examination including vital signs  
• Complete blood count (temozolomide patients only) 
• Toxicity according to CTCAE v.3 
6.3.1.2 
Evaluation at week 4 and 6 
• Physical examination including vital signs and neurological evaluation 
• WHO-ECOG performance status  
• Toxicity according to CTCAE v.3 
• Complete blood count, all serum chemistries including LDH (temozolomide patients only) 
• Corticosteroids intake  
6.3.1.3 
Evaluation 4 weeks after the end of radiotherapy 
• Physical examination including vital signs, and neurological evaluation 
• Corticosteroid intake 
• MMSE  
• Quality of Life C30 and BCM20 
• WHO-ECOG performance status  
• Toxicity according to CTCAE v.3 
• Complete blood count, all serum chemistries  
• Gd-enhanced MRI or contrast CT scan of the brain 
• Corticosteroid intake 
6.4 
After the end of radiotherapy 
Patients are followed every six months for disease assessment; in addition patients randomized to 
receive adjuvant temozolomide are followed every four weeks prior to the start of the next cycle of 
temozolomide. 
6.4.1 
Six monthly disease evaluation after the end of radiotherapy 
All patients would have six monthly disease and status assessment after the end of radiotherapy. 
• Physical examination including neurological evaluation 
• Corticosteroid intake 
• MMSE 
• Quality of Life C30 and BCM20  
• WHO-ECOG performance status  
• Toxicity according to CTCAE v.3 
• Gd-enhanced MRI or contrast CT scan of the brain 
• Cognitive exam; dedicated centers only, to be carried out yearly after the start of radiotherapy (e.g., 
12 months, 24 months, 36 months etc) 
6.4.2 
During adjuvant temozolomide treatment  
Patients randomized to adjuvant temozolomide will receive twelve cycles of adjuvant temozolomide, 
unless treatment needs to be discontinued earlier. In addition to the disease assessments, patients will 
be followed during this phase as indicated hereunder: 
 
 

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6.4.2.1 
Prior to each cycle of adjuvant therapy 
• Physical examination including vital signs 
• WHO-ECOG performance status 
• Toxicity according to CTCAE v.3 
• Complete blood count, all serum chemistries  
6.4.2.2 
Day 21 (+/- 48 hours) of each cycle of adjuvant therapy 
This is only needed in cycle 1 and in cycle 2 if the daily dosage is increased to 200 mg/m2, or in case 
significant hematological toxicity was observed in the prior cycle: 
• Complete blood count 
6.5 
After the documentation of first progression 
The patient must be followed every six months, in particular for performance status, quality of life, 
cognition and for documentation of further treatments.  
• Physical examination including neurological evaluation 
• Corticosteroid intake 
• MMSE  
• Quality of Life C30 and BCM20  
• WHO-ECOG performance status  
• Documentation of further treatments 
All patients will be followed until death. 
 
 

E O R T C- 2 6 0 5 3 _ 2 2 0 5 4  
PIII tri al of a n a pl astic gli o m a wit h o ut 1 p/ 1 9 q L O H  
V ersi o n 6. 0  
3 3  / 1 0 5 
S e pt e m b er 0 7, 2 0 2 0  
6. 6  
S u m m a r y t a bl e  
 
B as eli n e  
D uri n g r a di ot h er a p y  
w/ w o C o nc o mit a nt 
tr e at m e nt 
4 
w e e ks 
aft er 
R T X  
F oll o w u p  
Wit h or wit h o ut a dj u v a nt 
t e m oz ol o mi d e 
Aft er first 
pr o gr essi o n  
E v er y 6 
m o nt hs  
 
At 
r e gistr a-
ti o n 
Wit hi n 
1 4 -2 8 
d a ys 
pri or t o 
r a n d o m. 
W e e kl y  
W ks 4 
a n d 6  
 
A dj u v a nt 
tr e at m e nt 
( b ef. e ac h 
c y)♣ 
Dis e as e 
/ A d v ers e 
E v e nts 
ass ess m e nt 
e v er y 6 
m o nt hs  
M e dic al 
hist or y  
 
♦ 
 
 
 
 
 
 
P h ys. E x a m. 
Vit al si g ns  
 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
N e ur ol o gic al 
E x a m  
 
♦ 
 
♦ 
♦ 
 
♦ 
♦ 
W H O -E C O G P S  
 
♦ 
 
♦ 
♦ 
♦ 
♦ 
♦ 
Q OL 
q u esti o n n air e  
 
♦ 
 
 
♦ 
 
♦ 
♦ 
M M S E  
 
♦ 
 
 
♦ 
 
♦ 
♦ 
H a e m at ol o g y  
 
♦ 
♣ 
♣ 
♦ 
♦♪ 
 
 
S er u m 
c h e mistr y # 
 
♦ 
 
♣ 
♦ 
♦ 
 
 
T o xicit y  
 
♦ 
♦ 
♦ 
♦ 
♦ 
♦ 
 
Br ai n I m a gi n g  
 
♦( £) 
 
 
♦ 
 
♦ 
 
C ortic oi d 
i nt a k e 
 
♦ 
 
♦ 
♦ 
 
♦ 
♦ 
P ar affi n bl oc ks  
♦ 
 
 
 
 
 
 
 
Fr oz e n 
m at eri al 
 
∞ 
 
 
 
 
 
 
Bl o o d s a m pl es 
f or L O H 1 p/ 1 9 q 
♦ 
 
 
 
 
 
 
 
C o g niti v e e x a m  
 
∞*  
 
 
 
 
 
 
# s er u m c h e mistr y: el ectr ol yt es, tr a ns a mi n as es, g a m m a -G T, al k al. p h os p h., cr e ati ni n e, L D H, gl uc os e  
♦ m a n d at or y   
 
♣ m a n d at or y o nl y f or t e m oz ol o mi d e tr e at e d p ati e nts  
♪ t o b e r e p e at e d at d a y 2 1 of t h e fir st cy cl e of a dj u va nt t e m o zol o mi d e; a n d i n ca se t h e d o sa g e i n t h e se co n d cy cl e i s i n cr e a se d; 
a n d i n c as e of si g nific a nt h e m at ol o gic al t oxicit y d uri n g t h e pr evi o us c ycl e  
∞ o pti o n al tr a nsl ati o n al r es e arc h, d e dic at e d c e nt ers o nl y; * at b as eli n e a n d at y e arl y i nt er v als  
( £) T h e i niti al ass ess m e nt of dis e as e wit h M R or C T m ust b e p erf or m e d b et w e e n t h e s ur g er y a n d t h e st art of r a di ot h er a p y, 
u nl ess p ati e nts u n d er w e nt a bi o psy o nl y i n w hic h c as e t h e pr e -o p er ati v e i m a gi n g is s uffici e nt ( a n d o nl y a C T f or r a di ot h er a p y 
pl a n ni n g is r e q uir e d).  

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7 Criteria of evaluation 
7.1 
Progression free survival 
Disease progression is defined as radiological or neurological/clinical progression (whichever occurs first); 
progression free survival (PFS) is the time interval between the date of randomization and the date of 
disease progression or death whichever occurs first. If neither event has been observed, the patient is 
censored at the date of the last follow up examination. 
PFS will be assessed following the target lesion(s) as defined hereunder. 
7.1.1 
Schedule of disease evaluation 
The initial assessment of disease (including MRI or CT) must be performed between the surgery and the 
start of radiotherapy, unless patients underwent a biopsy only in which case the pre-operative imaging is 
sufficient. 
Follow-up assessments (including MRI or CT) will be performed as described in chapter 6 here above until 
disease progression (even after treatment discontinuation), or until the start of another treatment. 
The use of MRI is strongly recommended.  
7.1.2 
Definition of progression 
Special attention should be given so as to avoid labeling progressive enhancement or edema which 
develops immediately after the end of radiotherapy as tumor progression. Pseudo-progression within the 
first three months from completion of radiotherapy is recognized to occur. (Ref. 19) Such pseudo-
progression may continue for months, and may be accompanied by clinical signs and symptoms. 
Therefore, only in exceptional cases should the adjuvant treatment be discontinued or cancelled within 3 
months of radiotherapy. In addition, surgery may cause increased contrast uptake, which should be 
differentiated from tumor progression. The clinical follow-up must dictate how the initial progression of 
the lesion should be labeled. If the course of events shows that true progression indeed occurred, the 
date of the first increase is to be considered as the date of progression. The study coordinator may be 
contacted for further discussions on a case by case basis.  
7.1.2.1 
Radiological progression 
For follow-up it is required that the patients are followed with the same type of imaging throughout the 
whole study. The lesion –whether contrast enhancing or not- must be measured in the two largest 
perpendicular diameters, the area is defined as the product of these two diameters. 
• Increase of contrast enhancing area on MRI or CT scans of more than 25% as measured by two 
perpendicular diameters compared to the smallest measurements ever recorded for the same lesion 
by the same technique. 
• The appearance of new lesions with or without contrast enhancement 
• In case of predominantly non-enhancing tumors: an increase of 25% in bi-dimensional perpendicular 
product of signal hyperintensity area on MRI T2 weighted images or FLAIR images, or area with 
hypodensity on CT scan 
If there is radiological evidence of progression only before the first cycle of adjuvant treatment, patients 
may stop radiotherapy but should be continuing the adjuvant treatment. Such cases will be reviewed. 
 
 

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7.1.2.2 
Clinical /neurological progression 
Clinical/neurological progression is defined as the presence of the following conditions:  
• decrease in WHO performance status 
• for patients with baseline WHO performance status 0: deterioration to WHO performance status 
2 or worse for which no other explanation is present  
• for patients with baseline WHO performance status 1 or 2: deterioration to WHO performance 
status 3 or worse for which no other explanation is present 
• deterioration of neurological functions  
• appearance of signs/symptoms of increased intracranial pressure (headache, nausea and vomiting 
without other explanations) 
• and/or start of corticosteroid or increase of corticosteroid dosage by 50% for control of neurological 
signs and symptoms 
7.1.2.3 
Considerations in the diagnosis of clinical/neurological progression 
At all times in case of clinical/neurological progression, radiological confirmation of the progression is 
recommended. 
In case no clear progression is visible as compared to recent neuro-imaging procedures older images 
must be used for comparison to detect progression.  
If no clear progression is visible on neuro-imaging other explanations for the deterioration must be 
sought (e.g., anticonvulsant medication, metabolic disturbances) 
7.2 
Neurological deterioration free survival 
This study will assess neurological deterioration as a secondary endpoint to investigate if the 
prolongation of progression free survival translates into a better preservation of neurological function. 
Neurological deterioration is defined as a decrease in WHO performance status as follows:  
• decrease in WHO performance status 
• for patients with baseline WHO performance status 0: deterioration to WHO performance status 
2 or worse for which no other explanation is present, and which is maintained for at least three 
months 
• for patients with baseline WHO performance status 1 or 2: deterioration to WHO performance 
status 3 or worse for which no other explanation is present and which is maintained for at least 
three months 
The date of neurological deterioration will be the first date the persistent decrease in performance status 
was diagnosed. Neurological deterioration free progression is the time interval between the date of 
randomization and the date of neurological deterioration or death whichever occurs first. If neither event 
has been observed, the patient is censored at the date of the last follow up examination.  
7.3 
Evaluation of cognitive function 
Short cognitive screening with the Mini-Mental State Examination (MMSE) will take place at 
randomization, 4 weeks after radiotherapy and then at every scheduled follow-up visit as indicated in 
chapter 6. This 30-point test includes questions on orientation to time and place, registration, attention, 
calculations, recall, language, and visual construction. (See Appendix L) 

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Additional more comprehensive neurocognitive testing will be performed at dedicated centers only, as a 
side study to this protocol. (See Appendix I) 
7.4 
Overall survival 
All patients will be followed until death. The duration of survival is the time interval between 
randomization and the date of death due to any cause. Patients not reported dead or lost to follow up 
will be censored at the date of the last follow up examination. 
7.5 
Evaluation of toxicity 
7.5.1 
Adverse events and side effects 
All adverse events will be recorded on the case report forms; the investigator will decide if those events 
are drug related (unrelated, likely related, not assessable) and his decision will be recorded on the forms 
for all adverse events. 
Adverse events not drug related (i.e. reported as unrelated) will not be considered as side effects or 
toxicity. 
7.5.2 
General evaluation of side-effects 
This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 
3.0, for toxicity and adverse event reporting. A copy of the CTCAE can be accessed from the CTEP home 
page (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf ). A link to 
this page is provided on the EORTC web site http://www.eortc.org/; if the location is moved to another 
site, this link will be updated. Investigators who do not have any access to Internet can contact the 
EORTC Headquarters to receive a copy by mail. 
Hematological toxicity will be assessed on the basis of blood counts as indicated in chapter 6. The nadir 
count will be assessed for each cycle of therapy, and graded according to the International CTCAE v3.  
Non-hematological acute side effects will be assessed and reported separately for each cycle of therapy, 
and graded according to the International CTCAE v3. 
7.5.3 
Serious adverse events 
Serious adverse events are defined by the Good Clinical Practice Guideline. 
SERIOUS ADVERSE EVENTS SHOULD BE IMMEDIATELY REPORTED 
ACCORDING TO THE PROCEDURE DETAILED IN THIS PROTOCOL (see chapter on Reporting adverse 
events) 
7.5.4 
Toxic deaths 
Toxic death is defined as death due to toxicity. This must be reported on the summary form: the cause of 
death must be reported as "toxicity". 
The evaluation of toxic deaths is independent of the evaluation of activity (patients can die from toxicity 
after a complete assessment of the effect of therapy). 
7.5.5 
Evaluability of toxicity 
All patients receiving treatment will be considered evaluable for toxicity. 

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8 Statistical considerations 
8.1 
Statistical design 
8.1.1 
Sample size 
This is a 2 by 2 factorial design with Overall Survival as the primary endpoint when comparing:  
• Patients receiving RT alone or RT + adjuvant TMZ to those receiving RT & concurrent TMZ or RT & 
concurrent TMZ + adjuvant TMZ.  
 
 
[Question I: test for superiority of the concurrent TMZ chemotherapy] 
• Patients receiving RT alone and RT & concurrent TMZ to those receiving RT + adjuvant TMZ or RT & 
concurrent TMZ + adjuvant TMZ. 
 
 
[Question II: test for superiority of the adjuvant TMZ chemotherapy] 
The hypotheses are the following: 
• In the EORTC trial 26951 for Anaplastic Oligodendroglioma and Oligoastrocytoma tumors, patients 
with no combined 1p/19q LOH treated by RT alone had a median survival of 24 months. In the EORTC 
trial 26882 for Anaplastic Astrocytoma, patients treated by RT alone had a median survival of 24 
months. 
• No interaction is anticipated between the concurrent and adjuvant temozolomide treatment that are 
assumed to contribute equally to the survival improvement. 
• In the EORTC trial 26981, comparing RT & Concurrent TMZ + adjuvant to RT alone, the estimated 
Hazard Ratio was 0.63 and its 95% Confidence Interval [0.52-0.75].  
The following table summarizes the statistical parameters of the design. A Hazard Ratio (HR) of 0.775 is 
assumed for both questions.  
RT 
No adjuv CT 
(median OS) 
Adjuv CT 
(median OS) 
Question I 
Median OS 
HR 
No conc CT 
24 m 
31 m 
(24+31)/2=27.
5 
 
0.775 
Conc CT 
31 m 
40 m 
(31+40)/2=35.
5 
Question 
II 
Median OS 
27.5 
35.5 
 
HR 
0.775 
For both questions, to detect a reduction of the risk of death of 22.5%, based on a two-sided logrank test, 
at an overall significance level of 5% and a power of 83%, a total of 534 events are needed. With an 
estimated accrual rate of 150 patients per year, a total of 748 patients should be recruited within 
approximately 5 years. A minimum follow-up of 2 ½ years will be needed to observe the required number 
of events. One interim analysis for efficacy is planned when 41% of the events have been observed (219). 
To perform this interim look, 11 additional events are necessary. Power of the trial was slightly increased 
in order to compensate for the loss of information due to patients dropping out before starting the 
adjuvant treatment. It is estimated that 10% of the patients will fail during or within the month following 
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After evaluation of the first 183 patients entered, it appeared that the rate of patients not randomized 
was underestimated (45% vs 10%). The targeted registration sample size was re-estimated to 
approximately 1360. Recruitment will be continued till the planned 748 patients can be randomized.  
8.1.2 
Randomization and stratifications 
Patients will be centrally randomized (for practical details, see chapter on registration / randomization 
procedure). A minimization technique will be used for random treatment allocation stratifying by: 
• Institution,  
• WHO Performance Status (0 vs >0),  
• Age (≤50 vs >50),  
• The presence of 1p LOH only (yes vs no) ,  
• The presence of oligodendroglial elements (yes vs no) and  
• MGMT promoter methylation status (methylated vs unmethylated vs indeterminate).  
8.2 
Statistical analysis plan 
8.2.1 
Primary and secondary endpoints 
8.2.1.1 
Overall survival (primary endpoint) 
Overall Survival (OS) is calculated from the date of randomization up to the date of death (any cause). For 
patients still alive at the time of analysis, OS will be censored at last follow-up visit date. 
8.2.1.2 
Progression-free Survival (secondary endpoint) 
The Progression-free Survival (PFS) is calculated from the date of randomization up to the date of first 
progression or death (any cause) whichever comes first. In case a patient is still alive and without 
progression at the last follow up visit date, PFS will be censored at the date of last follow up visit date. 
8.2.1.3 
Neurological deterioration-free survival (secondary endpoint) 
The neurological deterioration-free survival (NPFS) is calculated from the date of randomization up to the 
date of first neurological deterioration (see section 7.2) or death (any cause) whichever comes first. In 
case a patient is still alive and without neurological deterioration at the last date of assessment of the 
WHO performance status, NPFS will be censored at that date.  
8.2.1.4 
Toxicity (secondary endpoint) 
The assessment of safety will be based on the frequency of Adverse Events graded according to the NCI-
CTCAE version 3.0 scoring system.  
8.2.1.5 
Mini Mental State Examination (MMSE) (secondary endpoint) 
The Mini Mental State Examination (MMSE) is a brief, standardized tool to grade patients’ cognitive 
function. It is an 11-question measure that tests five areas of cognitive function: orientation, registration, 
attention and calculation, recall, and language. The maximum score is 30. Since its creation in 1975 by 
Folstein et al (Ref. 20), the MMSE has been validated and extensively used in both clinical practice and 
research. Following Tangalos et al. (Ref. 21) and as previously used by Brown et al (Ref. 22) a decline of 
more than 3 points in the MMSE score will be considered to represent clinically significant deterioration. 
Following Brown et al, the patient’s cognitive function will be considered ‘impaired’ if the MMSE score is 
26 or less and ‘normal’ if it is 27 or more. MMSE questionnaire can be found in Appendix L.  

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8.2.2 
Analysis populations 
• Intention-to-treat population: All randomized patients will be analyzed in the arm they were allocated 
by randomization. 
• Per protocol population: All patients who are eligible (including 1p/19q LOH status at central review) 
and have started their allocated treatment (i.e. RT started in all arms). 
• Safety population: All patients who have started their allocated treatment (i.e. RT started in all arms). 
The safety of patients excluded from the safety population is separately reported.  
A patient will be considered to be eligible if he/she did not have any major deviations from the patient 
entry criteria listed in chapter 3 of the protocol. Eligibility will be assessed by the Study Coordinator 
based on the review of each patient file. 
8.2.3 
Statistical methods 
8.2.3.1 
Analyses populations 
All the analyses of the efficacy endpoints (overall survival and progression-free survival) will be 
performed in the intention-to-treat population. 
All the analyses of the safety endpoints will be performed in the safety population.  
8.2.3.2 
Analyses methods for efficacy endpoints 
For the primary analysis of overall survival and progression-free survival, the Cox proportional hazards 
model will be fitted with a question indicator variable (one for each question, I and II) and adjusted by 
the stratification factors at randomization. For overall survival the nominal significance level to be used at 
the interim look and final analysis is described in section 8.3 below.  
In the final report, important secondary analyses of overall survival will be 1) the Cox models with 
adjustment of the questions by MGMT promoter methylation status after randomization and the other 
stratification factors. 2) the Cox models with adjustment of the questions by IDH1 mutation status (in 
replacement of MGMT promoter methylation status ) and the other stratification factors. Significance 
level used for these two secondary analyses is the same as for the primary analysis. All analyses of 
progression free survival will be performed at a 5% significance. 
The Kaplan-Meier technique will be used to obtain estimates of the overall survival and progression-free 
survival. The hazard ratios will be estimated with their 95% confidence intervals. Medians will be 
presented with 95% confidence interval provided by the Reflected Method (Ref. 23). 5 year survival and 
progression-free survival rates will be presented with 95% confidence interval calculated by Greenwood 
formula’s estimation of the standard deviation.  
8.2.3.3 
Analyses methods for safety endpoints 
The safety analyses will be presented overall and by period as defined below:  
• The baseline (BL) period will include all information recorded up to the randomization date. 
• The radiation therapy (RT) or chemo/radiation period (RT&TMZ) will start on the day the radiation 
therapy is first given and end the day of the last administration of radiation therapy treatment plus 28 
days.  
• The adjuvant chemotherapy period (RT+TMZ) will start 29 days after the last dose of radiation 
therapy treatment and end-up 27 days after the first day of administration of the last cycle of 
adjuvant chemotherapy.  
• The follow-up period (FUP) will start 29 days after the last dose of radiation therapy treatment or 28 
days after the first day of administration of the last cycle of adjuvant chemotherapy. 

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The safety assessments include hematological toxicity, laboratory measurements and adverse events. 
Only the safety assessments performed before progression or within 7 days of progression and before 
start of any further anti-cancer therapy will be included in the analysis.  
8.2.3.3.1 
Hematological parameters 
For the whole treatment period, the worst value of each hematological parameter will be calculated for 
each patient. The worst value of each parameter will then be coded and the frequency of each category 
will be tabulated. A table with grade 3 or 4 rates will be provided.  
8.2.3.3.2 
Biochemical parameters 
For the whole treatment period, the worst value of each biochemical parameter will be calculated for 
each patient. The worst value of each parameter will then be coded and the frequency of each category 
will be tabulated. A table with grade 3 or 4 rates will be provided.  
8.2.3.3.3 
All AEs  
The worst grade of each AE item will be calculated as the maximum grade reported regardless of 
seriousness or relationship for that item over the whole treatment period. The frequency of the worst 
grade of each AE item will be tabulated. A table with grade 3 or 4 rates will be provided.  
8.2.3.3.4 
Related AEs  
The worst grade of each AE item will be calculated as the maximum grade reported as likely related for 
that item over the whole treatment period. The frequency of the worst grade of each AE item will be 
tabulated. A table with grade 3 or 4 rates will be provided.  
There will be no formal comparison of safety endpoints. No p-value will be carried out. 
Baseline AE grades will not be accounted for in any AE analyses. 
8.2.3.4 
Analysis of MMSE 
The distribution of the MMSE at each time point of evaluation (see chapter 6) will be described on the 
four treatment arms separately using means and their associated standard error (a longitudinal plot will 
be considered). Median and range will also be computed. 
Box-plots will be used to represent MMSE score distribution at baseline and at key time-points of 
evaluation (e.g. Baseline, 4 weeks of radiotherapy, at every 3 monthly visit where form compliance is 
sufficient). The proportion of patients with ‘normal’ and ‘impaired’ MMSE score will also be displayed.  
Similarly to Brown et al. the changes in MMSE scores over time will be summarized in the four treatment 
groups by the proportion of patients with significant increase (> plus 3 points), stable (- 3 points to + 3 
points) or significant decrease (> minus 3 points) of the MMSE score at the key time points of evaluation. 
For both questions (I and II), the distributions will be compared at each evaluation point using a Chi-
square test for trend. A Bonferroni adjustment of the type I error rate will be used to correct for multiple 
testing. 
8.2.3.5 
Quality of Life analysis 
See chapter 10. 

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8.2.4 
Pre-planned sensitivity or exploratory analyses 
8.2.4.1 
Pre-planned sensitivity analyses 
If the percentage of patients ineligible and/or who did not start allocated treatment is superior to 10%, 
sensitivity overall survival and progression-free survival analyses will be performed by fitting the Cox 
proportional hazard with a question indicator variable (one for each question, I and II) and adjusted by 
the stratification factors at randomization in the per protocol population.  
8.2.4.2 
Pre-planned exploratory analyses 
In addition to the questions, pairwise comparisons of overall survival and progression-free survival 
between the three chemotherapy arms and the radiotherapy alone arm will be performed.  
All comparisons will also be performed in each stratum of the following covariates: MGMT promoter 
methylation, 1p and 19q LOH and histological diagnosis. Factor or treatment by covariate interaction 
tests will be computed. Hazard Ratios with 99% confidence intervals will be tabulated. Forest Plots will be 
presented.  
The distribution of MGMT promoter methylation status, 1p and 19q LOH in each histological diagnosis 
will be presented.  
8.2.5 
Prognostic factor analyses 
Prognostic factor (PF) analyses for overall survival are prospectively planned. The main PF analysis will 
include: both questions (I and II), clinical covariates (WHO Performance Status, Age, Extent of Surgery, 
Tumor location, Previous surgery for Low Grade Glioma), Presence of oligodendroglial component, 
1p/19q LOH status and MGMT promoter methylation status, histopathology parameters and biomarkers 
available at the time of analyses. 
In the univariate stage, depending on its scale, each question and covariate will be screened by an 
appropriate two-sided logrank test (heterogeneity or trend). Kaplan-Meier curves will be computed. The 
Peto’ interaction test will be computed between questions and between questions and covariates. Main 
effects and interactions with p<0.15 will be considered for inclusion into the multivariate modeling stage. 
If an interaction is detected the main effects and interaction term will be included in the multivariate 
models. Variables will be included with their full categorization, no regrouping or selection of categories 
is allowed. 
All selected covariates will be included into a multivariate Cox proportional hazards model. Both the 
automatic backward and stepwise selection method (significance to enter and/or stay in the model at 
0.05) will be tested. The differences between the two selection methods will be documented. 
Nevertheless, in case of discrepancies, the selection of main effects and interactions provided by the 
stepwise selection method will be considered for the final model. As an internal validation, the bootstrap 
resampling technique will be used to estimate the probability of inclusion of each main effect or 
interaction term in Cox proportional hazards models with stepwise selection at 5% significance and 
identified the 10 models with the variables selected with the highest frequency. Only main effects or 
interactions with more than 60% probability of inclusion will be included in the final model.  
If the final model of the main PF analysis includes interactions, additional models might be fitted in each 
question and/or chemotherapy arm separately applying the methodology described above.  
The calibration, discrimination ability (Harrell’s C-index) and Akaike’s criteria (AIC) of final models will be 
estimated. Bootstrap technique will be used to correct parameters for “optimism” (Ref. 25).  

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Nomograms estimating individual patient’s risk of progression or death before starting treatment and to 
predict medians and 2 years probabilities (other relevant endpoints might be considered) will be 
developed.  
Proportional hazard assumptions will be checked by plotting the scale Schoenfeld residuals  
(Ref. 24) and by time-by-covariate interactions. If the data clearly do no follow proportional hazards, 
medical explanations should be identified and statistical solutions should be discussed with EORTC 
Applied Statistical Research group on non-proportional hazards models.  
These analyses might be completed by analyses based on new techniques or methods available by the 
time of PF analyses.  
8.2.6 
Data recording and display 
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical variables by the 
levels of the variables as they appear on the CRF (with %). Categories with a text field specification will be 
tabulated as categories and then supplemented by a listing with the following information for the 
patients fulfilling the condition for the specification (patient id, institution, treatment group, value of the 
item and text field contents). 
Dates relating to events prior to entry will be presented as the delay in days (or weeks, months, or years) 
between the past event and the date of entry (date of randomization – date of past event + 1) and 
presented using the median and range. For example, on the randomization checklist, the date of last 
administration of prior treatment (or the date of first diagnosis of the cancer) will be presented as the 
time elapsed (in days, weeks, months or years, as appropriate) since the day of the last administration 
and the date of entry on study (date of randomization – last administration/diagnosis +1). Other delays 
(e.g. re-treatment delays) are presented as continuous variables using the median and range. 
Continuous variables for which a coding system exists (such as for laboratory data) will be recoded into 
categories (for adverse events, the grading scale specified in the protocol will be used). Whenever no 
specific scale exists, lab data will be categorized based on the normal range: for example, below the 
lower normal limit (when appropriate), within the normal range, above the upper normal limit (UNL) and 
the degree to which it is above the UNL (for example > 2.5 x UNL, > 5 x UNL, > 10 x UNL). For laboratory 
data, the nadir is generally displayed. The nadir in a given cycle is the lowest laboratory value in that 
cycle; the overall nadir for a patient is the lowest laboratory value among all cycles. 
Other continuous variables (for example age, dose …) will be presented using the median and range 
(minimum, maximum).  
If appropriate, continuous data may also be presented in categories. 
8.3 
Interim analyses 
8.3.1 
Original plan 
One formal interim analysis is planned for both questions when 219 events (41%) have been observed. 
Based on the assumption of the statistical design, the interim analysis should take place approximatively 
4 years after the start of the trial when about 600 patients have been recruited.  
Only the rejection of H0, the hypothesis of no efficacy, will be considered. Based on stopping boundaries 
from the Rho family (Rho=2), at the interim analysis, the nominal significance level for rejecting H0 will be 
of 0.0084. The final analysis will be performed at a significance level of 0.0453. Power simulations were 
performed with EAST v 4.0.1.34 the results are presented in the table below based on 10000 simulations.  
 
 

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Prob. of rejection of H0 
Overall 
Power 
Scenario 
Interim analysis 
Final analysis 
 
HR=0.63 (-ln(HR)=0.462) 
79% 
21% 
99.9% 
HR=0.775 (-ln(HR)=0.255) 
23% 
61% 
83% 
HR=0.80 (-ln(HR)=0.223) 
16% 
56% 
72% 
HR=0.825 (-ln(HR)=0.192) 
11% 
47% 
59% 
The probability of early stopping the assumption of the design is 23% at the interim analysis and 61% at 
the final analysis. The design still performs well if the true treatment effect is somewhat smaller than 
expected: for HR=0.80 the overall power is 72% with a 16% probability of early stopping at the interim 
analysis. For the pessimistic scenario of HR =0.825 the design will have a poor performance and the 
overall power will drop to 59%. Should the true difference between the treatment arms be comparable 
to the one observed in the EORTC 26981 (HR=0.63) trial, the probability of early stopping after the 
interim look increases to 79%. 
The opportunity to stop the trial for futility (rejection of H1) was investigated. It was not possible to find a 
design allowing for rejection of H1 with sufficient power at an appropriate time of assessment before the 
end of the accrual period. 
8.3.2 
New plan 
Further to the original interim analysis, the IDMC formulated the following recommendations:  
a. To release and publish the results on all endpoints for the adjuvant TMZ comparison without delay.  
b. In doing, so, to pay particular attention to the impact on patients in arms 1-2, who may benefit from 
initiating adjuvant TMZ and for whom a therapeutic decision to initiate such treatment may ensue. In 
particular, those patients who are still receiving RTX (with or without concomitant TMZ), as well as those 
patients who have finished RTX treatment within the past three months.  
c. To continue the follow-up for the concurrent TMZ question. Because of the very long follow-up time 
required to reach data maturity for overall survival for this question, consideration may be given to 
implementing a further interim analysis. The IDMC would welcome proposals for a revised plan 
incorporating a second such interim analysis.  
d. To take the necessary steps to obtain data on the MGMT promoter status for all patients, including 
reanalysis of samples using more modern assays that may require less material than the early assays. The 
investigators should assess heterogeneity of results across subgroups.  
A new interim analysis plan was designed by an independent statistician. It includes an additional interim 
analysis for both efficacy and futility analysis at 2/3 of information (356 deaths) using the original 
spending function (stopping boundary from Rho family (Rho=2)) for the efficacy and an O’Brien Fleming 
stopping boundary for futility. This analysis will be binding in order to keep the same number of events 
and the 80% power at the final analysis. Based on these new assumptions, the trial will be stopped for 
futility if HR ≥ 0.882 and for early efficacy if HR<0.778. HR=0.882 corresponds to OS rate at 2 years of 
71.9% in the no concurrent TMZ chemotherapy arm versus 74.7% in the concurrent TMZ chemotherapy 
arm (less than 3% difference observed). The timing of this second interim analysis is at about 35 months 
after end of accrual i.e. September 2018. The final analysis is expected in 2022 at will be performed at a 
significance level of 0.044 (HR<0.841). 

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8.4 
End of study 
End of study occurs when all of the following criteria have been satisfied: 
1. Thirty days after all patients have stopped protocol treatment 
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol 
3. The database has been fully cleaned and frozen for this analysis 
9 Trial Governance and Data Monitoring  
9.1 
Study committees  
9.1.1 
Study Management Group (SMG) 
The Study Management Group is set up for this study. It consists of the EORTC Headquarters team in 
charge of running the study (clinical research physician, statistician, clinical scientist, clinical operations 
manager and data managers) and the principal study coordinator.  
The EORTC Headquarter team is responsible for the day -to-day conduct of the trial. The Study 
Coordinator will assist the team in case of problems with patient evaluation (eligibility, treatment 
compliance, safety).  
The Study management Group also performs the medical review as indicated below.  
9.1.2 
Study Steering committee (SSC)  
The Study Steering Committee for this study is composed of the study coordinators, the representatives 
of Academic Groups collaborating to the study, at least one representative of the EORTC Headquarters 
(Study Clinical Research Physician or Clinical Scientist) and one representative of the Sponsor, if the 
sponsor is not the EORTC. 
This committee provides the general oversight of the study and has the executive power. The SSC 
monitors study progress and conduct and advises on its scientific credibility. The SSC will consider and 
act, as appropriate, upon the recommendations of the independent data monitoring committee.  
9.1.3 
Independent data monitoring committee (IDMC)  
The independent data monitoring committee for EORTC studies (IDMC) is in charge of the independent 
oversight of this study. The composition of the IDMC is described in EORTC Policy "Independent Data 
Monitoring Committees for EORTC studies" (ref. EORTC POL004) and its functioning is ruled by the 
charter annexed to the Policy.  
The study-specific experts on the IDMC performing this review will be selected for their relevant 
expertise with the disease and/or treatments assessed in the study.  
The IDMC reports its recommendations in writing to the Study Management Group through the clinical 
operations manager to the Study Steering Committee and other relevant parties (supporting bodies, 
collaborative groups…).  
9.2 
Data Monitoring  
9.2.1 
Monitoring during medical review meetings  
The medical review will be performed on a regular basis by the clinical research physician assisted as 
needed by the study management group. The main study coordinator will, in particular, support the 

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Study Clinical Research Physician during the medical review process and will assist the team in case of 
problems with patient evaluation (safety, eligibility, treatment compliance). The main study coordinator 
is also responsible for the review and approval of the medical review plan and medical review reports.  
For blinded trials, the medical review is conducted blinded to treatment allocation. 
If at any time during the course of the study, the medical review identifies safety signals or other 
elements that could affect the potential risks and benefits to the study participants. These will be 
reported to the Study Steering Committee and may trigger a review by the EORTC Independent Data 
Monitoring Committee (IDMC).  
9.2.2 
Monitoring by the IDMC  
The IDMC will be asked to give advice on whether the accumulating data from the trial justifies 
continuing recruitment of further patients or further follow-up. 
The IDMC will review the trial whenever safety problems or other elements are identified during the 
medical review or by the SMG and/or SSC that could affect the potential risks and benefits for study 
participants.  
The IDMC will also review the intermediate reports of accumulating data according to the study interim 
monitoring plan described in the statistical section of this protocol. If a decision is made to continue 
without change, the IDMC may advise on the frequency of future reviews of the data on the basis of 
accrual and event rates. 
While the trial is ongoing the accumulating data will generally remain confidential, unless the SSC and 
IDMC agree that the data should be made public. 
10 Quality of life assessment 
Reducing mortality and morbidity is still the most important factor in clinical research. Nevertheless, 
issues such as reducing side effects, symptom relief and improving patients’ satisfaction have also 
become relevant parameters in the evaluation of medical strategies. Cancer treatments may produce 
adverse effects and diminish the quality of life (QoL) even when survival is extended. Progress in the 
acceptance of new cancer therapies is sometimes critically dependent on their QoL consequences. Health 
related QoL is a multidimensional concept, which represents the physiological, psychological and social 
influences of the disease and the therapeutic process from the patients’ perspective. It comprises four 
principal components: physical, psychological and social well-being, and daily-life functioning. 
10.1 Rationale / objectives and hypothesis (background literature) 
Patients with anaplastic glioma can have a poor QOL, but this has not been frequently assessed in large 
scale studies. It is highly likely that these patients will experience similar symptoms as recently reported 
in the 26951 and 26981 trials. That is, that patients can suffer from considerable levels of fatigue, have 
sleep problems, communication deficits, motor dysfunction and leg weakness with impairments in 
emotional and social functioning and express uncertainty regarding the future and an overall reduced 
QOL. Therefore, in this study, QOL is an important secondary endpoint. The main objective of QoL 
assessment within this clinical trial is to determine the impact of no adjuvant chemotherapy versus 
adjuvant therapy until progression for anaplastic glioma on overall health/QoL. Based on the recent 
EORTC study 26981, the hypothesis is that we expect no differences between arms using the global QOL 
scale during treatment, but there may be a later benefit to the adjuvant therapy arm if disease 
progression is achieved, thereby leading to a better global QOL. Several past neuro-oncological trials have 
shown an increased progression free survival after more intense initial treatment, without an effect on 

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overall survival. At present the impact of progression of high-grade glioma on the quality of life is not 
clear. It is not clear if increasing progression free survival is translated into a longer period with a better 
preserved quality of life. If that is the case, improvement of progression free survival would become a 
goal in itself. With this trial we will assess if QOL is decreased at the time of first progression, and if a 
longer progression free period is translated in a better QOL. To meet these objectives QOL questionnaires 
will also be administered after the first progression. 
A secondary objective is to evaluate the effect of temozolomide on the various symptoms and 
functioning scales as treatment related side-effects may have a (temporary) negative influence on the 
health related domains of QoL of these patients. Based on the past study, we may see a slight increase in 
fatigue and reduction on social functioning in the adjuvant chemotherapy arm. However, once off 
treatment, we expect to see no differences  
10.2 QL measures 
Quality of life will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. This is 
composed of multi-item and single scales. These include five functional scales (physical, role, emotional, 
social, and cognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health 
status/QOL scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and 
financial difficulties). All scales and single items meet the standards for reliability. The reliability and 
validity of the questionnaire is highly consistent across different language-cultural groups [Aaronson et 
al., Ref. 26]. While this standard is used in EORTC studies, it lacks some dimensions that pertain to the QL 
issues in certain cancers in brain cancer. Therefore we will use the EORTC Brain Cancer module (QLQ-
BN20) is designed for use with patients undergoing chemotherapy or radiotherapy. It includes 20 items 
assessing: visual disorders, motor dysfunction, communication deficit, future uncertainty, as well as other 
specific symptoms, such as headaches, seizures or drowsiness). A validation study has been performed 
with English-speaking patients from Canada, the UK and the USA. (Osoba et al 1996, Ref. 27). An 
additional validation analysis is planned and will be completed within the time frame of this clinical trial. 
10.3 Study design 
Patients are eligible for the quality of life assessment in this study if they fulfill the eligibility criteria 
(Chapter 3) and, more importantly, complete the baseline quality of life questionnaire before 
randomization. Given the important of QOL in this study, being able to provide a completed QOL form is 
an important eligibility criterion. Of course, should the QOL forms not be available in the required 
language then this should not exclude the patient from participating in the study. Patients will be 
informed in the patient informed consent form that they will have their quality of life assessment 
regularly while involved in this trial. QoL will be a secondary outcome and evaluated in a longitudinal 
design for in all patients entered in this study.  
10.3.1 
QoL data collection - Timing and where and how 
QoL questionnaires must be filled out at the hospital when the patient comes for a scheduled visit. The 
questionnaire will be handed out to the patients by the investigator or a study nurse prior to seeing the 
doctor for clinical evaluations. Patients will be asked to fill out the questionnaires as completely and 
accurately as possible. The average time to complete the entire questionnaire is approximately 10-15 
minutes. Master copies of the QoL questionnaires (EORTC QLQ-C30 and the QLQ-BN20) will be sent to 
the institution together with the CRFs. The clinical forms will include a question whether the QoL forms 
have been filled in -and if not, the reason why. Data collection procedures should be followed using the 
EORTC guidelines in Appendix D. Time windows for eligible follow-up assessment will be (+/-) 3 weeks the 
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The questionnaire should be completed within 14 days prior to randomization, than at 4 weeks off 
radiotherapy, then at every 3 monthly visit. After treatment discontinuation of treatments, QoL 
measurements are carried out every six months, at each follow-up visit up during coming five years or 
death if it occurred earlier. Even if patient’s progress, QOL forms should still be collected every six 
months until death. 
10.3.2 
Compliance 
Missing data may hamper assessment of QL in clinical trials. This may be because centers do not collect 
the questionnaires at the appropriate time (unit non-response), and because patients may miss questions 
within the questionnaires (item non-response). The latter problem occurs less than 2% on average and 
should not be a problem. The former problem will be minimized by ensuring that participating centers 
are properly informed and motivated towards QL assessment. 
During the study, compliance with completing QoL questionnaires will be investigated at each time point. 
The compliance of the QoL assessments will also be reviewed twice a year and will be a part of the 
descriptive report by the EORTC Headquarters for the Group's plenary sessions. Having high compliance 
is imperative to this QOL study and all reasonable attempts to collect QOL data must be made. The 
compliance data by institutes should be presented to the entire group in order to help identify centers 
that are struggling to obtain maximum QOL compliance levels and efforts to improve this should be 
included as corrective methods (e.g. Education to nurses and doctors about the importance of the data 
and how to collect it) 
The compliance rate between the 2 arms will be compared at each time point using a chi-square test. In 
order to adjust for the multiplicity of the tests, a Bonferroni adjustment will be made by which each test 
will be performed at the 0.01 significance level. Should serious volumes of missing questionnaires occur 
then the protocol writing committee would review the QL assessment in the trial. If compliance levels fall 
below 70% at any time point protocol writing committee would need to take remedial action to improve 
the position. 
10.4 Statistical considerations 
The sample size calculation has been performed based on overall survival data. This is the primary 
endpoint and therefore no calculation has been performed based on changes in QL. The primary QL 
endpoints that are considered relevant to this trial are global QOL. The QOL data will inform the 
hypothesis that we expect no differences between arms using the global QOL scale during treatment, but 
there may be a later benefit to the adjuvant therapy arm if disease progression is achieved, thereby 
leading to a better global QOL. Hence, the global quality of life scale of the QLQ-C30 will be used as the 
primary QL outcome of interest. Based on the work of Osoba et al. (Ref. 27), a difference of 10 points on 
a 100 point scale between the two treatment arms will be considered as clinically significant. The 
standard deviation of the global QoL scale is approximately 20 points. With a minimal effect size of 0.5 
(i.e. one-half standard deviation), with alpha set at 0.5 and beta at 0.20 (power 0.80), a minimum of 64 
patients per treatment arm is required. The other scales of fatigue and social functioning will be analyzed 
as secondary QOL endpoints. The remaining scales will only be analyzed on an exploratory basis. Data will 
be scored according to the algorithm described in the EORTC QLQ-C30 scoring manual. All scales and 
single items are scored on categorical scales and linearly transformed to 0-100 scales where:  
 
A high score for a symptom scale or item represents a high level of symptoms or problems. 
 
A high score for a functional scale represents a high or healthy level of functioning. 
 
A high score for the global health status/QoL represents high QoL.  

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When performing a QoL analyses complications may arise due to large quantities of missing data. This 
issue has a bearing on whether a valid comparison of the treatment arms is being made.  
In QoL research there are two main types of missing data: (1) item non-response, (2) unit non-response 
(the whole questionnaire is missing for a patient.) As item non-response occurs less than 2% on average 
in the QLQ-C30 it is not such a major problem and thus the methods described in the EORTC QLQ-C30 
scoring manual for handling item non-response will be used. For missing questionnaires, it is necessary to 
identify both the extent of missing questionnaires and the main process of missing data. Three different 
types of missing data processes may exist: missing completely at random (MCAR), missing at random 
(MAR), and missing not at random (MNAR, informative dropout mechanism). These have distinct 
consequences for data analysis. 
If the missing data process is considered to be non-ignorable (MNAR) then the quality of life will be 
compared between groups using longitudinal data modeling techniques (i.e. Proc mixed in SAS with 
either selection models or pattern-mixture models) in combination with a logistic regression for the 
dropout process.  
If the missing data mechanism can be considered ignorable (MAR), then standard longitudinal data 
analysis will be used (PROC mixed in SAS). 
If the data are MCAR then complete case analysis can be used without biasing the results. 
Statistical tests will be performed using a two-sided significance level of 5%. 
For all quality of life domains and items, cross-sectional descriptions of the average scores will be 
presented by treatment arm at each time point of assessment together with confidence intervals and a 
graphical display of the patterns of change over time will be provided. 
10.5 Additional analysis of the QOL scales as possible prognostic 
factors 
In addition, recent evidence from our last study (Bottomley et al 2005), suggested baseline QOL may be 
of some prognostic value, when combined with clinical variables. Hence, we also plan to undertake a 
prognostic factor analysis with the relevant clinical information and key QOL scales that have been shown 
to be prognostic in study 26981-22981/NCI-C CE3. These scales include cognitive functioning, fatigue, 
physical functioning, social functioning and the MMSE. We will use baseline scores to predict outcome, 
with the hypothesis that worse scores are related to poorer survival outcomes. This analysis will include 
the Cox modeling, along with a sensitivity analysis using the bootstrap validation technique. 
11 Translational research 
11.1 Generalities 
The timeframe of this study necessitates anticipating translational research projects to be performed in 5 
years, when all patients are accrued and all collected biological material will be available. Thus, the main 
goal at this time is to organize the structure for collection and preservation of biological patient material 
in an efficient way for future analysis. This strategy will allow adjustment of the translational research 
project by integrating the latest advances in cancer research and taking advantage of progresses in 
molecular biology techniques. A definitive comprehensive translational research project will be proposed 
at the latest at completion of accrual by a translational research committee formed by representatives of 
the trial steering committee and the translational research committee of the BTG, interested members of 
the BTG, and representatives of participating groups. Any translational research project using the 

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material and data of this trial will require approval of the translational research committee of this trial, 
and formal approval by the EORTC protocol review committee.  
11.2 Rational 
Little molecular data is available for anaplastic glioma that are relatively rare, difficult to define by 
pathology, and consist of a morphologically heterogeneous group of tumors (astrocytoma grade 3, 
anaplastic oligoastrocytoma, and oligodendroglioma grade 3, for this study with the exception of tumors 
with 1p/19q deletions). This study provides a unique opportunity to fill this gap allowing association of 
molecular profiles and clinical parameters with response to therapy. Furthermore, respective 
comprehensive translational research projects are ongoing or planned in other trials of the EORTC Brain 
Tumor Group for low grade glioma (EORTC LGG 22033-26033), and glioblastoma (EORTC 26981/22981, 
NCIC CE.3; RTOG 0525, EORTC) that all test response to Temozolomide treatment, although using 
different modalities. Since most of the tumors will recur, cross over of therapies are expected, thus, 
informed consent needs to be acquired for optional translational research also on subsequently resected 
tumor tissue (frozen or paraffin embedded). 
11.3 Goals 
Global Molecular Profiling of tumors to establish correlations with tumor classification, prognosis, 
response to treatment, and overall survival. Development of evidence based, individually tailored patient 
management. 
• Classification of tumors based on their molecular patterns to improve reproducible diagnosis. 
• Identification of predictive factors (e.g. differentially expressed genes/proteins, methylation 
patterns) associated with response to therapy and outcome. 
• Test predictive value of candidate genes/proteins on tissue arrays constructed from a large panel of 
gliomas representative for the distinct experimental arms and for EORTC and RTOG/NCIC centers. 
• Identification of new therapeutic targets 
• Rational design of new clinical trials for anaplastic glioma 
• Improve understanding of molecular mechanisms driving tumor progression and resistance to 
treatment. 
11.4 Approaches 
Based on our preliminary findings in the EORTC/NCIC study we propose that global molecular profiling 
should be a high priority in this EORTC/RTOG trial. Frozen tumor tissue is most suitable for high quality 
molecular profiling using high through put analysis for gene expression, genomic copy number 
aberrations, aberrant promoter methylation, proteomics, etc., although efforts are ongoing to adapt the 
methodology to include also paraffin embedded tissues. Thus, collection of frozen tumor tissue is a high 
priority, beside collection of tissue blocks.  
The obtained information will allow generating a statistically evaluable data base for correlations with 
treatment response, currently badly missing in this field. This data base may serve as reference for 
studies investigating molecular mechanisms of classical or targeted cancer drugs allowing integration of 
information obtained in in vitro model systems or murine models. Furthermore, this data would be a 
strong link to the database we have from the EORTC/NCIC trial. Molecular Profiling should include gene 
expression profiling, array-CGH or SNP chip analysis, global analysis of inappropriate promoter 
methylation, and integrated proteomics. Gene expression profiling should be performed on a widely used 
platform for comparability. SNP-chip analysis in addition allows determination of polymorphisms relevant 
for treatment response. This investigation requires availability of normal DNA from each patient (DNA 

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derived from PBLs) that is also asked for in the context of 1p/19q deletion analysis. The analysis of 
polymorphisms in key genes has been shown to be of importance for the cancer process.  
11.5 Collection of patient material 
To reach these goals the following biological patient material is collected: 
The informed consent for trial participation will explain the need for material for translational research of 
the initial resection, and including subsequent resections. 
• frozen tumor biopsies 
• paraffin blocks 
• respective serum and blood lymphocytes 
• construction of tissue arrays from paraffin embedded material of tumor biopsies 
11.6 Routing and banking of biologic al patient material 
For EORTC, the tumor material and blood should be sent to Erasmus Medical Centrum, Rotterdam by 
express carrier (as specified in section 17.3.3). Details on the procedure are to be found in the appendix 
“Procedures and routing of tumor and blood samples prior to randomization”  
(Appendix K). The procedure for other participating group is detailed in the corresponding Group Specific 
Appendix. 
11.7 IDH mutations analysis 
Recently discovered, isocitrate dehydrogenase (IDH) mutations in glial tumors are mainly found in grade 
II and grade III glial tumors, and in secondary glioblastoma. The presence of these mutations confers a 
much better overall prognosis. 
Indeed, shortly after the start of the CATNON study, a genome wide sequencing study described somatic 
mutations in the gene encoding IDH1 in 12% of glioblastoma (GBM) samples. (Ref. 30) The authors 
further observed that IDH1 mutations predominantly occur in patients of lower age and in glioblastomas 
that have progressed from lower grade gliomas (‘secondary’ GBM), and that IDH1 mutations were 
associated with a longer survival. Subsequent studies have shown a 60-80% mutation rate in grade II and 
grade III glioma, both in tumors with 1p/19q co-deletion and TP53 mutations. (Ref. 31) These 
observations, together with follow-up studies showing a consistent pattern of IDH1 status over time 
suggest that IDH1 mutations mark an early event in grade II and III glioma. Moreover, clinical studies 
show that IDH1 mutated tumors have an improved outcome, regardless of other prognostic factors. (Ref. 
32, Ref. 33)  
Therefore, further investigation into IDH genes has become crucial for the understanding of the outcome 
of clinical trials in glioma. For this reason, the tumors of the patients treated within CATNON will also be 
investigated for mutations in IDH genes. 
Material: tumor at initial diagnosis (FFPE block or 30 unstained slides) which is already covered by the 
material requested before randomization (no extra material is needed to perform the test). 
Methods: Tumor DNA will be extracted from FFPE block or unstained slides. IDH mutational analysis will 
be done by targeted next generation sequencing. This approach was validated in the EORTC 26951 
study.(Ref. 35) To this TERT promoter mutational status assessment will be added, using snapshot DNA 
phenotyping as this has been instrumental in further subclassifying gliomas. Required amount of tissue 
for the various tests: IDH mutational analysis using glioma targeted NGS: 40 ngr; TERT analysis using 
snapshot, few ng; Whole genome methylation array 200 ngr. If little material is available (<200 ngr), IDH 
analysis be done on a targeted NGS platform, followed by TERT analysis. For samples with more than 200 

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ng but less than 400 ng, first the glioma NGS platform will be run with TERT analysis, then the 
methylation array. For samples with more than 450 ng both the methylation array and targeted NGS will 
be done. In cases where no unstained FFPE material is available but we have an H & E stained slide: after 
digitizing this slide will be sacrificed to asses IDH status using a targeted glioma NGS platform. IDH 
mutations will be investigated by PCR and/or immunohistochemistry. (Ref. 34) 
Statistics: See section 8.2.5 (Prognostic factors analysis) 
12 Result dissemination policy 
12.1 Study disclosure 
12.1.1 
Trial Registration 
This trial will be registered in a public database (https://www.clinicaltrialsregister.eu). As the clinical trial 
(CT) regulation 536/2014 of the European Union (EU) becomes applicable, more information about this 
trial will be uploaded in this public database in compliance with European requirements on transparency. 
Information posted, among others, will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further information 
on appropriate trial locations and trial site contact information.  
In accordance with applicable EU regulations, a summary of the trial results will be made publically 
available within one year of the end of study declaration.  
EORTC as Sponsor of this trial will submit the summary of the results based on the final analysis report in 
compliance with the regulations. 
12.1.2 
Final Analysis Report  
A Final Analysis Report that reports summary statistics of all the data collected for the study and presents 
an interpretation of the study results will be issued by the EORTC Headquarters. It will form the basis for 
the manuscript intended for publication. The Final Analysis Report or a summary thereof will be 
distributed to all participating groups, the supporting companies and ethics committees and the results 
will be posted in relevant public databases (as in section 12.1.1).  
12.2 Publication policy 
All publications must comply with the terms specified in the EORTC Policy 009 “Release of Results and 
Publication Policy” version 4.2 dated March 2018 or later. 
In accordance with the Policy 009, results of the present study will be made public once the study data 
are mature for the final analysis of the primary study endpoint (as described in the section “statistics” of 
the present protocol), irrespective of the findings (positive or negative). Deviations from the results 
disclosure rules specified in the Policy require authorization by the Independent Data Monitoring 
Committee (IDMC).  
The primary trial publication will be written on the basis of the final analysis report and shall be published 
in a peer-reviewed scientific journal within 1 year of the date of the database lock. 
Prior to submission, all publications (papers, abstracts, presentations…) will be submitted for review to 
the EORTC Headquarters statistician and clinical research physician, to all co-authors and to the 
designated representative of the pharmaceutical company supporting the study, if any as per contractual 
agreement. Approval of the manuscript by EORTC Headquarter representatives is required before 
submission of the manuscript reporting on an EORTC study for publication. 

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The authorship rules conform to the recommendations of the International Committee of Medical 
Journal Editors defining the roles of authors and contributors 
(http://icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-
contributors.html) and will be attributed for each publication in line with the EORTC Policy referred 
above. All other investigators and scientific contributors to the study who do not qualify for authorship 
will be acknowledged in the publication.  
Sources of funding or support to the study will be disclosed and acknowledged in the publication. 
The name “EORTC” and of any collaborative Group must be visible in the publication's header of all 
publications.  
12.3 Data sharing 
EORTC is committed to ensuring that the data generated from its studies be put to good use by the 
cancer research community and, whenever possible, are translated to deliver patient benefit.  
It is therefore EORTC's policy to consider for sharing upon request from qualified scientific and medical 
researchers all data generated from its research whilst safeguarding intellectual property, the privacy of 
patients and confidentiality.  
Considering that ongoing research contributing to the completion of datasets must not be compromised 
by premature or opportunistic sharing and analysis of data, the EORTC will not release the data of its 
study until the primary study results have been published; unless authorization for release has been 
granted according to the terms of EORTC Policy 009. 
Requests for accessing the data of published trials should be filed through the data sharing tab on the 
EORTC website (www.eortc.org). 
13 Investigator authorization procedure 
Investigators will be authorized to register and/or randomize patients in this trial only once they have 
returned the following documents to their Data Center (for the EORTC investigators see chapter 21: 
Administrative responsibilities, for non-EORTC investigators: see your group specific appendix): 
• The updated signed and dated Curriculum Vitae of the Principal Investigator 
• The (updated) list of the normal ranges, for their own institution, signed and dated by the head of the 
laboratory. Please make sure normal ranges are provided also for those tests required by the protocol 
but not routinely done at the investigator’s institution. 
• A Commitment Statement and Study Agreement between EORTC and Principal Investigator, stating 
that the investigator will fully comply with the protocol. This must include an estimate of yearly 
accrual and a statement on any conflict of interest that may arise due to trial participation. 
• A signed conflict of interest disclosure form will be required only if a possible conflict is declared 
on the Commitment Statement and Study Agreement.  
• A copy of the favorable opinion of the local or national (whichever is applicable) ethics committee 
mentioning the documents that were reviewed (including the version numbers and version dates of 
all documents). A list of all members of the ethics committee is also requested. 
• A copy of the translated and adapted (according to all national requirements) Patient Information / 
Informed Consent sheet. Version numbers and dates must be clearly stated on each page. 
• The signature log-list of the staff members with a sample of each authorized signature and the 
indication of the level of delegations. In case patients receive treatment at a satellite institution, i.e. 

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outside the authorized institution, details on the satellite institution, including the CV of the local 
investigator, normal lab ranges and the approval of an ethics committee will have to be transmitted 
to the EORTC Headquarters. Please keep in mind that all communication is done ONLY between the 
primary institution and the EORTC Headquarters. 
• The full name, address, phone numbers and e-mail address of the local pharmacist who will be 
responsible for the trial medication (for any trial where the drug will be provided). 
• An accreditation, a certification, an established quality control/external quality assessment or another 
validation should be provided for the own laboratory. 
The center specific applicable list of required documents will be included in the protocol activation 
package, with proper instructions as required by this protocol, your group and / or the applicable 
national law. 
The new investigator will be added to the “authorization list”, and will be allowed to register/randomize 
patients in the trial as soon as 
• All the above mentioned documents are available at their Data Center 
• All applicable national legal and regulatory requirements are fulfilled 
Patient registration/randomization from centers not (yet) included on the authorization list will not be 
accepted. 
14 Patient registration and randomization procedure 
14.1 Registration before molecular testing (step 1) 
Patient registration will only be accepted from authorized investigators (see chapter on "investigator 
authorization procedure"). 
A patient can only be registered only after verification of eligibility. This must be done before molecular 
testing. 
An exhaustive list of questions to be answered during the registration procedure is included in the 
registration checklist, which is part of the case report forms. This checklist should be completed by the 
responsible investigator before the patient is registered. 
STANDARD INFORMATION REQUESTED: 
• institution number  
• protocol number (26053-22054) 
• step number: (1 – New patient) 
• name of the responsible investigator 
• patient's code (maximum 4 alphanumerics) 
• patient's birth date (day/month/year) or year of birth (as allowed per applicable legislation) 
PROTOCOL SPECIFIC QUESTIONS 
• all eligibility criteria will be checked one by one 
• actual values for the eligibility parameters will be requested when applicable 
Stratification factors 
• date of written informed consent (day/month/year) 
Date foreseen for protocol treatment start 

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At the end of the registration procedure, a sequential patient identification number (“seqID”) will be 
allocated to the patients. This number is to be recorded on the registration checklist, along with the date 
of registration. The completed checklist must be signed by the responsible investigator and returned to 
the Data Center with the baseline data of the patient. 
All SAMPLE SHIPMENTS and REPORTS must be identified with the EORTC Id (Seqid) attributed at 
registration 
14.2 Blinded MGMT methylation status (Step 2) 
Blinded for the sites and performed by the EORTC HQ. MGMT methylation status is used for stratification 
at randomization. 
14.3 Randomization (Step 3) 
A patient who has not been registered before the molecular testing will not be accepted for the study at 
a later date and cannot be randomized for the second step of the study. 
An exhaustive list of questions to be answered during the randomization procedure is included in the 
registration checklist, which is part of the case report forms. This checklist should be completed by the 
responsible investigator before the patient is randomized. 
Standard questions 
• institution number  
• protocol number (26053-22054) 
• step number: (3 – Existing patient) 
• name of the responsible investigator 
The patient will have to be selected in the list of patients that have already been registered in the first 
step. Once the patient has been identified in the list, select the corresponding patient’s code. The 
patient’s code and date of birth will automatically be inserted in the identification screen. 
Protocol specific questions 
• eligibility criteria 
 
all randomization criteria will be checked; 
 
actual values of the eligibility parameters will be requested when applicable 
• stratification factors  
At the end of the procedure, the treatment will be randomly allocated to the patients, as well as a patient 
sequential identification number. This number and the allocated treatment have to be recorded on the 
randomization checklist, along with the date of randomization. The completed checklist must be signed 
by the responsible investigator and returned to the Data Center with the initial data of the patient. The 
sequential identification number attributed to the patient at the end of the randomization procedure 
identifies the patient and must be reported on all case report forms. 
All participants from non-EORTC groups should contact the Data center mentioned in their Group Specific 
Appendix. 
All EORTC participants should randomize patients directly on the EORTC online randomization system 
(ORTA = online randomized trials access), accessible, 24 hours a day, 7 days a week, through the internet. 
To access the interactive randomization program, the investigator needs a username and a password 
(which can be requested at: www.eortc.be/random). 

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In case of problems EORTC participants can phone the EORTC Headquarters from 9.00 am to 5.00 pm 
(Belgian local time) from Monday through Friday to randomize patients via the EORTC call center. 
Randomization via the phone is not available on Belgium holidays. A list of these holidays is available on 
the EORTC web site (www.eortc.be/random) and it is updated annually. 
Through Internet: www.eortc.be/random 
In case of problems by phone: +32 2 774 16 00 
15 Forms and procedures for collecting data 
15.1 Case report forms and schedule for completion 
Data will be reported on the forms specifically designed by the EORTC Headquarters for this study. 
Those forms will be used by all cooperative groups. Each group can eventually customize the heading 
frame but not the contents of the forms. Appropriate forms will be distributed to each investigator by 
their own Data Center. 
All participants from non-EORTC groups should send forms to the Data Center mentioned in their Group 
Specific Appendix. 
All EORTC participants should send forms directly to the EORTC Headquarters: 
BTG Data Manager 
EORTC Headquarters 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
A. Before the treatment starts: 
• The patient must be registered/randomized through your Data Center. 
• The registration checklist should be returned to your Data Center. 
The optimal way to work is to complete the registration checklist first and to register/randomize the 
patient as soon as it is completed. The date of registration/randomization and patient sequential 
identification number are then completed on the checklist, and this form can be sent to the Data Center. 
B. During/after treatment 
The list of forms to be completed for this study and their submission schedule is appended to the set of 
case report forms. 
ALL Forms must be dated and signed by the responsible investigator  
or one of his/her authorized staff members 
 
 

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15.2 Data flow 
The case report forms must be completed, dated and signed by the investigator or one of his/her 
authorized staff members as soon as the requested information is available. 
The list of staff members authorized to sign case report forms (with a sample of their signature) must be 
sent to the investigator’s group Data Center (the one mentioned in the particular Group Specific 
Appendix for non-EORTC investigators; EORTC Headquarters for EORTC investigators) by the responsible 
investigators before the start of the study. 
In all cases, it remains the responsibility of the principal investigator to check that original case report 
forms are sent to the adequate Data Center as soon as possible and that they are filled out completely 
and correctly. 
The original copy must be immediately returned to the investigator’s group Data Center and the 
investigator must keep a copy. 
The EORTC Headquarters will perform extensive consistency checks on the CRFs and issue Query Forms in 
case of inconsistent data. These Query Forms will be sent via the group Data Center to non-EORTC 
investigators and directly to EORTC investigators. They must be immediately answered and signed by the 
investigator (or an authorized staff member). The original must be returned to the investigator’s group 
Data Center and a copy must be attached to the CRF copies stored by the investigator. 
When satellite institutions are involved all contacts are done exclusively with the primary institution, for 
purposes of data collection and all other study related issues. 
If an investigator (or an authorized staff member) needs to modify a CRF after the original form has been 
returned to the investigator’s group Data Center, he/she should notify the group Data Center by using 
the Data Correction Form. The original Data Correction Form should be sent to the group Data Center 
and a copy should be kept with the other CRF copies. 
The investigator's copy of the CRFs may not be modified unless modifications are reported on a Query 
Form or a Data Correction Form and the Query Form or Data Correction Form reference is indicated on 
the CRF. 
16 Reporting of Serious Adverse Events 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors follow specific 
procedures when notifying and reporting adverse events/reactions in clinical trials. These procedures are 
described in this section of the protocol.  
16.1 Definitions 
These definitions reflect the minimal regulatory obligations; specific protocol requirements might apply 
in addition. 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment”. An adverse event can therefore be any unfavorable and 
unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal 
laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated 
with the use of the protocol treatment, whether or not considered related to the investigational 
medicinal product. 

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AR: An Adverse reaction of an investigational medicinal product is defined as “any noxious and 
unintended response to a medicinal product related to any dose administered”. 
All adverse events judged by either the reporting investigator or the sponsor as having a reasonable 
causal relationship to a medicinal product qualify as adverse reactions. The expression reasonable causal 
relationship means to convey in general that there is evidence or argument to suggest a causal 
relationship. 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of which is not 
consistent with the applicable product information" (e.g. investigator's brochure for an unapproved 
investigational product or summary of product characteristics (SmPC) for a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product information this 
adverse reaction should be considered as unexpected. 
Severity: The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate or severe, or as described in CTC grades); the event itself, however, may be of relative 
minor medical significance (such as severe headache). This is not the same as “serious,” which is based 
on patient/event outcome or action criteria usually associated with events that pose a threat to patient’s 
life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations.  
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a patient, 
whether or not considered related to the protocol treatment, that at any dose: 
• results in death 
• is life-threatening (i.e. an event in which the subject was at risk of death at the time of event; it does 
not refer to an event which hypothetically might have caused death if it were more severe) 
• requires inpatient's hospitalization or prolongation of existing inpatients´ hospitalization 
• results in persistent or significant disability or incapacity 
• is a congenital anomaly or birth defect 
• results in any other medically important condition (i.e. important adverse reactions that are not 
immediately life threatening or do not result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed above), e.g. 
secondary malignancy, AE as a result of an overdose 
SAR: A Serious Adverse Event (SAE) which is considered related to the protocol treatment is defined as a 
Serious Adverse Reaction 
SUSAR: Suspected Unexpected Serious Adverse Reaction.  
SUSARs occurring in clinical investigations qualify for expedited reporting by the sponsor to the 
appropriate Regulatory Authorities in accordance with Directive 2001/20/EC and with respective national 
regulations. 
Inpatient or in-patient's hospitalization: A patient who is admitted to a hospital or clinic for at least one 
overnight stay. 
16.2 Exceptions 
The following situations are not considered to be SAEs and should not be reported on the SAE form:  
• Elective hospitalization for pre-existing conditions that have not been exacerbated by trial treatment 
• A hospitalization which was planned before the patient consented for study participation and where 
admission did not take longer than anticipated 

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• Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads to the 
procedure is an (S)AE  
• Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital, palliative care, rehabilitation, overdose without occurrence of an adverse 
event)  
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
By EORTC convention, clinical events related to the primary cancer progression are not to be reported as 
SAEs, even if they meet any of the seriousness criteria from the standard SAE definition, unless the event 
is more severe than expected and therefore the investigator considers that their clinical significance 
deserves reporting.  
16.3 Severity assessment 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE v3.0 
(https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf). 
16.4 Causality assessment 
The investigator is obligated to assess the relationship between protocol treatment and the occurrence 
of each SAE following definitions in this table: 
Relationship to the 
protocol treatment  
Description 
UNRELATED 
There is no evidence of any causal relationship to the protocol 
treatment 
LIKELY RELATED 
There is (some) evidence to suggest a causal relationship to the 
protocol treatment and influence of other factors is unlikely or 
absent. 
NOT ASSESSABLE 
There is insufficient or incomplete evidence to make a clinical 
judgment of the causal relationship to the protocol treatment. 
 
The investigator will use clinical judgment to determine the relationship. Alternative causes, such as 
natural history of the underlying diseases, medical history, concurrent conditions concomitant therapy, 
other risk factors, and the temporal relationship of the event to the protocol treatment will be 
considered and investigated. 
The decision will be recorded on the Serious Adverse Event form, if necessary with the reasoning of the 
principal investigator.  
16.5 Expectedness assessment 
The expectedness assessment is the responsibility of the sponsor of the study, unless otherwise specified 
in the Group specific appendix. The expectedness assessment will be performed against the following RSI 
(reference safety information): 
• For Temozolomide: RSI Section 4.8 of Summary of Product Characteristics (SmPC) which can be found 
on the European Medicines Agency’s website. 

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16.6 Reporting procedure for investigators 
This procedure applies to all Serious Adverse Events (SAE) occurring from the time a subject is 
randomization until 30 days after last protocol treatment and to any SAE that occurs outside of the SAE 
detection period (after the 30-days period), if it is considered to be likely related to the investigational 
product or study participation. 
Randomization till 30 days after last protocol treatment: All SAEs 
From day 31 after last protocol treatment: 
Only related SAEs 
 
All reporting must be done by the principle investigator or authorized staff member (i.e. on the signature 
list) to confirm the accuracy of the report. 
All SAE data must be collected on the study-specific SAE form. 
All SAEs must be reported immediately and no later than 24 hours from the time the investigator or staff 
became aware of the event.  
All SAE-related information needs to be provided in English. 
All additional documents in local language must be accompanied by a translation in English, or the 
relevant information must be summarized in a follow-up SAE report form. 
Investigators participating through EORTC must fax/e-mail all SAE-related information to: 
 
EORTC Pharmacovigilance: 
 
Fax No. +32 2 772 8027 
E-mail: Pharmacovigilance@eortc.org 
Investigators participating through non-EORTC groups should consult their group specific appendix for 
further details on the reporting of Serious Adverse Events. 
To enable the EORTC to comply with regulatory reporting requirements, all initial SAE reports should 
always include the following minimal information: an identifiable patient (SeqID), a suspect medicinal 
product if applicable, an identifiable reporting source, the description of the medical event and 
seriousness criteria, as well as the causality assessment by the investigator. Complete information 
requested on the SAE form of any reported serious adverse event must be returned within 7 calendar 
days of the initial report. If the completed form is not received within this deadline, the EORTC 
Pharmacovigilance will make a written request to the investigator. 
Queries sent out by the EORTC Pharmacovigilance need to be answered within 7 calendar days. 
All forms need to be dated and signed by the principle investigator or any authorized staff member (i.e. 
on the signature list). 
16.7 Reporting to investigators and competent authorities 
The EORTC Pharmacovigilance will forward all SAE reports within 24 hours of receipt to the appropriate 
persons within the EORTC Headquarters, the EORTC Study Coordinator and the pharmacovigilance 
contact at Merck. 
All SUSARs will additionally be notified to all EORTC participating investigators, Ethics committees (of 
EORTC centers) and all central Data Managers of all Cooperating Groups.  

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The EORTC Pharmacovigilance will take in charge the expedited reporting to all Competent Authorities 
and EVCTM, whenever applicable. 
The EORTC Pharmacovigilance will prepare the Annual Safety Report/ Development Safety Update Report 
and distribute it to the central Data Managers of all Cooperating Groups, the European Competent 
Authorities and Merck. 
Every Group shall be responsible for distribution of Safety information to their investigators and 
respective Ethics Committees, whenever applicable. 
16.8 Pregnancy reporting 
Pregnancy occurring during a patient’s participation in this trial, although not considered an SAE, must be 
notified to the EORTC Pharmacovigilance of the respective group Data Center within the same timelines 
as an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy should be 
followed up carefully and any abnormal outcome of the mother or the child should be reported. This also 
applies to pregnancies following the administration of the investigational product to the father prior to 
sexual intercourse. 
• Any pregnancy in a female subject or in a female partner of a male subject diagnosed during the 
treatment period or within 30 days after last study treatment administration must be reported to the 
EORTC Pharmacovigilance of the respective group Data Center 
• This must be reported within 24 hours of first becoming aware of the event by fax, to EORTC 
Pharmacovigilance on a Pregnancy Notification Form/Fax  
• If a Serious Adverse Event (SAE) occurs in conjunction with the pregnancy, please also complete an 
SAE form as explained in the SAE chapter 
• Upon notification of a pregnancy, it will be the responsibility of the pharmaceutical company, Merck, 
to follow-up the development and outcome of the pregnancy. 
17 Quality assurance 
17.1 Control of data consistency 
Data forms will be entered into the database of the EORTC Headquarters by a double data entry 
procedure. Computerized and manual consistency checks will be performed on newly entered forms; 
queries will be issued in case of inconsistencies. Consistent forms will be validated by the data manager. 
Inconsistent forms will be kept "pending" until resolution of inconsistencies. 
17.2 Audits 
The EORTC is responsible for the performance of the EORTC investigators. 
The investigator, by accepting to participate in this protocol, agrees that EORTC, any third party (e.g. a 
CRO) acting on behalf of the EORTC, or any domestic or foreign regulatory agency, may come at any time 
to audit or inspect their site and all subsites, if applicable.  
This audit consists of interviews with the principal investigator and study team, review of documentation 
and practices, review of facilities, equipment and source data verification. 
The investigator will grant direct access to paper and/or electronic documentation pertaining to the 
clinical study (e.g. CRFs, source documents such as hospital patient charts and investigator study files) to 
these authorized individuals. All site facilities related to the study conduct could be visited during an 

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audit (e.g. pharmacy, laboratory, archives …). The investigator agrees to co-operate and provide 
assistance at reasonable times and places with respect to any auditing activity. 
If applicable, the company(ies) supplying the study drug(s) may have access to anonymized data but will 
not have access to source documents. 
If a regulatory authority inspection is announced, the investigator must inform the EORTC Headquarters 
Compliance and Audits immediately (contact at: Complianceandaudits@eortc.org). 
In this way EORTC can provide support in preparing and/or facilitating the inspection. EORTC 
representatives/delegates may also attend the inspection. 
17.3 External review of histology and molecular diagnosis 
17.3.1 
Central review of histology 
Samples shipments should be addressed to Martin J. VAN DEN BENT (see section 17.3.3 for instructions). 
The central pathology review will be carried out by J.M. Kros and P. Wesseling. 
For the review, material embedded in paraffin must be sent to the above laboratory (same block will be 
used for the determination on 1p/19q, see section 17.3.3). 
17.3.2 
Central review of molecular diagnosis  
Eligible for this study are patients with a histological diagnosis of an anaplastic astrocytoma, anaplastic 
oligoastrocytoma and anaplastic oligodendroglioma, without combined 1p/19q loss. Patients can be 
entered into the study either based on the local diagnosis or on central histology review and 1p/19q 
assessment. Centers must decide prior to the site initiation whether they will include patients based on 
local or on central histology and 1p/19q diagnosis.  
Different techniques are available to assess loss of 1p and 19q (FISH, LOH, array CGH). Only centers that 
fulfill minimum quality requirements for 1p/19q testing and that are cleared by the EORTC Headquarters 
will be allowed to enter patients based on local diagnosis (see Appendix J). This must be determined prior 
to study activation by the EORTC datacenter and the study coordinator. Tumors from patients from 
centers that use central 1p/19q testing for eligibility assessment will simultaneously undergo histological 
review; patients are only eligible if at least one of the two central reviewers has confirmed the 
histological diagnosis and in the absence of combined 1p/19q loss. 
To allow stratification of the patients according to MGMT status immediate post-surgery shipping of 
tumor material together with the required blood samples is an absolute requirement. This also concerns 
tumor material from patients from centers that enter patients based on local 1p/19q testing. 
Stratification for MGMT status will be either ‘methylated’, ‘non-methylated’ or ‘undeterminate’. Patients 
in whom MGMT status cannot be determined because of insufficient material, material not timely 
received etc will still be eligible for the study (and will be stratified for MGMT status as ‘undeterminate’). 
Both the 1p/19q testing and the MGMT promoter methylation determination are essential for the study. 
The submission of tissue for these assays is therefore mandatory. The procedures for Europe are 
explained below. For non-European centers, a similar procedure is covered by Group Specific Appendices. 
For patients that are included in the trial based on local determination the histological and molecular 
diagnosis will be centrally reviewed. Thus, for all patients 1p/19q status will be centrally assessed as 
part of the trial. 

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17.3.2.1 
Centers without local 1p/19q testing 
Centers relying on inclusion based on central histological review and 1p/19q testing must submit tumor 
material to the Erasmus University Hospital for eligibility assessment. Only samples received from sites 
that have activated the study will be reviewed and investigated for 1p/19q loss. Both the center and the 
EORTC will receive the 1p/19q test result and the histology review outcome. The central pre-
randomization histology review and 1p/19q testing requires the registration of patients with an eligible 
local histological diagnosis at the EORTC Data Center after obtaining patient approval using the 
registration consent form. This form covers the submission of tumor material and blood for central 
testing. Once the patient is found eligible at both central histology review and 1p/19q assessment he can 
be entered into the study. 
17.3.2.2 
Centers with local 1p/19q testing facilities 
Patients with eligible histologies as diagnosed by the local pathologist and in whom local testing has 
assessed intact 1p, 19q or both can be randomized directly into the trial. However, because pre-
radiotherapy assessment of MGMT status is vital for the study stratification, it is still requested to submit 
a tumor sample and a blood sample as soon as possible. The patient must therefore as soon as possible 
be registered at the EORTC Headquarters after obtaining approval using the registration consent form. 
This form covers the submission of tumor material and blood for central testing. The result of the central 
histology review and 1p/19q assessment will be made available to the center after randomization. 
17.3.2.3 
Central review for MGMT 
MGMT central testing requires shipment of a tumor sample to the central Laboratory. MGMT status 
determination may be time consuming and may therefore not be compatible with the maximum time to 
elapse between diagnosis and start of radiotherapy which is of 7 weeks. The central facility will be set up 
but central MGMT status determination will not be made mandatory during the first year to test the 
feasibility. If central testing for MGMT is deemed to be feasible, it will be enforced for the rest of the trial. 
Regardless, it will be tried to determine MGMT determination prior to study entry in all patients. 
The material requested for MGMT testing will be sent by the central histopathology laboratory in 
Rotterdam to MDxHealth (Liège, Belgium). 
17.3.3 
Sample requirements and routing 
Following registration of the patient the following items must be collected:  
• A paraffin embedded tumor sample (preferably a tumor block, otherwise 30 unstained slides) 
• The local pathology report (including local diagnosis of 1p/19q status if available) 
• 20 ml whole blood collected in EDTA tubes for 1p/19q status determination  
• the pathology review and 1p/19q form (in case of local evaluation) with the fax number of the center.  
and must be sent by express carrier to:  
 
M.J. van den Bent/I. van Heuvel 
 
Dept Neuro-Oncology 
 
Groene Hilledijk 301 
 
3075EA Rotterdam 
 
the Netherlands 
 
e-mail: m.vandenbent@erasmusmc.nl 
 
phone: +31-10-704 14 15 
 
fax: 
+31-10-704 10 31 

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This material must be sent as soon as possible after surgery, once the patient has given consent for the 
shipment of his material and after he has been registered at the EORTC Headquarters into the trial 
(registration step). Blood samples should be sent within 24 hours from taking the sample, together with 
the tumor specimen.  
1p/19q analysis for assessment of eligibility purposes will be made available to the site, results can be 
expected within 14 days. Central review of 1p/19q status will be done in batches at a later stage (after 
randomization), the results will not be made available to the site unless quality concerns arise. The 
results of the MGMT promoter methylation assay will not be made available to the local center, but only 
to the EORTC Headquarters.  
All SAMPLE SHIPMENTS AND REPORTS must be identified with the EORTC Id (Seqid) attributed at 
registration 
17.3.4 
Post randomization tissue studies 
Following central pathology review, central 1p/19q assessment and MGMT promoter methylation status 
determination, the H&E stained slides will be entered into the EORTC virtual tumor bank.  
Thereafter, material from patients that have consented for optional translational research will be stored 
centrally. If tissue blocks have been made available these will be centrally stored if permission for central 
storage has been obtained. In case consent for optional translational research has been obtained but not 
for central storage of tissue blocks tissue micro arrays will be made after which the blocks will be 
returned to the center. 
17.4 Other central review procedures 
17.4.1 
Central review for Imaging 
The study primary end-point is survival. No central review of imaging is planned for this trial. 
17.4.2 
Central review for Quality Assurance in Radiotherapy 
17.4.2.1 
Facility Questionnaire 
For participating EORTC institutes, which are not members of the EORTC Radiotherapy Group or for Brain 
Tumor Group members, who have not yet filled in the facility questionnaire or have filled in the 
questionnaire longer than 1.5 years ago, the EORTC Facility Questionnaire aiming to assess the 
techniques and infrastructure of each institute delivering radiotherapy in this trial must be completed 
prior to study activation. The Facility Questionnaire is available on the website of the EORTC 
Radiotherapy Group and can be downloaded and submitted online. The exact location (website address) 
and procedure of filling in the FQ will be explained in the starting letter being included in the starting 
package of this trial.  
17.4.2.2 
Case Review 
The QA team of the EORTC Radiotherapy Group, including the study chairperson being responsible for 
radiotherapy issues will review the irradiation technique in randomly selected patients. The objectives 
will be to check compliance to the protocol guidelines regarding PTV definition, planning technique and 
documentation. This will include image co-registration and treatment technique. 
17.4.2.3 
Complex Dosimetry Check for IMRT 
Intensity-modulated radiation therapy (IMRT) will be allowed providing sufficient proof of external IMRT 
credentialing is submitted to and approved by the EORTC QART team. 
 

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Chapters 18 through 21 pertain specifically to the participation of EORTC investigators. Participants from 
other organizations should consult the appendix that is specific to their group to determine if the 
contents of these chapters are superseded by procedures specific to their group. 
 
 
 
 

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18 Ethical considerations 
18.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either the 
Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh amendments) and/or 
the laws and regulations of the country, whichever provides the greatest protection of the patient. 
The protocol has been written, and the study will be conducted according to the ICH Harmonized 
Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 
https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-
practice_en.pdf). 
The protocol must be approved by the competent ethics committee(s) as required by the applicable 
national legislation. 
18.2 Subject identification 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. A sequential 
identification number will be automatically allocated to each patient registered in the trial. This number 
will identify the patient and must be included on all case report forms. In order to avoid identification 
errors, the patient’s code (maximum of 4 alphanumerics) and date of birth or year of birth (as allowed 
per applicable legislation) will also be reported on the case report forms. 
18.3 Informed consent 
All patients will be informed about 
• the aims of the study 
• the possible adverse events 
• the procedures and possible hazards to which the patient will be exposed 
• the mechanism of treatment allocation 
• strict confidentiality of any patient data 
• medical records possibly being reviewed for trial purposes by authorized individuals other than their 
treating physician. 
The template of the patient’s informed consent statement is given as an appendix to this protocol. 
It is the responsibility of the Coordinating Investigators for this trial (sometimes called National 
Coordinators) to translate the enclosed informed consent document. The translated version should be 
dated and version controlled. 
The translated informed consent documents are to be submitted to ethics committees for approval. 
The competent ethics committee for each institution must approve the informed consent documents 
before the center can join the study. It is the responsibility of the competent ethics committee to ensure 
that the translated informed documents comply with ICH-GCP guidelines and all applicable national 
legislation. 
It is emphasized in the patient information sheet that participation is voluntary and that the patient is 
free to refuse further participation in the protocol whenever he/she wants to. This will not have any 
impact on the patient’s subsequent care. Documented informed consent must be obtained for all 
patients included in the study before they are registered and/or randomized at the EORTC Headquarters. 

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The written informed consent form must be signed and personally dated by the patient or by the 
patient’s legally acceptable representative”. 
All of the above must be done in accordance with the applicable national legislation and local regulatory 
requirements. 
19 Administrative responsibilities 
19.1 The study coordinator 
The Study Coordinator (in cooperation with the EORTC Headquarters) will be responsible for writing the 
protocol, contributing to the medical review, discussing the contents of the reports with the Data 
Manager and the Statistician, and for publishing the study results. He will assist the Clinical Research 
Physician for answering some clinical questions concerning eligibility, treatment, and the medical review 
of the patients. 
Study coordinators:  
EORTC Brain Tumor Group 
 
Martin J. Van Den Bent 
 
ERASMUS UNIVERSITY MEDICAL CENTER 
 
Postbus 5201 (Groene Hilledijk 301) 
 
NL-3008 AE Rotterdam 
 
The Netherlands 
 
Phone: +31 10 704 14 15 
 
Fax: 
+31 10 704 10 31 
 
e-mail: m.vandenbent@erasmusmc.nl 
EORTC Radiation Oncology Group 
 
Brigitta Baumert 
 
MAASTRO - MAASTRICHT RADIATION ONCOLOGY 
 
AzM, Dr Tanslaan 12 
 
NL-6219 ET Maastricht 
 
The Netherlands 
 
Phone: +31 88 5566666 
 
Fax: 
+31 88 5566667 
 
e-mail: brigitta.baumert@maastro.nl 
The study coordinators will be assisted by: 
 
Riccardo Soffietti 
 
OSPEDALIERA SAN GIOVANNI BATTISTA -UNIVERSITÀ DI TORINO 
 
Via Cherasco, 15 
 
I-10126 Torino 
 
Italy 
 
Phone: +39 011 6334904 
 
Fax: 
+39 011 6963487 
 
e-mail: riccardo.soffietti@unito.it 
 
 
 

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Wolfgang Wick 
UNIVERSITAETSKLINIKUM HEIDELBERG 
Im Neuenheimer Feld 400 
69120 Heidelberg 
Germany 
Phone +49 6221566703 
Fax: 
+49 6221567554 
e-mail: wolfgang.wick@uni-tuebingen.de 
 
Antonio Omuro 
 
CHU PITIE-SALPETRIERE 
 
47-83, boulevard de l'Hôpital 
 
F-75651 Paris CEDEX 13 
 
France 
 
Phone: +49 7071 2982141 
 
Fax: 
+49 7071 295260 
 
e-mail: antonio.omuro@psl.ap-hop-paris.fr 
19.2 The EORTC Headquarters 
The EORTC Headquarters will be responsible for writing the protocol and PIS/IC, reviewing the protocol, 
setting up the trial, collecting case report forms, controlling the quality of the reported data, organizing 
the medical review and generating reports and analyses in cooperation with the Study Coordinator. All 
methodological questions should be addressed to the EORTC Headquarters. 
EORTC HEADQUARTERS 
 
Avenue E. Mounierlaan 83/11 
 
Brussel 1200 Bruxelles 
 
België - Belgique 
 
Fax: +32 2 7723545 
 
e-mail: eortc@eortc.org 
Registration of patients: 
 
http://www.eortc.be/random 
 
Or 
 
Phone (in case of problems): +32 2 774 16 00 
19.3 The EORTC group 
All questions concerning ongoing membership in the group should be addressed to the chairman and/or 
secretary of the group. 
For new membership contact Membership Committee at membership@eortc.org 
 
 

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EORTC Brain Tumor Group 
Chairman: 
Michael Weller  
UniversitaetsSpital Zurich 
Department of Neurology 
Frauenklinikstrasse 26 
8091 Zurich 
Switzerland 
Phone: +41 44 255 5500 
Fax: 
+41 44 255 4507 
e-mail: michael.weller@usz.ch 
Secretary: 
Jaap Reijneveld 
 
Amsterdam UMC - VU University Amsterdam 
 
Department of Neurology 
 
P.O. Box 7057 -(De Boelelaan 1117) 
 
1007 MB Amsterdam 
 
The Netherlands 
 
Phone: +31 20 4442821 
 
Fax: 
+31 20 4442800 
 
e-mail: jc.reijneveld@vumc.nl 
20 Trial sponsorship and financing 
EORTC is the legal Sponsor for all EORTC participants. 
The contact details of the EORTC are: 
 
EORTC Headquarters 
 
Avenue E. Mounierlaan 83/11 
 
Brussel 1200 Bruxelles 
 
België - Belgique 
 
Phone: +32 2 7741611 
 
Fax: 
+32 2 7723545 
 
e-mail: eortc@eortc.org 
The study is supported by an educational grant of Merck. 
21 Trial insurance 
A clinical trial insurance has been taken out according to the laws of the countries where the study will be 
conducted. An insurance certificate will be made available to the participating sites at the time of study 
initiation. 
Clinical trial insurance is only valid in centers authorized by the EORTC Headquarters. For details please 
refer to the chapter on investigator authorization. 

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Patients treated at satellite institutions are only covered by clinical trial insurance, if these satellite 
institutions are properly reported to the EORTC Headquarters. For details please refer to the chapter on 
investigator authorization. 
 

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Appendix A: References 
Ref. 1 
Cairncross G, Macdonald D, Ludwin S, et al.: Chemotherapy for anaplastic oligodendroglioma. J 
Clin Oncol 12:2013-2021, 1994 
Ref. 2 
Kappele AC, Postma TJ, Taphoorn MJ, et al.: PCV chemotherapy for recurrent glioblastoma 
multiforme. Neurology 56:118-120, 2001 
Ref. 3 
van den Bent MJ, Taphoorn MJ, Brandes AA, et al.: Phase II study of first-line chemotherapy with 
temozolomide in recurrent oligodendroglioma: the European Organisation of Research and 
Treatment of Cancer Brain Tumor Group study 26971. J Clin Oncol 21:2525-2528, 2003 
Ref. 4 
Yung WKA, Prados M, Yaya-Tur R, et al.: Multicenter phase II trial of temozolomide in patients 
with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17:2762-
2771, 1999 
Ref. 5 
Yung WKA, Albright RE, Olson J, et al.: A phase II study of temozolomide vs. procarbazine in 
patients with glioblastoma multiforme at first relapse. Br J Cancer 83:588-593, 2000 
Ref. 6 
Reifenberger J, Reifenberger G, Liu L, et al.: Molecular genetic analsysis of oligodendroglial 
tumors shows preferential allelic deletions on 19q and 1p. Amer J Pathol 145:1175-1190, 1994 
Ref. 7 
Smith JS, Perry A, Borell TJ, et al.: Alterations of chromosome arms 1p and 19q as predictors of 
survival in oligodendrogliomas, astrocytoma, and mixed oligoastrocytomas. J Clin Oncol 18:636-
645, 2000 
Ref. 8 
Cairncross JG, Ueki K, Zlatescu MC, et al.: Specific genetic predictors of chemotherapeutic 
response and survival in patients with anaplastic oligodendrogliomas. J Natl Canc Inst 90:1473-
1479, 1998 
Ref. 9 
van den Bent MJ, Carpentier AF, Brandes AA, et al.: Adjuvant PCV improves progression free 
survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and 
oligoastrocytomas: a randomized EORTC phase III trial. J Clin Oncol (in press) 
Ref. 10 Cairncross JG, Berkey B, Shaw E, et al.: Phase III trial of chemotherapy plus radiotherapy (RT) 
versus RT alone for pure and mixed anaplastic oligodendroglioma (RTOG 9402): an intergroup 
trial by the RTOG, NCCTG, SWOG, NCI CTG and ECOG. J Clin Oncol (in press) 
Ref. 11 Stupp R, Mason WP, van den Bent MJ, et al.: Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 
Ref. 12 Hegi ME, Diserens A-C, Gorlia T, et al.: MGMT gene silencing and benefit from temozolomide in 
glioblastoma. N Engl J Med 352:997-1003, 2005 
Ref. 13 Fischbach AJ, Martz KL, Nelson JS, et al.: Long-term survival in treated anapalstic astrocytomas. A 
report of combined RTOG/ECOG studies. Am J Clin Oncol 14:365-370, 1991 
Ref. 14 Friedman HS, McLendon RE, Kerby T, et al.: DNA mismatch repair and 06-alkylguanine-DNA 
alkyltransferase and response to temodal in newly diagnosed malignant glioma. J Clin Oncol 
16:3851-3857, 1998 
Ref. 15 Gilbert MR, Friedman H, Kuttesch JF, et al.: A phase II study of temozolomide in patients with 
newly diagnosed supratentorial malignant glioma before radiation therapy. Neuro-Oncology 
4:261-267, 2002 

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Ref. 16 Chang SM, Prados MD, Yung WKA, et al.: Phase II study of neoadjuvant 1, 3-bis (2-chloroethyl)-1-
nitrosourea and temozolomide for newly diagnosed anaplastic glioma: a North American Brain 
Tumor Consortium Trial. Cancer 100:1712-1716, 2004 
Ref. 17 Rao RD, Krishnan S, Fitch TR, et al.: Phase II trial of carmustine, cisplatin, and oral etoposide 
chemotherapy before radiotherapy for grade 3 astrocytoma (anaplastic astrocytoma): results of 
North Central Cancer Treatment Group trial 98-72-51. Int J Radiat Oncol Biol Phys 61:380-386, 
2005 
Ref. 18 International Commission on Radiation Units and Measurements. ICRU Report 62. Prescribing, 
recording, and reporting photon beam therapy (Supplement to ICRU Report 50). Bethesda, MD: 
ICRU, 1999 
Ref. 19 de Wit MCY, de Bruin HG, Eijkenboom WMH, et al.: Immediate post-radiotherapy changes in 
malignant glioma can mimic tumor progression. Neurology 63:535-537, 2004 
Ref. 20 Folstein MF, Folstein SE, McHugh PR. Mini-mental state: A practical method for grading the 
cognitive state of patients for the clinician. Journal of Psychiatric Research 1975;12(3):189-198  
Ref. 21 Tagalos EG, Smith GE, Ivnik RJ et al: The Mini-Mental State Examination in general medical 
practice: clinical utility and acceptance. May Clin Proc 71: 829-837, 1996) 
Ref. 22 Brown PD, Buckner JC, O’Fallon JR, Iturria NL, Brown CA, O’Neill B, Sheithauer BW, Dinapoli RP, 
Arusell RM, Curran WJ, Abrams R and Shaw EG. Effects of radiotherapy on cognitive function in 
patients with low grade glioma measured by the Folstein Mini-Mental State Examination) 
Ref. 23 Slud,E.V., Byar,D.P., and Green,S.B., Biometrics 40, 587-600 (1984) 
Ref. 24 Schoenfeld D: Partial residuals for the proportional hazards regressioin model. Biometrika 
69:239-241, 1982 
Ref. 25 Harrell FE jr, Lee KL, Mark DB: Tutorial in Biostatistics. Multivariable Prognostic Models: Issues in 
Developing Models, Evaluating Assumptions and Adequacy, and Measuring and Reducing Errors. 
Stat Med 15:361-387, 1996 
Ref. 26 Aaronson-NK; Ahmedzai-S; Bergman-B; Bullinger-M; Cull-A; Duez-NJ; Filiberti-A; Flechtner-H; 
Fleishman-SB; et-al. The European Organization for Research and Treatment of Cancer QLQ-C30: 
a quality-of-life instrument for use in international clinical trials in oncology. J-Natl-Cancer-Inst. 
1993 Mar 3; 85(5): 365-76 
Ref. 27 Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of changes in health related 
quality-of-life scores. J Clin Oncol 16:139-144, 1998 
Ref. 28 Bottomley A, Efficace F, Stupp R, Van Steen K, Coens C, Osoba D, Van den Bent M, Mason W, 
Cairncross G, Eisenhauer E, Wong R, Villa S, Mirimanoff R, Reni M, Taphoorn MJ. A bootstrap 
model averaging technique to investigate the prognostic value for survival of quality of life 
information. 12th Annual Conference of the International Society for Quality of Life Research, 
San Francisco, CA (USA). Quality of Life Research, 14, 9, 2136, abs 1022, Oct 2005 
Ref. 29 Hartmann C, Mueller W, Lass U, et al.: Molecular genetic analysis of oligodendroglial tumors. J 
Neuropathol Exp Neurol 64:10-14, 2005 
Ref. 30 Parsons DW, Jones S, Zhang X, et al.: An integrated genomic analysis of human glioblastoma 
multiforme. Science 321:1807-1812, 2008 

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Ref. 31 Watanabe T, Nobusawa S, Kleihues P, et al.: IDH1 mutations are early events in the development 
of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149-1153, 2009 
Ref. 32 Dubbink HJ, Taal W, van Marion R, et al.: IDH1 mutations in low-grade astrocytomas predict 
survival but not response to temozolomide. Neurology 73:1792-1795, 2009 
Ref. 33 Wick W, Hartmann C, Engel C, et al.: NOA-04 Randomized Phase III Trial of Sequential 
Radiochemotherapy of Anaplastic Glioma With Procarbazine, Lomustine, and Vincristine or 
Temozolomide. J Clin Oncol 27:5874-5880, 2009 
Ref. 34 Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation 
analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J 
Neuropathol Exp Neurol. 2009 Dec;68(12):1319-25 
Ref. 35 Dubbink HJ, Atmodimedjo PN, Kros JM, et al.: Molecular classification of anaplastic 
oligodendroglioma using next generation sequencing . A report of the prospective randomized 
EORTC Brain Tumor Group 26951 phase III trial. Neuro Oncol 18:388-400, 2016 

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Appendix B: WHO performance status scale 
Grade 
Performance scale 
0 
Able to carry out all normal activity without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out light work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work; up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair. 
 
 

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Appendix C: Common Terminology Criteria for Adverse 
Events 
In the present study, adverse events and/or adverse drug reactions will be recorded according to the  
Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. 
At the time this protocol was issued, the full CTC document was available on the NCI web site, at the 
following address:  
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40. 
The EORTC Headquarters web site https://www.eortc.be/services/doc/ctc/ provides a link to the 
appropriate CTC web site. This link will be updated if the CTC address is changed. 
 

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Appendix D: EORTC Quality of Life evaluation: 
guidelines for administration of questionnaires 
(Revised June 2008) 

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EORTC Quality of Life evaluation: guidelines for administration of questionnaires (revised June 2008) 
The instructions given below are intended to provide some general guidelines for collecting quality of life 
(QoL) data in EORTC studies. These instructions apply for all types of questionnaires. 
1. Who is the responsible person (RP) for QoL data collection? 
The overall-responsible person for QoL data collection is the study-co-ordinator of the trial. 
However, in each institution one person should be appointed as the responsible for the local organization 
of QoL data collection. This can be a physician, data manager, (research) nurse or a psychologist. Such a 
person should have the full protocol at his/her disposal as well as the questionnaire(s). This person would 
also be the intermediate contact point in case of any necessary clarification asked by the EORTC 
Headquarters. 
2. Who should fill out the questionnaire? 
In principle it is the patient him/herself who has to fill out QoL forms and preferably without help from 
others. In case a patient is too sick to fill out the questionnaire or if the patient is not able to fill out the 
questionnaire for reasons such as forgetting his/her glasses, another person could read the questions 
without making any comments and report the answers on the forms. If a patient received this type of 
help, please note this on the form. 
3. What instructions should be given to the patient? 
At entry in a study, the RP should give the patient an explanation of the objective of the study and 
instructions for filling out questionnaires. 
The patient should be informed that participation in the QoL protocol is voluntary and that the 
information provided is confidential (identification is only for administrative purposes). 
The following issues should be explained to the patient: 
• The schedule of assessments. 
• The questionnaire is a self-administered questionnaire that should be filled out preferably by the 
patient him (her) self. 
• The patient should circle the choice that best corresponds to his/her situation. 
• There is no right or wrong answer to any of these questions. 
• All questions should be answered. 
The RP should make sure that the patient understands the instructions and that a questionnaire is 
available in the preferred language of the patient (questionnaires in additional languages can be obtained 
via the EORTC HQ). 
At each subsequent assessment as defined by the protocol, the patient should receive the questionnaire 
from the RP or by other appropriate staff if the RP is not available. 

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4. Where should the patient fill out the questionnaire? 
The patient should complete the questionnaire in the clinic, ideally in a quiet, private room. In general it 
does not take more than 5 to 10 minutes to fill out a questionnaire, but patients should be given the time 
they need to answer all questions. 
5. When should the patient fill out the questionnaire? 
When a QoL assessment is planned, the questionnaire should be given to the patient preferably before 
the meeting with the physician, ensuring that the patient has enough time to complete the 
questionnaire. If the patient receives a therapy, the questionnaire should be filled out before 
administration of the treatment. The questionnaire should not be taken home and/or mailed. 
6. Review of the completed questionnaire. 
After the patient has filled out the questionnaire, the person handling the questionnaire should: 
• Check that the date of today is correctly filled in. 
• Check the answers for omissions, for incorrectly completed questions and for inconsistent answers; 
If this is the case: 
• Please ask the patient for the reason for omissions or incorrect answers. If the patient prefers not to 
answer a question this should be noted on the form; 
• Additional explanation may be provided, but the questions should not be rephrased; 
• Any additional comments could be added by the person handling the questionnaire (if possible in 
English) followed by their name and signature. 
7. Missing forms 
If for some reason the patient is unable or does not wish to complete a quality of life questionnaire the 
reason and date of visit should be documented on the questionnaire and returned to the person 
responsible for completing the CRFs (case report forms). 
8. Mailing to the EORTC Headquarters 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, while the 
original source document should be kept on site. As it is impossible to retrospectively collect missing 
quality of life data, please make sure the patient completes the questionnaire at the time-point when 
he/she is supposed to complete it. 
Thank you very much for your cooperation .As it is not possible to retrospectively collect missing QoL 
data, please make sure the patient completes the questionnaire at the time-point when he/she is 
supposed to fill it out. 
Thank you very much for your cooperation 

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EORTC Quality of Life evaluation: instructions for Monitors 
• Check if all QoL questionnaires have been filled out on schedule 
• If not, the Monitor should inform the person in charge of data collection and explain again the 
schedule of the QoL questionnaires. 
• Make sure the QoL questionnaires are correctly completed 
• If not, tell the responsible person to explain again to the patient how to fill out the QoL 
questionnaires at the next visit. 
EORTC Quality of Life evaluation: instructions for Data Managers 
• When a response is missing, it should be coded as “9” for missing data (cfr Scoring Manual) 
• When two adjacent categories have been circled by the patient, the category which represents the 
worst QoL will be taken. 
 
For a symptom item, the highest score will be taken. 
 
For a functional item, the lowest score will be taken. 
• When the response is not legible or ambiguous (eg. two categories which are not adjacent have been 
circled) then the response is not evaluable and it should be coded as “8”. 
 

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Appendix E: World Medical Association Declaration of 
Helsinki 
Ethical Principles for 
Medical Research Involving Human Subjects 
Adopted by the 18th World Medical Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983 
41st World Medical Assembly, Hong Kong, September 1989 
48th General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. INTRODUCTION 
1. 
The World Medical Association has developed the Declaration of Helsinki as a statement of ethical 
principles to provide guidance to physicians and other participants in medical research involving 
human subjects. Medical research involving human subjects includes research on identifiable 
human material or identifiable data. 
2. 
It is the duty of the physician to promote and safeguard the health of the people. The physician’s 
 
knowledge and conscience are dedicated to the fulfillment of this duty. 
3. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, 
"The health of my patient will be my first consideration," and the International Code of Medical 
Ethics  declares that, "A physician shall act only in the patient's interest when providing medical 
care which might have the effect of weakening the physical and mental condition of the patient." 
4. 
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
5. 
In medical research on human subjects, considerations related to the well-being of the human 
subject should take precedence over the interests of science and society. 
6. 
The primary purpose of medical research involving human subjects is to improve prophylactic, 
diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis 
of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must 
continuously be challenged through research for their effectiveness, efficiency, accessibility and 
quality. 
7. 
In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic 
 
procedures involve risks and burdens. 
8. 
Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights. Some research populations are vulnerable and need special 
protection. The particular needs of the economically and medically disadvantaged must be 

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recognized. Special  attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will not 
benefit personally from the research and for those for whom the research is combined with care. 
9. 
Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or 
eliminate any of the protections for human subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. 
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of 
 
the human subject. 
11. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and on adequate laboratory and, where appropriate, animal experimentation. 
12. 
Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
13. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol. This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review  committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence. This independent committee should be in conformity with the laws 
and regulations of the country in which the research experiment is performed. The committee has 
the right to monitor ongoing trials. The researcher has the obligation to provide monitoring 
information to the committee, especially any serious adverse events. The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
14. 
The research protocol should always contain a statement of the ethical considerations involved 
and should indicate that there is compliance with the principles enunciated in this Declaration. 
15. 
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the 
subject of the  research, even though the subject has given consent. 
16. 
Every medical research project involving human subjects should be preceded by careful 
assessment of  predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others. This does not preclude the participation of healthy volunteers in medical 
research. The design of all studies should be publicly available. 
17. 
Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians should cease any investigation if the risks are found to outweigh the 
potential benefits or if there is conclusive proof of positive and beneficial results. 
18. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important 
when the human subjects are healthy volunteers. 

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19. 
Medical research is only justified if there is a reasonable likelihood that the populations in which 
the research is carried out stand to benefit from the results of the research. 
20. 
The subjects must be volunteers and informed participants in the research project. 
21. 
The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient’s information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
22. 
In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of 
the researcher, the anticipated benefits and potential risks of the study and the discomfort it may 
entail. The subject should be informed of the right to abstain from participation in the study or to 
withdraw consent to participate at any time without reprisal. 
After ensuring that the subject has understood the information, the physician should then obtain 
the subject's freely-given informed consent, preferably in writing. If the consent cannot be 
obtained in writing, the non-written consent must be formally documented and witnessed. 
23. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress. In that case the informed consent should be obtained by a well-informed physician who is 
not engaged in the  
investigation and who is completely independent of this relationship. 
24. 
For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to promote the 
health of the population represented and this research cannot instead be performed on legally 
competent persons. 
25. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to 
the consent of the legally authorized representative. 
26. 
Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population. The specific reasons for 
involving research subjects with a condition that renders them unable to give informed consent 
should be stated in the experimental protocol for consideration and approval of the review 
committee. The protocol should state that consent to remain in the research should be obtained 
as soon as possible from the individual or a legally authorized surrogate. 
27. 
Both authors and publishers have ethical obligations. In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results. Negative as well as positive 
results  should be published or otherwise publicly available. Sources of funding, institutional 
affiliations and any possible conflicts of interest should be declared in the publication. Reports of 
experimentation not in accordance with the principles laid down in this Declaration should not be 
accepted for publication. 
 
 

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C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
28. 
The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical 
research is combined with medical care, additional standards apply to protect the patients who 
are research subjects. 
29. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists. 
30. 
At the conclusion of the study, every patient entered into the study should be assured of access to 
the best proven prophylactic, diagnostic and therapeutic methods identified by the study. 
31. 
The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the patient-
physician relationship. 
32. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do 
not exist or have been ineffective, the physician, with informed consent from the patient, must be 
free to  use unproven or new prophylactic, diagnostic and therapeutic measures, if in the 
physician’s judgement it offers hope of saving life, re-establishing health or alleviating suffering. 
Where possible, these measures should be made the object of research, designed to evaluate 
their safety and efficacy. In all cases, new information should be recorded and, where 
appropriate, published. The other relevant  guidelines of this Declaration should be followed. 
 

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Appendix F: Patient information sheet and Informed 
consent document for registration in the clinical trials 
including mandatory research on biological material 
 
“Patient information sheet and informed consent document for registration in the clinical trials including 
mandatory research on biological material” is a separate document. 
 

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Appendix G: Patient information sheet and informed 
consent document for randomization in the clinical trial 
 
“Patient information sheet and informed consent document for randomization in the clinical trial” is a 
separate document. 
 

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Appendix H: Patient information sheet and informed 
consent document for future and optional research on 
biological material 
 
“Patient information sheet and informed consent document for future and optional research on 
biological material” is a separate document. 
 
 
 

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Appendix I: Neurocognitive testing for dedicated 
centers – Side study 
The assessment of neurocognitive testing as specified in this appendix relates to a side study to the main 
protocol. This study will be performed at a number of dedicated centers, on a voluntary basis. Institutions 
with patients participating in the quality of life/neurocognitive function components of this study must 
meet certification requirements for administering neurocognitive assessments. See Appendix II for 
details. 
1. Schedule and tests performed 
Comprehensive neurocognitive testing will be performed at randomization and at every year from 
randomization up to tumor progression or death. 
The tests that constitute the neurocognitive function battery were selected because they are widely used 
standardized psychometric instruments that have been shown to be sensitive to the neurotoxic effects of 
cancer treatment in other clinical trials. Neurocognitive function has also been demonstrated to predict 
tumor progression and independently predict survival for patients with CNS tumors. This battery has 
furthermore been demonstrated to be practical in terms of cost and burden to the patient, with good 
compliance in multicenter trials. They are widely used, standardized psychometric instruments with 
published normative data that take into account age and, where appropriate, education, gender and 
handedness. The tests were also selected to minimize the effects of repeated administration. These tests 
are to be administered by a certified examiner and require 25 minutes or less to complete. 
To reduce practice effects, parallel versions of the tests will be developed and will be made available to 
all participating centers. 
Self-reported cognitive function will be assessed with a six-item scale developed for use in the Medical 
Outcomes Study (MOS scale). This scale assesses day-to-day problems with cognitive function, such as 
difficulty with reasoning and problem solving, slowed reaction time, forgetfulness, and problems with 
concentration. 
2. Neurocognitive Function Testing Certification 
The healthcare professional (e.g., nurse, psychologist) who is responsible for test administration in this 
study requires pre-certification by M. Klein in order to participate in this protocol. For the exact 
procedure see appendix II. 
In short, test and data recording forms are available on a password-protected website:  
 
www.vumc.nl/neurooncology  
Test instructions and administration procedures will be provided upon agreement to participate in the 
side-study. A training video of test administration and data collection procedures are accessible through 
a password-protected website at M. D. Anderson Cancer Center for review and reference during this 
study. This video must be reviewed with the test Instructions for the Neurocognitive Function Battery by 
anyone who will administer neuropsychological assessments. The post test associated with this video 
must be completed and faxed to M. Klein. Passwords for the website will be provided by M. Klein, for 
which he can be contacted by e-mail (see below). 
3. Statistical analysis 
Overall power calculation for estimating sample size requirements were based on the following criteria: 
(1) 4 treatment arms, (2) a minimal effect size f(V) of 0.25, (3) power (1-ß) of 0.95, and (4) 3 

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neurocognitive follow-up assessments after randomization. With α = 0.05, 129 patients in total (n=32 per 
treatment arm) are needed to perform repeated measures MANOVA, with potential within and between 
groups interactions. With a minimal effect size f(V) of 0.15 353 patients in total (n=88 per treatment arm) 
are needed. Considering that not all centers will participate in the neurocognitive side-study, the present 
study meets these sample size requirements. 
We will use various models, including the Cox proportional hazards model and mixed and hierarchical 
linear models. Alternatively, we can use multilevel modeling to detect differences between the four 
groups over time. These repeated measure analyses can also be supplemented with a psychometric 
analysis of changes in test performance using the Reliable Change (RC) Index [10]. The difference 
between the pre-treatment baseline and follow-up assessments will be evaluated by the RC index. This 
index is derived from the standard error of measurement (SEM) for each test in the battery. The SEM is 
calculated from the test-retest reliability (r) and the standard deviation of test scores (SD): SEM=SD(1- 
r)½. The standard error of difference is then calculated: SE diff=[2(SEM2)]½. A reliable change (RC) in test 
scores from baseline to follow-up is considered significant if it is within + (1.64)(SE diff), a 90% confidence 
interval. For each subject, the difference between the pre-treatment baseline and each follow-up 
assessment will be coded (according to the RC index) as 1 (deterioration), 2 (no change), and 3 
(improved). Frequency tables will show the percentage of patients in each treatment protocol who show 
meaningful losses or gains in the various test domains over the course of the study. Treatment group 
differences can be compared using chi-square analysis and Cochran’s and Mantel-Haenszel statistics. 
4. Data Management 
All tests will be identified by the date of assessment and EORTC patient identification number (seqid). 
The test results from all participating centers and groups will be sent to the EORTC Headquarters 
together will the regular patient documentation. The EORTC Headquarters will then transfer the forms 
relating to the neurocognitive assessment side study to the Coordinator of the Side Study (Martin Klein, 
VU University Medical Center, Amsterdam, The Netherlands). 
The information related to the side study will be entered in a specific database in Amsterdam. Care will 
be taken that the patient identification is recorded. 
At the end of the clinical trial after publication of the main trial results, the information from the clinical 
database that is needed for the analysis of the side study data will be transferred to the Coordinator of 
the Side Study, after completion and approval of the Request for External Release of Data as specified in 
EORTC Policy number 8. 
The neurocognitive side study coordinator will be responsible for assuring the statistical analysis of the 
neurocognitive testing results. The Study Coordinator will also lead the preparation of a publication 
relating to the findings of this side study. Other co-authors on this publication will be the Study 
Coordinators of the Clinical Trial, the statistician who performed the analysis of the side study results and 
other contributors to the side study. All participants to the side study will be acknowledged. 
5. Scientific Committee and publication policy 
This project is coordinated by the side study coordinators in collaboration with the PI of the clinical study. 
The PI Side Study coordinator is responsible for the preparation of the manuscript and will be the leading 
author. Other co-authors on this publication will be all Side Study Coordinators, the Study Coordinators of 
the Clinical Trial, the statistician who performed the analysis of the side study results and other main 
contributors to the side study according to the general EORTC BTG policy. All participants to the side 
study will be acknowledged.  
 
 

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Side study coordinators:  
For EORTC (and PI Side Study):  
M. Klein 
Department of Medical Psychology 
VU University Medical Center 
Van der Boechorststraat 7 
1081 BT Amsterdam 
The Netherlands 
T +31 20 4448432 
F +31 20 4448230 
Email: m.klein@vumc.nl 
Webadress: 
www.vumc.nl/neurooncology  
For CTSU:  
Jeffrey Wefel 
Assistant Professor 
Section of Neuropsychology 
Department of Neuro-Oncology, Unit 431 
University of Texas M.D. Anderson Cancer Center 
P.O. Box 301402 
Houston, TX 77230-1402 
phone: 713.563.0514 
fax: 
713.794.4999 
email:  jwefel@mdanderson.org 
 
 

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Appendix II 
Certification and administration procedures for the neurocognitive test battery 
General Procedures: Certification for Test Administration 
The healthcare professional (e.g., nurse, psychologist) who is responsible for test administration in this 
study requires pre-certification by M. Klein in order to participate in this protocol.  
• Test and data recording forms are available on the password-protected website provided by M. Klein. 
Test instructions and administration procedures are provided in Appendix III. The instructions must 
be reviewed along with the test forms and retained for reference. 
• A training video of test administration and data collection procedures are accessible through a 
password-protected website at M. D. Anderson Cancer Center for review and reference during this 
study. 
• This video must be reviewed with the “Test Instructions for the Neurocognitive Function Battery” 
found in Appendix III by anyone who will administer neuropsychological assessments. 
• The post test associated with this video must be completed and faxed to M. Klein.  
To obtain website and password information for the training video, contact: 
Martin Klein 
VU Medical Center 
Amsterdam, The Netherlands 
Tel: + 31 20 4448432 
e-mail: m.klein@vumc.nl 
• Prior to the enrollment of any patient onto the study, the healthcare professional who will be 
evaluating patients must complete a “practice” assessment, including completion of test forms/score 
sheets, neurocognitive evaluation summary form, and complete and sign the Certification Worksheet 
(Appendix IV). Fax the practice tests, score sheets, neurocognitive evaluation summary form, training 
video post test, and signed Certification Worksheet to the attention of M. Klein, FAX: +31 20 4448230. 
• If there are administration or procedural errors, M. Klein will discuss the test administration and 
scoring issues over the phone with the healthcare professional (5-10 minutes). If the health 
professional meets criteria for certification, notification of certification will be sent to both the site 
and to EORTC, and study enrollment may commence. 
• The first case for each certified examiner should be faxed to M. Klein. Please send the test forms and 
all test summary and score sheets and include contact information (name, phone, email) for the 
certified examiner. M. Klein will review test forms and summary sheets for quality control purposes. 
Procedural deviations (if any) will be identified, and sites will be notified of the results of the review. 
If significant procedural variations are noted, re-training (‘re-certification’) of the test administrator 
will be requested.  
• Completed test forms must be signed by the certified test administrator. M. Klein will be available by 
telephone and e-mail if questions arise about the testing procedures. M. Klein may be contacted at 
phone: +31 20 4448432 or email: m.klein@vumc.nl.  
• Results of the HLVT-R, COWA, and Trail Making Tests should be recorded on the Neurocognitive 
Evaluation Summary Form (CS), and the original patient tests/forms will not be submitted to M. Klein 
(copies of test forms and summary sheets for the first case will be sent to M. Klein per Appendix II). 
All tests will be identified by the date of assessment and EORTC patient identification number (seqid). 
The test results will be sent to the EORTC Headquarters together will the regular patient 
documentation. The EORTC Headquarters will then transfer the forms relating to the neurocognitive 

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assessment side study to the Coordinator of the Side Study (Martin Klein, VU University Medical 
Center, Amsterdam, The Netherlands). 
Summary of Requirements for Examiner Approval for EORTC 26053_22054 
Prior to testing a patient, potential examiners must:  
1. 
Read Appendix II and III 
2. 
Obtain copies of the neurocognitive tests 
3. 
Watch the training video available on a password-protected website. To obtain website and 
password information, contact Martin Klein. (m.klein@vumc.nl). 
4. 
Complete the training video post test 
5. 
Complete a “practice” assessment 
6. 
Complete the Certification Worksheet (Appendix IV) 
7. 
All materials (i.e., post test, complete practice assessment and scoring forms, certification 
worksheet) must be faxed to M. Klein, who will score it and review any procedural errors with the 
trainee. If the trainee demonstrates competency, he/she will be notified of the approval to 
administer the tests to study subjects as part of EORTC 26053_22054. An approval notice will be 
sent to EORTC for their records and to ensure that only EORTC 26053_22054-approved examiners 
are testing subjects on protocol EORTC 26053_22054. 
8. 
After certification, each examiner must fax to M. Klein all test forms and data summary sheets for 
their first case. 
Neurocognitive Assessment 
The tests that constitute the neurocognitive function (NCF) battery were selected because they are 
widely used standardized psychometric instruments that have been shown to be sensitive to the 
neurotoxic effects of cancer treatment in other clinical trials. NCF has been demonstrated to predict 
tumor progression and independently predict survival for patients with CNS tumors. This battery has also 
been demonstrated to be practical in terms of cost and burden to the patient, with good compliance in 
multicenter trials. They are widely used, standardized psychometric instruments with published 
normative data that take into account age and, where appropriate, education, gender and handedness. 
The tests were also selected to minimize the effects of repeated administration. These tests are to be 
administered by a certified examiner and require 25 minutes or less to complete. 
Cognitive Domain 
Test 
Time to 
Administer 
(minutes) 
Memory 
Hopkins Verbal Learning Test–Revised 
8 
Visual-motor processing speed 
Trail Making Test Part A 
5 
Executive Function 
Trail Making Test Part B 
7 
Verbal fluency 
Controlled Oral Word Association 
5 
 
 
Total time: 25 
minutes 
 
 

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Neurocognitive Assessment – Sequencing of Alternate Forms 
Two of the tests to be administered have alternate forms or versions in order to reduce the effects of 
practice. See the table below for the versions to be administered at pre-entry and subsequent sessions. 
The forms should continue to be alternated in this order for the duration of the study. The forms packet 
will contain alternate versions of these neuropsychological tests. 
TEST 
Study 
Registration 
1 month 
post 
RT/TMZ 
3rd visit 
4th 
visit 
5th 
visit 
6th 
visit 
7th visit 
HVLT-R 
Form 1 
Form 2 
Form 3 
Form 4 
Form 5 
Form 6 
Form 1 
COWA 
‘C-F-L’ 
‘P-R-W’ 
‘C-F-L’ 
‘P-R-W’ 
‘C-F-L’ 
‘P-R-W’ 
‘C-F-L’ 
Additional comments: 
1. 
Testing should be completed in one session. Test instructions must be followed verbatim with 
every patient at every study visit. All tests should be completed in black pen. 
2. 
Tests should be administered in the following order to every patient and at every study visit: 
HVLT-R Free Recall; Trail Making Test Part A; Trail Making Test Part B; COWA; HVLT-R Delayed 
Recall; and the HVLT-R Delayed Recognition. 
3. 
You may fill the 20-minute delay interval between COWA and HVLT-R Delayed Recall with QOL 
 
questionnaires. 
4. 
Follow the instructions on the Forms Packet Index before submission of forms to M. Klein. 
5. 
Please keep all original test records. In the event of questions, contact M. Klein. Copies of the test 
forms and summary sheets for the first case from each site must be reviewed by M. Klein. 
Additionally, test results are not submitted to M. Klein. All tests will be identified by the date of 
assessment and EORTC patient identification number (seqid). The test results will be sent to the 
EORTC Headquarters together will the regular patient documentation. The EORTC Headquarters 
will then transfer the forms relating to the neurocognitive assessment side study to the 
Coordinator of the Side Study (Martin Klein). 
6. 
All test results are recorded on the Neurocognitive Evaluation Summary Form (CS), which is found 
in the Forms Packet. Study/case specific labels must be applied to all forms. 
7. 
Patients should not be given copies of their tests to avoid learning the material between test 
 
administrations. 
8. 
Before dismissing the patient, thank the patient for his/her cooperation. Remind the patient of 
his/her next appointment and that these tests will be repeated.  
9. 
In the event that a patient cannot complete a given test, please write the reason(s) on the test 
form AND the data summary form. 

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Appendix III 
Test instructions for the neurocognitive function battery 
Administer the tests in the following order to every patient at every visit: 
HVLT-R FREE RECALL 
TRAIL MAKING TEST PART A 
TRAIL MAKING TEST PART B 
CONTROLLED ORAL WORD ASSOCIATION 
HVLT-R DELAYED RECALL 
HVLT-R DELAYED RECOGNITION 
1. 
HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R) 
This test has three parts and six alternate forms: 
Part A - Free Recall: Complete the three learning trials first 
Part B - Delayed Recall: Complete after a 20 minute delay that includes administration of Trail Making 
Tests and COWA 
Part C - Delayed Recognition: Complete immediately after Delayed Recall 
Part A – Free Recall: Trial 1  
Examiner: “I am going to read a list of words to you. Listen carefully, because when I am through, I’d 
like you to tell me as many of the words as you can remember. You can tell them to me in any order. 
Are you ready?” 
• Read the words at the rate of one word every 2 seconds.  
Examiner: “OK. Now tell me as many of those words as you can remember.” 
• Check off the words the patient recalls on the form. 
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form 
and say nothing to the patient about the word not being on the list. 
• There is no time limit for each recall trial. However, if the patient does not produce any words for 10-
15 seconds, ask the patient if he/she can remember any more words. 
• If not, move on to trial 2. Later, you can record the number of words that were correctly repeated on 
the summary form. 
Part A – Free Recall: Trial 2  
Examiner: “Now we are going to try it again. I am going to read the same list of words to you. Listen 
carefully, and tell me as many of the words as you can remember, in any order, including the words 
you told me the first time.”  
• Read the words at the rate of one word every 2 seconds.  
• Check off the words the patient recalls on the form. 
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form 
and say nothing to the patient about the word not being on the list. 
• There is no time limit for each recall trial. However, if the patient does not produce any words for 10-
15 seconds, ask the patient if he/she can remember any more words. 

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• If not, move on to trial 3. Later, you can record the number of words that were correctly repeated on 
the summary form. 
Part A – Free Recall: Trial 3  
Examiner: “I am going to read the list one more time. As before, I’d like you to tell me as many of the 
words as you can remember, in any order, including all the words you’ve already told me.” 
• Read the words at the rate of one word every 2 seconds.  
• Check off the words the patient recalls on the form. 
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form 
and say nothing to the patient about the word not being on the list. 
• There is no time limit for each recall trial. However, if the patient does not produce any words for 10-
15 seconds, ask the patient if he/she can remember any more words. 
• Do not tell the respondent that recall of the words will be tested later. 
• Record the time on the clock that you complete ‘Part A – Free Recall’ (for example, 10:00 am) on the 
designated space on the HVLT-R form. 
2. 
TRAIL MAKING TEST [Timed Test] 
Part A – Sample: The Sample for Part A must be completed/attempted by each patient at every 
assessment. Place the Sample A worksheet flat on the table, directly in front of the patient (the bottom of 
the worksheet should be approximately six inches from the edge of the table). Give the patient a black 
pen and say: 
Examiner: “On this page (point) are some numbers. Begin at number 1 (point to 1) and draw a line from 
1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4), and so on, in order, until you reach the end 
(point to the circle marked END). Draw the lines as fast as you can. Ready, begin.” 
If the patient completes Sample A correctly and in a manner demonstrating that s/he understands what 
to do, proceed immediately to Test A. If the patient makes a mistake on Sample A, point out the error 
and explain it. 
The following explanations of mistakes serve as illustrations: 
• “This is where you start (point to number 1)”  
• “You skipped this circle (point to the circle omitted)” 
• “You should go from number 1 to 2, 2 to 3, and so on, until you reach the circle marked END” 
If it is clear that the patient intended to touch a circle but missed it, do not count it as an omission. 
Remind the patient, however, to be sure to touch the circles. If the patient still cannot complete Sample 
A, take his/her hand and guide him/her through the trail using the opposite end of the pen, lightly 
touching the worksheet to avoid making marks on the copy. Then say:  
Examiner: “Remember, begin at number 1 (point to 1) and draw a line from 1 to 2 (point to 2), 2 to 3 
(point to 3), 3 to 4 (point to 4) and so on, in order, until you reach the circle marked END (point). Do not 
skip around, but go from one number to the next in proper order. Remember to work as fast as you 
can. Ready, begin.” 
If the patient does not succeed, or it becomes evident that s/he cannot do the task, DISCONTINUE testing 
and indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A 
correctly and appears to understand what to do, proceed immediately to Part A. 
Part A – Test: After the patient has completed Sample A, place the Part A test worksheet directly in front 
of the patient and say: 

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Examiner: “Good! Let’s try the next one. On this page are numbers from 1 to 25. Do this the same way. 
Begin at number 1 (point) and draw a line from 1 to 2 (point to 2), 2 to 3 (point to 3), 3 to 4 (point to 4) 
and so on, in order, until you reach the circle marked END (point). Do not skip around, but go from one 
number to the next in proper order. Remember to work as fast as you can. Ready, begin.”  
• Start timing as soon as the instruction is given to “begin” 
• Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call 
it to his/her attention immediately and have him/her proceed from the point the mistake occurred 
• The patient must complete the test in 3 minutes or less 
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END” 
• If the patient does not complete the test within 3 minutes terminate the testing. The test can also be 
discontinued if the patient is extremely confused and is unable to perform the task. Collect the 
worksheet and complete the Trail Making Data Sheet indicating the reason the test was terminated 
and the last correct number reached on the test.  
• If the patient successfully completes the test collect the worksheet and record the time to completion 
on the Trail Making Data Sheet in minutes and seconds. Then say, “That’s fine. Now we’ll try another 
one.” 
Part B – Sample: The Sample for Part B must be completed/attempted by each patient at every 
assessment. Place the Sample B worksheet flat on the table, directly in front of the patient (the bottom of 
the worksheet should be approximately six inches from the edge of the table) and say: 
Examiner: “On this page (point) are some numbers and letters. Begin at number 1 (point to 1) and draw 
a line from 1 to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3), 3 to C (point to C) 
and so on, in order, until you reach the end (point to the circle marked END). Remember, first you have 
a number (point to 1), then a letter (point to A), then a number (point to 2), then a letter (point to B), 
and so on. Draw the lines as fast as you can. Ready, begin.” 
If the patient completes Sample B correctly, and in a manner demonstrating that s/he understands what 
to do, proceed immediately to Part B. If the patient makes a mistake on Sample B, point out the error and 
explain it. 
The following explanations of mistakes serve as illustrations: 
• “You started with the wrong circle. This is where you start (point to number 1)” 
• “You skipped this circle (point to the circle omitted)”  
• “You should go from number 1 (point) to A (point), A to 2 (point to 2), 2 to B (point to B), B to 3 
(point to 3) and so on, until you reach the circle marked END (point)” 
If it is clear the patient intended to touch a circle but missed it, do not count it as an omission. Remind 
the patient, however, to be sure to touch the circles. If the patient still cannot complete Sample B, take 
their hand and guide them through the trail using the opposite end of the pen, lightly touching the 
worksheet to avoid making marks on the copy. Then say:  
Examiner: “Now you try it. Remember, begin at number 1 (point to 1) and draw a line from 1 to A 
(point to A), A to 2 (point to 2), 2 to B (point to B), B to 3 (point to 3) and so on, in order, until you 
reach the circle marked END (point). Ready, begin.” 
If the patient does not succeed or it becomes evident that s/he cannot do the task, DISCONTINUE testing 
and indicate the corresponding reason on the Trail Making Data Sheet. If the patient completes Sample A 
correctly and appears to understand what to do, proceed immediately to Part A. 
 
 

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Part B – Test:  
After the patient has completed Sample B, place the Part B Worksheet directly in front of the patient and 
say: 
Examiner: “Good! Let’s try the next one. On this page are both numbers and letters. Do this the same 
way. Begin at number 1 (point) and draw a line from 1 to A (point to A), A to 2 (point to 2), 2 to B (point 
to B), B to 3 (point to 3), 3 to C (point to C) and so on, in order, until you reach the circle marked END 
(point). Remember, first you have a number (point to 1), then a letter (point to A), then a number 
(point to 2), then a letter (point to B), and so on. Do not skip around, but go from one circle to the next 
in the proper order. Draw the lines as fast as you can. Ready, begin.”  
• Start timing as soon as the instruction is given to “begin” 
• Watch closely in order to catch any errors as soon as they are made. If the patient makes an error, call 
it to his/her attention immediately and have him/her proceed from the point the mistake occurred 
• The patient must complete the test in 5 minutes or less 
• DO NOT STOP TIMING UNTIL HE/SHE REACHES THE CIRCLE MARKED “END” 
• Collect the worksheet and record the time to completion on the Trail Making Data Sheet in minutes 
and seconds 
• If the patient does not complete the test within 5 minutes terminate the testing. The test can also be 
discontinued if the patient is extremely confused and is unable to perform the task. Collect the 
worksheet and complete the Trail Making Data Sheet indicating the reason the test was terminated 
and the last correct number or letter reached on the test.  
• At the top of both Sample forms and Test forms please write: patient code, case number, date of 
evaluation, institution name, name of certified tester, and the certified tester’s phone number.  
3. 
CONTROLLED ORAL WORD ASSOCIATION TEST (COWAT) [Timed Test] 
This test has three parts (letters) and two alternate forms. 
Examiner: “I am going to say a letter of the alphabet, and I want you to say as quickly as you can all of 
the words that you can think of that begin with that letter. You may say any words at all, except proper 
names such as the names of people or places. So you would not say ‘Rochester’ or ‘Robert’. Also, do 
not use the same word again with a different ending, such as ‘Eat,’ and ‘Eating.’ 
“For example, if I say ‘s,’ you could say ‘son’, ‘sit,’ ‘shoe,’ or ‘slow.’ Can you think of other words 
beginning with the letter ‘s’?” 
Wait for the patient to give a word. If it is a correct response, say “good”, and ask for another word 
beginning with the letter “s”. If a second appropriate word is given, proceed to the test itself. 
If the patient gives an inappropriate word on either occasion, correct the patient, and repeat the 
instructions. If the patient then succeeds, proceed to the test. 
If the patient fails to respond, repeat the instructions. If it becomes clear that the patient does not 
understand the instructions or cannot associate, stop the procedure, and indicate the reason(s) on the 
scoring sheet. 
If the patient has succeeded in giving two appropriate words beginning with the demonstration letter, 
say: 
Examiner: “That is fine. Now I am going to give you another letter and again you say all of the words 
beginning with that letter that you can think of. Remember, no names of people or places, just 

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ordinary words. Also, if you should draw a blank, I want you to keep on trying until the time limit is up 
and I say STOP.” 
“You will have a minute for each letter. The first letter is ‘___’. Begin” (Start timing immediately. See 
scoring sheet). 
**Allow exactly one minute for each letter** 
• If the patient discontinues before the end of the time period, encourage him/her to try to think of 
more words. 
• If he/she is silent for 15 seconds, repeat the basic instruction and the letter (e.g., “Tell me all the 
words you can think of that begin with a “c”). 
• No extension on the time limit is made in the event that instructions are repeated. 
• Continue the evaluation with the remaining two letters, allowing one minute for each. 
Recording and Scoring: 
• The record sheet provides lines on which the patient’s responses can be entered (e.g., write in the 
word that is said by the patient). If his/her speed of word production is too fast to permit verbatim 
recording, a “+” should be entered to indicate a correct response.  
• Incorrect responses should be recorded and struck through with a single line followed by your initials 
and the date in the margin next to the error. 
• If the patient provides more responses than there are lines on the record sheet, place check marks in 
the boxes to indicate correct responses only. 
• Count all the correct responses. The number of correct words should be indicated below each column 
on the recording sheet and on the summary data form that is sent to M. Klein. 
Comments on scoring: 
• Note: It can be helpful for the first several patients and for patients known to be fast with their 
word production to tape record the session for transcription at a later time. 
• The instructions include a specific prohibition against giving proper names or different forms of the 
same word. Therefore, inflections of the same word (e.g., eat-eating; mouse-mice; loose-loosely; ran-
run-runs) are not considered correct responses.  
• Patients often give both a verb and a word derived from the verb or adjective (e.g., fun-funny; sad-
sadness). These are not considered correct responses. On the other hand, if the word refers to a 
specific object (e.g., foot-footstool; hang-hanger), it would be counted as a correct answer. 
• Many words have two or more meanings (e.g., foot; can; catch; hand). A repetition of the word is 
acceptable IF the patient definitely indicates the alternative meaning to you. 
• Slang terms are OK if they are in general use. 
• Foreign words (for example, pasta; passé; lasagna) can be counted as correct if they can be 
considered part of the lexicon of the relevant language, the criterion being their listing in a standard 
dictionary of that language. All incorrect and repeated responses MUST be crossed out with one 
single line, initialed and dated. Additionally, all duplicate entries that have been verified to have 
different meanings must be marked “ok”, initialed and dated. Refer to the descriptions above for 
guidelines for acceptability. Add the total number of correct responses in each column and input the 
totals where indicated on the COWA worksheet.  
• If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate 
the reason.  
 
 

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4. 
HOPKINS VERBAL LEARNING TEST - REVISED (HVLT-R) 
Part B – Delayed Recall 
• DO NOT READ THE WORD LIST AGAIN. 
• Record the time on the clock that you start ‘Part B – Delayed Recall’ (for example, 10:20 am) on the 
designated space on the HVLT-R form. 
• Administer ‘Part B – Delayed Recall’ after completing all Trail Making Tests and the COWA. There 
should be at least 20 minutes between ‘Part A’ and ‘Part B’ of the HVLT-R. If the time is too short, 
allow the patients to complete a questionnaire.  
Examiner: “Do you remember that list of words you tried to learn before? Tell me as many of those 
words as you can remember.” 
• Check the box on the corresponding line of the HVLT-R worksheet for each word the patient 
accurately recalls. 
• If a word is said that is not in the list (for example, “intrusion”), do not write that word on the form 
and say nothing to the patient about the word not being on the list. 
• There is no time limit for each recall trial. However, if the patient does not produce any words for 10-
15 seconds, ask the patient if he/she can remember any more words. 
• If not, record the number of words that were correctly recalled on the summary form. 
Part C – Delayed Recognition 
Examiner: “Now I’m going to read a longer list of words to you. Some of them are words from the 
original list, and some are not. After I read each word, I’d like you to say “Yes” if it was on the original 
list or “No” if it was not. Was [word] on the list?” 
• Read the words from the top of the columns down. 
• Check either the “Y” (Yes) or “N” (No) box next to each word to indicate the patient’s response. 
• Guessing is allowed. 
• If the test is discontinued or omitted, please mark this on the bottom of the test form and indicate 
the reason. 
• The score for this portion of the HVLT-R is the number of list words (i.e., words that in CAPS) correctly 
identified (“yes” response) minus the number of non-list words (i.e., words in lower case) incorrectly 
identified (“yes” response). Therefore, the actual score can range from –12 (no list words identified 
and all non-list words identified) to +12 (all list words identified and no non-list words identified). 
5. 
Medical Outcome Studies (MOS) EVALUATION SUBJECTIVE COGNITIVE FUNCTIONNING 
Items from the cognitive function scale 
(1) How much of the time during the past month did you have difficulty reasoning and solving problems, 
for example making plans, making decisions or learning new things? 
(2) During the past month how much of the time did you forget, for example things that happened 
recently, where you put things or appointments? 
(3) How much of the time during the past month did you have trouble keeping your attention on any 
activity for long? 
(4) During the past month how much of the time did you have difficulty doing activities involving 
concentration and thinking? 
(5) How much of the time did you become confused and start several actions at a time? 

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(6) Did you react slowly to things that were said or done? 
Response options: all of the time, most of the time, a good bit of the time, some of the time, a little of 
the time or none of the time. 
Ref.: 
Stewart AL, Ware JE, Sherbourne CD, Wells KB. Psychological distress/well-being and cognitive 
 
functioning measures. In: Stewart AL, Ware JE, eds. Measuring functioning and well-being. The  
 
Medical Outcomes Study approach. Durham and London: Duke University Press, 1992: 102-142. 

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Appendix IV 
Certification worksheet for test administrator 
EORTC 26053_22054 
PHASE III TRIAL ON CONCURRENT AND ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY IN NON-1P/19Q 
DELETED ANAPLASTIC GLIOMA: THE CATNON INTERGROUP TRIAL 
This worksheet must be completed and signed by the person requesting certification and submitted to 
M. Klein prior to the registration of any patients to EORTC 26053_22054. Refer to protocol Appendix II for 
details. 
----(Y)   1. 
Have you reviewed the Certification and Administration Procedures for the Neurocognitive 
 
 
 
Test Battery in Appendix II of the protocol, as well as the Test Instructions for the 
 
 
 
 
Neurocognitive Function Battery in Appendix III? 
----(Y)    2. 
Have you watched the Neuropsychological Test Administration video? 
----(Y)    3. 
Have you completed and submitted the post test associated with the training video and a 
 
 
 
 
“practice” Neuropsychological Assessment (See Appendix II)? 
 
 
 
 
 
 
 
Signature of test administrator 
 
 
Date 
(person who read Appendix II and III, watched video and completed a “practice” Assessment) 
 
 
 
 
 
 
Printed name of test administrator  
 
Institution number/Name 
 
 
 
 
 
 
Telephone number of test administrator 
 
Fax number of test administrator 
If you have any questions regarding the certification, please contact M. Klein. Once you have completed 
this form, please attach both the Neuropsychological Assessment forms from the “practice” subject and 
the training video post test and submit to: 
M. Klein 
Phone +31 20 4448432 
FAX +31 20 4448230 
m.klein@vumc.nl 
For M. Klein’s Use Only (to fax to EORTC +32 2 771 38 10) 
----(Y/N) The above individual has been certified for administering the neurocognitive 
assessments for this study. 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
Date 
 
 

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Appendix J: Minimum requirements for local 1p/19q 
diagnostics 
Circumscribed deletions on 1p and 19q are not restricted to oligodendroglial tumors but are also 
frequent in astrocytic tumors. Large deletions on 1p and 19q are very characteristic of oligodendroglial 
tumors and this type of deletion is associated with better prognosis and more favorable response to 
therapy.  
1p/19q determination with FISH  
1. 
The laboratory should have at least one year experience with clinical 1p/19q testing in gliomas.  
2. 
There must be regular quality control/assurance procedures (e.g. validation of new batches of 
probe, routine - weekly/monthly - of anomaly rate) 
3. 
Appropriate control probes for 1q and 19p should be included in each batch- to accurately 
determine the 1p/1q and 19q/19p ratios as well as to determine ploidy.  
4. 
A positive deletion control should be included with each batch - a normal control is also useful. 
5. 
Two hybridizations using two slides should be performed, a single hybridization for both 1p and 
19q assessment is not appropriate 
6. 
Each case is reviewed by a neuropathologist prior to FISH to ensure that at least 40% tumor is 
present and to mark the area where the technologist will count. 
7. 
At least 60-100 nuclei need to be enumerated.  
8. 
Cut-offs may vary from one institution to another, and should be based on normal values studies - 
ideally using normal brain - for the establishment of deletion (and gain) criteria. This could be 
defined in terms on % of cells showing twice the number of reference vs test signals (e.g. 2 and 1, 
4 and 2, 6 and 3, etc., e.g., total score 20%), or an overall ratio of test to reference signals instead 
(e.g., cut-off of 0.8). 
Loss of heterozygosity tests 
1. 
The laboratory should have at least one year experience with clinical 1p/19q testing in gliomas.  
2. 
There must be regular quality control/assurance procedures.  
3. 
The LOH assays for determining losses should not be restricted to a single locus on chromosomes 
1p and 19q, but multiple microsatellite probes must be used covering large area’s of both 1p and 
19q. A  reasonable set of probes is given in (Ref. 29). 
4. 
A comparison must be made with normal patient DNA (e.g., extracted from leukocytes).  
5. 
All samples need to be checked under the microscope for tumor content prior to analysis by a 
qualified neuropathologist. 

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Appendix K: Procedures and routing of tumor and blood 
samples prior to randomization 
1. General remarks 
• Eligible for this study are patients with  
• a histological diagnosis of an anaplastic astrocytoma, an anaplastic oligoastrocytoma or an 
anaplastic oligodendroglioma 
• without combined 1p/19q loss. 
• Patients can be entered into the study either based on a) the local diagnosis including 1p/19q 
assessment or b) on central histology review and central 1p/19q assessment.  
• Centers must decide prior to the activation of the center whether they will include patients based on 
local or on central histology and 1p/19q diagnosis. Only centers that fulfill basic quality requirements 
for 1p/19q testing and that are cleared by the EORTC Headquarters will be allowed to randomize 
patients based on the local diagnosis (see Appendix J). 
• Both the 1p/19q testing and the MGMT promoter methylation determination are essential for the 
study. The submission of tissue for these assays is therefore mandatory.  
• To allow stratification of the patients according to MGMT status immediate post-surgery shipping of 
tumor material together with the required blood samples is an absolute requirement for all patients 
regardless of the 1p/19q procedure: this also concerns material from patients from centers that 
enter patients based on local 1p/19q testing.  
• Stratification for MGMT status will be either ‘methylated’, ‘non-methylated’ or ‘unknown’. Patients in 
whom MGMT status cannot be determined because of insufficient material, material not timely 
received etc will still be eligible for the study (and will be stratified for MGMT status as ‘unknown’).  
• Test results from tumor blocks are superior compared to the results from slides. All investigators are 
urged to send blocks. 
• The procedures for Europe are explained below. For non-European centers, a similar procedure is 
covered by Group Specific Appendices. 
2. Registration procedure 
• As a first step, all patients (regardless of 1p/19q testing procedure) must be registrated into the study 
prior to randomization using the Registration Consent form (see Appendix F). This is also necessary 
for patients from sites with approved local 1p/19q testing.  
• The submission of the blood and tumor samples as part of the study is covered by this Registration 
Consent form. 
3. Procedure for centers without accepted local 1p/19q testing 
Centers relying on inclusion based on central histological review and 1p/19q testing must submit tumor 
material to the Erasmus University Hospital for eligibility assessment. Only samples received from sites 
that are on the list of activated centers of the EORTC Headquarters will be reviewed and investigated for 
1p/19q loss.  
After the registration of the patient using the Registration Consent into the trial the following items must 
be sent: 
• A paraffin embedded tumor sample (preferably a tumor block, otherwise 30 unstained slides) 
• The local pathology report (including local diagnosis of 1p/19q status if available) 

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• 20 ml whole blood collected in an EDTA tube 
• the pathology review and 1p/19q form (with the EORTC id given at registration, the fax number of the 
center and with information regarding the 1p/19q status) 
Samples will first be reviewed for the pathological diagnosis, if at review the tumor is considered not 
eligible the sample will not be tested for 1p/19q loss and the patient will not be eligible.  
For eligibility, both central histology review and1p/19q assessment must confirm eligibility. Cases that 
are not eligible according to the review pathologist will not be examined for 1p/19q loss and MGMT 
promoter gene methylation. Both the center and the EORTC will receive the 1p/19q test result and the 
histology review outcome, results can be expected within 14 days from arrival. Once the patient is found 
eligible he can be randomized into the study. 
4. Procedure for centers with accepted local 1p/19q testing facilities 
Patients with eligible histologies as diagnosed by the local pathologist and in whom local testing has 
assessed intact 1p, 19q or both can be randomized directly into the trial. However, because pre-
radiotherapy assessment of MGMT status is vital for the study stratification, these patients must also as 
soon as possible be registrated at the EORTC Headquarters after obtaining approval using the 
Registration Consent form. After the registration of the patient into the trial the following items must be 
sent: 
• A paraffin embedded tumor sample (preferably a tumor block, otherwise 30 unstained slides) 
• The local pathology report (including local diagnosis of 1p/19q status) 
• 20 ml whole blood collected in an EDTA tube 
• the pathology review and 1p/19q form (with the EORTC id given at registration, the fax number of the 
center and with information regarding the 1p/19q status) 
Central review of 1p/19q status will be done in batches at a later stage (after randomization), the results 
will be made available to the site.  
5. Addresses 
Tumor and blood samples must be sent by express carrier to: 
 
M.J. van den Bent/I. van Heuvel 
 
Dept Neuro-Oncology 
 
Groene Hilledijk 301 
 
3075EA Rotterdam 
 
The Netherlands 
 
e-mail: m.vandenbent@erasmusmc.nl 
 
phone: +31-10-704 14 15 
 
fax: 
+31-10-704 10 31 
The material requested for MGMT testing will be sent by the central histopathology laboratory in 
Rotterdam to MDxHealth (Liège, Belgium). The results of the MGMT promoter methylation assay will not 
be made available to the local center, but only to the EORTC Headquarters for stratification purposes. 

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Appendix L: Mini-Mental State Examination (MMSE) 
Patient’s Name:  
 
 
 
 
 
Date:  
 
 
 
Instructions: Score one point for each correct response within each question or activity. 
Maximum 
Score 
Patient’s 
Score 
Questions 
 
5 
 
“What is the year? Season? Date? Day? Month?” 
5 
 
“Where are we now? State? County? Town/city? Hospital? Floor?” 
3 
 
The examiner names three unrelated objects clearly and slowly, then 
the instructor asks the patient to name all three of them. The 
patient’s response is used for scoring. The examiner repeats them 
until patient learns all of them, if possible. 
5 
 
“I would like you to count backward from 100 by sevens.” (93, 86, 79, 
72, 65, …) 
Alternative: “Spell WORLD backwards.” (D-L-R-O-W) 
3 
 
“Earlier I told you the names of three things. Can you tell me what 
those were?” 
2 
 
Show the patient two simple objects, such as a wristwatch and a 
pencil, and ask the patient to name them. 
1 
 
“Repeat the phrase: ‘No ifs, ands, or buts.’” 
3 
 
“Take the paper in your right hand, fold it in half, and put it on the 
floor.”(The examiner gives the patient a piece of blank paper.) 
1 
 
“Please read this and do what it says.” (Written instruction is “Close 
your eyes.”) 
1 
 
“Make up and write a sentence about anything.” (This sentence must 
contain a noun and a verb.) 
1 
 
“Please copy this picture.” (The examiner gives the patient a blank 
piece of paper and asks him/her to draw the symbol below. All 10 
angles must be present and two must intersect.) 
 
30 
 
TOTAL 
Source: 
Folstein MF, Folstein SE, McHugh PR: “Mini-mental state: A practical method for grading the cognitive 
state of patients for the clinician.” J Psychiatr Res 1975;12:189-198. 
 

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Appendix M: Specific protocol instructions during the 
COVID-19 crisis 
Note: all instructions listed in this Appendix will be solely applicable during the COVID-19 
crisis. 
Due to the current circumstances with the COVID-19 pandemic, we would like to inform you about the 
following set of recommendations for EORTC study/clinical trial 26053-22054 titled “Phase III trial on 
Concurrent and Adjuvant Temozolomide chemotherapy in non-1p/19q deleted anaplastic glioma. The 
CATNON Intergroup trial”. 
The study has completed patient enrolment and all patients have completed the study treatment. 
Therefore, all remaining patients are followed up for disease progression and survival.  
Included patients need to come for regular visits to the hospital, and this may not be possible in the 
current circumstances, depending on local hospital, regional, or country measures.  
Please ensure that any protocol deviations resulting from COVID-19 are: 
• Adequately documented in the eCRFs as well as the patient’s medical records or 
in a Note To File (NTF) to be stored in your Study binder (ISF). 
• Always begin deviation text with “COVID-19”. 
 
Strategy for patients already included 
With respect to study imaging procedures: 
For on-study imaging procedures, it is preferred that the patient have imaging performed at the 
investigative site as directed in the protocol. 
If difficulties are encountered to perform the imaging as per the protocol, there are several possibilities, 
in order of preference:  
• Have the imaging performed offsite, locally according to the protocol-specified timing. Guidance 
should be given by the site to the local imaging facility about conducting scans with requirements 
(modality etc… as per Imaging Guidelines).  
• Have the imaging performed at the site but delayed to a significant extent from theoretical 
planned date per protocol) due to travel restriction / safety of the participant. 
• Have the imaging performed offsite but delayed due to travel restriction / safety of the 
participant. 
• Skip the imaging only if impossible to perform due to travel restriction / safety. 
 
Site needs to report this in the comment fields of the applicable CRFs and in the Source Data as well. 
 
With respect to patient physical visits: 
• Patient Physical Visits can be changed in phone visits where needed. 
 
 

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With respect to Patient Reported Data: 
• Patient reported data (e.g. Quality of Life) can be collected through phone. Voice scripts for the 
QLQ-C30 questionnaire are available on the study web documentation. 
• If phone assessment cannot be arranged, patient reported data (e.g. Quality of Life) can be 
collected by providing the questionnaires to the patients. Patients should be instructed to 
complete the questionnaires within the intended time point (according to protocol). Patients 
should also complete the date on the form with the date they completed the questionnaire. Sites 
are requested to make their own guidelines to patients in their own language. 
With respect to collection of biomaterial: 
• Please postpone the collection of sample(s) if impossible to perform due to travel restriction / 
safety to a later date. 
With respect to serious adverse event reporting:  
Sites should follow the SAE reporting as described in the protocol e.g. the sites should continue to report 
SAEs immediately and no later than 24 hours from the time the investigator or site staff became aware of 
the event, as described in the protocol. There are no specific adaptations to the protocol defined SAE 
reporting procedure due to COVID-19. 
• Should sites have any SAE reporting related questions, please contact us at 
pharmacovigilance@eortc.org 
• Should there be a suspected or confirmed serious case of COVID-19 infection, report it as SAE: 
• Please remember to provide the mandatory SAE information as per protocol and as per the 
CRF completion guidelines.  
• Please indicate if the COVID-19 infection was confirmed by a test.  
• Please provide as much information as available.