High-precision Radiotherapy of Motor Deficits Due to Metastatic Spinal Cord Compression
Phase: NA
Conditions: Spinal Cord Compression Due to Metastasis to Spine
Sponsor: University Hospital Schleswig-Holstein

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High-PREcision Radiotherapy  
of MOtor DEficits due to  
Metastatic Spinal Cord Compression  
 
Study name: PRE-MODE 
 
A phase 2 multi-center study 
 
Sponsor: 
University Hospital Schleswig-Holstein (UKSH) 
 
Study management: 
 
Prof. Dr. Dirk Rades 
Department of Radiation Oncology, University of Lübeck 
Department of Radiation Oncology, University Hospital Schleswig-Holstein  
 
 
Version 4.0 (06-05-2019) 

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Sponsor: 
University Hospital Schleswig-Holstein (UKSH), Campus Lübeck 
Ratzeburger Allee 160, 23538 Lübeck, Germany 
 
Coordinating Investigator (contact) 
 
Prof. Dr. Dirk Rades 
Department of Radiation Oncology, University of Lübeck &  
Department of Radiation Oncology, University Hospital Schleswig-Holstein 
Ratzeburger Allee 160, 23538 Lübeck, Germany 
Tel.: 0049 (0)451-500-45400 
Fax: 0049 (0)451-500-45404 
Email: dirk.rades@uksh.de 
 
 
Participating Centers:  
 
(1)       Department of Radiation Oncology, Cruces University Hospital, Barakaldo, Vizcaya, Spain  
(2)       Department of Radiation Oncology, Consorcio Hospital Provincial de Castellón, Spain 
(3)       Department of Radiation Oncology, Christian-Albrechts University Kiel, Germany 
(4)       Department of Radiation Oncology, University of Lübeck, Germany 
(5)       Department of Radiation Oncology, Sealand University Hospital, Naestved, Denmark 
(6)       Department of Radiation Oncology, Odense University Hospital, Denmark  
(7)       Department of Radiation Oncology, Mayo Clinic Scottsdale, Arizona, U.S.A. (data   
      analysis and interpretation)  
(8)  
Department of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia     
(9)       Radiation Oncology Department, High Technology Medical Center, University Clinic     
      Tbilisi, Tbilisi, Georgia 
(10) 
Department of Radiation Oncology, University Hospital Germans Trias i Pujol, Badalona,  
      Spain 
(11) 
Department of Radiation Oncology, University Hospital Salamanca, Salamanca, Spain 
(12) 
Department of Radiation Oncology,  University Hospital HM Sanchinarro, Madrid, Spain 

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Confidentiality statement 
 
The information contained in this protocol are confidential and may not be communicated to third 
parties either in spoken or in written form without the explicit permission of the study management. 
This excludes communication of the required information to the ethics commission responsible or 
informing the regulatory authorities.  

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Signature Page: 
 
High-precision radiotherapy of motor deficits due to metastatic spinal 
cord compression 
 
 
 
Protocol code:  
 
PRE-MODE 
Version: 
 
 
4.0 (06-05-2019)  
 
 
 
It has been confirmed that the protocol, the case report forms and appendices contain all 
information and regulations necessary for the implementation of the clinical study, and that the 
study will be conducted and documented in line with this protocol, abiding by the legal regulations 
and agreements described therein. 
 
 
Sponsor of the study: 
 
University Hospital Schleswig-Holstein, Campus Lübeck 
 
Represented by Prof. Dr. Dirk Rades 
Department of Radiation Oncology, University Hospital Schleswig-Holstein, Campus Lübeck 
Ratzeburger Allee 160,  
23538 Lübeck, Germany 
 
 
 
 
Place, date: 
 
 
 
 
Signature 
 
 
 
Coordinating investigator: 
 
Prof. Dr. Dirk Rades 
Department of Radiation Oncology, University of Lübeck &  
Department of Radiation Oncology, University Hospital Schleswig-Holstein, Campus Lübeck 
Ratzeburger Allee 160,  
23538 Lübeck, Germany 
 
 
 
 
Place, date: 
 
 
 
 
Signature 
 
 
 

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INDEX 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIGNATURE PAGE  
 
 
 
 
 
 
 
 
 
  4 
 
1A SYNOPSIS (ENGLISH version) 
 
 
 
 
 
 
 
  7 
 
1B SYNOPSIS (GERMAN version) 
 
 
 
 
 
 
 
10 
 
2 LIST OF ABRREVIATIONS 
 
 
 
 
 
 
 
 
14 
 
3 BACKGROUND AND RATIONALE  
 
 
 
 
 
 
15 
 
3.1 Background 
 
 
 
 
 
 
 
 
 
15 
 
3.2 Rationale  
 
 
 
 
 
 
 
 
 
16 
 
4 ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
17 
 
4.1 Primary endpoint  
 
 
 
 
 
 
 
 
17 
 
4.2 Criteria for secondary endpoints  
 
 
 
 
 
 
17 
 
5 STUDY DESIGN AND PATIENT SELECTION 
 
 
 
 
 
18 
 
5.1 General study design and duration 
 
 
 
 
 
 
18 
 
5.2 Patient selection  
 
 
 
 
 
 
 
 
18 
 
 
5.2.1 General prerequisites  
 
 
 
 
 
 
18 
 
 
5.2.2 Inclusion and exclusion criteria 
 
 
 
 
 
19 
 
 
5.2.3 Termination criteria for individual patients 
 
 
 
 
19 
 
 
5.2.4 Termination criteria for the study in general  
 
 
 
19 
 
 
5.2.5 Definition of the end of the study 
 
 
 
 
 
19 
 
6 TREATMENT 
 
 
 
 
 
 
 
 
 
 
20 
 
6.1 Patient registration 
 
 
 
 
 
 
 
 
20 
 
6.2 Treatment  
 
 
 
 
 
 
 
 
 
20 
6.2.1 Radiotherapy 
 
 
 
 
 
 
 
 
20 
 
 
6.2.2 Concomitant treatment  
 
 
 
 
 
 
20 
 
 
6.2.3 Possible side effects of high-precision radiotherapy  
 
 
20 
 
7 SAFETY MANAGEMENT 
 
 
 
 
 
 
 
 
21 
 
7.1 Definitions 
 
 
 
 
 
 
 
 
 
21 
7.1.1 Adverse events  
 
 
 
 
 
 
 
21 
7.1.2 Unexpected adverse events 
 
 
 
 
 
 
21 
7.1.3 Serious adverse events  
 
 
 
 
 
 
21 
7.2 Assessment and documentation of adverse events 
 
 
 
 
21 
 
7.3 Reporting of adverse events 
 
 
 
 
 
 
 
22 
 
8 ASSESSMENTS  
 
 
 
 
 
 
 
 
 
23 
 
8.1 Summary of assessments  
 
 
 
 
 
 
 
23 
 
8.2 Data assessment prior to start of radiotherapy  
 
 
 
 
23 
 
8.3 Assessments with respect to primary and secondary endpoints  
 
 
24 
 
 
8.3.1 Local progression-free survival 
 
 
 
 
 
24 
8.3.2 Motor function / Ability to walk 
 
 
 
 
 
24 
 
 
8.3.3 Sensory function / Sphincter dysfunction 
 
 
 
 
25 
8.3.4 Overall survival  
 
 
 
 
 
 
 
25 
 
 
8.3.5 Pain 
 
 
 
 
 
 
 
 
 
25 

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8.3.6 Distress (as an indicator of quality of life) 
 
 
 
 
25 
 
 
8.3.7 Toxicity  
 
 
 
 
 
 
 
 
25 
 
9 COMPARISON TO HISTORICAL CONTROL GROUP 
 
 
 
 
26 
 
10 STATISTICS 
 
 
 
 
 
 
 
 
 
 
27 
10.1 Sample size calculation  
 
 
 
 
 
 
 
27 
10.2 Statistical analyses 
 
 
 
 
 
 
 
 
28 
 
10.2.1 Primary endpoint 
 
 
 
 
 
 
 
28 
 
10.2.2 Secondary endpoints  
 
 
 
 
 
 
28 
 
11 ETHICAL AND LEGAL PRINCIPLES 
 
 
 
 
 
 
29 
 
11.1 Ethics committee vote  
 
 
 
 
 
 
 
29 
 
11.2 Official registration 
 
 
 
 
 
 
 
 
29 
 
11.3 Insurance 
 
 
 
 
 
 
 
 
 
29 
 
11.4 Patient information and informed consent 
 
 
 
 
 
29 
 
11.5 Declaration of Helsinki  
 
 
 
 
 
 
 
29 
 
11.6 Data protection  
 
 
 
 
 
 
 
 
29 
 
12 DATA AND QUALITY MANAGEMENT 
 
 
 
 
 
 
30 
 
12.1 Patient identification list 
 
 
 
 
 
 
 
30 
 
12.2 Documentation forms 
 
 
 
 
 
 
 
 
30 
 
12.3 Monitoring 
 
 
 
 
 
 
 
 
 
30 
 
12.4 Direct access to source data / documents 
 
 
 
 
 
30 
12.5 Storage of study documents 
 
 
 
 
 
 
 
30 
 
13 REFERENCES  
 
 
 
 
 
 
 
 
 
31 
 
APPENDIX I: 
 
PATIENT INFORMATION 
 
 
 
 
32 
 
APPENDIX II: 
 
INFORMED CONSENT FORM  
 
 
 
37 
 
APPENDIX III: 
 
DISTRESS (QUALITY OF LIFE) ASSESSMENT 
 
40 
 
APPENDIX IV: 
 
PERFORMANCE STATUS (ECOG) 
 
 
 
41 
 
APPENDIX V: 
 
ETHICS COMMITTEE VOTE 
 
 
 
 
42 
 
APPENDIX VI: 
 
INSURANCE 
 
 
 
 
 
 
43 
 
 

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1A Synopsis (English version) 
Study title 
High-precision radiotherapy of motor deficits due to metastatic 
spinal cord compression 
Study designation 
PRE-MODE 
Sponsor 
University Hospital Schleswig-Holstein, Campus Lübeck 
Coordinating 
Investigator 
Prof. Dr. D. Rades, 
Department of Radiation Oncology, 
University of Lübeck & University Hospital Schleswig-Holstein, 
Campus Lübeck, Germany  
Study start 
January 2017 
Study period 
30 months: recruitment = 18 months, follow up = 6 months, 
analyses, reporting and publication = 6 months 
Type of protocol 
Multinational phase 2 multi-center study (single arm) 
supplemented by a comparison to a historical, propensity score 
matched control group (superiority study) 
Indication 
Motor deficits of the lower extremities due to metastatic spinal 
cord compression (MSCC) 
Rationale 
For MSCC, conventional radiotherapy (RT) with 10x3 Gy in 2 
weeks results in similar motor function but better local 
progression-free survival (LPFS) than conventional RT with 5x4 
Gy in 1 week. Since patients with MSCC are often significantly 
impaired, a RT regimen with an overall treatment time of only 1 
week would be preferable if it resulted in similar LPFS as 10x3 
Gy in 2 weeks. This may be achieved with 5x5 Gy in 1 week, 
since the equivalent dose in 2 Gy fractions (EQD2) with respect 
to tumor cell kill of 5x5 Gy and 10x3 Gy are similar. Taking into 
account the tolerance dose of the spinal cord, 5x5 Gy can be 
safely administered with high-precision RT such as volumetric 
modulated arc therapy (VMAT) or stereotactic body radiotherapy 
(SBRT). This phase 2 study investigates LPFS after high-
precision RT with 5x5 Gy in 1 week. The patients of the phase 2 
study will be compared for LPFS to a historical control group 
receiving conventional RT with 5x4 Gy in 1 week. If superiority 
regarding LPFS is shown for high-precision RT with 5x5 Gy, 
patients with MSCC would benefit from this regimen, since high 
LPFS rates can be achieved with an RT regimen of only 1 week 
(5x5 Gy) instead of 2 weeks (10x3 Gy).  
Treatment 
Study arm: 5x5 Gy of high-precision RT in 1 week  
Historical control: 5x4 Gy of conventional RT in 1 week 
Follow-up directly and at 1, 3 and 6 months following RT 
Primary endpoint 
LPFS at 6 months following RT 
Secondary endpoints 1. Motor function/Ability to walk 
Assessment directly and at 1, 3 and 6 months following RT  

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2. Sensory function  
Assessment directly and at 1, 3 and 6 months following RT  
3. Sphincter dysfunction  
Assessment directly and at 1, 3 and 6 months following RT  
4. Local progression-free survival 
Additional evaluation directly and 1 and 3 months following RT 
5. Overall survival  
Evaluation directly and at 1, 3 and 6 months following RT 
6. Pain 
Evaluation directly and at 1, 3 and 6 months following RT 
7. Distress (as an indicator of quality of life)  
Evaluation directly and at 1, 3 and 6 months following RT 
8. Toxicity 
Evaluation during plus directly, 1, 3 and 6 months following RT 
Number of patients 
44 patients (phase 2 study)  
Inclusion criteria 
1. Motor deficits of the lower extremities resulting from MSCC, 
which have persisted for no longer than 30 days 
2. Confirmation of diagnosis by magnetic resonance (MR) 
imaging (computed tomography (CT) allowed) 
3. Age 18 years or older 
4. Written informed consent 
5. Capacity of the patient to contract 
Exclusion criteria 
1. Previous RT or surgery of the spinal areas affected MSCC 
2. Symptomatic brain tumor or symptomatic brain metastases  
3. Metastases of the cervical spine only 
4. Other severe neurological disorders 
5. Pregnancy, lactation period  
6. Indication for decompressive surgery of affected spinal areas 
Statistics/Sample size 
calculation 
The primary endpoint of this phase 2 study is to assess high-
precision RT with 5x5 Gy in 1 week with respect to 6-month 
LPFS and to demonstrate that this rate is superior to conventional 
RT with 5x4 Gy (hypothesis). 
 
To ensure with 80% power that – in the phase 2 study- the 95% 
confidence interval for the true 6-month LPFS rate has a 
precision of +/-20% a total of 44 patients should be enrolled. For 
comparison of the prospective study results with historical 
controls, a propensity score approach will be applied to account 
for baseline differences between treatment arms to balance 
covariates and remove bias that may arise due to these 
confounders. Ten relevant prognostic factors will be included. 
Assuming that roughly 400 historical controls qualify for this 
comparison, a power of at least 80% will be ensured assuming 
that the true 6-month LPFS rate with conventional RT with 5x4 
Gy is roughly 67% and a 20% percentage increase is considered 
as clinically relevant.     
End of study 
The study is completed when all patients have either died or been 
followed for at least 6 months and analyses, reporting and 
publication have been finished, or when the study has been 
terminated due to other reasons (for example patient safety). 

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Flow Chart 
 
 
 
Prior to  
RT 
 End of  
RT 
Follow up  
at 1 month  
(+/- 2 weeks) 
following RT  
Follow up  
at 3 months  
(+/- 2 weeks) 
following RT 
Follow up  
at 6 months  
(+/- 2 weeks) 
following RT  
Informed Consent 
X 
 
 
 
 
Medical History/Concomitant 
Diseases 
X 
 
 
 
 
Prognostic factors 
X 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Motor Function  
X 
X 
X 
X 
X 
Sensory Function 
X 
X 
X 
X 
X 
Sphincter Dysfunction 
X 
X 
X 
X 
X 
Ambulatory Status  
X 
X 
X 
X 
X 
Pain   
X 
X 
X 
X 
X 
Distress (quality of life)  
X 
X 
X 
X 
X 
Toxicity* 
X 
X 
X 
X 
X 
LPFS 
 
X* 
X 
X 
X 
Overall survival 
 
X* 
X 
X 
X 
 
*also during RT

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1B Synopsis (German version) 
Studientitel 
Hochpräzisions-Strahlentherapie bei motorischen Defiziten 
aufgrund metastatisch bedingter Rückenmarkskompression 
Studienbezeichnung 
PRE-MODE 
Sponsor 
Universitätsklinikum Schleswig-Holstein, Campus Lübeck 
Studienleiter 
Prof. Dr. D. Rades 
Klinik für Strahlentherapie 
Universität zu Lübeck & Universitätsklinikum Schleswig-
Holstein, Campus Lübeck, Deutschland 
Studienstart 
Januar 2017 
Studiendauer 
30 Monate: Rekrutierung = 18 Monate, Follow up = 6 Monate, 
Analysen, Berichte und Publikation = 6 Monate 
Art des Protokolls 
Multinationale Phase 2 Multicenter-Studie (einarmig), ergänzt 
durch den Vergleich mit einer historischen Kontrollgruppe 
mittels Propensity Score Matching (Überlegenheitsstudie) 
Indikation 
Motorische Defizite der unteren Extremitäten aufgrund einer 
metastatisch bedingten Rückenmarkskompression 
Rationale 
Bei 
der 
metastatisch 
bedingten 
Rückenmarkskompression 
(MSCC) führt die konventionelle Bestrahlung mit 10x3 Gy in 2 
Wochen zu ähnlicher motorischer Funktion aber zu einem 
besseren lokalen progressionsfreien Überleben (LPFS) als eine 
konventionelle Bestrahlung mit 5x4 Gy in 1 Woche. Da Patienten 
mit MSCC oft deutlich beeinträchtigt sind, wäre eine 
Strahlentherapie mit einer Gesamtbehandlungszeit von nur einer 
Woche zu bevorzugen, wenn diese zu einem ähnlichen LPFS 
führen würde wie 10x3 Gy in 2 Wochen. Dies könnte mit 5x5 Gy 
in 1 Woche erreicht werden, da die EQD2s von 5x5 Gy und 10x3 
Gy hinsichtlich Tumorzellvernichtung ähnlich sind. Wenn man 
die Toleranzdosis des Rückenmarks berücksichtigt, kann das 
Regime 5x5 Gy sicher mit einer Hochpräzisions-Strahlentherapie 
(VMAT oder SBRT) verabreicht werden. Darum untersucht diese 
Phase 2 Studie die LPFS nach Hochpräzisions-Strahlentherapie 
mit 5x5 Gy in 1 Woche. Die Patienten/innen der Phase 2 Studie 
werden hinsichtlich LPFS mit einer historischen Kontrollgruppe 
verglichen, die eine konventionelle Bestrahlung mit 5x4 Gy in 1 
Woche 
erhalten 
hat. 
Kann 
eine 
Überlegenheit 
der 
Hochpräzisions-Strahlentherapie mit 5x5 Gy gezeigt werden, 
würden Patienten mit MSCC von diesem Regime profitieren, da 
sie eine hohe LPFS-Rate mit einem Regime erreichen können, 
das nur 1 Woche (5x5 Gy) statt 2 Wochen (10x3 Gy) dauert. 
Behandlung 
Studienarm:  
Hochpräzisions-Strahlentherapie mit 5x5 Gy in 1 Woche  
 

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Historische Kontrollgruppe:  
 
konventionelle Strahlentherapie mit 5x4 Gy in 1 Woche 
Nachuntersuchungen direkt sowie 1, 3 und 6 Monate nach 
Strahlentherapie  
Primärer Endpunkt 
LPFS 6 Monate nach Strahlentherapie 
Sekundäre 
Endpunkte 
1. Motorische Funktion / Gehfähigkeit 
Beurteilung direkt sowie 1, 3 und 6 Monate nach Strahlentherapie 
2. Sensibilität 
Beurteilung direkt sowie 1, 3 und 6 Monate nach Strahlentherapie 
3. Blasen-Mastdarm-Störungen 
Beurteilung direkt sowie 1, 3 und 6 Monate nach Strahlentherapie 
4. Lokales progressionsfreies Überleben 
Zusätzliche Beurteilung direkt sowie 1 und 3 Monate nach 
Strahlentherapie 
5. Gesamtüberleben  
Beurteilung direkt sowie 1, 3 und 6 Monate nach Strahlentherapie 
6. Schmerz 
Beurteilung direkt sowie 1, 3 und 6 Monate nach Strahlentherapie 
7. Distress (als Indikator für Lebensqualität)  
Beurteilung direkt sowie 1, 3 und 6 Monate nach Strahlentherapie
8. Toxizität 
Beurteilung während sowie direkt, 1, 3 und 6 Monate nach 
Strahlentherapie  
Anzahl der Patienten 44 Patienten (Phase 2 Studie)  
Einschlußkriterien 
1. Motorische Defizite der unteren Extremitäten als Ergebnis 
einer 
metastatisch 
bedingten 
Rückenmarkskompression 
welche nicht länger als 30 Tage bestanden hat 
2. Bestätigung der Diagnose mittels Kernspintomographie (CT 
genehmigt) 
3. Alter 18 Jahre oder älter 
4. Schriftliche Einverständniserklärung 
5. Geschäftsfähigkeit des Patienten/der Patientin 
Ausschlußkriterien 
1. Frühere Strahlentherapie oder Operation der von der 
metastatisch bedingte Rückenmarkskompression betroffenen 
Wirbelsäulenregionen 
2. Symptomatischer Hirntumor oder symptomatische 
Hirnmetastasen  
3. Ausschließlich Metastasen der Halswirbelsäule 
4. Andere schwere neurologische Erkrankungen 
5. Schwangerschaft, Stillzeit  
6. Indikation für eine Dekompressions-Operation der 
betroffenen Wirbelsäulenregionen 
Statistik/Fallzahl-
Berechnung 
Der primäre Endpunkt dieser Phase 2 Studie beinhaltet die 
Erfassung der LPFS-Rate nach 6 Monaten nach Hochpräzisions-
Strahlentherapie mit 5x5 Gy in 1 Woche sowie den Nachweis, 
dass 
diese 
Rate 
höher 
ist 
als 
nach 
konventioneller 
Strahlentherapie mit 5x4 Gy (Hypothese). 

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Um mit einer statistischen Power von 80% zu gewährleisten, dass 
in dieser Phase 2 Studie das 95%-Konfidenzintervall für die 
wahre LPFS-Rate nach 6 Monaten eine Genauigkeit von +/-20% 
aufweist, müssen 44 Patienten/innen eingeschlossen werden. Für 
den Vergleich mit der historischen Kontrollgruppe wird ein 
Propensity Score Matching durchgeführt, um Unterschiede 
zwischen beiden Gruppen hinsichtlich Patientencharakteristika 
und Kovariablen auszugleichen und eine durch mögliche 
Unterschiede resultierende Verzerrung (Bias) zu vermeiden. Zehn 
relevante Prognosefaktoren werden hierbei berücksichtigt. Unter 
der Annahme, dass sich ungefähr 400 Patienten/innen für die 
historische Kontrollgruppe qualifizieren, wird eine statistische 
Power von 80% erreicht, wobei davon ausgegangen wird, dass 
die 
wahre 
LPFS-Rate 
6 
Monate 
nach 
konventioneller 
Strahlentherapie mit 5x4 Gy 67% beträgt und eine Verbesserung 
von absolut 20% als klinisch relevant angesehen wird.       
Ende der Studie 
Die Studie ist abgeschlossen, wenn alle Patienten entweder 
verstorben sind oder für wenigstens 6 Monate nachbeobachtet 
wurden 
und 
Analysen, 
Berichte 
und 
die 
Publikation 
abgeschlossen sind oder die Studie aus anderen Gründen beendet 
wurde (zum Beispiel Patientensicherheit).  
  

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Ablaufplan 
 
 
 
Vor  
Strahlentherapie
Am Ende der  
Strahlentherapie 
 1 Monat 
(+/- 2 Wochen)  
nach 
Strahlentherapie 
3 Monate  
(+/- 2 Wochen)  
nach 
Strahlentherapie  
6 Monate  
(+/- 2 Wochen)  
nach 
Strahlentherapie  
Einverständniserklärung 
X 
 
 
 
 
Anamnese/Begleiterkrank
ungen 
X 
 
 
 
 
Prognosefaktoren 
X 
 
 
 
 
Ärztliche Untersuchung 
X 
X 
X 
X 
X 
Ein-/Ausschlusskriterien 
X 
 
 
 
 
Motorische Funktion  
X 
X 
X 
X 
X 
Sensibilität 
X 
X 
X 
X 
X 
Blasen-Mastdarm-
Störungen 
X 
X 
X 
X 
X 
Gehfähigkeit  
X 
X 
X 
X 
X 
Schmerz   
X 
X 
X 
X 
X 
Distress (Lebensqualität)  
X 
X 
X 
X 
X 
Toxizität* 
X 
X 
X 
X 
X 
LPFS 
 
X* 
X 
X 
X 
Gesamt Überleben 
 
X* 
X 
X 
X 
 
*ebenfalls während der Strahlentherapie 

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2 List of Abbreviations  
 
AE 
adverse event 
ASIA 
American Spinal Injury Association 
GCP 
good clinical practice 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEGRO 
German Society for Radiation Oncology 
ECOG 
Eastern Cooperative Oncology Group 
EQD2 
equivalent dose in 2 Gy fractions 
LPFS 
local progression-free survival 
MR 
magnetic resonance 
MSCC 
metastatic spinal cord compression 
OS 
overall survival 
PR 
partial response 
PTV 
planning target volume 
QUANTEC 
Quantitative Analyses of Normal Tissue Effects in the Clinic 
RT 
radiotherapy 
SAE 
serious adverse event 
SBRT 
stereotactic body radiotherapy 
UAE 
unexpected adverse events 
UKSH 
University Hospital Schleswig-Holstein 
VMAT 
volumetric modulated arc therapy 

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3 Background and Rationale 
 
3.1 Background 
 
Metastatic spinal cord compression (MSCC) occurs in 5-10% of all cancer patients during the 
course of their disease [1, 2]. Radiotherapy (RT) alone is the most common treatment. However, the 
most appropriate radiation schedule is still a matter of debate. The survival prognosis of many 
patients with MSCC is poor measured in months [1-3]. Every radiotherapy session may be 
associated with discomfort for the often significantly impaired patients in a palliative situation, in 
particular regarding the transport to the radiotherapy department and the patient’s positioning on the 
treatment couch. Thus, a more patient convenient radiation schedule with a short overall treatment 
time (short-course radiotherapy such as 5x4 Gy in 1 week) would be preferable if it was as effective 
as the most commonly used radiation schedule for MSCC, 10x3 Gy in 2 weeks. Both retrospective 
and prospective studies have shown that 5x4 Gy in 1 week and 10x3 Gy in 2 weeks are similarly 
effective with respect to their effect on motor function [3, 4].  
However, a prospective non-randomized study has demonstrated that longer-course radiotherapy 
programs such as 10x3 Gy in 2 weeks resulted in better local progression-free survival (LPFS) than 
short-course programs such as 5x4 Gy in 1 week [5]. LPFS was defined as freedom from 
progression of motor deficits during RT and freedom from an in-field recurrence of MSCC (i.e. 
freedom from motor deficits due to a recurrence of MSCC in the previously irradiated parts of the 
spine) following RT. In that study, which compared longer-course to short-course radiotherapy, the 
vast majority of the patients in the longer-course RT group had received 10x3 Gy and the vast 
majority of patients in the short-course RT group 5x4 Gy [5]. The LPFS at 6 months were 86% after 
longer-course RT and 67% after short-course RT, respectively (p=0.034). Local progression of 
MSCC is a serious situation, since spinal surgery or a second course of radiotherapy in the same 
area of the spinal cord may not be possible. Therefore, such a progression must be avoided.  
The ideal RT schedule for MSCC would be both short and effective in improving LPFS. The 
biological effect of radiotherapy depends on both the total dose and the dose per fraction [6]. The 
biologically effective doses of different RT schedules can be compared by calculating the 
equivalent dose in 2 Gy fractions (EQD2) [7]. The EQD2 with respect to tumor cell kill is 23.3 Gy 
for 5x4 Gy and 32.5 Gy for 10x3 Gy, respectively. RT of MSCC can be intensified with the use of 
high-precision techniques such as volumetric modulated arc therapy (VMAT) and stereotactic body 
radiotherapy (SBRT) considering the tolerance doses of the spinal cord and the vertebral bone [8-
11]. The EDQ2 of high-precision RT with 5x5 Gy in 1 week is 31.3 Gy, which is similar to the 
EQD2 of 10x3 Gy (32.5 Gy). Thus, with 5x5 Gy of high-precision RT in 1 week, one can expect 
similar LPFS as with 10x3 Gy in 2 weeks. The EQD2 of 5x5 Gy for radiation-related myelopathy is 
43.8 Gy, which is below the tolerance dose of the spinal cord (45-50 Gy). The EQD2 of 5x5 Gy for 
damage to the vertebral bone is 41.7 Gy, which is well below the tolerance dose of bone (52 Gy) [9-
11]. Therefore, high-precision RT with 5x5 Gy can be considered a safe treatment regarding the risk 
of radiation myelopathy and damage to the vertebral bone.  
In contrast to other countries, decompressive surgery prior to RT has become increasingly popular 
for MSCC in Germany during the last 10 years, although it has been recommended only for selected 
patients [12-15]. Thus, the proportion of patients treated with RT alone for MSCC in Germany is 
decreasing, and a randomized, prospective clinical trial comparing 5x5 Gy of high-precision RT to 
5x4 Gy of conventional RT with a sufficiently large sample size will be quite difficult to perform 
within a reasonable period of time. Therefore, the present study is designed as a single-arm phase 2 
study. Subsequently, the patients of the phase 2 study will be compared to a historical control 
group. Propensity score matching will be performed to balance covariates and remove bias that may 
arise due to these confounders. Ten potential prognostic factors will be included. This design can be 

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considered appropriate to answer the question whether high-precision RT with 5x5 Gy results in 
significantly better LPFS than 5x4 Gy of conventional RT in patients irradiated for MSCC.                  
  
 
3.2. Rationale 
 
In patients treated with RT alone for MSCC, conventional RT with 10x3 Gy in 2 weeks results in 
similar motor function but significantly better LPFS than conventional RT with 5x4 Gy in 1 week. 
Since patients with MSCC are often significantly impaired, a RT regimen with an overall treatment 
time of only 1 week would be preferable if it resulted in similar LPFS as 10x3 Gy in 2 weeks. This 
may be achieved with 5x5 Gy in 1 week, since the EQD2 with respect to tumor cell kill of 5x5 Gy 
and 10x3 Gy are similar. Taking into account the tolerance dose of the spinal cord, 5x5 Gy can be 
safely administered with high-precision RT such as VMAT (or SBRT). Therefore, the present phase 
2 study investigates the LPFS after high-precision RT with 5x5 Gy in 1 week. To demonstrate 
superiority when compared to conventional RT with 5x4 Gy in 1 week, the patients of the phase 2 
study will be compared to a historical control group receiving conventional with 5x4 Gy in 1 week. 
If superiority regarding LPFS can be shown for high-precision RT with 5x5 Gy, patients with 
MSCC would benefit from this regimen, since they can achieve high LPFS rates with an RT 
regimen lasting only 1 week (5x5 Gy) instead of 2 weeks (10x3 Gy). This study aims to make a 
significant contribution to the most appropriate RT schedule for patients with MSCC. 

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4 Endpoints 
 
4.1. Primary endpoint 
 
The primary aim of this study is to investigate the LPFS of MSCC after 5x5 Gy of high-precision 
RT (VMAT = preferred technique, SBRT = allowed for patients with involvement of only one 
vertebra, if the required constraints [please see 6.2.1] can be met) and to demonstrate that this 
regimen results in significantly better 6-month LPFS than conventional RT with 5x4 Gy. LPFS is 
defined as freedom from progression of motor deficits during RT and freedom from an in-field 
recurrence of MSCC (i.e. freedom from motor deficits due to a recurrence of MSCC in the 
previously irradiated parts of the spine) following RT. The LPFS rate will be assessed 6 months 
after the end of RT.  
 
 
4.2. Criteria for secondary endpoints 
 
In addition, the following endpoints will be evaluated: 
 
1. Motor function/Ability to walk: Assessment directly and at 1, 3 and 6 months after RT 
2. Sensory function: Assessment directly and at 1, 3 and 6 months after RT 
3. Sphincter dysfunction: Assessment directly and at 1, 3 and 6 months after RT 
4. Local progression-free survival: Additional evaluation directly and at 1, 3 and 6 months after RT 
5. Overall survival: Evaluation directly and at 1, 3 and 6 months after RT 
6. Pain: Evaluation directly and at 1, 3 and 6 months after RT 
7. Distress: Evaluation directly and at 1, 3 and 6 months after RT 
8. Toxicity: Evaluation during RT, and directly, 1, 3 and 6 months after RT 
 
 

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5 Study Design and Patient Selection 
 
5.1 General design and duration 
This is a single-arm study, which will investigate the effect of high-precision RT with 5x5 Gy on 
LPFS in patients irradiated for MSCC. 
 
The recruitment of all 44 patients (40 patients + 10% for potential drop-outs) should be completed 
within 18 months. The follow-up period will be 6 months. Another 6 months are required for 
analyses, reporting and publication. This equals a total running time for the study of 30 months. 
 
 
In accordance with a previous study assessing local control of MSCC, the following patient 
characteristics will be recorded to allow adequate comparison with the historical, propensity-score 
matched control group [16]:  
 
- Age (2 groups, depending on median age)  
- Gender 
- Type of primary tumor (breast cancer vs. prostate cancer vs. myeloma/lymphoma vs. lung cancer  
  vs. other tumors) 
- Interval from tumor diagnosis to MSCC (≤15 months vs. >15 months) 
- Number of involved vertebrae (1-2 vs. ≥3)  
- Other bone metastases at the time of RT (no vs. yes) 
- Visceral metastases at the time of RT (no vs. yes) 
- Time developing motor deficits prior to RT (1-7 days vs. 8-14 days vs. >14 days) 
- Ambulatory status prior to RT (no vs. yes) 
- Eastern Cooperative Oncology Group (ECOG) performance score (1-2 vs. 3-4) 
 
 
 
5.2 Patient selection 
 
5.2.1 General prerequisites 
Patients have to be adequately informed about their diagnosis and about the nature, significance and 
scope of the study. Patients may only be included after completing the pre-therapy clarification and 
on fulfilment of all inclusion criteria and on non-fulfilment of all exclusion criteria. Prior to 
inclusion in the study, it should be clear that the patient is no clear candidate for decompressive 
surgery of the parts of the spinal cord involved by MSCC.  

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5.2.2 Inclusion and exclusion criteria 
 
Inclusion criteria 
1. Motor deficits of the lower extremities resulting from 
MSCC*, which have persisted for no longer than 30 days 
2. Confirmation of diagnosis by MR-imaging (CT allowed) 
3. Age 18 years or older 
4. Written informed consent 
5. Capacity of the patient to contract 
Exclusion criteria 
1. Previous RT or surgery of the spinal areas affected MSCC 
2. Symptomatic brain tumor or symptomatic brain metastases  
3. Metastases of the cervical spine only 
4. Other severe neurological disorders 
5. Pregnancy, Lactation  
6. Indication for decompressive surgery of affected spinal areas
*MSCC may affect single or multiple spinal sites 
 
5.2.3 Termination criteria for individual patients 
 
The patient may terminate participation in the study at any time and without giving any reasons. 
Otherwise, the reasons for terminating participation in the study are the same as those for 
individually breaking off treatment with radiotherapy.  
 Serious adverse event (SAE), which necessitates termination of treatment 
 Unacceptable toxicities 
 Pregnancy 
 
Date and reason for termination of treatment have to be documented, if indicated by the patient. 
 
 
5.2.4 Termination criteria for the study in general 
 
The clinical study can be terminated by the coordinating investigator if new findings and/or risks 
should come to light that necessitate a reassessment of the risk/benefit ratio and which results in a 
negative result.  
 
 
5.2.5 Definition of the end of the study 
 
The study is completed when all patients have either died or been followed up for at least 6 months, 
or the study has been terminated.  
 
The patient will continue to receive treatment at the clinic in question after the 6-month follow-up 
period, or the premature termination of the study for the patient. 
 

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6 Treatment 
 
6.1 Patient registration 
The patients were assigned 2 code numbers, the number of the contributing center plus a patient ID 
number starting with 001 and chronologically ongoing.  
 
Coordination and supervision of the inclusion of the patients will be performed by the Department 
of Radiation Oncology of the University of Lübeck, Germany.  
Patients can be registered by e-mail (dirk.rades@uksh.de) or by fax (0049-451-500 45404). 
 
6.2 Treatment 
6.2.1 Radiotherapy 
Radiotherapy is administered as high-precision radiotherapy with 25.0 Gy in 1 week, i.e. with 5.0 
Gy per fraction on 5 days per week (representing an EQD2 of 43.8 Gy for radiation myelopathy) [6, 
7]. An EQD2 of 45 Gy is estimated to be associated with a risk of radiation-related myelopathy of 
0.03% and is therefore considered safe [8]. VMAT (6-10 MeV photon beams) is the preferred 
technique. SBRT is allowed for patients with involvement of only one vertebra, if the following 
constraints can be met. The clinical target volume (CTV) includes the vertebral and soft tissue 
tumor as seen on the planning computed tomography and diagnostic MR-imaging, the spinal canal, 
the width of the involved vertebrae, and half a vertebra above and below those vertebrae involved 
by MSCC. The planning target volume (PTV) should include the CTV plus 0.8 cm and should be 
covered by the 95%-isodose. The maximum relative dose allowed to the spinal cord is 101.5% of 
the prescribed dose (representing an EQD2 of 44.9 Gy for radiation myelopathy). This maximum 
dose is estimated to be associated with a risk of radiation-related of <0.03% and is, therefore, also 
considered safe [8]. Both the EQD2 of the prescribed dose (41.7 Gy) and the EQD2 of the 
maximum dose (43.8 Gy) are well below the tolerance dose of bone [9-11]. In accordance with the 
Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) data, the mean doses 
(EQD2) for esophagus, heart and lung must be <34 Gy, <26 Gy and ≤7 Gy, respectively [9]. Taking 
into account a radiation regimen of five fractions, the corresponding mean doses per fraction are 4.5 
Gy, 3.8 Gy and 1.54 Gy, respectively [6, 7]. MSCC may affect single or multiple spinal sites. All 
sites need to be treated with high-precision RT following the dose presciptions and constraints 
given above.    
 
6.2.2. Concomitant treatment 
It is recommended that the patients receive concomitant dexamethasone during the period of 
radiotherapy if indicated [1, 2]. [Regarding dose, type and duration of treatment, contraindications, 
side effects, pharmacological characteristics and pharmaceutical details about dexamethasone, 
please see relevant product information in the patient information leaflet included in the drug 
package.] 
 
6.2.3. Possible side effects of high-precision RT 
 
High-precision RT in the thoracic spinal area may be associated with nausea and vomiting, whereas 
RT in the lumbar spine may be associated with diarrhea. In case of grade 3 toxicity according to 
Common Terminology Criteria for Adverse Events (CTCAE), RT may be delayed for a maximum 
of 7 days. If the symptoms persist, RT will be terminated. If RT has to be terminated, the head of 
the clinical study has to be informed. 

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7 Safety Management 
 
7.1 Definitions 
 
7.1.1 Adverse events 
An adverse event (AE) is any event experienced by a patient or subject of a clinical study, which 
does not necessarily have a causal relationship to treatment. An AE can therefore be any adverse or 
inadvertent occurrence (including notable laboratory findings), symptom or illness that occurs in the 
treatment period, no matter whether there is a causal relationship or not. Existing illnesses that 
deteriorate during the study should be reported as AE. They may lead to SAEs if they fulfil the 
criteria below.  
Events covered by the documentation for concomitant diseases, the skin status or the radiation 
related acute toxicity grade (CTCAE v4.03) Grade 1 do not have to be additionally documented as 
adverse events. If an additional concomitant disease appears after the start of the study an adverse 
event form has to be completed. 
 
7.1.2 Unexpected adverse events 
Unexpected adverse events (UAEs) are those whose type, frequency and degree of severity are not 
expected based on current knowledge. 
 
7.1.3. Serious adverse events 
Serious adverse events (SAEs) are those which fulfil one of the following criteria at any dose level: 
• Lethal (resulting in death) event (Note: death is the result, not the event itself) 
• Life-threatening event (Note: the term “life-threatening” refers to an event in which the 
patient was in danger of death at the time the event occurred but not to an event that 
may have resulted in death had it been more serious.) 
• Patient had to be admitted to hospital or his/her hospital stay had to be extended as a 
result of the event 
• Any event leading to permanent or significant disability. 
• Birth defects or malformations 
• Any medically significant intervention in order to prevent one of the outcomes 
mentioned above 
 
Hospitalization should be defined as such that the hospitalization was necessary in order to treat the 
AE. Hospital stay as part of the treatment outlined in the protocol or as a result of a planned, 
elective operation is not classified as SAE. Likewise, an elective hospitalization to facilitate the 
study process does not count as SAE.  
 
7.2 Assessment and documentation of adverse events 
 
The severity of AEs should be assessed for clinical effects according to the following scale:  
1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening and 5 = fatal. 
 
The following scale should be used to describe the likelihood that the event was caused by the study 
treatment: 1 = certain/definitely caused by study treatment; 2 = probable; 3 = possible; 4 = 
unlikely; 5 = not related; and 9 = not assessable. 
 

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7.3 Reporting of adverse events 
 
SAEs and UAEs must be reported within 24 hours after their detection/onset by fax to the 
address below (see separate document attached to the case report form): 
 
Prof. Dr. Dirk Rades 
 
Klinik für Strahlentherapie, Universität zu Lübeck 
Ratzeburger Allee 160; 23538 Lübeck, Germany 
 
Tel.: +49 (0)451 500 45400  
Fax: +49 (0)451 500 45404 
 
Email: dirk.rades@uksh.de 
 

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8 Assessments 
 
8.1 Summary of assessments 
 
The following assessments will be performed as part of this study: 
 
 
 
Prior to  
RT 
 End of  
RT 
Follow up  
at 1 month  
(+/- 2 weeks) 
following RT  
Follow up  
at 3 months  
(+/- 2 weeks) 
following RT 
Follow up  
at 6 months  
(+/- 2 weeks) 
following RT  
Informed Consent 
X 
 
 
 
 
Medical HistoryCconcomitant 
Diseases 
X 
 
 
 
 
Prognostic factors 
X 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
Motor Function  
X 
X 
X 
X 
X 
Sensory Function 
X 
X 
X 
X 
X 
Sphincter Dysfunction 
X 
X 
X 
X 
X 
Ambulatory Status  
X 
X 
X 
X 
X 
Pain   
X 
X 
X 
X 
X 
Distress (quality of life)  
X 
X 
X 
X 
X 
Toxicity* 
X 
X 
X 
X 
X 
LPFS 
 
X* 
X 
X 
X 
Overall Survival 
 
X* 
X 
X 
X 
 
*also during RT 
 
8.2 Data assessment and prior to start of high-precision RT 
 
The following parameters will be recorded at the start of the study:  
Date of birth (age), gender, time between onset of motor deficits and start of RT, type of imaging 
used for diagnosis of MSCC, interval between initial tumor diagnosis and MSCC, dexamethasone 
treatment, surgical consultation, localization and number of involved vertebrae, type of primary 
tumor / histology, presence of other bone metastases or visceral metastases prior to RT, 
performance status (ECOG-PS, Appendix IV), motor function / ambulatory status (according to the 
modified Tomita scale [17], sensory function, sphincter dysfunction, pain score, and distress (as an 
indicator of quality of life) score [18] (Appendix III).  
 

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8.3 Assessments with respect to primary and secondary endpoints 
 
The following parameters will be assessed continuously throughout the course of the study: 
 
8.3.1 Local progression-free survival  
 
Local progression-free survival (LPFS) is defined as freedom from progression of motor deficits 
during RT and freedom from an in-field recurrence of MSCC (i.e. freedom from motor deficits due 
to a recurrence of MSCC in the previously irradiated parts of the spine) following RT [5]. LPFS 
time will be calculated from the last day of the radiotherapy treatment. LPFS will be regularly 
assessed clinically (physical examination) at 1, 3 and 6 months following RT. In case of a suspected 
recurrence of MSCC (i.e. progression of existing or development of new motor deficits), a spinal 
MR-imaging will be performed to confirm or exclude an in-field recurrence of MSCC. In case of 
progression of existing or development of new motor deficits between two regular follow-up visits, 
spinal MR-imaging will be performed at any time. The number of MR-imaging sessions is 
minimized to clinically relevant situations, since patients with MSCC are often quite debilitated. 
Thus, diagnostic procedures, which may be burdensome for the patients, may not be performed for 
study purposes alone. The medical history/concomitant diseases will be assessed once at baseline. 
Newly developed diseases have to be documented as adverse events.     
 
8.3.2 Motor function / Ability to walk 
Motor function will be evaluated using the following scale according to Tomita et al. [17] prior to 
RT, at the end of RT, and at 1, 3 and 6 months following RT. Improvement or deterioration of 
motor function was defined as a change of at least 1 point.  
 
0 = Normal strength 
1 = Ambulatory without aid 
2 = Ambulatory with aid 
3 = Not ambulatory  
4 = Complete paraplegia 
 
Motor function will additionally be evaluated separately for each leg using the following scale in 
reference to the American Spinal Injury Association (ASIA) classification [19] resulting in total 
points of 0 to 14. Improvement or deterioration of motor function was defined as a change of at 
least two points.  
0 = Complete paraplegia 
1 = Palpable or visible muscle contractions 
2 = Active movement, without gravity 
3 = Active movement, against gravity 
4 = Active movement, against mild resistance 
5 = Active movement, against intermediate resistance 
6 = Active movement, against strong resistance 
7 = Normal strength 

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8.3.3 Sensory function / Sphincter dysfunction 
 
Sensory function: 
Sensory function will be evaluated using the following scale, modified in accordance to the ASIA 
classification [19].  
0 = Absent 
1 = Impaired 
2 = Normal 
9 = Cannot be assessed 
 
Sphincter dysfunction:     
Sphincter dysfunction will be evaluated as yes vs. no.      
 
 
8.3.4 Overall survival 
Overall survival (OS) time will be calculated for each patient from the last day of radiotherapy up to 
6 months following RT. Patients will be followed up until death or for at least 6 months. 
 
8.3.5 Pain  
Vertebral pain will be evaluated with a numeric rating scale (self-assessment by patients) from 0 to 
10 points (0=no pain, 10=worst pain) prior to RT and directly, 1, 3 and 6 months following RT. 
Improvement by two points is rated partial response (PR), 0 points complete response (CR). Pain 
will be assessed prior to RT and directly and 1, 3 and 6 months following RT. 
 
8.3.6 Distress (as an indicator of quality of life) 
Distress will be assessed using the distress thermometer (Appendix III) [18]. Patients can rate their 
distress between 0 and 10 (0 = no distress, 10 = extreme distress). Distress will be assessed prior to 
RT and directly and 1, 3 and 6 months following RT. Improvement of distress was defined as a 
decrease by at least two points compared to the distress-score prior to RT (baseline). 
 
 
8.3.7 Toxicity 
 
Toxicity will be assessed according to CTCAE 4.03 during RT, directly after RT and at 1, 3 and 6 
months following RT [20]. If radiation myelopathy is suspected (i.e. deterioration according to the 
modified ASIA scale [19]), spinal MR-imaging will be performed.  
 

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9 Comparisons to Historical Control Group 
 
The patients of this study who received high-precision RT with 5x5 Gy for MSCC will be matched 
to historical control group treated with 5x4 Gy of conventional RT between 2001 and 2016. This 
data set consists of 680 patients. 
 
The patients of the control group are part of an already existing anonymized database. To be 
eligible for control group, patients fulfilling the same inclusion criteria and exclusion criteria as 
defined in the prospective phase II study are considered. Furthermore, to be consistent with efficacy 
analysis of phase II study, patients of the historical control group must have received at least 80% of 
the planned RT dose. This will lead to more than 600 patients qualifying for the comparison with 
the prospectively collected phase 2 data. 
 
For comparison purposes, a propensity score approach will be applied to account for baseline 
differences between treatment arms to balance covariates and remove bias that may arise due to 
these confounders. A propensity score is a conditional probability of assignment to a particular 
treatment given a number of baseline covariates. Except for unmeasured potential confounding 
factors, patients having the same propensity score but assigned to different treatments will tend to 
have the same (or nearly the same) distributions on their background covariates and thus are 
considered to be similar to random assignment of treatments. To estimate the odds of receiving a 
specific radiotherapy a non-parsimonious multivariable logistic regression model will be estimated. 
Covariates to be included in the model will be the following ten prognostic factors [16]: 
 
- Age (2 groups, depending on median age)  
- Gender 
- Type of primary tumor (breast cancer vs. prostate cancer vs. myeloma/lymphoma vs. lung cancer  
  vs. other tumors) 
- Interval from tumor diagnosis to MSCC (≤15 vs. >15 months) 
- Number of involved vertebrae (1-2 vs. ≥3)  
- Other bone metastases at the time of RT (no vs. yes) 
- Visceral metastases at the time of RT (no vs. yes) 
- Time developing motor deficits prior to RT (1-7 days vs. 8-14 days vs. >14 days) 
- Ambulatory status prior to RT (no vs. yes) 
- Eastern Cooperative Oncology Group (ECOG) performance score (1-2 vs. 3-4) 
 
Once estimated, adjustment will be accomplished by stratifying the data set on the propensity score, 
calculating the treatment effect within strata and then pooling the strata-specific treatment effect 
estimates.  
Rosenbaum and Rubin have shown that perfect stratification based on the propensity score will 
produce strata where the average treatment effect within strata is an unbiased estimate of the true 
treatment effect [21]. Due to the differences in total sample size between the phase II study and the 
historical data set, the stratum boundaries will be based on the values of the propensity score for the 
phase II data alone.  
One approach is to use quintiles of the estimated propensity scores to determine the cut-offs for the 
different strata. The success of propensity score approach will be examined by examining the 
covariate imbalance between treatment arms before and after adjusting for their propensity quintile. 
This will be done using a two-was analysis of variance model which includes main effects for 
propensity score quintile (codes as a class variable with 4 degrees of freedom) and treatment arm.  
The F-statistic for treatment arm after adjustment for propensity score quintiles will then be 
compared with the F-statistics for treatment arm prior to adjustment for propensity score quintile to 
determine whether balance was achieved after stratification based on the propensity score. 

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Furthermore, the propensity score will be evaluated for good calibration as measured by the 
propensity score predicted and observed proportions of treatment group arms within quintiles of the 
propensity score. To investigate whether propensity scores removed bias due to differences in 
covariates between studies and to compare binary study endpoints after stratification of patients by 
propensity scores Cochran-Mantel-Haenszel tests were performed. 
Comparisons between the patients of the phase 2 study and the historical control group will be 
performed for LPFS, OS, motor function and ambulatory status.  
 
10 Statistics 
 
10.1 Sample size calculation 
 
The primary goal of this study is to assess high-precision RT with 5x5 Gy in 1 week with respect to 
6-month LPFS and to demonstrate that this rate is superior to conventional RT with 5x4 Gy with 
respect to LPFS of MSCC (hypothesis). 
 
With respect to tumor cell kill, the equivalent dose in 2 Gy fractions (EQD2) of 5x5 Gy is similar to 
the EQD2 of 10x3 Gy (31.3 Gy vs. 32.5 Gy) and higher than the EQD2 of 5x4 Gy (23.3 Gy) . In a 
previous prospective non-randomized study, the 6-month LPFS rates were 86% after longer-course 
RT and 67% after short-course RT, respectively (p=0.034). In that study, 95 of 117 patients (81%) 
in the longer-course RT group had received 10x3 Gy, and 91 of 114 patients (80%) in the short-
course RT group had received 5x4 Gy. Thus, assuming - for the present study – that conventional 
RT with 5x4 Gy in fact results in a 6-month LPFS rate of 67%, an increase by roughly 20 
percentage point is considered to be clinically minimal relevant and even appears to be realistic 
when applying high-precision RT with 5x5 Gy. 
 
The sample size is chosen to firstly obtain prospective phase 2 data that can be interpreted on its 
own and to secondly allow for comparison with historical data:  
• A sample size of at least 40 eligible patients is needed to estimate the probability of LPFS at 6 
month with adequate precision, based on the following assumptions: 
o 6-month LPFS can be assumed to be 87% 
o 6-month LPFS is to be estimated with a precision of plus/minus 20 percentage points 
expressed as the half length of the associated two-sided confidence interval with a 
confidence coefficient of 95%. 
o The power -i.e. the probability to obtain this precision, should be at least 80% 
o Clopper-Pearson confidence limits are used as the approach for sample size. 
Assuming that roughly 10% of enrolled patients will not be eligible for efficacy analysis due to 
early lost-to-follow-up or due to premature discontinuation of high-precision RT, a total of 44 
patients should be enrolled in the prospective part of the trial. 
 
• As described in section 8, the confirmatory study aim is to compare the prospectively collected 
phase II data with a historical, propensity-score matched cohort collected up to the time of data 
analysis. Assuming for simplicity and conservative power calculation that this comparison could 
be conducted with a simple Pearson-Chi-Square test using a two-sided significance level of 5% 
(10%), a power of 79% (86%) is reached, if 40 patients are treated with high-precision RT and 
roughly 400 patients of the historical control group qualify for Propensity-Score adjusted 
comparison and assuming that the expected 6-month LPFS are 87% and 67%, respectively. 
Taking into account that the more sophisticated propensity-score adjusted statistical analysis 
(see section 8) will increase statistical power, the power for treatment arm comparison reached 

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with 40 eligible patients in the prospective phase 2 part of the study can be assumed to be at 
least 80%. 
 
 
10.2. Statistical analyses  
 
10.2.1 Primary endpoint: 
 
The primary endpoint (LPFS of MSCC) will be evaluated based on the sample size calculations 
described above. The evaluation will be performed in those patients, who are available for 
assessment of the primary endpoint and have received at least 80% of the planned RT dose. Due to 
the open nature of the study, a blind data review is not necessary. The safety population includes all 
patients who have received at least 1 fraction of high-precision RT.  
LPFS is defined as freedom from progression of motor deficits during RT and freedom from an in-
field recurrence of MSCC (i.e. freedom from motor deficits due to a recurrence of MSCC in the 
previously irradiated parts of the spine) following RT [5]. Deterioration of motor deficits during RT 
will be counted as LPFS of 0 months. Freedom from an in-field recurrence following RT will be 
referenced from the last day of RT. To investigate clinically important, sustainable effects of 
precision radiotherapy and avoid over-evaluation of early temporal shifts without any longer term 
relevance, study design and analysis focuses on binary endpoints evaluated at 6-months rather than 
time-to-event analyses.  
 
10.2.2 Secondary endpoints: 
Secondary endpoints: 
An improvement or deterioration of the motor function will be defined as a change of at least 1 
point on a 5-point scale [17]. Effect of RT on motor function and post-RT ambulatory rates will be 
evaluated directly after RT and at 1, 3 and 6 months following RT in those patients who are alive 
and available for assessment. To investigate whether propensity scores removed bias due to 
differences in covariates between studies and to compare binary study endpoints after stratification 
of patients by propensity scores Cochran-Mantel-Haenszel tests were performed. P-values of <0.05 
are considered significant.  
Overall survival (OS) will be counted from the last day of RT. To investigate clinically important, 
sustainable effects of precision radiotherapy and avoid over-evaluation of early temporal shifts 
without any longer term relevance, study design and analysis focuses on binary endpoints evaluated 
at 6-months rather than time-to-event analyses. The analysis of OS will be conducted in the intent-
to-treat population. 
Data regarding sensory deficits, sphincter dysfunction, pain, distress and toxicity will only be 
assessed in the phase 2 study.  

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11 Ethical and Legal Principles 
 
The examinations to be carried out as part of this study are all considered standard procedures. 
There are no additional laboratory tests, X-rays or other examinations that could be potentially 
burdensome for the patient.  
 
11.1 Ethics committee vote 
The study protocol will be submitted to the ethics committee responsible. The positive vote of the 
ethics committee has to be communicated to the coordinating investigator. (AppendixV)  
 
11.2 Official registration 
Because the study includes radiotherapy, an application must be submitted to the Expert Committee 
of the German Society for Radiation Oncology (DEGRO) and, if required by the Expert Committee, 
additionally to the Bundesamt für Strahlenschutz (German Federal Office for Radiation Protection). 
 
11.3 Insurance 
Insurance for patients in Germany participating in this study is covered by: 
Allianz Versicherungs-Aktiengesellschaft, 10900 Berlin, Germany  (insurance policy no. AS-
9100160845). (AppendixVI) 
  
11.4 Patient information and informed consent 
Patient information and informed consent will be submitted along with the study protocol for 
evaluation by the ethics committee responsible. Before inclusion in the study, each patient will be 
fully informed about the content and procedure of the study (Appendix I). 
 
If the potential study patient has received the necessary information and if the investigator is sure 
that the patient has understood this information, the patient will be asked to give his/her consent by 
signature (Appendix II).  
 
The patient will receive a copy of the patient information and the signed informed consent form. 
The investigator must also inform the patient that he/she has the right to withdraw consent to 
participate in the study at any time and without having to give any reasons. Patients must be 
informed that the data collected as part of the study will be documented anonymously and will then 
be forwarded for scientific evaluation. This is also the appropriate point to indicate the patient 
consent to data protection. 
 
11.5 Declaration of Helsinki  
The study will be conducted in accordance with the principles laid out in the Declaration of 
Helsinki and in accordance with the principles of good clinical practice (GCP).  
 
11.6 Data protection 
Data will be collected in accordance with the regulations set out in the Data Protection Act. All 
findings from the clinical study will be stored on electronic data storage devices and treated with 
utmost confidentiality. Organization measures have been taken in order to prevent the data from 
being communicated to unauthorized persons. Patients will only be identified via their individual 
patient numbers throughout the entire documentation and evaluation phase and their full name will 
not be used. 

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12 Data Management 
 
12.1 Patient identification list 
All data relating to patients will be recorded in a pseudonymous way. Each patient will be 
identifiable only by the unique patient number. A patient identification list will only be kept in the 
relevant study centers and will not be forwarded to the sponsor.  
 
12.2 Documentation forms 
Data collection will be done using the case report forms (CRFs) (separate document). 
 
The data documentation forms have to be filled in using a ballpoint pen. Do not use fountain pens 
or pencils. Corrections have to be made as follows: cross the error out once with a straight line, 
enter the correct information next to it and note the date and/or reason for correction. Comments 
have to be made if data fields cannot be filled in because of missing information. 
 
The forms should be filled in as soon as possible and should be submitted to the principal 
investigator of the contributing center for review, signed, dated and forwarded to the coordinating 
investigator. After review and clarifying potential questions, the coordinating investigator will 
forward the forms to the study management office (“Zentrum für Klinische Studien” at the 
University of Lübeck).  
 
12.3 Monitoring 
Monitoring will be performed by the “Zentrum für Klinische Studien” at the University of Lübeck. 
The frequency of monitoring visits per site will be defined depending on the recruitment rate and 
the quality of data. 
 
12.4 Direct access to source data / documents 
The sponsor should ensure that it is specified in the protocol or other written agreement that the 
investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s), providing direct access to source data/documents. 
 
12.5 Storage of study documents 
The central study documents, including the documentation sheets, will be kept at the sponsor for a 
minimum of 10 years after the final report according to the current GCP guidelines. The principle 
investigator of each study center will keep all administrative documents (written correspondence 
with the ethics committee, regulatory authorities, study management office, coordinating 
investigator/study coordinating office), the patient identification list, the signed informed consent 
forms, copies of the documentation sheets and the general study documentation (protocol, 
amendments) of his/her center for the above mentioned period. Original patient data (patient files) 
have also to be kept for the length of time stipulated for the study centres, but not for less than 10 
years. 
 

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13 References 
 
 
1. Prasad D and Schiff D. Malignant spinal cord compression. Lancet Oncol 2005;6:15-24. 
2. Rades D and Abrahm J. The role of radiotherapy for metastatic epidural spinal cord compression. Nat 
Rev Clin Oncol 2010;7:590-598. 
3. Rades D, Stalpers LJA, Veninga T, et al. Evaluation of five radiation schedules and prognostic factors 
for metastatic spinal cord compression in a series of 1304 patients. J Clin Oncol 2005;15:3366-3375. 
4. Rades D, Šegedin B, Conde-Moreno AJ, et al. Radiotherapy with 4 Gy × 5 versus 3 Gy × 10 for 
metastatic epidural spinal cord compression: Final Results of the SCORE-2 Trial (ARO 2009/01). J Clin 
Oncol 2016;34:597-602. 
5. Rades D, Lange M, Veninga T, et al. Preliminary results of the SCORE (Spinal Cord cOmpression 
Recurrence Evaluation) study comparing short-course versus long-course radiotherapy for local control 
of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2009;73:228-234. 
6. Barendsen GW. Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int 
J Radiat Oncol Biol Phys 1982;8:1981-1997. 
7. Joiner MC, Van der Kogel AJ: The linear-quadratic approach to fractionation and calculation of isoeffect 
relationships, in Steel GG (ed): Basic clinical radiobiology. New York, Oxford University Press, 1997, 
pp 106-112. 
8. Schultheiss TE. The radiation dose-response of the human spinal cord. Int J Radiat Oncol Biol Phys 
2008;71:1455-1459. 
9. Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue complication probability models in the 
clinic. Int J Radiat Oncol Biol Phys 2010;76(3 Suppl):S10-9. 
10. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat 
Oncol Biol Phys 1991;21:109-122. 
11. Emami B. Tolerance of the normal tissue to therapeutic irradiation. Rep Radiother Oncol 2013;1:35-48. 
12. Patchell R, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of 
spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366:643-648. 
13. Van den Bent MJ. Surgical resection improves outcome in metastatic epidural spinal cord compression. 
Lancet 2005;366:609-610. 
14. Kunkler I. Surgical resection in metastatic spinal cord compression. Lancet 2006;367:109. 
15. Rades D, Huttenlocher S, Dunst J, et al. Matched pair analysis comparing surgery followed by 
radiotherapy and radiotherapy alone for metastatic spinal cord compression. J Clin Oncol 2010;28:3597-
3604. 
16. Rades D, Fehlauer F, Schulte R, et al. Prognostic factors for local control and survival after radiotherapy 
of metastatic spinal cord compression. J Clin Oncol 2006;24:3388-3393.  
17. Tomita T, Galicich JH, Sundaresan N. Radiation therapy for spinal epidural metastases with complete 
block. Acta Radiol Oncol 1983; 22: 135-143. 
18. Holland, JC. Update: NCCN practice guidelines for the management of psychosocial distress. Oncology 
1999; 13: 459–507. 
19. Curt A, Dietz V. Zur Prognose traumatischer Rückenmarkläsionen. Nervenarzt 1997;68:485-495. 
20. National Institutes of Health/National Cancer Institute (2009) Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 
21. Rosenbaum PR and Rubin DB. The central role of the propensity score in observational studies for 
causal effects. Biometrika 1983;70:41-55. 
22. Kaplan EL and Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc 
1958;53:457-481. 

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Appendix I Patient information 
 
Address of the Center (Stamp): 
 
 
 
Name of the Physician: 
 
phone: 
 
 
phone: 
 
 
 
Patient information regarding the clinical study 
High-precision radiotherapy of motor deficits due to metastatic spinal cord compression 
 
Study designation: PRE-MODE 
 
Sponsor of the clinical study: 
University Hospital Schleswig-Holstein, Campus Luebeck 
 
Coordinating investigator: Prof. Dr. med. Dirk Rades 
 
Patient-No.: |___|___|___|  
 
Patient-Initials: |___|___| 
 
Please read this information sheet carefully, before making a decision. This sheet includes 
important information regarding this clinical study. Your treating physician will directly talk 
to you about this study. Please ask your physician, if you do not understand arts of this 
information sheet or if you have additional questions. 
 
 
Dear Patient, 
We would like to ask you to read this information sheet very carefully. It contains important 
information about this clinical study. Your treating physician will answer any questions.  
 
You have been diagnosed with malignant metastases of the vertebral bodies, which are to be treated 
with radiotherapy. For this reason, you are invited to take part in the study:  
High-precision radiotherapy of motor deficits due to metastatic spinal cord compression.  
 
This study investigates high-precision radiotherapy as a treatment of motor deficits (weakness) of 
the legs caused by compression of the spinal cord by vertebral metastases (metastatic spinal cord 
compression). The treatment includes 5 radiotherapy sessions (1 session per day) and takes 1 week.  

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It is supposed that high-precision radiotherapy with 5 fractions (with a dose of 5 Gy each) can 
reduce the risk of recurrent motor deficits due to metastatic spinal cord compression in the 
irradiated parts of the spine more effectively than conventional radiotherapy with 5 (with a dose of 
4 Gy each) fractions. High-precision radiotherapy allows the delivery of a higher dose to the 
vertebral metastases causing metastatic spinal cord compression due to better sparing of the spinal 
cord when compared to conventional radiotherapy. The higher dose is supposed to result in better 
control of the metastases.    
 
Study procedure 
If you give your consent to take part in this clinical study, you will have to undergo a physical 
examination before the start of the study. In addition, you will also be asked about any pain you 
experience as well as about your quality of life. Before the start of your radiotherapy, a computed 
tomography required for treatment planning will be performed. You will receive such a computed 
tomography also if you do not take part in this study. After completion of treatment planning, you 
will receive your radiation treatment, which consists of 5 sessions (fractions) of high-precision 
radiotherapy, generally administered on 5 consecutive working days.  
 
You will have to undergo a physical examination and answer questions about any pain and about 
your quality of life directly after the end of your radiotherapy treatment and at 1 month, at 3 months 
and at 6 months following radiotherapy. These procedures are necessary to evaluate the course of 
your disease and your state of health.  
 
Aims of the clinical study 
The major goal of this clinical study is to investigate to which extent high-precision radiotherapy 
with modern techniques can prevent progression or recurrence of motor deficits (weakness) of the 
legs following radiotherapy. In addition, it will be evaluated to which extent radiotherapy can lead 
to improvement of motor function, ambulatory status, sensory function and sphincter dysfunction, 
to pain relief and to improvement in quality of life, side effects and overall survival.  
 
Structure of the clinical study 
A total of 44 patients from Germany, Denmark and Spain are planned to take part in the clinical 
study, who will receive modern high-precision radiotherapy treatment for the metastases on their 
vertebral bodies.  
 
The coordinating investigator of this study is: 
 
Prof. Dr. med. Dirk Rades 
Klinik für Strahlentherapie 
Universitätsklinikum Schleswig-Holstein, Campus Lübeck 
Ratzeburger Allee 160 
23538 Lübeck 
phone: 0049 (0) 451 500-45400/-45401 
 
Your treating radiation oncologist will inform you about the radiotherapy in detail.  
 
Your responsibilities during the study 
For a successful treatment, it is important that you keep the appointments during the treatment and 
the follow up period and that you follow the instructions of your study physicians. Concurrent 

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participation in another study is only allowed in agreement with your study physicians. You may be 
excluded from the study due to medical reasons. The data collected within this study will be further 
analyzed; no additional data will be collected. 
If you experience ambiguous symptoms during the course of this clinical study, you have to inform 
your treating physicians. In case of severe symptoms, you have to inform your treating physicians 
immediately, if necessary by phone (see contact data on the first page of this information sheet). 
This is mandatory to allow your physicians to identify the measures that are most appropriate for 
you in this situation.    
 
Potential side effects of treatment 
Each type of radiotherapy may cause skin reactions (erythema) and fatigue. Radiotherapy in the 
region of the thoracic spine may cause nausea and vomiting, while radiotherapy in the region of the 
lumbar spine may cause diarrhea. As a late effect, radiotherapy may possibly lead to damage to the 
spinal cord with neurologic deficits. However, the dose administered in this study does not exceed 
the tolerance dose of the spinal cord such as sensory disorders and motor weakness of the legs. The 
radiation dose administered within this study will not exceed the tolerance dose of the spinal cord. 
According to the literature, the risk of radiation-related spinal cord damage is estimated to be less 
than 0.03%.   
 
Radiotherapy for metastatic spinal cord compression often requires concomitant administration of 
cortisone (mostly dexamethasone). Therefore, it is likely that you will receive daily cortisone 
treatment during the period of radiotherapy. Because cortisone can lead to gastritis and may even 
cause gastric ulcers, you will also receive medication to protect the stomach. In very rare cases, you 
may experience temporary psychological changes. Your treating physicians will take into account 
your individual situation, possible risks and side effects when defining your dose of cortisone. For 
potential side effects, please see also the patient information leaflet included in the drug package. 
 
Alternative treatment options 
Radiotherapy alone is the most frequently used treatment option in case of metastatic spinal cord 
compression. Different treatment concepts are available. 
The two most frequently used concepts consist of 5 sessions with a dose of 4 Gy each (comparator 
group in the course of this clinical study) or 10 sessions with a dose of 3 Gy each. The effect of 10 
sessions with 3 Gy each directed to the metastases equates the effect of 5 sessions with 5 Gy each 
(concept of this clinical study). 
For selected patients an additional surgery conducted before radiotherapy might be an option. It will 
be clarified with a neurosurgeon or an orthopedic surgeon if you are eligible for surgery before start 
of treatment. 
In single cases (extremely bad prognosis) a relinquishment of radiotherapy might be considered and 
the treatment might be reduced to palliative care. 
 
Voluntary participation 
You will be informed in detail about this study by your physician and will have to give your written 
consent before taking part. Your participation in this study is voluntary, and you can withdraw your 
consent at any time and without giving any reason. This will not result in any disadvantage for you. 
If you prematurely terminate your participation in this study, it is very important for you and for the 
study that you come to a final examination.  
 
During the clinical study you have to inform your study physician about any medical treatment you 
receive outside this study.  
  

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Your treating physicians will answer any other questions you may have regarding the examinations 
you will undergo as part of this study and about the results of the findings regarding your treatment 
and any consequences.  
 
Premature termination of the study 
Under certain circumstances, it may be possible that your study physician or the sponsor decides to 
prematurely terminate your participation in the study and that you will have no influence on this 
decision. Potential reasons for premature termination are:   
• 
Your further participation in the study is no longer medically acceptable.  
• 
The entire study will be terminated. 
• 
You are not suitable for participating in the study due to the results of the initial clinical 
examination.  
 
Insurance 
A specific clinical studies insurance policy will be taken out for you during this clinical study. 
During this clinical study, you may only receive additional medical treatment with the agreement of 
your study physician. This does not apply in a medical emergency but the study physician has to be 
informed immediately of any emergency medical treatment.  
 
Any detriment to your health that may have resulted from this clinical study has to be 
communicated to the insurance without delay:  
 
Allianz Versicherungs-AG, 10900 Berlin, Germany 
insurance policy no. AS-9100160845. 
 
In case the patient dies in the course of treatment, the legal successor of the patient should inform 
the insurance company by fax within 48 hours.  
You are obliged to fulfil all measures that serve to explain the cause or extent of any damage 
suffered or its reduction. In case you not fulfil this obligation on purpose or out of gross negligence, 
the insurance policy is no longer valid. In the case of gross negligence, the obligation to perform 
still exists as long as the breach does not influence the insurance claim or the extent of the same.  
We would like to point out that no insurance for commuting accidents has been taken.  
 
Data protection: 
During the clinical study, medical findings and personal information will be recorded at the 
center in your personal patient file or saved in electronic form. The key data for the clinical 
study will additionally be saved in pseudonymous form, evaluated and possibly communicated to 
third parties if relevant. Pseudonymous means that neither your name nor your initials will be 
used, but instead a numerical code. The data will be protected against unauthorized access. This 
data will only be decrypted under the conditions stipulated by law. The data may be forwarded 
under conditions that ensure their confidentiality to health authorities or other institutions of the 
sponsor. Due to legal regulations, certain authorized persons have the right to inspect your 
personal data. These persons include monitors, auditors and other representatives of the 
sponsor. The inspection will be performed only as a part of their tasks as regulated by law, 

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namely for data review. Depending on national law, you might have the right to inspect and 
correct your stored personal data. You might also have the power of veto regarding the transfer 
of data protected by professional secrecy that could be used and processed within this study.   
You may claim these rights from the physician, who guides you within this study and knows 
your identity. The transfer and storage of your data in pseudonymous form is mandatory for this 
clinical study. The results of this study in anonymous form are planned be published as a 
scientific paper and/or presented at scientific meetings.  
 
Further notes 
If you are ready to give your informed consent to participate in this study, please sign the informed 
consent form below to confirm the knowledge of the consequences of the study. 

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Appendix II Informed consent form 
Header/Stamp of the treating clinic 
 
 
 
 
 
 
Informed consent form for participation in the clinical study 
High-precision radiotherapy of motor deficits  
due to metastatic spinal cord compression 
 
Sponsor of the clinical study 
University Hospital Schleswig-Holstein, Campus Lübeck 
Coordinating Investigator: Prof. Dr. med. Dirk Rades 
 
 
Patient: 
Full Name: 
___________________________________________ 
 
 
 
Date of birth:  ___________________________________________ 
 
 
Physician: 
Full Name: 
___________________________________________ 
 
 
I have been informed by the above mentioned physician in detail about the nature, extent and 
significance of this study, including the study aim and duration, requirements and possible side 
effects, my rights and obligations, insurance coverage and voluntariness of participation. I was 
assured that the informing was complete. I have received, read and understood the patient 
information and a copy of the informed consent form. The questions I had with respect to these 
have been answered adequately and completely. I was given sufficient time to decide whether I 
would like to take part in this study or not.  
 
The following topics were discussed in addition to the written information: 
 
___________________________________________________________________________ 
___________________________________________________________________________ 
___________________________________________________________________________ 
___________________________________________________________________________ 
 

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I am aware that this study primarily serves to expand scientific knowledge in the field and that it 
may not necessarily result in any personal benefit for me.   
 
I have been informed that I may withdraw my consent to participate in this clinical study at any 
time without giving any reasons, without any negative consequences for me. The responsible 
physician may terminate the clinical study any time if she/he deems it a medical necessity.  
 
Data protection: 
 
I am aware that personal data collected during this clinical study, in particular medical 
findings, will be recorded, stored and evaluated. The use of my medical data will be in 
accordance with legal stipulations and requires my voluntary consent prior to my participation 
in the study. This means that without the following consent, I cannot take part in the clinical 
study.  
 
1. I agree that personal data collected within this clinical study, in particular medical data, will 
be collected and stored both in paper form and on electronic data storage devices. If 
necessary, the data collected may be communicated in pseudonymous form (encoded): 
 
a) to the sponsor and a representative of the sponsor responsible for scientific evaluation 
(study management). 
 
b)  in case of adverse events: to the sponsor, the study management, and the ethics 
committee responsible. 
 
2. In addition, I agree that persons authorized by the sponsor and subject to confidentiality, as 
well as the regulatory authorities, may access the personal data stored by the investigator, in 
particular medical data, if this is necessary to verify that the study is being conducted 
according to protocol. In this respect, I release the investigator from the confidentiality 
agreement.  
 
3. The consent to the storing and processing of my personal data, in particular my medical 
data, is irrevocable. I have been informed that I may terminate my participation in the 
clinical study at any time. In the case that I withdraw my consent to participate in the 
clinical study, I agree that all data saved until that point may continue to be used if 
necessary in order to:  
 
a) evaluate the effects of the radiation regimen investigated.  
 
b) ensure that my interests are not affected.  
 
c) provide complete documentation for assessment of radiotherapy for metastatic spinal   
            cord compression.  
 
4. I agree to the condition that my data will be stored for at least 10 years after the end of the 
study or the termination of my participation therein, as stipulated by guidelines for the 
conduct of clinical studies. After this period, my personal data will be deleted, except if 
longer storage periods are required according due to other reasons (law, contracts, 
constitutions). 
 
5. I have been informed about the following legal requirements: In case that I withdraw my 
consent to take part in the clinical study, all locations storing my personal data, in particular 
my medical data, must check whether the data stored for purposes a) to c) are still required.  
 
Any data that is no longer required must be deleted without delay.  

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6. I agree that my GP 
 
 
................................................................................................................................... 
 
(Name, address) 
 
 
 
if necessary, will be informed of my participation in the clinical study (if not desired, please 
cross out).  
 
7. I understood that I may withdraw my consent, and therefore I can require the deleting of 
the documented data but for any operation of law. 
 
 
I have received 1 copy of the patient information and 1 copy of the informed consent form 
including the data privacy statement. 
 
I had the possibility and sufficient time to ask questions. These questions I had have been answered 
adequately and completely and I accept them.  
 
I am aware, that I may withdraw my consent to participate in this clinical study at any time without 
giving any reasons (written or verbally), without any negative consequences of my medical therapy. 
 
I was given sufficient time to decide. 
 
I herewith agree to participate voluntarily in the above name clinical study. 
 
 
Name of the patient (block capitals) 
 
 
______________________________________________________________________________ 
Name of the patient   
Location, Date 
 
 
 
 
 
Signature 
 
 
 
I hereby confirm that the above-named patient, who has given his/her consent to take part in this 
clinical study, has been informed in full about the purpose, nature and risks of the study.  
 
 
Name of the investigator (block capitals) 
 
 
______________________________________________________________________________ 
Name of the investigator  
 
Location, Date 
 
 
 
 
Signature 
 
 
 
 
 

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Appendix III Distress (quality of life) (JC Holland distress thermometer) 
 
 
 
Holland, JC. Update: NCCN practice guidelines for the management of psychosocial distress. Oncology 1999; 13: 459–
507. 
How much distress have you 
been experiencing in the 
past week, including today?
Please indicate to what extent you have felt distress on the 
thermometer and indicate the reasons for this distress below.  
 
Practical Problems 
Physical Problems 
 
      Very distressed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Not at all distressed 
 
    
 __ Living situation 
 __ Insurance 
 __ Work/school  
 __ Transportation 
 __Child care 
 __ Pain 
 __ Nausea 
 __ Exhaustion 
 __ Sleep 
 __ Movement/mobility 
 __ Washing, dressing  
 __ Appearance 
 __Breathing 
 __Mouth sores  
 __Food/eating 
 __ Digestion 
 __ Constipation/diarrhoea 
 __ Gastrointestinal changes 
 __ Changes in urination 
 __ Fever 
 __ Dry/itching skin 
 
 __ Dry/congested nose  
 __ Tingling in hands and feet 
 __ Feeling swollen 
 __ Sexual problems 
Family Problems 
 __ Partner 
 __ Children 
Emotional Problems 
 __ Worry 
 __ Fears 
 __ Sadness 
 __ Depression 
 __ Anxiety 
Spiritual/Religious Concerns 
 __ Relating to God 
 __ Loss of faith  
Other Problems: 
 
 

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Appendix IV  
 
Eastern Cooperative Oncology Group (ECOG) – Performance Status 
 
Grade
ECOG performance status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; 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 
5 
Dead 
 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol 1982; 5: 649-655. 

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 Appendix V: Ethics committee vote 

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Appendix VI: Insurance