PROTHYM - Phase II Non-randomized Study on Proton Radiotherapy Of Thymic Malignancies
Phase: NA
Conditions: Cardiotoxicity, Pulmonary Toxicity, Thymus Neoplasms
Sponsor: Ass. Prof. Jan Nyman

 
 
 
 
 
PROTHYM 
 
Phase II non-randomized study on proton radiotherapy of 
thymic malignancies 
 
Version 2.2 
 
21 June 2017 
 

 
2
Phase II non-randomized study on   
Proton 
Radiotherapy 
Of 
Thymic  
Malignancies 
 
Version 2.2 
 
Supported by SLUSG: 
 
Swedish Lung cancer Study Group 
 
 
 
Investigator signature: 
 
 
 
Date: 
 
__________________________________________________________ 
 
Principal investigator 
 
Jan Nyman, MD, PhD 
Department of Oncology 
Sahlgrenska University Hospital 
 

 
3
Gothenburg 
jan.nyman@oncology.gu.se 
 
Study Coordinating center:  Department of Oncology, Sahlgrenska University Hospital, 
Gothenburg, Sweden 
 
 
Study Participants/ Co investigator 
Dr Andreas Hallqvist, MD 
 
Dr Hedvig Björkestrand, MD 
Department of Oncology  
 
 
Department of Oncology 
Sahlgrenska University Hospital 
 
University Hospital Karolinska 
Gothenburg 
 
 
Stockholm 
andreas.hallqvist@oncology.gu.se  
hedvig.bjorkestrand@karolinska.se 
 
Dr Signe Friesland, MD, PhD  
Dr Annica Ravn-Fischer, MD, PhD 
Department of Oncology 
 
 
Department of Cardiology 
University Hospital Karolinska 
 
Sahlgrenska University Hospital 
Stockholm 
 
 
Gothenburg 
signe.friesland@karolinska.se 
 
annica.ravn-fischer@vgregion.se 
 
Dr Kristina Nilsson, MD, PhD  
Anna Bäck, Med Phys, PhD 
Department of Oncology 
 
 
Department of Radiotherapy 
University Hospital Uppsala   
 
Sahlgrenska University Hospital  
Uppsala 
 
 
Gothenburg 
kristina.nilsson@akademiska .se 
 
anna.back@vgregion.se 
 
Dr Per Bergström, MD   
 
Dr Jens Engleson, MD 
Department of Oncology 
 
 
Department of Radiotherapy 
University Hospital Norrland  
 
Skåne University Hospital 
 
 
Umeå 
 
 
Lund 
per.bergström@vll.se 
 
 
jens.engleson@med.lu.se 
 
Dr Jan Rzepecki, MD 
 
 
Dr Hillevi Rylander, MD 
Department of Oncology 
 
 
Department of Oncology 
University Hospital Linköping  
 
Sahlgrenska University Hospital 
Linköping 
 
 
Göteborg 

 
4
jan.rzepecki@regionostergotland.se  
Hillevi.rylander@vgregion.se 
 
 
 
 
Dr Erik Lundin, MD 
 
 
Dr Michael Gubanski, MD, PhD 
Department of Oncology 
 
 
Department of Oncology 
University Hospital Örebro 
 
 
University Hospital Karolinska 
Örebro 
 
 
Stockholm 
erik.lundin@regionorebrolan.se 
 
michael.gubanski@karolinska.se 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
5
Table of contents 
 
 
1.0 Synopsis 
 
2.0   Abbreviations 
 
3.0   Introduction and background  
 
4.0   Objective of the study 
4.1    
Objective  
4.1.1 Primary objective  
4.1.2 Secondary objective 
 
4.2    
Exploratory objectives 
 
5.0  Study Design 
5.1    
Description 
5.2   
Time Schedule 
5.3     
Treatment schedule 
5.4     
Treatment duration 
5.5    
Reason for discontinuation of treatment      
 
5.6     
Follow-up 
5.7     
Stopping rules 
5.8     
Ending and completion of the study 
5.9     
Patient registration 
5.10 
Quality control and quality assurance 
5.11 
Records retention/subject identification 
5.12 
Data management 
5.13 
Ethics 
 
6.0 Study Population 

 
6
6.1   
Source 
6.2   
Inclusion Criteria 
6.3   
Exclusion Criteria    
 
7.0 Evaluations 
7.1   
Pre-study evaluations 
7.2   
On treatment evaluation 
7.3   
Post treatment evaluation/Follow up 
7.4                 Cardiologic examinations 
7.5  
Schedule of assessments 
  
8.0 Radiotherapy 
8.1     
Fractionation and duration 
8.2                 Planning target volume 
8.3    
Doses to organ at risk 
8.4    
OAR priority 
8.5    
Treatment planning 
8.6    
Patient monitoring before and during treatment 
8.7    
Interruption of radiotherapy 
8.8     
Quality assurance 
  
 
 
9.0 Adverse events and serious adverse events 
9.1   
Definitions 
9.2   
Recording of Adverse events 
9.3   
Reporting of serious adverse events 
 
10.0 
Criteria for Efficacy 
10.1 
RECIST criteria for response 
10.2 
Safety analysis 
10.3 
Quality of life analysis 
 

 
7
11.0 
Statistics 
 
12.0 
Publication 
 
13.0 
References 
 
14.0 
Appendix 
 
14.1 Prothym – transthoracic echocardiogram (TTE) protocol 
 
14.2 Performance status 
 
14.3 CTC version 4.0 
 
14.4 Masaoka-Koga staging system 
 
14.5 WHO classification system of thymoma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
8
1.0 Synopsis 
Title of study 
PROTHYM Trial  
Proton radiotherapy of thymic malignancies 
 
The study is supported by SLUSG, Swedish Lung Cancer Study 
Group 
Principal investigator  Jan Nyman MD PhD 
Co-investigators 
Per Bergström MD 
Anna Bäck Med Phys. PhD 
Hedvig Björkestrand MD 
Jens Engleson MD 
Signe Friesland MD, PhD 
Andreas Hallqvist MD, PhD 
Erik Lundin MD 
Kristina Nilsson MD, PhD 
Hillevi Rylander MD 
Annica Ravn Fischer MD, PhD 
Jan Rzepecki MD 
Michael Gubanski, MD, PhD 
 
Study centres  
Skandion Clinic, Uppsala, Sahlgrenska University Hospital, 
Gothenburg, Karolinska University Hospital, Stockholm, 
Akademiska Hospital, Uppsala, Norrlands University Hospital, 
Umeå, Örebro University Hospital, Linköping University Hospital, 
Skåne University Hospital, Lund 
Study phase 
Prospective, non-randomized phase II study 
Number of patients 40 patients  
Study Start  
Sep 2017 
Planned study 
period 
Recruitment Start Date : Sep/2017 
Target recruitment period:60 months Sep/2022) 
Follow up period. End date:  5 years from last treatment. 
 
Study objectives 
 
Primary: 
Toxicity (e.g. cardiac and pulmonary toxicity) and 
Local control at 5 year 
Secondary: 
PFS  

 
9
Overall survival 
Quality of life, measured by EORTC QLQ 30 + LC 14 
Relapse pattern 
Study design and 
plan 
This is a multicentre non-randomized phase II study of proton 
beam radiotherapy in patients with thymic epithelial tumours (i.e. 
thymoma and thymic carcinoma) in the post-operative setting or in 
inoperable patients with localized disease. 
Patients not willing or for any reason unsuitable to undergo proton 
treatment will be asked to participate in a follow-up assessment 
after the regular photon treatment in the same manner as the 
included patients. 
Methodology 
All doses are recorded in Gy(RBE). 
After having checked all eligibility criteria patients will receive: 
 
• 
Patients with radical surgery and unfavourable histology 
(B2, B3, C) and/or Masaoka-Koga stage III, IVa: 2 
Gy(RBE), once daily, five days a week to a total dose of 50 
Gy(RBE).  
 
• 
Patients with non-radical surgery (R1 resection) regardless 
of stage and histology: 2.3 Gy(RBE), once daily, 5 days a 
week to a total dose of 57.5 Gy(RBE) 
 
• 
Inoperable patients regardless of stage and histology and 
patients  with R2 non-radical resection: 2.5 Gy (RBE), once 
daily, 5 days a week to a total dose of 62.5 Gy(RBE) 
 
• 
Patients not willing to participate in study will receive photon 
therapy according to local practice (≥45 Gy) 
 
Induction or adjuvant chemotherapy may be used according to 
local practice. Concomitant chemotherapy is not allowed. For 
radiotherapy volumes see below. 
 
Criteria for 
inclusion and 
exclusion 
 
Inclusion Criteria: 
 

 
10
• 
Histological or cytological diagnosis of thymoma or thymic 
carcinoma.  
• 
With radical surgery: stage III and IVa and selected stage II 
with type B2, B3 and thymic carcinoma according to local 
routine.                                                                            With 
non-radical surgery (R1 or R2) or inoperable patient/ patient 
refusing surgery: stage I -  IVa, any histology 
• 
PS WHO 0 - 2. 
• 
FEV1  1L or 40 % of predicted and CO diffusion capacity 
 40% of predicted (postoperative measures) 
• 
Age 18 years, no upper age limit. 
• 
Written informed consent from patients. 
 
Exclusion Criteria: 
 
• 
Masaoka-Koga stage IVb (distant metastases).  
• 
Pregnancy. 
• 
Serious concomitant systemic disorder incompatible with 
the study. 
• 
Tumour motion > 0.5 cm on two repeated 4DCT 
 
Radiotherapy 
planning 
Treatment will be given by PBS (pencil beam scanning) technique 
at Skandion in Uppsala but all patients must have a photon backup 
plan, preferably with VMAT or IMRT technique. 
• 
Pre-treatment preparation: 
Fixation, wingstep 
• 
Pre-treatment imaging: 
4DCT 
• 
Specification of treatment prescription 
o Volume specification: GTV, ITV, CTV, PTV, OAR’s 
GTV = visible tumour growth 
CTV = post-operative tumour bed and/or defined 
margin to GTV: 0,5 cm to lung tissue and 1 cm 
elsewhere. Adjustment to airways, big vessels, bone 
will be performed. No adjuvant volumes, except for 

 
11
pleura/pericardium in between separate GTV’s 
(stage IVa) 
ITV includes CTV in all breathing phases defined 
according to local routines 
PTV = ITV + 5 mm. PTV is used for dose 
prescription and reporting according to ICRU 
recommendations  
OAR’s: heart, LADCA ,lung, spinal cord, esophagus 
• 
Registration of volumes for GTV, PTV and doses to OAR’s:  
Lung: V5, V20, V40, MLD. 
Esophagus: D2%, mean dose, 
Heart: D2%, mean dose, V40. 
LADCA D2% and mean dose. 
Spinal cord: D2% 
o Absorbed dose prescription 
Group I: 2 Gy(RBE), once daily, five days a week to 
a total dose of 50 Gy(RBE), 5 weeks. 
Group 2: 2.3 Gy(RBE), once daily, 5 days a week to 
a total dose of 57.5 Gy(RBE), 5 weeks. 
Group 3: 2.5 Gy(RBE), once daily, 5 days a week to 
a total dose of 62.5 Gy(RBE), 5 weeks. 
In case of interruptions for technical or 
administrative reasons the total treatment time 
should not exceed 6 weeks. If protons could not be 
delivered in stipulated 6 weeks photon back-up plan 
should be used instead. 
• 
Relation to other therapies 
Up to three cycles of adjuvant/induction chemotherapy may 
be administered according to local routine. Radiation should 
start within 4-8 weeks after chemotherapy or surgery. 
 

 
12
 
 
 
Pre-study evaluation: 
The treatment should start within four weeks from registration. 
The following are required prior to protocol entry: 
• 
CT scan thorax not older than 4 weeks,  
• 
Medical history 
• 
Weight and length 
• 
Physical examination 
• 
Performance status according to WHO  
• 
Assessment of quality of life according to QLQ 30+LC 14 
• 
ECG 
• 
Cardiac ultrasound  
• 
Cardiac markers: NT-ProBNP and TNT 
• 
Spirometry including CO diffusion capacity 
• 
Assessment of symptoms at baseline according to NCI-
CTCAE criteria version 4.0. 
• 
Pregnancy test, if applicable 
• 
   Haematology  
Haemoglobin 
 
 
WBCC (White Blood Cells Count) 
 
              
Platelets count 
• 
Chemistry               CRP, serum creatinine 
   
                     Serum calcium and albumin 
                
Bilirubin, Alkaline Phosphates 
 
                                  LDH, ASAT and ALAT         
 
  
 
Hematology and blood chemistry need to be reassessed if older 
than one week before treatment start. 
UCG and ECG has to be performed within two weeks before start 
of treatment 

 
13
 
On treatment evaluation: 
 
• 
Recording of toxicity, performance status, ECG, NT-
ProBNP, TNT, CRP at week 3 and end of treatment. 
• 
Weight weekly. If weight change >5%, a new CT-scan and 
replanning should be considered. 
• 
QLQ30 + LC14 at end of treatment 
• 
At end of treatment visit patient shall be referred to TTE/UCG 
which shall preferably be performed one week after completion 
of therapy, but at least within two weeks 
Follow up assessment: 
First follow-up 4 weeks after completion of therapy and three 
months thereafter. Then every three months during the first two 
years. Thereafter every six months until end of study 
• 
Recording of persistent or new toxicity 
• 
Performance status 
• 
Weight 
• 
Tumour response evaluation with CT scan at 4, 7, 13 
months and every 6 months thereafter or if clinically 
indicated.  
• 
Spirometry including CO diffusion capacity at 6 months  
• 
ECG at each visit the first year. Thereafter annually or if 
clinically indicated 
• 
Cardiac markers: NT-ProBNP, TNT  
• 
Quality of life according to QLQ30+LC14 at baseline, week 3 
during treatment, 1, 3, 6 and 12 months after completed 
radiotherapy. Thereafter at 2, 3 and 5 years after treatment.  
 
Statistical methods: We will perform a Kaplan-Meier analysis with the aim to compare 
our data with published historic data from the ITMIG international 
database and other datasets. Toxicity data will be analysed 
descriptively and there will be a comparison between the proton 
patients and photon control group. 40 patients will be included in 
the study 

 
14
2.0  Abbreviations 
 
AE 
Adverse event 
ALAT 
Alanine aminotransferase 
ASAT 
Aspartate aminotransferase 
CO-diff 
Carbon oxide diffusion 
CRP 
C-reactive protein 
CT 
Computed tomography 
4DCT 
4-dimensional computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CTV 
Clinical target volume 
ECG 
Electrocardiography 
EORTC 
Europena Organization for Research and Treatment of Cancer 
FEV1 
Forced expiratory volume, one second 
Gy 
Gray 
Gy(RBE)  
RBE-weighted absorbed dose in Gy 
GCP 
Good Clinical Practice 
GTV 
Gross tumour volume 
βHCG 
Human Chorionic Gonadotropin 
ICRU 
International Commission on Radiation Units and Measurements 
IMRT 
Intensity-modulated radiotherapy 
ITMIG 
International Thymic Malignancy Interest Group 
LADCA 
Left anterior descending coronary artery 
LC14 
Lung Cancer 14, QL-questionnaire 
LDH 
Lactate dehydrogenase 
NCI 
National Cancer Institute 
NT-ProBNP N-terminal pro b-type Natriuretic Peptide 
OAR 
Organ at risk 
OD 
Once daily 
OS 
Overall survival 
PBS 
Pencil  beam scanning 
PFS 
Progression-free survival 

 
15
PORT 
Post operative radiotherapy 
PS 
Performance status 
PTV 
Planning target volume 
RBE 
Relative Biological Effectiveness 
R1 
Microscopic residual tumour directly at the resection margin 
R2 
Macroscopic residual tumour locally 
RIHD 
Radiation induced heart disease 
RILD 
Radiation induced lung disease 
SAE 
Serious adverse event 
TET 
Thymic epithelial tumour 
TnT 
Troponin T 
UCG 
Ultrasonic cardiography 
VMAT 
Volumetric modulated  arc therapy 
QLQ30 
Quality of life questionnaire 
 
 
3.0     Introduction and background  
 
Thymic epithelial tumours (TETs or thymic malignancies) which comprise thymoma and thymic  
carcinoma, are rare cancers worldwide. The annual incidence is approximately 0.15/100.000 
in the United States (1) and 0.32/100.000 in the Netherlands (2). According to the Swedish 
National Cancer Register 33 patients were diagnosed with either thymoma or thymic 
carcinoma in 2013 which is an approximative incidence of 0.33/100.000. TETs are 
heterogenous  both morphologically as well as clinically. Thymomas may be associated with a 
spectrum of autoimmune conditions, whereas this is rare in thymic carcinomas. Thymic 
carcinomas are more prone to distant metastatic spread. In a Japanese retrospective analysis 
the survival rates differs between the groups with a median OS of patients with thymoma of 
235 months compared with 32 months for those with thymic carcinomas (3) which is 
comparable with other reports. There is no official stage classification for thymic malignancies 
defined by the Union Internationale Contre le Cancer (UICC) and the American Joint 
Commission for Cancer (AJCC). ITMIG in collaboration with the International Association for 
the Study of Lung Cancer (IASLC) have published a proposal for a new staging system for the 
forthcoming edition of the TNM classification of Malignant Tumors (4-5).Until this system is 

 
16
definitely defined ITMIG has proposed staging according to the Masaoka-Koga stage 
classification (6) which is generally spread and used worldwide. 
Surgery remains the cornerstone in the management of TETs. Minimally invasive techniques 
including thoracoscopic and robotic surgery for early stage disease are gradually increasing. 
Chemotherapy, although often with a moderate response, has a role in downstaging as well 
as managing more advanced disease. There is also evolving data on targeted drugs. The role 
for radiotherapy is a matter of ongoing debate but the use of postoperative radiotherapy 
(PORT) after incomplete surgery and/or advanced stage (III/IV according to Masaoka) is more 
or less standard (7-9). There is considerably less evidence and weaker consensus for the 
efficacy of PORT of stage II patients (10) and the use of it varies worldwide. It could, however, 
be used in selected cases such as B3 and C patients in accordance with local routines. 
Radiotherapy with photons for TET patients has been reported feasible and with acceptable 
toxicity. Treatment is generally given with IMRT-technique and doses in the literature varies 
between 45 and 60 Gy with 1.8 or 2 Gy/fraction. 
Many of the thymoma patients will become long time survivors and thus may suffer from late 
toxicities such as radiation induced lung disease (RILD) (11) or radiation induced heart disease 
(RIHD) (12-13). For many years RIHD has been of major concern when irradiating patients 
with left-sided breast cancer and Hodgkin’s disease. It is considered a late side effect which 
may become manifest 5-10 years after completion of radiotherapy, although earlier onset may 
occur. It includes a wide range of symptoms such as pericarditis, myocardial infarction, valvular 
heart disease and coronary heart disease (14-15). Lately this has become a greater concern 
when treating thoracic malignancies such as lung and esophageal cancer (16). Depending on 
the good prognosis, there is a strong rationale as to try to limit the cardiac dose to the thymoma 
patients.  Comparing treatment plans for protons vs photons has shown that it is possible to 
reduce the cardiac dose with protons (personal communication Nyman & Bäck). 
How to detect and follow-up on RIHD is an ongoing subject for discussion. Different imaging 
techniques have been suggested (17-18) and there is also some data on biomarkers predicting 
cardiac toxicity after chemotherapy and radiation therapy (19). There is, however, no golden 
standard regarding screening for RIHD.  
Radiotherapy with protons have emerged as a potential possibility to achieve local control and 
eventually reduce the risk for late toxicity and secondary tumors. From early on, thymic 
malignancies was recognized as a group who would eventually benefit from proton therapy 
(20-21). Treating thoracic malignancies with protons is cumbersome because of many 
reasons; tumor and organs at risk motion may result in interplay effects which compromise 
dose distribution being one of them. Movement of mediastinal structures occurs but seems to 

 
17
be minor compared to the movement in the lung parenchyma and patients with Hodgkins’ 
disease has been successfully treated with protons. TETs are generally located in close 
proximity to the mediastinum.  Recent years more and more data have been published showing 
superior dose distribution and feasibility regarding toxicity while treating thymomas with 
protons (22-24). The majority of previous thoracic proton therapies have been given with 
passively-scattered technique. At the Skandion Clinic all patients will be treated with pencil 
beam scanning (PBS) with proton energies ranging from 60 to 230 MeV. This technique may 
further optimize dose distribution although planning, quality assurance and motion 
management is even more crucial (25-26). 
 
 
4.0 Rationale and Objective of the study   
4.1       Objective  
To explore whether proton radiotherapy is feasible and results in an acceptable local control   
 
4.1.1  Primary Objective  
Toxicity (eg cardiac and pulmonary toxicity). 
Local control at 5 years. Local control is defined as freedom of locally progressive disease; ie 
CR (complete remission) or SD (stable disease) based on CT or PET/CT evaluation 
 
4.1.2   Secondary Objective 
Overall survival, progression-free survival, relapse pattern, quality of life measured with QLQ 
30 + LC 14.  
 
5.0 Study Design 
5.1 Description 
This is an open, non-randomized multicentre, phase II trial, to investigate the efficacy and 
toxicity in PBS proton therapy of thymic malignancies 
 
5.2 Time Schedule  

 
18
The trial is expected to start after Ethics Committee has approved the protocol. 
Target recruitment period is estimated to be 60 months.  
End date is estimated to be five years from last treatment. 
 
5.3 Treatment Schedule       
The study population will consist of three  patient categories;  
A patients who have undergone radical surgery 
B patients who have undergone non-radical surgery  
C patients who are considered inoperable. 
Radiotherapy doses will differ between the groups. We have assumed that RBE for protons 
is1.1 and the prescribed dose is the corresponding dose for photons (Gy(RBE). Within 
brackets is the physical dose. 
Patients who have undergone radical surgery but has an unfavorable histology (B2, B3, C) 
and/or Masaoka stage III or IVa (selected stage II-patients can be considered according to 
local practice) will receive 2 Gy(RBE) once daily, five days a week to a total dose of 50 
Gy(RBE) (1.82 Gy OD, total dose 45.5 Gy) 
Patients who have undergone non radical surgery (R1), regardless of stage and histology, 
will receive 2.3 Gy(RBE) once daily, five days a week, to a total dose of 57.5 Gy(RBE) (2.09 
Gy OD, total dose 52.25 Gy) 
Patients who are considered medically inoperable, or refuses surgery, regardless of stage 
and histology, and patients who have undergone R2 non-radical resection will receive 2.5 
Gy(RBE) once daily, five days a week, to a total dose of 62.5 Gy(RBE) (2.27 Gy OD, total 
dose 56.75 Gy) 
Patients not willing to participate in study, but willing to be included in follow-up according to 
study protocol will receive photon therapy according to local practice. The total dose must be 
≥45 Gy. 
Up to three cycles of chemotherapy may be administered prior to start of radiation according 
to local practice. Radiation therapy shall then start within 4-6 weeks after completion of the 
third cycle. Use of concomitant chemotherapy is not allowed. 
If surgery has been performed, radiation therapy shall start 4-8 weeks thereafter 

 
19
5.4 Treatment duration 
The radiotherapy overall treatment time in all of the patient categories should preferably be 
five weeks. In case of interruptions for either technical or administrative reasons the 
treatment time should not exceed six weeks. If protons cannot be delivered in stipulated six 
weeks, photon backup plan shall be used instead. 
 
5.5 Reason for discontinuation of treatment 
• 
Progressive disease under any time of treatment is reason for stopping the treatment 
• 
Adverse reaction that is severe or life threatening that precludes further treatment. 
• 
Major protocol violations such as unjustified substantial modifications of the 
radiotherapy treatment.  
• 
Missing essential data as for safety and/or efficacy assessment that cannot be 
recovered are missing 
• 
Patient refusal, or withdrawal of informed consent. 
 
5.6  Follow-up 
First follow-up 4 weeks after completion of therapy, then at four months and every three 
months thereafter for the first year, then every six months for a maximal five years in total. 
Recording of persistent or new toxicity, performance status and weight will be done at all 
visits. 
 
Tumour response evaluation with CT scan will be done at 4, 7, 10 and 13 months after 
therapy and every 6 months thereafter or if clinically indicated. 
  
Quality of life according to QLQ30 + LC 14 will be measured at baseline, week 3 during 
treatment, and of treatment, 1, 3, 6 and 12 months after completion of radiotherapy. 
Thereafter at 2, 3 and 5 years after treatment. The administration of the questionnaires will 
be handled centrally by the Clinical Trial Unit at the Oncology Departent,  Sahlgrenska 
University Hospital. 
 
Spirometry including CO diffusion capacity will be repeated at 6 months after therapy and at 
end of study 

 
20
UCG will be performed within two weeks after completion of therapy and at end of study, i e 
5 years after treatment 
ECG will be recorded at each visit 
 
5.7  Stopping Rules 
The trial will stop prematurely for the following considerations: 
- If emerging toxicities are of such a serious nature that continuation of the trial becomes 
unacceptable. 
- If the recruitment is too low to expect completion of the study in its present form within an 
acceptable period of time (inclusion estimated to be 60 months) 
- If the number of dropouts as described above (5.5) is too high and this situation cannot be 
acceptable for a period of time. 
 
5.8 Ending and completion of the study 
The study is finished when an estimated number of 40 evaluable patients have completed 
the treatment according to the protocol and are followed for 60 months. 
 
5.9 Patient registration 
Before patients agree to participate in this trial all patients will be given oral and written 
information. A “Patient information sheet” and a consent form, prepared in the local language 
will be handed out to the patients. The formal consent form must be signed and dated by the 
patients and investigator before they are submitted to any study-specific procedure.  
Patients that fulfil the eligibility criteria and have signed and dated the formal consent will be 
registered by phone to the Clinical Trial Unit, Sahlgrenska University Hospital, Göteborg at 
phone number +46 700 90 60 97. Treatment should start within four weeks from registration. 
 
 
5.10 Quality control/monitoring 
The study will be monitored according to ICH/GCP by visits and calls to the investigator. 
During site visits, the monitor shall review original patient records and document retention. 
Additionally, the monitor shall observe study procedure and will discuss any problem with the 

 
21
investigator. The investigator will provide direct access to source data/documents for trial 
related monitoring audits, EC review and regulatory inspections.  
Monitoring will be provided by Clinical trial Unit at the Oncology Department at Sahlgrenska 
University Hospital. 
 
5.11 Records retention/subject identification 
It is the investigator’s responsibility to retain sufficient information regarding the identity of the 
patients, so that any Health Authorities may access this information, if needed. Copies of all 
pertinent information, including patient identity and allocation number and individual patient 
data records, will be retained in a confidential manner by the investigator for a minimum 
period of 15 years from study completion. 
 
5.12 Data management 
Data collection during the study will be performed by the monitor and data management will 
be performed at Study coordinating center. 
 
5.13 Ethics 
The study will start after approval from authority and Ethical committee and it is the 
responsibility of the Investigator-Sponsor to supply the co-investigators with a copy of the 
final assessment. This study will be conducted in compliance with the protocol and in 
accordance with the ethical principles put forward in the Declaration of Helsinki and in 
accordance with GCP rules. 
The rights, safety and well-being of the trial subjects are the most important considerations 
and should prevail over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training and 
experience to perform their respective tasks. 
 
6.0 Study Population 
6.1 Source 
Patients with histologically confirmed thymoma or thymic carcinoma 

 
22
 
6.2 Inclusion Criteria 
• 
Histological or cytological diagnosis of thymoma or thymic carcinoma  
• 
With radical surgery stage III, IVa and selected stage II with type B2, B3 or thymic 
carcinoma according to local routine 
• 
With non-radical surgery (R1 or R2), stage I -  IVa, any histology 
• 
Medically inoperable, or patient refusing surgery, stage I - IVa, any histology 
• 
PS WHO 0 - 2. 
• 
FEV1  1L or  40% of predicted and CO diffusion capacity > 40% of predicted (post-
operative measures). 
• 
Age 18 years, no upper age limit. 
• 
Written informed consent from patients. 
 
6.3 Exclusion Criteria 
• 
Masaoka-Koga stage IVb (distant metastases) 
• 
Pregnancy. 
• 
Serious concomitant systemic disorder incompatible with the study. 
• 
Tumour motion > 0.5 cm on two repeated 4DCT 
 
7.0 Evaluations 
7.1 Pre-study evaluations 
• 
CT scan thorax and upper abdomen including adrenals, not older than 4 week,   
documentation of measurable and unmeasurable disease sites. 
• 
Medical history 
• 
Physical examination 
• 
Performance status according to WHO 
• 
Assessment of quality of life according to QLQ 30+LC14 

 
23
• 
Pre-treatment weight loss registration 
• 
Electrocardiogram (ECG) 
• 
Transthoracic echocardiogram (TTE)/UCG 
• 
Spirometry with CO diffusion capacity 
• 
Body weight and length 
• 
Assessment of symptoms at baseline according to NCI-CTCAE criteria, version 4.0 
• 
Pregnancy Test 
      All women of childbearing potential must have a negative serum or urine pregnancy test                
(minimum sensitivity 25 IU/L of -HCG) within 72 hours prior to the start of study.  
• 
Haematology: Haemoglobin, WBCC, Neutrophils and Platelets count. 
• 
Chemistry: Serum creatinine, calcium and albumin, Bilirubin, Alkaline Phosphates, LDH, 
ASAT, ALAT,CRP, TNT, NT-proBNP 
 
7.2 On Treatment evaluation 
• 
Recording of toxicity and performance status, at week 1, 3 and 5 during treatment 
• 
Weight every week 
• 
Registration of volumes for GTV, PTV, constraints doses to normal tissues: Lung: V5, V20, 
V40, MLD. Esophagus: D2%,mean dose. Heart: mean dose, V40. LADCA: D2%,  mean dose  
Spinal cord: D2% 
 
7.3 Post Treatment evaluation/Follow up 
First follow-up 4 weeks after completion of therapy, then at four months and every three 
months thereafter during the first year. After that follow-up every six months until end of study 
• 
Recording of persistent or new toxicity 
• 
Performance status 
• 
Weight 
• 
Tumour response evaluation with CT scan at 4, 7 and 13 months after therapy and every 
6 months thereafter or if clinically indicated. Chest x-ray is sufficient at other follow-up 
visits. 

 
24
• 
Quality of life according to QLQ30+LC14 at baseline, week 3 during treatment, end of 
treatment, 1, 3, 6 and 12 months after completion of radiotherapy. Thereafter at 2, 3 
and 5 years after treatment.  
• 
Spirometry with CO diffusion capacity at 6 months after therapy and at end of study 
 
7.4 Transthoracic echocardiogram (TTE)/UCG 
A comprehensive TTE examination will be performed at three times: within two weeks prior to 
radiation therapy, within two weeks from completion of radiation therapy and at the end of the 
study. The TTE examinations are performed using the existing equipment at the local hospital. 
Age, gender, length and weight of the patient are recorded before start. During examination 
heart rate and presence of arrhythmias are documented. Image sampling follows a 
standardised protocol (Appendix) and is performed by a biomedical scientist or cardiologist at 
the local hospital. The examination is thereafter transferred (by CD/DVD) for central evaluation 
by study responsible cardiologist. All values are related to the age, gender and body size of 
the patient. 
 
7.5 Schedule of assessments 
Table 1 
 
Prior to RT 
During RT 
End of RT 
Within 2 
weeks from 
RT 
4 weeks 
Medical history 
X 
 
 
 
 
Physical examination 
X 
X 
X 
 
X 
Weight & PS 
X 
X 
X 
 
X 
NT-Pro-BNP, TNT, CRP 
X 
X 
X 
 
X 
Hematology 
X 
 
X 
 
X 
Creatinine, calcium, 
albumin, bilirubin, ALP, 
ASAT, ALAT, LDH 
X 
 
X 
 
X 
Electrocardiogram 
X 
X 
X 
X 
X 
PET-CT-scan 
optional 
 
 
 
 
Tumor assessment by CT1 
 
X 
 
 
 
 
TTE/UCG 
X 
 
 
X 
 

 
25
Spirometry3 
X 
 
 
 
 
Assessment symptoms 
and toxicity 
X 
X 
X 
 
X 
QLQ² 
X 
 
X 
 
 
 
 
4 
months 
from 
RT 
6 months from 
RT 
Follow up 
End of study 
 
Medical history 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
 
Weight & PS 
X 
 
X 
X 
 
NT-Pro-BNP, TNT, CRP 
X 
 
X 
X 
 
Hematology 
X 
 
optional 
 
 
Creatinine, calcium, 
albumin, bilirubin, ALP, 
ASAT, ALAT, LDH 
X 
 
optional 
 
 
Electrocardiogram 
X 
 
X 
X 
 
PET-CT-scan 
optional 
 
 
 
 
Tumor assessment by CT1 
 
X 
 
X 
X 
 
TTE/UCG 
X 
 
 
X 
 
Spirometry3 
 
X 
 
X 
 
Assessment symptoms and 
toxicity 
X 
 
X 
X 
 
QLQ² 
X 
X 
X 
X 
 
 
1. CT scan will be performed before inclusion (not older than 4 weeks), at 4, 7, 10 and 13 months 
after therapy and every 6 months thereafter during follow up or until progressive disease. 
2. Quality of life will be measured by using QLQ C30 and LC14 module at baseline, week 3 of 
treatment, end of treatment ,1, 3, 6 and 12 months after completion of therapy. Thereafter at 2, 3 
and 5 years after treatment. 
3.   Spirometry including CO diffusion capacity will be performed before inclusion, after 6 months and  
      at end of study 
 

 
26
8.0 Radiotherapy 
All patients included in the study must be able to receive prescribed dose to the target volume 
without exceeding absorbed doses to the organs at risk. Dose planning shall be performed 
with a CT-based system. A 4DCT for the planning is mandatory and has to be repeated before 
start of treatment. If tumour motion exceeds 0.5 cm proton therapy  will not be given. All 
patients needs to have a photon backup plan, preferably with IMRT/VMAT technique although 
3DCRT is allowed. Treatment planning can be performed on either average CT from the 4D-
CT or a regular CT. Slice thickness is to be maximally 3 mm. If the photon plan is superior to 
the proton plan, the photon plan is to be used and the patient will be excluded from the study 
and followed up according to the photon cohort protocol. 
 
8.1 Fractionation and duration 
 
Proton therapy will be given with pencil beam scanning (PBS) with proton energies in the range 
of 60 – 230 MeV at reference point according to ICRU 78. 
For details on fractionation and treatment se section 5.3 
Patients with a photon plan superior to the proton plan will receive fractionation and total 
dose according to local routine 
 
8.2 Planning Target Volume 
The different volumes of interest shall be defined in agreement with ICRU 78. 
OAR’s: heart, LADCA ,lung, spinal cord, esophagus 
 
Gross Tumour Volume (GTV): 
Visible tumour growth 
 
Clinical Target Volume (CTV): 
Post-operative tumour bed and/or defined margin to GTV: 0,5 cm to lung tissue and 1 cm 
elsewhere. Adjustment to airways, big vessels, bone will be performed. No adjuvant 
volumes, except for pleura/pericardium in between separate GTV’s (stage IVa)  
 

 
27
Internal Target Volume (ITV) 
The ITV volume includes CTV in all breathing phases defined according to local routines 
 
Planning Target Volume (PTV): 
Includes ITV + 5 mm margin. PTV is used for dose prescription and reporting according to 
ICRU recommendations 
 
 
The volumes of GTV, CTV, ITV and PTV shall be recorded in the CRF. 
 
 
 
8.3 Doses to organs at risk 
 
• 
Spinal cord 
The maximum dose to the spinal cord is 48 Gy EQD2. The spinal cord shall be defined as 
the content of the spinal canal. 
 
• 
Lung 
Normal lung tissue is to be spared as much as possible. The volume of the lung (minus GTV) 
that should not receive doses above 20 Gy should be ≤ 35 % (V20 < 35 %). Dose-volumes 
histograms should be performed and the percentage of the lung volume minus GTV receiving 
a dose >5, >20 and >40 Gy as well as mean lung dose shall be recorded (V5, V20, V40, MLD) 
 
• 
Esophagus 
The esophagus shall be delineated from the esophageal entrance to cardia. The mean dose 
should be < 45 Gy EQD2. The mean dose as well as the volume of the esophagus receiving 
> 50 Gy EQD2 (V50 )  shall be recorded. 
 
• 
Heart 

 
28
The whole heart shall be delineated including the atriums and chambers but not the great 
vessels. No constraint is used, but the aim is to keep the dose as low as possible. Mean 
dose and volume receiving > 10 Gy EQD2 ,> 20 Gy EQD2 and > 40 Gy EQD2 (MHD, V10, 
V20, V40)  shall be recorded. 
 
• 
LADCA 
 
LADCA (Left Anterior Descending Coronary Artery) shall be delineated. No constraint will be 
used but D2% and Dmean shall be recorded 
 
8.4 OAR priority 
 
Table 2 Prioritized dose volume objectives and constraints in EQD2 
Priority 
Volume 
Objectives and constraints in 
biological dose Gy(RBE) 
Objectives and constraints 
in physical dose Gy 
1 
Spinal cord 
48  
43.64 
2 
Lung (total) 
V20 < 35 % 
V18.2 < 35 % 
3 
Esophagus 
Mean dose < 45  
Mean dose < 40.1  
4 
GTV 
D100% > 100 % 
D100% > 100 % 
5 
CTV / ITV 
D98% > 95 % 
D98% > 95 % 
6 
PTV* 
D2% < 105 % 
D98% > 95 % 
D2% < 105 % 
D98% > 95 % 
7 
Heart 
As low as possible 
 
8 
LADCA 
As low as possible 
 
*Dose volume objectives for PTV may be disregarded if other strategies like robust optimization 
are used to ensure CTV coverage 
 
8.5 Treatment planning 
 
Treatment technique 
 
The radiation treatment can be given with protons or photons (3DCRT/IMRT/VMAT). 

 
29
Dose computation and optimization 
 
Dose calculation 
Reference dosimetry is carried out according to the IAEA report
 
 
TRS 398 (2000). 
 
 
The absorbed dose in the patient geometry shall be calculated by
 
 
using validated algorithms. 
 
 
The calculation grid shall be at maximum 3 mm. 
In order to facilitate the optimization procedure, help structures and volumes may be defined. 
For proton treatments, see treatment planning and optimization guidelines in the Skandion 
Clinic treatment planning instruction manual (Delprocess 5 / Gör dosplanering och QA-plan 
och godkänn dosplan / Dosplaneringsmanual)  
 
Treatment plan evaluation 
A robustness test should be performed for each proton treatment in 12 test cases according 
to the recommendations in the Skandion Clinic treatment planning instruction manual 
(Delprocess 5 / Gör dosplanering och QA-plan och godkänn dosplan / 
Dosplaneringsmanual). Tolerance levels that should be fulfilled in the robustness test for 
treatments with the prescribed doses are described in table 2 
 
Table 3. Tolerance levels that should be fulfilled in the robustness test. RBE value/model 
1.10 is used. 
 
Tolerance levels 
CTV: all test cases 
D98% ≥ 90% 
CTV: for at least 10 of 12 robustness test 
cases 
D98% ≥ 95% 
GTV: all test cases 
  D95% ≥ 100% 
GTV: for at least 10 of 12 robustness test 
cases 
  D98% ≥ 100% 
Spinal cord: all test cases 
           V48 Gy (RBE) ≤ 100% 

 
30
DVH parameters of OARs used for 
definition of objectives and constraints 
(table 2) 
              According to clinical judgement 
 
 
 
8.6 Patient monitoring before and during treatment 
Before treatment starts patients will undergo a control 4D-CT at Skandion Clinic. If tumour 
motion exceeds 0.5 cm proton treatment will not be given and patient will receive the photon 
backup plan instead. 
 
Image guided and adaptive treatment delivery 
The position of the patient shall be verified based on MV imaging, CBCT, kV imaging  and/or 
surface imaging. 
For photons, the position of the patient shall be verified daily, or at least the first 3 days and 
then weekly during the treatment. A statistical analysis shall be performed after the first 3 
treatments. Based on the analysis, the treatment delivery shall be adapted according to 
protocol for corrective action. 
For protons daily imaging is required. Patient weight will be controlled once a week. If weight 
loss/gain > 5% a control CT will be performed at Skandion Clinic, otherwise control CT will be 
performed weekly with the possibility to re-plan if the difference between the dose distribution 
of the original treatment plan and the dose distribution based on this new CT is not in 
accordance with the tolerance levels specified for the robustness test (see table 3). 
 
8.7 Interruption of radiotherapy 
After radiotherapy starts, efforts should be made to avoid interruptions in the planned schedule. 
If an interruption must be made due to technical or administrative reasons the following policy 
will be applied. At least four fractions a week must be given. If this is not possible with protons 
the photon backup plan must be used. Try to maintain the total treatment time as close to 5 
weeks as possible. 
 
 
8.8 Quality assurance 

 
31
 
The absorbed dose to the patient shall be estimated based on in vivo measurements according 
to clinical routine procedures. If in-vivo dosimetry is not applicable, pre-treatment patient 
specific quality assurance (QA) must be performed. 
Treatment plan parameters should be recorded for quality assurance purposes. The volume 
of GTV and PTV should be registered as well as dose/volume-parameters to organs at risk: 
Lung: V5, V20, V40, MLD. Esophagus: V60, V80, mean dose.  Heart: V10, V20, V40, mean 
dose, Spinal cord: Dmax. 
 
 
9 Adverse events 
 
9.1 Definition 
Adverse events (or adverse experience) (AE): 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
treated within a study protocol and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the 
radiation treatment, whether or not considered related to the radiotherapy 
Due to regulatory requirements, events occurring during pre- and post-treatment periods 
should also be designated as AEs. Therefore, safety surveillance - reporting of (S)AEs -
commences at the time when the subject is enrolled into the study (date of signature of the 
informed consent) until the End of Study Visit has been performed.  
 
Serious adverse event or reaction/experience (SAE): 
• A serious AE (experience) or reaction is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• NOTE: The term ”life-threatening” in the definition of ”serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 

 
32
• Is a congenital anomaly/birth defect or 
• Is an important medical event 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in cases of important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room, or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse, or malignant tumors when they are 
histologically different from the primary tumor. 
 
Events not to be treated as SAEs 
Progression of disease is not to be regarded as a SAE. 
Due to the seriousness of the disease in this study, certain conditions defined as SAEs will 
be excluded from expedited reporting on a SAE report form: 
• Elective hospitalization and surgery for treatment of disease 
• Elective hospitalization to simplify treatment or study procedures 
 
 
9.2 Recording of Adverse Events  
All AEs must be documented in the appropriate section of the CRF. For SAEs, a SAE report 
form (initial or follow up) must be completed in addition. 
The following aspects must be recorded for each event in the CRF: 
• A description of the AE in medical terms, not as reported by the subject; 
• The date of onset (start date) 
• The date of recovery (stop date) 
At each contact with the subject, the investigator must seek information on adverse events 
by specific questioning and, as appropriate, by examination. Information on all adverse 
events should be recorded immediately on the Adverse Event module of the CRFs using the 
CTCAE Version 4.0 

 
33
A written version will be available at each study site, see also. CTCAEv4.0. 
Version 4.0 http://ctep.cancer.gov/reporting/ctc.html 
 
Serious adverse events should be noted on the Serious Adverse Event Report form.  
All adverse events occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilisation or until it has been determined 
that study treatment or participation is not the cause. Serious adverse events, which are still 
ongoing at the end of the study period, must be followed up to determine the final outcome. 
Any serious adverse event, which occurs after the study period and is considered to be 
possibly related to study treatment or study participation should be recorded and reported 
immediately. 
The grade as assessed by the investigator according to the definitions in CTCAE v4.0.  
Grade 1 = mild 
Grade 2 = moderate 
Grade 3 = severe 
Grade 4 = life-threatening or disabling 
Grade 5 = death related to AE  
• The causal relationship to therapy as assessed by the investigator; the decisive factor in 
the documentation is the temporal relation between the AE and the study drug. The 
following judgments of the causality to study procedures are to be used: 
Not Related; There is not a temporal relationship to study treatment.  
Not Likely; There is a temporal relationship to study treatment, but there is not a reasonable 
causal relationship between the treatment and the AE. 
Possible; there is a reasonable causal relationship between the study treatment and the 
AE.  
Probable; there is a reasonable causal relationship between the study treatment and the 
AE.  
Certain/Definite; there is a reasonable causal relationship between the study treatment 
and the AE. Action taken (none, treatment discontinued, dose reduction, treatment delayed, 
concomitant medication given, new or prolonged hospitalization, procedural surgery). 
• The outcome according to the following definitions:  

 
34
- Recovered with sequelae. 
- Recovered without sequelae. 
- Ongoing, no therapy. 
- Ongoing, therapy. 
- Died. 
- Change in toxicity grade/severity. 
• Seriousness: yes or no 
• In case of SAEs it must be indicated whether the SAE is the leading event, i.e. the primary 
medical reason for SAE reporting. 
 
9.3 Reporting of Serious Adverse Events 
In the event of the occurrence of any clinical AE or abnormal laboratory test value that is 
serious or medically important during the course of the study or the post-treatment period, 
irrespective of the treatment received by the subject, the co-investigator is obliged to 
immediately inform the Investigator-Sponsor. 
The immediate report by the co-investigator to the Investigator shall be followed by detailed, 
written reports using the SAE report form (for an “initial” SAE or for “follow-up” information on 
a previous SAE). The immediate and follow up reports shall identify subjects by unique code 
numbers assigned to the latter. 
For names, addresses, telephone and fax numbers, see below. 
If the adverse event is life-threatening or results in death it should be recorded and reported 
as soon as possible or within 7 days and for all other suspected serious unexpected adverse 
reaction shall be recorded and reported as soon as possible but within a maximum of fifteen 
days of the first knowledge. The Investigator shall ensure that for a reported death of a 
subject, the investigator shall supply the Ethics Committee with any additional information as 
requested.  
A copy of the reports to the Regulatory Authorities and Ethics committees should be sent to 
the Investigator (principal investigator), Hillevi Rylander fax no: 0046 31 823931.  
Annually throughout the clinical trial, the Investigator shall provide the local Regulatory 
Authority, Ethics committee, with a listing of all suspected serious adverse reactions which 
have occurred over this period and a report of the subject´s safety.  
The finally listing and report will be 60 days after data-lock point. 

 
35
 
9.4 Monitoring of subjects with adverse events 
Any AE that occurs in the course of a clinical study must be monitored and followed up until 
the End of Study Visit. In addition SAEs must be reported via a SAE report form (see section 
9.3  Reporting of serious adverse events). 
It is the responsibility of the investigator that any necessary additional therapeutic measures 
and follow-up procedures are performed. 
 
 
9.5 Patient Removal from Study Therapy due to Adverse Events 
Any subject who experiences an adverse event may be withdrawn at any time from the study 
at the discretion of the investigator.  
If a subject is withdrawn wholly or in part because of an adverse event, this should be noted 
on the Study treatment form in addition to the Adverse Event section. The monitor should be 
informed without delay of all subjects who are withdrawn for this reason. 
 
9.6 Death on Study 
Any death occurring between the study inclusion and 30 days following the last radiotherapy 
treatment must be reported as a SAE within 7 days, regardless of the relation to the 
radiotherapy. Death occurring during the study follow-up period (i.e. later than 30 days after 
the last infusion) need only to be reported as serious adverse event if it is thought that there 
is a possible relation to the radiotherapy (possible, probable). All deaths should be reported 
on the death report form section on the CRF regardless of cause. 
 
 
10.1 RECIST 1.1 criteria for response 
 
Complete response (CR): Disappearance of all clinical evidence of tumor (target and non-
target lesions), determined by two observations not less than four weeks apart. 
 

 
36
Partial response (PR): 30% or greater decrease in the sum of the longest diameter of target 
lesions, determined by two observations not less than 4 weeks apart. No unequivocal 
increase in the size of non-target lesions or the appearance of new lesions may occur. 
 
Stable disease (SD): Steady state of response (i.e. not PR and not PD) of at least 9 weeks 
duration. There may be no appearance of new lesions for this category. 
 
Progressive disease (PD): 20% or greater increase in the sum of the longest diameter of 
target lesions or unequivocal progression of non-target lesions. Appearance of new lesions 
will also constitute progressive disease. 
 
The duration of response will be measured from the time measurement criteria are met for 
CR/PR until the first date the recurrent or progressive disease is objectively documented. 
 
 
10.2 Safety analysis 
 
A safety analysis regarding toxicity will be performed by the principal investigator after 
inclusion of 15 subjects. The analysis will be focused on the frequency of unwanted side 
effects and their severity. 
 
10.3 Quality of life analysis 
 
Quality of life will be measured by using QLQ C30 and LC14 module at baseline, week 3 of 
treatment, end of treatment ,1, 3, 6 and 12 months after completion of therapy. Thereafter at 
2, 3 and 5 years after treatment. 
 
11.0 Statistics  
 

 
37
We will perform a Kaplan-Meier analysis with the aim to compare our data with published 
historic data from the ITMIG international database and other datasets. Since there is a 
limited amount of published thymoma data concerning heart we will also try to relate heart 
toxicity with published data from Hodgkin and breast cancer studies. Toxicity data will be 
analysed descriptively and there will be a comparison between the proton patients and 
photon control group. 40 patients will be included in the study 
 
 
12.0 Publication 
The aim is that the study will be published in international journals. A separate publication will 
include result of the cardiological data                
The Vancouver declaration (Br Med J:296, 401-405, 1988) should be followed in all 
publications based on this study.  
 
13.0 References 
1 Engels EA, Pfeiffer RM, Int J Cancer 2003 Jul 1; 105(4):546-51 Malignant thymoma in the 
United States: demographic patterns in incidence and associations with subsequent 
malignancies 
2 de Jong WK, Blaauwgeers JL, Schaapveld M, Timens W, Klinkenberg TJ, Groen HJ Eur J 
Cancer 2008 Jan; 44(1):123-30 Thymic epithelial tumours: a population-based study of the 
incidence, diagnostic procedures and therapy 
3 Okuma Y, Hosomi Y, Watanabe K, Yamada Y, Horio H, Maeda Y, Okamura T, Hishima T. 
BMC Cancer. 2014 May 20;14:349  Clinicopathological analysis of thymic malignancies with a 
consistent retrospective database in a single institution: from Tokyo Metropolitan Cancer 
Center  
4 Detterbeck FC, Stratton K, Giroux D, Asamura H, Crowley J, Falkson C, Filosso PL, Frazier 
AA, Giaccone G, Huang J, Kim J, Kondo K, Lucchi M, Marino M, Marom EM, Nicholson AG, 
Okumura M, Ruffini E, Van Schil P; Staging and Prognostic Factors Committee.; Members of 
the Advisory Boards.; Participating Institutions of the Thymic Domain.. J Thorac Oncol. 2014 
Sep;9(9 Suppl 2):S65-72. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: 
proposal for an evidenced-based stage classification system for the forthcoming (8th) edition 
of the TNM classification of malignant tumors 

 
38
5 Marx A, Chan JK, Coindre JM, Detterbeck F, Girard N, Harris NL, Jaffe ES, Kurrer MO, 
Marom EM, Moreira AL, Mukai K, Orazi A, Ströbel P. J Thorac Oncol. 2015 Oct;10(10):1383-
95. The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity 
and Changes 
6 Detterbeck FC, Nicholson AG, Kondo K, Van Schil P, Moran C. J Thorac Oncol. 2011 Jul;6(7 
Suppl 3):S1710-6. The Masaoka-Koga stage classification for thymic malignancies:clarification 
and definition of terms 
7 Perri F, Pisconti S, Conson M, Pacelli R, Della Vittoria Scarpati G, Gnoni A, D'Aniello C, 
Cavaliere C, Licchetta A, Cella L, Giuliano M, Schiavone C, Falivene S, Di Lorenzo G, 
Buonerba C, Ravo V, Muto P. Onco Targets Ther. 2015 Jun 8;8:1345-9. Adjuvant treatment in 
patients at high risk of recurrence of thymoma: efficacy and safety of a three-dimensional 
conformal radiation therapy regimen 
8 Lim YJ, Kim HJ, Wu HG. J Thorac Oncol 2015 Sep;10(9):1357-63. Role of postoperative 
radiotherapy in nonlocalized thymoma: Propensity-matched analysis of surveillance, 
epidemiology, and end results database 
9 Komaki R, Gomez DR Front Oncol. 2014 Jan 10;3:330. Radiotherapy for thymic carcinoma: 
adjuvant, inductive, and definitive 
10 Berman AT, Litzky L, Livolsi V, Singhal S, Kucharczuk JC, Cooper JD, Friedberg JR, Evans 
TL, Stevenson JP, Metz JM, Hahn SM, Rengan R. Cancer. 2011 Aug 1;117(15):3502-8. 
Adjuvant radiotherapy for completely resected stage 2 thymoma 
11 Moiseenko V, Craig T, Bezjak A, Van Dyk J. Radiother Oncol 2003 Jun;67(3):265-74 Dose-
volume analysis of lung complications in the radiation treatment of malignant thymoma: a 
retrospective review                            
12 Andratschke N, Maurer J, Molls M, Trott KR. Radiother Oncol. 2011 Aug;100(2):160-6. 
Late irradiation-induced heart disease after radiotherapy. Clinical importance, radiobiological 
mechanisms and strategies of prevention  
13 Yusuf SW, Sami S, Daher IN. Cardiol Res Pract. 2011 Feb 27;2011:317659. Radiation-
induced heart disease: a clinical update 
14 Schellong G, Riepenhausen M, Bruch C, Kotthoff S, Vogt J, Bölling T, Dieckmann K, Pötter 
R, Heinecke A, Brämswig J, Dörffel W. Pediatr Blood Cancer 2010;55:1145-1152. Late 
Valvular and Other Cardiac Diseases After Different Doses of Mediastinal Radiotherapy for 
Hodgkin Disease in Children and Adolescents:Report From the Longitudinal GPOH Follow-Up 
Project of the German-Austrian DAL-HD Studies 

 
39
15 van den Bogaard V, Ta BDP, van der Schaaf A, Bouma AB, Middag AMH, Bantema-Joppe 
EJ, van Dijk LV, van Dijk-Peters FBJ, Marteijn LAW, de Bock GH, Burgerhof JGM, Gietema 
JA, Langendijk JA, Maduro JH, Crijns APG. ascopubs.org/journal/jco 2017. Validation and 
Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer 
Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac 
Substructures 
16 Beukema JC, van Luijk P, Widder J, Langendijk JA, Muijs CT. Radiother Oncol. 2015 
Jan;114(1):85-90. Is cardiac toxicity a relevant issue in the radiation treatment of esophageal 
cancer? 
17 Kongbundansuk S, Hundley WG. JACC Cardiovasc Imaging. 2014 Aug;7(8):824-38. 
Noninvasive imaging of cardiovascular injury related to the treatment of cancer 
18 Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bogaert J, Davin L, Cosyns B, 
Coucke P, Dulgheru R, Edvardsen T, Gaemperli O, Galderisi M, Griffin B, Heidenreich PA, 
Nieman K, Plana JC, Port SC, Scherrer-Crosbie M, Schwartz RG, Sebag IA, Voigt JU, Wann 
S, Yang PC; European Society of Cardiology Working Groups on Nuclear Cardiology and 
Cardiac Computed Tomography and Cardiovascular Magnetic Resonance.; American Society 
of Nuclear Cardiology.; Society for Cardiovascular Magnetic Resonance.; Society of 
Cardiovascular Computed Tomography.. Eur Heart J Cardiovasc Imaging. 2013 
Aug;14(8):721-40. Expert consensus for multi-modality imaging evaluation of cardiovascular 
complications of radiotherapy in adults: a report from the European Association of 
Cardiovascular Imaging and the American Society of Echocardiography 
19 Tian S, Hirshfield KM, Jabbour SK, Toppmeyer D, Haffty BG, Khan AJ, Goyal S. Front 
Oncol. 2014 Oct 9;4:277. Serum biomarkers for the detection of cardiac toxicity after 
chemotherapy and radiation therapy in breast cancer patients 
20 Björk-Eriksson T, Bjelkengren G, Glimelius B. Acta Oncol. 2005;44(8):913-7. The 
potentials of proton beam radiation therapy in malignant lymphoma, thymoma and sarcoma 
21 Gomez D, Komaki R. J Thorac Oncol. 2010 Oct;(10 Suppl 4):S336-43. Technical advances 
of radiation therapy for thymic malignancies 
22 Figura N, Hoppe BS, Flampouri S, Su Z, Osian O, Monroe A, Nichols RC. J Thorac Onc                        
ol. 2013 May;8(5):e38-40. Postoperative proton therapy in the management of stage III 
thymoma 
23 Vogel J, Berman AT, Lin L, Pechet TT, Levin WP, Gabriel P, Khella SL, Singhal S, 
Kucharczuk JK, Simone CB 2nd. Radiother Oncol. 2016 Mar;118(3):504-9. Prospective study 

 
40
of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic 
carcinoma: Early response and toxicity assessment                                                                                          
24 Parikh RR, Rhome R, Hug E, Tsai H, Cahlon O, Chon B, Goenka A. Clin Lung Cancer. 
2016 Sep;17(5):362-366. Adjuvant Proton Beam Therapy in the Management of Thymoma: A 
Dosimetric Comparison and Acute Toxicities 
25 Chang JY, Li H, Zhu XR, Liao Z, Zhao L, Liu A, Li Y, Sahoo N, Poenisch F, Gomez DR, 
Wu R, Gillin M, Zhang X. Int J Radiat Oncol Biol Phys. 2014 Nov 15;90(4):809-18. Clinical 
implementation of intensity modulated proton therapy for thoracic malignancies 
26 Inoue T, Widder J, van Dijk LV, Takegawa H, Koizumi M, Takashina M, Usui K, Kurokawa 
C, Sugimoto S, Saito AI, Sasai K, Van't Veld AA, Langendijk JA, Korevaar EW. Int J Radiat 
Oncol Biol Phys. 2016 Nov 1;96(3):661-9. Limited Impact of Setup and Range Uncertainties, 
Breathing Motion, and Interplay Effects in Robustly Optimized Intensity Modulated Proton 
Therapy for Stage III Non-small Cell Lung Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
41
 
 
 
 
 
 
 
 
 
14.0 Appendix 
 
Appendix 14.1 
PROTHYM - TRANSTHORACIC ECHOCARDIOGRAM (TTE) PROTOCOL 
Image sampling is performed by a biomedical scientist or cardiologist at the local 
hospital. The examination is thereafter transferred (by CD/DVD) for evaluation by 
study responsible cardiologist. 
 
To be noticed and listed: 
Age  
Gender 
Length (cm) and weight (kg) of the patient 
Heart rate (per minute) 
Arrhythmias (all kind of arrhythmias should be documented) 
Long axis:  
1. Left ventricle end-diastolic diameter (LVEDD) 
2. Left ventricle outflow tract diameter (zoom LVOT) 
3. Aortic valve color 
4. Mitral valve color 
5. Ascending aorta (diameter) 
Short axis:  
1. Left ventricle mid-section view 
2. Left ventricle M-MODE (just below the mitral valve) 
3. Aorta mid-section view (valve morphology) 
4. Pulmonary valve: color and doppler CW+PW  
4CH: 
 

 
42
1. 4 Chamber view (motion) 
2. Left ventricle zoom (motion/volume) 
3. Atrium size (Right atrium / Left atrium) 
4. Pulmonary vein: doppler PW (for S/D measure) 
5. Mitral valve: color and doppler CW+PW (for E/A measure) 
6. Aortic valve: color and doppler CW+PW (for VTI measure) 
7. Tricuspidal valve: color and doppler CW (gradient) 
8. Tissue doppler (1. Lateral RV, 2. Septum, 3. Lateral LV) 
2CH: 
 
1. 2 Chamber view (motion) 
2. Left ventricle zoom (motion/volume) 
3CH: 
 
1. 3 Chamber view (motion) 
Subcostal view:  
1. 4 Chamber view 
2. Vena Cava diameter and variation during sniffing (central vein pressure) 
 
Appendix 14.2 
 
Performance Status: WHO = Zubrod = ECOG 
 

 
43
Activity Status 
 
Description 
 
0 
Asymptomatic, fully active, and able to carry on all predisease 
performance without restrictions. 
 
1 
Symptomatic, fully ambulatory but restricted in physically 
strenuous activity and able to carry out performance of a light 
or sedentary nature, eg, light housework, office work. 
 
2 
Symptomatic, ambulatory and capable of all self-care but 
unable to carry out any work activities.  Up and about more 
than 50% of waking hours: in bed less than 50% of day. 
 
3 
Symptomatic, capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours, but not 
bedridden. 
 
4 
Completely disabled.  Cannot carry on any self-care.   Totally 
bedridden. 
 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
Appendix 14.3 
 
CTC version 4.0 
 

 
44
Adverse 
event 
1 
2 
3 
4 
5 
Dysphagia 
Symptomatic, 
able to eat 
regular diet 
Symptomatic and 
altered  
eating/swallowing 
Severely 
altered eating/ 
swallowing, 
tube feeding 
or TPN or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
death 
Esophagitis 
Asymptomatic, 
clinical or 
diagnostic 
observations 
only; 
interventions 
not indicated 
Symptomatic, 
altered 
eating/swallowing; 
oral supplements 
indicated 
Severely 
altered eating/ 
swallowing, 
tube feeding 
or TPN or 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
death 
Nausea 
Loss of 
appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased without 
significant weight 
loss, dehydration 
or malnutrition 
Inadequate 
oral caloric or 
fluid intake; 
tube feeding, 
TPN or 
hospitalization 
indicated 
- 
- 
Fatigue 
Fatigue 
relieved by rest 
Fatigue not 
relieved by rest, 
limiting 
instrumental ADL 
Fatigue not 
relieved by 
rest, limiting 
sel care ADL 
- 
- 
Cough 
Mild 
symptoms; 
non-
prescription 
intervention 
indicated 
Moderate 
symptoms, 
medical 
intervention 
indicated; limiting 
instrumental ADL 
Severe 
symptoms, 
limiting self 
care ADL 
- 
- 
Dyspnea 
Shortness of 
breath with 
moderate 
exertion 
Shortness of 
breath with 
minimal exertion; 
limiting 
instrumental ADL 
Shortness of 
breath at rest; 
limiting self 
care ADL 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
death 
Pneumonitis Asymptomatic, 
clinical or 
diagnostic 
observations 
only; 
interventions 
not indicated 
Symptomatic; 
medical 
intervention 
indicated; limiting 
instrumental ADL 
Severe 
symptoms, 
limiting self 
care ADL; 
oxygen 
indicated 
Life-threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated 
(e.g.tracheotomy 
or intubation) 
death 

 
45
Febrile 
neutropenia 
- 
- 
present 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
death 
 
 
Appendix 14.4 
 
Masaoka-Koga Staging System 
 
Stage 
 
Definition 
 
I 
Grossly and microscopically completely encapsulated 
tumour 
IIa 
Macroscopic transcapsular invasion 
IIb 
Macroscopic invasion into thymic or surrounding fatty tissue, 
or grossly adherent to but not breaking through mediastinal 
pleura or pericardium 
III 
Macroscopic invasion into neighboring organ (ie 
pericardium, great vessel, or lung) 
IVa 
Pleural or pericardial metastases 
IVb       
Lymphogenous or hematogenous metastasis 
Adapted from Pathol Int 1994;44:359-367 
 
 
 
 
 
 
 
 
Appendix 14.5 
 
World Health Organization Classification of Thymoma 

 
46
 
Type 
 
Histological Description 
 
A 
 
Medullary thymoma 
AB 
 
Mixed thymoma 
B1 
 
Predominantly cortical thymoma 
B2 
 
Cortical thymoma 
B3 
 
Well-differentiated thymic carcinoma