Multicentre Phase III Study: Addition of Radiotherapy to Standard Medical Treatment for Stage IV NSCLC
Phase: NA
Conditions: Radiotherapy, Non Small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer, Quality of Life
Sponsor: Swedish Lung Cancer Study Group

  
 
MARS 
Protocol  
 
 
 
Multicentre phase III study: Addition of Radiotherapy to Standard 
medical treatment for stage IV NSCLC 
 
 
 
 
Version :  2019-10-17 
 
 
 
 
 
         
 
 
 
            
                                                                      
 
 
 
 
 
 
Principal Investigator 
 
 
Jan Nyman, Göteborg  
 
 
 
 

MARS; VERSION 191017 
 
 
2 
STUDY CO-ORDINATOR 
Name: Jan Nyman 
 
   
     Address: Department of Oncology 
 
   
 
Sahlgrenska University Hospital 
 
   
 
413 45  GÖTEBORG  SWEDEN 
 
   
      Tel: +46 (0)31 3421000 
 
   
 
e-mail: jan.nyman@oncology.gu.se 
PROTOCOL COMMITTEE  
 
Bengt Bergman, Göteborg 
 
   
 
Mikael Johansson, Umeå 
 
   
 
Hirsh Koyi, Gävle 
 
 
  
 
Karl-Gustav Köhlbeck, Stockholm 
 
  
 
Kristina Lamberg, Uppsala 
 
  
 
Jan Nyman, Göteborg 
 
  
 
Hillevi Rylander, Göteborg 
 
  
 
Gunnar Wagenius, Stockholm 
 
STUDY CO-ORDINATION 
 
RCC Väst 
 
   
 
  
 
   
  
 
SPONSOR  
 
Jan Nyman 
 
 
   
  
  
INVESTIGATORS, SWEDEN 
 
See separate list 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3 
PROTOCOL AGREEMENT FORM 
 
I, the undersigned participating physician, have examined this Protocol 
 
 
 
Entitled:  
 
Multicentre phase III study: Addition of Radiotherapy to Standard 
medical treatment for stage IV NSCLC 
 
And I have fully discussed the objectives of this study and the contents of this protocol with the 
sponsors' representative(s). 
 
I agree to conduct the study according to this protocol and to comply with its requirements, subject to 
ethical considerations. 
 
I agree to keep confidential the content of this protocol, not to disclose it to any third party and to use 
it only for the purpose of conducting this study. 
 
 
PARTICIPATING PHYSICIAN 
 
NAME:________________________ 
SIGNATURE:________________________ 
 
DATE: _________________________________________________ 
 
 
 
FOR THE PRINCIPAL INVESTIGATOR 
 
NAME: Jan Nyman 
SIGNATURE:  
 
DATE: __________________________________________________ 

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TABLE OF CONTENTS 
 
1 STUDY SUMMARY ........................................................................................................... 7 
2 LIST OF ABBREVIATIONS ........................................................................................... 10 
3 STUDY RATIONALE ...................................................................................................... 11 
3.1 
Disease background and standard treament ...................................................... 11 
 
3.2 
 Abscopal effect……………..……………………………………………….…12 
 
3.3 
 Hypothesis…………………………………………………………………..… 12 
4 STUDY OBJECTIVES ..................................................................................................... 13 
4.1 
Objectives ......................................................................................................... 13 
4.1.1 
Primary Objectives ............................................................................................ 13 
4.1.2 
Secondary Objectives ........................................................................................ 13 
 
5 DESIGN .............................................................................................................................. 13 
6 SELECTION OF PATIENTS .......................................................................................... 13 
6.1 
Inclusion criteria ............................................................................................... 13 
6.2 
Exclusion criteria .............................................................................................. 14 
7 FLOW CHART ................................................................................................................. 15 
8 VISIT SCHEDULE AND  TREATMENT ASSESSMENTS ........................................ 16 
8.1 
Pre study Assessment ...................................................................................... 16 
 
8.2 
Response evaluation after chemotherapy..…………………………………..16                              
8.2.1 
Reassessment…………………………………………………………………16 
8.3 
Randomization ................................................................................................ 17 
8.3.1 
Follow-up 1 ...................................................................................................... 17 
 
8.3.2 
Follow-up 2-6…………………………..………………………………………17 
8.4 
Quality of life…………………………………………………………………18 
8.5 
Exploratory Objectives ................................................................................... 18 
9 RADIOTHERAPY ............................................................................................................ 19 

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9.1 
Patient pre-treatment preparation………………………………………….19 
9.2 
Pre-treatment imaging .................................................................................... 19 
 
9.3 
Specification of radiation treatment……………….………………   ……… 19 
10 MEDICAL TREATMENT……………………………………………………………....21 
10.1 
Chemotherapy ................................................................................................... 21 
 
10.2 
  Chemo-immunotherapy……………………………………………………...21 
 
10.3 
 Immunotherapy……………………………………………………………….21 
11  DISCONTINUATION OF TREATMENT ..................................................................... 21 
12 SAFETY ASSESSMENTS AND REPORTING............................................................. 22 
12.1 
Follow-up assessment ....................................................................................... 22 
12.2 
Recording of adverse events (AE) .................................................................... 22 
12.3 
Patient withdrawal ............................................................................................ 24 
13 MANAGEMENT OF DATA ............................................................................................ 24 
13.1 
Case Report Form Handling ............................................................................. 24 
13.2 
Patient data collection and handling ................................................................. 24 
13.3 
Site data quality control and monitoring and stopping rules ............................ 24 
14 STATISTICAL CONSIDERATIONS............................................................................. 25 
14.1 
Statistical analysis plan ..................................................................................... 25 
15 TASKS AND RESPONSIBILITIES................................................................................ 25 
15.1 
Responsibilities of the study committee ........................................................... 25 
15.2 
Participating Physicians .................................................................................... 26 
15.3 
Responsibilities of the sponsor ......................................................................... 26 
15.4 
Record retention and confidentiality ................................................................. 26 
15.5 
Data Protection .................................................................................................. 27 
16 ETHICAL AND ADMINISTRATIVE CONSIDERATIONS ...................................... 27 
16.1 
Informed Consent .............................................................................................. 27 
17 REPORTING AND PUBLICATIONS............................................................................ 27 

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18 APPENDIX ........................................................................................................................ 29 
18.1 
WHO Performance Status ................................................................................. 29 
 
18.2 
Lung Cancer Symptom Scale………………………………………………….30 
 
18.3 
Recist criteria………………………………………………………………..…31 
 
18.4 
Biological sampling…………………………………………………………….32 
 
 

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1 
STUDY SUMMARY 
Title 
 
Multicentre phase III study: Addition of Radiotherapy to 
Standard medical treatment for stage IV NSCLC 
 
Endpoints 
Primary 
To assess whether the addition of radiotherapy to the remaining 
thoracic tumor burden following standard medical treatment results 
in a superior quality of life measured with lung cancer symptom 
scale (LCSS) in patients with stage IV non-small cell lung cancer. 
The measurements will be assessed at three months after 
randomization. 
 
Secondary 
Overall survival, progression-free survival, toxicity, longitudinal 
quality of life measurements  
Design 
 
Multicentre, randomized phase III trial. 
 
Patients will be registered for the study up-front but 
randomization will be performed after evaluation of response 
after three months of medical treatment. Randomization to 
thoracic radiotherapy or follow-up.   
 
Population 
 
 
 
 
Inclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients with histologically verified NSCLC stage IV amenable 
to standard chemotherapy.  
 
 
 
 Histological or cytological confirmed non-small cell lung 
cancer (NSCLC) 
 Mixed histology allowed if all components are consistent 
with NSCLC.  
 Stage IV disease 
 Previously untreated disease (before first line 
chemotherapy) 
 No symptomatic brain metastases 
 Performance status (WHO) 0-2 
 FEV1 ≥ 1 L or >40% of predicted Written informed consent  
 Life expectancy ≥ 12 weeks  
 Platelet count ≥ 100,00/mm3  
 Hemoglobin ≥ 10 g/dL  

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Exclusion criteria 
 
 
 
 
 
 WBC ≥ 3,000/mm3  
 Kidney function allowing chemotherapy 
 Patients scheduled for standard platinum based 
chemotherapy, chemo-immunotherapy or immunotherapy in 
first line 
 Willing and able to comply with study treatment  
 
 Requirement for daily supplemental oxygen  
 Second primary malignancy within 3 years, except for any of 
the following which can be included even if diagnosed within 
the past 3 years: 
 Carcinoma in situ of the cervix  
 Non-melanoma skin cancer  
 History of low-grade (Gleason score ≤ 6) localized 
prostate cancer 
 Definitely treated Stage I breast cancer.  
 Other malignancy that was diagnosed and definitely 
treated ≥ 3 years ago with no subsequent evidence 
of recurrence  
 Concurrent severe and/or uncontrolled medical condition, 
including any of the following: 
o Angina pectoris  
o Congestive heart failure within the past 3 months, 
unless LVEF > 40%  
o Myocardial infarction within the past 6 months  
 Clinically significant infection  
 Psychiatric illness or social situation that would limit 
compliance with study requirements  
 EGFR mutation or ALK transformation detected 
Treatment (s) 
4 courses of platinum-based chemotherapy according to local 
tradition or 4 courses of chemo-immunotherapy or three months 
treatment of single immunotherapy. If stable disease (SD) or 
response (CR/PR) to initial therapy the patient will be randomized to 
standard follow-up or radiotherapy 3 Gy to a total dose of 36 Gy to 
primary tumor. 
Palliative radiotherapy for distant metastases outside thorax is 
allowed whenever needed. If need for symptom palliation, all 

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patients could have radiotherapy even to the thorax. 
Maintenance chemotherapy or immunotherapy is allowed according 
to local practice, but should then be decided before randomization 
for both study groups. Bevacizumab maintenance is not allowed. 
Second line chemotherapy or immunotherapy is allowed when 
indicated. 
 
Statistical analyses 
and sample size 
determination 
 
 
The primary endpoint in the present trial is health-related QoL as 
measured with the LCSS, at three months. The sample size was 
calculated on the hypothesis that a scale score difference of >10 in 
the total LCSS scale (range 0-100) constitutes a clinically relevant 
group difference. With a power of 80% to detect this group 
difference as significant (p=0.05, two-sided test), with an assumed 
standard deviation of 22 and a loss of follow up of 20%, at least 162 
randomized patients in total were required, 81 per group. 
 
 
 
Timelines 
 Study duration per subject 
 Enrolment duration 
First patient In : Feb 2017 
Last patient In : Feb 2022 
Last patient Out : Feb 2024 
Estimated enrolment duration: 4 years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2 
LIST OF ABBREVIATIONS 
       
AE 
 
Adverse event 
ALAT 
 
Alanine aminotransferase 
ALK 
 
Anaplastic Lymphoma Kinas 
ALP 
 
Alkaline phosphatase 
ANC 
 
Absolute neutrophil count 
CR 
 
Complete response 
CRF 
 
Case report form 
CT 
 
Computerized tomography 
CTC 
 
Common toxicity criteria 
EC 
 
Ethics committee 
EGFR          
Epidermal growth factor receptor  
GCP 
 
Good clinical practice 
Hb 
 
Haemoglobin 
HrQoL  
Health related Quality of Life 
MC 
 
Monitoring committee 
 
RCC 
 
Regionalt Cancer Centrum 
RC 
 
Review Committee 
SAE 
 
Serious adverse event 
SD 
 
Stable disease 
SRC 
 
Scientific and Review Committee 
WBC 
 
White blood cells 
WHO 
 
World Health Organisation 

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3 
 STUDY RATIONALE 
3.1 
Disease background and standard treament 
Approximately 3.500 new cases of lung cancer are diagnosed in Sweden each year. Eighty percent 
have non-small-cell lung cancer NSCLC while the remaining has other histology, mainly small cell 
lung cancer. In the NSCLC population, approximately 50 % are diagnosed in stage IV, metastatic 
disease, and of them 70 % are in WHO performance status 0-2, adding up to 980 patients per year, 
which is the target population for this study. All these data are published from the Swedish National 
Lung Cancer Registry.   
 
The standard treatment for this group of patients has been chemotherapy with a platinum doublet in 
four to six courses (cis- or carboplatin combined with either of vinorelbine, gemcitabine, paclitaxel, 
docetaxel or pemetrexed). Concomitant bevacizumab is sometimes used. For a proportion of patients 
with a good performance status and response to therapy, could maintenance therapy with pemetrexed 
or erlotinib or bevacizumab be an option. Radiotherapy is mainly used for symptom palliation, either 
to the primary tumor (dyspnea, cough, hemoptysis, vena cava superior syndrome etc.) or for 
treatment of distant metastases. In 2019 is treatment with a combination of a platinum doublet 
chemotherapy and immunotherapy with the PD-1 blocker pembrolizumab introduced for patients 
with a good performance status (WHO 0-1). Studies have shown survival advantages for this 
combination compared to chemotherapy alone (Gandhi et al 2018). For patients with tumors 
expressing high values of PD-L1 (> 50 %) immunotherapy with pembrolizumab alone showed better 
survival than chemotherapy (Reck et al 2019). This treatment is also now recommended in first line, 
according to the Swedish national guidelines. 
 
There are some clinical data supporting radiotherapy upfront to the primary lung tumor to patients in 
stage IV and advanced non-curable stage III patients, where a prolongation of survival and 
improvement in quality of life have been observed. Two retrospective series in stage IV patients are 
published with 93 and 78 patients respectively, with 3 years overall survival of 25 and 13 % (Su et al 
2014, Lopez Guerra et al 2012). 
 
The Norwegian Lung Cancer Study Group has performed a randomized phase III trial for stage III 
patients not eligible for curative chemo-radiotherapy. 191 patients were randomized between four 
courses of chemotherapy (carboplatin and vinorelbine) or the same chemotherapy combined with 
radiation to 42 Gy in 15 fractions to the primary tumor and involved nodes. Overall survival was the 
primary endpoint and health-related quality of life and toxicity were secondary endpoints. The results 
showed a significant better overall survival for patients also receiving radiotherapy, median survival 
12.6 and 9.7 months respectively (p<0.01), and a better quality of life but some more hospital 
admission due to toxicity. (Strøm et al 2013). 
References: 
Gandhi L, Rodríguez‑ Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab 
plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-92. 
 

MARS; VERSION 191017 
 
 
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Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Updated analysis of 
KEYNOTE-024:pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell 
lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019;37(7):537-46. 
 
Su S, Hu Y, Ouyang W, Ma Z, Lu B, Li Q, LI H, Wang Z, Wang Y. The survival outcomes and 
prognosis of stage IV non-small-cell lung cancer treated with thoracic three-dimensional 
radiotherapy combined with chemotherapy. Radiotherapy and Oncology 290, 2014. 
Lopez Guerra J, Gomez D, Zhuang Y, Hong D, Heymach J, swisher S, Lin S, Komaki R, Cox J, Liao 
Z. Prognostic impact of radiation therapy to the primary tumor in patients with non-small cell lung 
cancer and oligometastases at diagnosis. Int J Radiat Biol Phys 84, e61-67, 2012. 
Strøm H, Bremnes R, Sundstrøm  S, Helbekkmo N, Fløtten Ø, Assebø U. Current palliative 
chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-
cell lung cancer: a randomized trial by the Norwegian Lung Cancer Study Group. British Journal of 
Cancer 109, 1467-1475, 2013. 
 
3.2 
Abscopal effect 
There is a growing body of evidence for the phenomenon called abscopal effect.  This is described as 
an immunologic response to localized radiation in areas outside the radiation field. This is initiated 
by cascades of complex downstream biological responses in tissue far away from the irradiated area. 
Release of tumor antigens is thought to stimulate the immune system (Reynders et al 2015, Siva et al 
2013). This has also been shown in animal studies of Lewis lung carcinoma in mice, where local 
radiotherapy is essential for the effect (Camphausen et al 2003). It seems that addition of 
immunotherapy could even enhance this abscopal response, which has been shown for lung cancer 
patients with ipilimumab for example (Golden et al 2013). 
 
References:  
Reynders K, Illidge T, Siva S, Chang JY, de Ruysscher D. The abscopal effect of local radiotherapy: 
using immunotherapy to make a rare event clinically relevant. Cancer treatment reviews 41, 503-510, 
2015. 
Siva S, Mac Manus M, Martin R, Martin O. Abscopal effects of radiation therapy: a clinical review 
for the radiobiologist. Cancer letters 356, 82-90, 2015. 
Campenhausen K, Moses M, Ménard C, Sproull M, Beecken WD, Folkman J, O´Reilly S. Radiation 
abscopal antitumor effect is mediated through p53. Cancer research 63, 1990-1993, 2003. 
Golden E, Demaria S, Schiff P, Chachoua A, Formenti S. An abscopal response to radiation and 
ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 365-372, 
2013. 
 
  
3.3 
Hypothesis 
The hypothesis for this study is that addition of radiotherapy to the primary tumor and mediastinal 
nodes to medical treatment could reduce the tumor burden, partly as an abscopal effect, and thereby 
improving quality of life and possible also prolonging survival. 

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4 
STUDY OBJECTIVES  
4.1 
Objectives 
4.1.1 Primary Objectives 
To assess whether the addition of radiotherapy to the remaining thoracic tumor burden following 
standard medical treatment results in a superior quality of life measured with lung cancer symptom 
scale (LCSS) in patients with stage IV non-small cell lung cancer. The comparison will be made at 
three months after randomization. 
4.2.1 Secondary Objectives 
Overall survival, progression-free survival, toxicity and longitudinal quality of life measurements.  
 
5 
DESIGN 
Multicentre, randomized, phase III trial. Patients will be registered for the study up-front but 
randomization will be performed after evaluation of response, three months after initiating 
medical treatment with chemotherapy/ chemo-immunotherapy or immunotherapy. 
Randomization will be to thoracic radiotherapy or follow-up (1:1).   
 
 
6 
SELECTION OF PATIENTS 
6.1 
Inclusion criteria for registration 
 Histological or cytological confirmed non-small cell lung cancer (NSCLC) 
 Mixed histology allowed if all components are consistent with NSCLC.  
 Stage IV disease  
 Previously untreated disease (before first line treatment) 
 No symptomatic brain metastases 
 Performance status (WHO) 0-2 
 FEV1 ≥ 1 L or >40% of predicted  
 Written informed consent  
 Life expectancy ≥ 12 weeks  
 Platelet count ≥ 100,00/mm3  
 Hemoglobin ≥ 10 g/dl  
 WBC ≥ 3,000/mm3  
 Kidney function allowing chemotherapy 
 Patients scheduled for standard platinum based chemotherapy, chemo-immunotherapy or 
immunotherapy 
 Willing and able to comply with study treatment  

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6.2 
 
Exclusion criteria 
 Requirement for daily supplemental oxygen  
 Second primary malignancy within 3 years, except for any of the following which can be 
included even if diagnosed within the past 3 years: 
 Carcinoma in situ of the cervix  
 Nonmelanoma skin cancer  
 History of low-grade (Gleason score ≤ 6) localized prostate cancer 
 Definitely treated Stage I breast cancer.  
 Other malignancy that was diagnosed and definitely treated ≥ 3 years ago with no 
subsequent evidence of recurrence  
 Concurrent severe and/or uncontrolled medical condition, including any of the following: 
o Angina pectoris  
o Congestive heart failure within the past 3 months, unless LVEF > 40%  
o Myocardial infarction within the past 6 months  
 Clinically significant infection  
 Psychiatric illness or social situation that would limit compliance with study requirements 
 EGFR mutation or ALK-EML4 rearrangement detected 
 
 
 
 
 
 
 
 
 
 

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7 
FLOW CHART  
 
 
 
SCREENING/ 
BASELINE 
 
Reassess
ment 
Randomizat
ion 
ASSESSMENT  
AFTER 
Randomization 
 
 
POST START OF STUDY 
TREATMENT (PSOST) 
FOLLOW-UP  
 
CLINICAL VISIT 
1 
 
 
Follow-up 1 
 
2 
3 
4 
5 
6 
 
MONTH 
 
 
X 
 
 
 
 
 
3 
 
 
6 
 
 
9 
 
 
12 
 
 
18 
 
 
24 
 
 
EOS 
 
 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Computerized             
Tomography, CT1   
X 
 
x 
 
X 
X 
X 
X 
X 
X 
 
PET1 
(X, optional) 
 
 
 
 
 
 
 
 
 
 
QoL 
 
X 
x 
 
X 
x 
X 
x 
X 
x 
 
Medical history  
x 
 
x 
 
 
 
 
 
 
 
 
Physical examination 
 
X 
x 
 
X 
X 
X 
X 
X 
X 
 
Body weight  
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Pre-treatment weight 
loss 
X 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Performance status 
according to WHO 
 
X 
 
x 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Haematology5 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
Biochemistry5 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
Biological sampling4 
 
x 
 
x 
 
X 
 
 
 
 
 
 
Assessment of 
symptoms/Adverse 
events (NCI-CTC) 
Version 4.03 3 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
x 
 
X 
 
x 
Spirometry6 
X 
 
X7 
 
 
 
 
 
 
 
1.  Should not be more than 6 weeks before inclusion 
2. Recommended but not mandatory 
3. Serious Adverse Events should be reported within 24h. SAE have to be declared up to 30 days  
   after last study drug infusions 
4. Optional, see 8.5 
5. Within 72 hours 
6. Should be done within 8 weeks 
7. If spirometry is done without CO-diffusion measurements, a new spirometry should be done for patients randomized to radiotherapy 
including this test 
 

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8 
 
VISIT SCHEDULE AND  TREATMENT ASSESSMENTS 
 
8.1 
Pre study Assessment    
Screening < 7 days before start of chemotherapy 
 
 TNM classification (7th edition) 
 Histologically or cytologically confirmed diagnosis 
 Localization of metastases  
 Medical history 
 Physical examination 
 Performance status according to WHO  
 Assessment of quality of life according to LCSS 
 Pre-treatment weight loss (In the 6 months prior to study enrollment) 
 Body Weight and height 
 Assessment of symptoms at baseline according to NCI-CTC criteria version 4.03. 
 
 
The following assessments must be performed: 
 
 CT of thorax and upper abdomen (allowed up to 6 weeks). 
 Spirometry and DLCO (allowed up to 8 weeks). If DLCO is not included in the 
spirometry, an additional spirometry must be performed for patients randomized to 
radiotherapy including that. 
 
 
 
 Haematology (Haemoglobin, Hb, White Blood Cell Count, WBCC, Total Platelet 
Count, TPK, Absolute Neutrophil Count, ANC) within 72 hours. 
 
Biochemistry (Serum creatinine, Serum calcium and albumin, Bilirubin, Alkaline 
Phosphatase, Aspartate transaminase - SGOT (ASAT), Alanine transaminase - SGPT 
(ALAT), Lactate Dehydrogenase – LD, Sodium, Potassium, Magnesium) Within 72 
hours. 
 
 Biological sampling- Optional (Plasma and whole blood sampling for Exploratory 
Objectives) 
 PET-CT –Optional 
 
 
8.2 
Response evaluation after chemotherapy should be performed day 8-21 in the 
fourth chemotherapy cycle. 
8.2.1 Reassessment 
   
 CT thorax and upper abdomen. 
 
Evaluation of known metastatic sites with appropriate method 
 
Hematology 

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 
Biochemistry 
 
Performance status WHO 
 
Quality of life assessment LCSS 
 
Physical examination and weight 
 Biological sampling -Optional (Plasma and whole blood sampling for 
Exploratory Objectives) 
8.3 
Randomization 
If the reassessment shows SD, PR or CR according to RESIST criteria (see 18.3) patients 
should be randomized 1:1 to receive thoracic radiotherapy or not. Randomization should be 
done within 7 days from evaluation of tumor response. Decision on maintenance with 
chemotherapy or immunotherapy or not should be taken before randomization. 
Randomization is done by telephone to RCC Väst 010-4412823, phone is open 8-16. 
 
8.3.1     Follow-up 1, 3 months after randomization 
  
 Physical examination 
 Recording of persistent or new toxicity 
 Performance status (WHO) 
 CT 
 Weight 
 Haematology and biochemistry sampling 
 Quality of life assessment LCSS 
 Biological sampling –Optional (Plasma and whole blood sampling for Exploratory 
Objectives) 
 
 
8.3.2 Follow-up 2-6  
6, 9, 12, 18 and 24 months after start of study therapy 
 
 Physical examination  
 Recording of persistent or new toxicity 
 Performance status (WHO) 
 Weight 
 Haematology and biochemistry  
 Quality of life assessment LCSS. 
 CT 
 
 

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8.4 
Quality of life 
Quality of life assessment 
The Lung Cancer Symptom Scale (LCSS) is a site-specific quality-of-life (QoL) measure focusing 
on physical and functional dimensions of health-related QoL. It consists of nine visual analogue 
scales (0-100 mm) assessing QoL in the past 24 hours, including symptom measures (i.e. appetite, 
fatigue, cough, dyspnea, hemoptysis, and pain), effects on activities of daily living, and overall QoL 
(12). A summary score of all nine scales could be calculated (range 0-100, lower scores representing 
less symptoms) and used as outcome measure. 
 
Content validity of the LCSS has been confirmed by expert and patient surveys, indicating a 96% 
agreement for all items among experts (24 medical oncologists), and a good matching with own 
experience in patients (121 patients with advanced lung cancer) (1). Reliability has been documented 
with an internal consistency of >0.8 in the total score, a good test-retest reliability (r>0.75), and a 
high inter-rater agreement (95-100%) among experts (2). Construct and criterion validity (i.e. 
comparison and correlations with gold standard measures) has been proven (1). 
 
The LCSS has been extensively used in trials of lung cancer (3). 
 
The LCSS will be administered at baseline, 3, 6, 9, 12, 18 and 24 months after randomization.  
 
 
1. Hollen PJ, Gralla RJ, Kris MG, Potanovich LM. Quality of life assessment in individuals with 
lung cancer: Testing the lung cancer symptom scale (LCSS) Eur J Cancer. 1993;29A Suppl 1:S51–
S58. 
2. Hollen PJ, Gralla RJ, Kris MG, Cox C, Belani CP, Grunberg SM, et al. Measurement of quality of 
life in patients with lung cancer in multicenter trials of new therapies. psychometric assessment of 
the lung cancer symptom scale. Cancer. 1994 Apr 15;73(8):2087–2098. 
 
3. LCSS bibliography. www.lcss-ql.com/bibliography.htm 
 
 
8.5 
Exploratory Objectives 
 
For subjects who provide a separate informed consent, blood-sampling for exploratory biomarker 
analyses will be collected at visits 1, 2 and 4. The sampling and storage procedure are defined in a 
separate protocol (Biological sampling). Investigations will be carried out in blood samples in order 
to explore candidate predictive and prognostic biomarkers in blood. A customized panel of tumour 
and tumour stroma related proteins will be assessed using the Luminex platform (Luminex corp, 
Austin TX) for multiplex targeted analysis of changes in the proteome. Based on these findings 
further analysis of metabolic changes downstream the proteome will be conducted using unbiased 
mass-spectrometic metabolomic profiling. Changes in the proteomic and metabolomics fingerprints 
will be analysed using multivariate methods. The main objective of the exploratory part of the study 
is to find clinically useful predictive and prognostic biomarkers for lung cancer treatment. 
 
 
 
 
 

MARS; VERSION 191017 
 
 
19 
 
 
 
 
 
 
9.0  
RADIOTHERAPY 
 
 
 
 
9.1  
Patient pre-treatment preparation 
 
The patient shall be positioned with the arms above the head in supine position. Immobilization 
devices, such as vacuum bags, Wing Step are used according to local routines. For patients 
randomized to radiotherapy, the spirometry must contain a CO-diffusion test. If that is done at 
inclusion in the study, it must be completed. 
 
The patient reference coordinate system is defined by using tattoos or ink marks  
 
 
9.2  
Pre-treatment imaging 
 
For structure delineation CT imaging shall be performed with ≤ 5 mm slice thickness. The use of i.v. 
contrast is optional. 
 
The CT scanning shall be performed from larynx to 5 cm below the diaphragm.  
  
 
9.3  
Specification of radiation treatment  
 
Volume specification 
 
The different volumes of interest shall be defined in agreement with ICRU Report 83 
 
Gross Tumour Volume (GTV): 
The GTV includes the primary lung tumour and pathological lymph nodes defined from post-
chemotherapy CT, pre-treatment PET-CT (if performed - optional) and pre-treatment bronchoscopy. 
Atelectasis, if present, shall be included in the GTV if it is not possible to separate from the primary 
tumour 
 
Clinical Target Volume (CTV) 
The CTV includes GTV + local subclinical extension. Approximately 1 cm margin shall be added to 
the GTV, with proper adjustment to big vessels, heart, esophagus, vertebrae etc. If a mediastinal 
pathological lymph node is located with a distance from the primary tumor, resulting in two separate 
target volumes, the unaffected node level in between should be included in the CTV. Apart from that, 
no adjuvant volumes shall be included. If CR is achieved after chemotherapy, CTV will include the 
area of former primary tumor and previously affected nodal stations without margin 
 
 
Planning Target Volume (PTV) 

MARS; VERSION 191017 
 
 
20 
Appropriate margins shall be added to the CTV to take into account the effects of organ and patient 
motions and inaccuracies in beam and patient setup in order to ensure that the prescribed dose is 
actually absorbed in the CTV according to local routines 
 
Organs at risk 
Organs at risk are the heart, lungs, spinal cord and the esophagus and shall be delineated as follows.  
OAR: Heart, lungs and esophagus are outlined without margins. 
PRVspinal cord is outlined with limit to bone and the volume then includes a margin to the spinal cord. 
 
Absorbed dose prescription 
The prescribed total dose is 36 Gy, specified as dose to CTV. 
For treatment planning optimization physical objectives and constraints shall be prioritized according 
to priority list 
 
Priority list 
Priority 
Volume 
Constraints  
1 
PRV spinal cord 
D max 36 Gy (100%) 
2 
CTV 
> 95 % 
3 
PTV 
>90% 
4 
OAR lungs (both lungs minus 
GTV) 
V20 < 45% 
5 
OAR esophagus 
Max dose <37,8 Gy (105%) 
6 
OAR heart 
Not applicable 
 
 
 
  
Fractionation and treatment time 
Radiotherapy is given 5 days/week with 12 fractions of 3 Gy 
Maximum treatment days is 20 days 
 
Relation to other therapies 
Radiotherapy is given after 4 cycles of standard chemotherapy to patients with proven SD/PR/CR. 
Radiotherapy shall start within 2 weeks from randomization. No concomitant chemotherapy or 
immunotherapy should be given, i.e. five days before and after first and last fraction of radiotherapy. 
 
Treatment planning and delivery 
The radiation treatment shall be given with photon therapy. 3DCRT, IMRT or rotational technique 
(for example VMAT) should be used. 
 
 
 
Potential radiation toxicity: 
 
Lungs 
Radiation-induced lung toxicity is defined as an early side- effect, pneumonitis (1-6 months after 
radiotherapy) and late fibrosis (> 6 months after radiotherapy). A reduction in lung function is 
initially usually reversible and later more persistent. 
 

MARS; VERSION 191017 
 
 
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The estimated risk of lung injury is correlated to mean lung dose, irradiated lung volume, 
fractionation and normal tissue complication probability. An acceptable estimated risk of side- 
effects can be about 20-25 % risk of grade 2 pneumonitis. This risk estimation seems to correspond 
to a mean lung dose < 18-20 Gy, and V20 < 30 % (Kong, Hayman et al. 2006)). For patients with 
previous lung disease, the risk can be higher. 
 
 
Esophagus 
Esophagitis, an inflammatory reaction due to cell depletion in the mucosa is seen two to three weeks 
after start of radiotherapy. With the actual fractionation schedule this will be transient and mostly 
fade away after one or two weeks. Occasionally mild analgesics and softer nutrients are needed. 
 
Spinal cord 
The doses to the spinal cord are below the tolerance level for injury in this protocol. 
 
Heart 
There is no consensus for recommended maximum doses to the heart. The spinal cord and the lungs 
will often be the dose-limited organs. It is recommended to keep the irradiated volume of the heart as 
small as possible without compromising the target volume. 
 
 
 
 
 
10 MEDICAL TREATMENT 
 
 
10.1Chemoterapy 
Chemotherapy is given before randomization with 4 courses of a platinum-based doublet in 
accordance with local practice. A minimum of three courses must be given before randomization. 
If maintenance chemotherapy is planned, the radiotherapy is preferably given in between cycles.  
 
      10.2Chemo-immunotherapy 
 
Chemo-immunotherapy is given before randomization with 4 courses of a platinum-based 
doublet in combination with a PD-1 blocker in accordance with local practice. A minimum of 
three courses must be given before randomization. If maintenance immuno- or chemo-
immunotherapy is planned, the radiotherapy is preferably given in between cycles.  
 
     10.3Immunotherapy 
 
Patients scheduled for primary immunotherapy as single agent should receive three months of 
therapy (i.e. 5 courses normally, if a schedule with treatment every third week is used) before 
evaluation and randomization. If prolonged treatment is planned immunotherapy should not be 
given concomitant with radiotherapy. 
 
 

MARS; VERSION 191017 
 
 
22 
11 DISCONTIUATION OF TREATMENT 
 Patient refusal – patients are free to discontinue the study or treatment at any time by 
withdrawing their consent, without giving any reason.  
 If the patient for any reason refuses further treatment, but does not withdraw consent, the 
patient will continue to be followed up according to the study schedule 
 Progressive disease at any time during treatment is a valid reason for stopping the treatment 
 Adverse reactions that are severe, life threatening or unacceptable, will preclude further 
treatment. 
 
12 SAFETY ASSESSMENTS AND REPORTING   
12.1 Follow-up assessment 
All Adverse Events (AEs) or Serious Adverse Events (SAEs) are recorded in appropriate CFR 
form and reported using NCI-CTCAE v 4. http://ctep.cancer.gov/reporting/ctc.html 
 
All SAEs are reported on specific SAE forms and sent to Klinisk Prövningsenhet, Department 
of Oncology, Sahlgrenska University Hospital, Göteborg 
fax number: 031-823931 (telephone number: 031-3427654) within 24 hours, or as soon as it 
comes to the investigators knowledge. The investigator at the respective site is responsible for 
this being done according to GCP rules. 
12.2 Recording of adverse events (AE) 
All AEs must be documented in the appropriate section of the CRFs. 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 time of onset in case the event started on the day of cetuximab administration (start 
time) 
 The date of recovery (stop date) 
 
During clinical visits, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by physical examination. Information on all adverse events 
should be recorded immediately in the Adverse Event module of the CRFs using the CTCAE 
version 4. 
 
All adverse events, present at entry to the study and occurring during the study period must be 
recorded. The clinical course of each event should be followed until resolution, stabilization 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 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. 
 

MARS; VERSION 191017 
 
 
23 
The grade as assessed by the investigator according to the definitions in NCI CTC version 4 : 
 Grade 1 = mild 
 Grade 2 = moderate 
 Grade 3 = severe 
 Grade 4 = life-threatening or disabling 
 Grade 5 = death related to AE 
 
Not Related; There is no temporal relationship to the study treatment = radiotherapy, or there is a 
reasonable causal relationship between another drug, concurrent disease or circumstance and the 
AE. 
Not Likely; There is a temporal relationship to the radiotherapy, but there is not 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.  
Other action (none, concomitant medication given, new or prolonged hospitalization, procedural 
surgery 
The outcome according to the following definitions:  
- 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.  
 
 
A Serious Adverse Event (SAE) is an event which 
 Results in death 
 Is life-threatening 
 Is disabling 
 Requires hospitalization, whether initial or prolonged, and does not include planned 
hospitalization 
 Requires intervention to prevent permanent impairment/damage 
 
The term “life-threatening” in the definition of “serious” refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death had it been more severe. 
 
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: 

MARS; VERSION 191017 
 
 
24 
 Elective hospitalization and surgery for treatment of disease 
 Elective hospitalization to simplify treatment or study procedures 
 
 
12.3 Patient withdrawal 
 Any subject who experiences an adverse event may be withdrawn at any time from the study 
treatment at the discretion of the investigator 
 If the adverse event is related to an overdose of study medication, the SPC should be 
consulted for details of any specific actions to be taken.  
 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 sponsor-
investigator should be informed without delay of all subjects who are withdrawn for this 
reason. 
 Any death occurring between the study inclusion and 30 days following the last infusion 
must be reported as a SAE within 24 hours, regardless of the relation to study medication. 
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 study drug(s) (possible, probable). All deaths should be reported on the 
death report form section on the CRF regardless of cause. 
 
13 MANAGEMENT OF DATA  
13.1 Case Report Form Handling 
Case record forms (CRFs) will be provided to record all the study data. Data must be entered onto 
the case report forms completely and legibly. The investigator will ensure that all copies of the forms 
are readable and will also verify that all data contained on these forms are accurate. All the forms 
should be signed.  
 
Any subsequent alterations to the data must be made by striking out the previous entry with a single 
line and by writing the new value next to it. All such changes must be initialled and dated.. Whiting 
or scribbling out the errors is not acceptable. 
 
When the monitor reviews the CRFs, certain queries may arise. These will be documented in writing 
and the resolution will also be noted in writing.  
 
13.2 Patient data collection and handling 
Regionalt Cancer Centrum Väst (RCC) will be responsible for Data Management in the study. All 
data will be recorded in the Case Report Form. Monitoring of data must be performed by qualified 
designated personnel. 
  
 
13.3 Site data quality control and monitoring and stopping rules  
 

MARS; VERSION 191017 
 
 
25 
Monitoring  
The study will be monitored according to ICH/GCP by site visits. During site visits, the monitor 
should review original patient records and document retention. Additionally, the monitor should 
observe study procedure and will discuss any problem with the investigator. The investigator will 
provide direct access to source data/documents for trial related monitoring, audits, Ethics Committee 
review and regulatory inspections.  
Monitoring will be provided by Klinisk Prövningsenhet, Department of Oncology, Sahlgrenska 
University Hospital, Göteborg. 
 
Stopping rules 
Toxicity of radiotherapy will be evaluated and protocol modification considered if excessive toxicity 
is observed. Late toxicities will be evaluated by Quality of Life questionnaire.  
 
The trial will stop prematurely for the following considerations: 
 When emerging adverse events are of such a serious nature that continuation of the trial 
becomes unacceptable. 
 When 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 24 months). 
 When the number of dropouts as described above (10.7) is too high and this situation is not 
acceptable for a period of time. 
 
 
14 STATISTICAL CONSIDERATIONS 
14.1 Statistical analysis plan 
Sample size 
The primary endpoint in the present trial is health-related QoL as measured with the LCSS, at three 
months. The sample size was calculated on the hypothesis that a scale score difference of >10 in the 
total LCSS scale (range 0-100) constitutes a clinically relevant group difference. With a power of 
80% to detect this group difference as significant (p=0.05, two-sided test), with an assumed standard 
deviation of 22 and a loss of follow up of 20%, at least 162 randomized patients in total were 
required, 81 per group. 
 
 
15 TASKS AND RESPONSIBILITIES 
15.1 Responsibilities of the study committee 
The Scientific and Review Committee (SRC) consisting of SLUSG, Swedish Lung cancer Study 
Group, will be responsible for scientific advice and recommendations on: 
- 
Protocol and data collection form 
     -     Assess efficacy and safety issues in this study  
     -     Verify patient eligibility 
 
- 
Methodology 
- 
Data analysis plan 
- 
Development of publication guidelines 
- 
Secure Good Clinical Practice (GCP) to be followed 
 

MARS; VERSION 191017 
 
 
26 
 
 
In a situation where other countries (regions) will enter the study, this committee will expand so that 
a balanced representation will be pursued. The committee will take decisions with a simple majority 
as the basic principle in case a consensus based decision can otherwise not be reached. The 
committee will ensure that all participants are encouraged to engage themselves in sub-studies as 
well as in translational research projects originating from the basic study population. If individual 
trial lists or centers are interested in specific sub-analyses or specific subgroup studies, the committee 
has to be addressed through a formal application and the committee will give approval with 
delineation of the details of the conduct of the study as well as the publication principles. In order to 
speed up the processing of similar applications the committee will be able to take decisions through 
mailing and/or telephone conferencing. Again simple majority principles will be applied. The 
committee will be competent to make decisions provided that half of the delegates are present or 
have given their written approval. If the written approval not is obtained, the opinion of the majority 
of the present members will be applied. 
 
 
15.2 Participating Physicians 
The investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator’s responsibility, should fully inform the subject of all 
pertinent aspects of the registry including the written information.  
The Participating Physicians will perform the study in accordance with this protocol and will verify 
and check that the information reported in the CRF is as precise and accurate as possible. 
It is the Participating Physician's responsibility to fill in the CRF, to record all data pertinent to the 
clinical investigation and obtain written informed consent from patients prior to inclusion in the 
study. 
 
15.3 Responsibilities of the sponsor 
The Sponsor of the study is responsible for taking all reasonable steps and providing adequate 
resources to ensure the proper conduct of the study as regards: 
- local submission(s) complying with data protection rules 
- any other local regulations  
- validity of the data recorded (Quality control of the data collected will be performed on site  
on a predefined percentage of sites and patients). 
 
15.4 Record retention and confidentiality 
The Participating Physician shall arrange for the retention of the subject identification codes after the 
completion or discontinuation of the study. Also patients' files and other source data shall be kept for 
the maximum period of time permitted by the hospital, institution or private practice. 
In addition the investigator will comply with specific local regulations/ recommendations with 
regards to patient record retention. 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. 
 

MARS; VERSION 191017 
 
 
27 
The investigator is responsible for keeping a list of all patients (who have received study treatment) 
including patient numbers, full names and last known addresses. The patients should be informed in 
writing that the results will be stored and analysed in a computer, that national data laws will be 
followed and subject confidentiality will be maintained. 
 
 
The patients should also be informed in writing about the possibility of audits by authorised 
representatives of the  regulatory authorities, in which case a review of those parts of the hospital 
records relevant to the study may be required, with due consideration for patient integrity. 
 
15.5 Data Protection 
The patient’s personal data and Investigator’s personal data which may be included in the Sponsor 
database shall be treated in compliance with all local applicable laws and regulations. When 
archiving or processing personal data pertaining to the Investigator and/or to the patients, the 
Sponsor shall take appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
 
16 ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
This study will be conducted in accordance with the protocol and the ethical principles put forward 
in the Declaration of Helsinki (52nd WMA General Assembly, Edinburgh, Scotland, October 2000) 
and in accordance with GCP (CPMP/ICH/135/92) rules. 
 
The subject’s personal data and Investigator’s personal data which may be included in the Sponsor 
database shall be treated in compliance with all local applicable laws and regulations. 
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. 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC), in agreement with local rules, for formal approval.  
 
16.1 Informed Consent 
The subject should be informed to the fullest extent possible about the study, in language and terms 
they are able to understand. 
 
Prio to a subject’s participation in the study, the written Informed Consent Form should be  
signed, name filled in and personally dated by the subject and by the person who conducted the 
informed consent discussion. A copy of the signed and dated written Informed Consent Form will be 
provided to the subject. 
 
 
17 REPORTING AND PUBLICATIONS 
A study report will be prepared after the end of the study. The study will be published once it is 
completed and the final analysis has been performed. Any publication based on the data from this 
study proceeds from the investigator group, with specification of the participating clinics and 

MARS; VERSION 191017 
 
 
28 
responsible contacts. The names on the author list will be given according to the active participation 
in the design of the protocol, in the recruitment of eligible and evaluable patients, in the compilation 
of results and in the production of the article. Investigators recruiting >10% of patients will be 
cosidered as authors. All participating clinics with responsible investigator will be named in a special 
appendix. 
 
 
 

MARS; VERSION 191017 
 
 
29 
 
18 APPENDIX 
 
 
18.1 
WHO Performance Status 
 
  
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 
 
 
 
 
 
 
 
 
 
 

MARS; VERSION 191017 
 
 
30 
 
18.2 Lung Cancer Symptom Scale 
 
 
LUNG CANCER SYMPTOM SCALE (LCSS): Patient scale (Swedish version) 
Anvisningar: Var snäll och markera utefter varje linje där symtomen av din lungcancer UNDER 
SENASTE DAGEN (inom sista 24 timmarna) beskrivs bäst. 
1. 
Hur är din aptit? 
 
Så bra den kan vara 
Så dålig den kan vara 
 
 
 
 
2. 
Hur mycket trötthet känner du? 
 
Ingen 
Så mycket som det är möjligt att känna 
 
 
 
 
3. 
Hur mycket hosta har du? 
 
Ingen 
Så mycket den kan vara 
 
 
 
 
4. 
Hur mycket andfåddhet känner du av? 
 
Ingen 
Så mycket som det är möjligt att känna 
 
 
 
 
5. 
Hur mycket blod ser du i ditt slem? 
 
Inget 
Så mycket det kan vara 
 
 
 
 
6. 
Hur mycket smärta känner du? 
 
Ingen 
Så mycket som det är möjligt att känna 
 
 
 
 
7. 
Hur svåra är dina symtom av lungcancer? 
 
Jag har inga 
Så svåra de kan vara 
 
 
 
 
8. 
Hur mycket har din sjukdom påverkat din förmåga att utföra normala aktiviteter? 
 
Inte alls 
Så mycket att jag inte kan 
göra något för mig själv 
 
 
 
 
9. 
Hur skulle du bedöma din livskvalitet idag? 
 
Mycket hög 
Mycket låg 
 
 
 
 

MARS; VERSION 191017 
 
 
31 
18.3 
Recist criteria 1.0 
 
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. 
 
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. 
 

MARS; VERSION 191017 
 
 
32 
Biological sampling 
 
18.4 
PROCEDUR FÖR PROVOMÄNDERTAGANDE MARS 
Syftet med ovan rubricerade studie är att hitta radiologiska och biologiska markörer på respons tidigt 
under strålbehandlingen. Under studien tas blodprover enligt studiemallen. Nedan beskrivs 
proceduren för omhändertagande av blodprover inom ramen för studien. 
Studieprover  
Studieprover tas för att möjliggöra senare analyser av biomarkörer. Provtagningen samordnas med de 
tillfällen patienten skall genomgå procedur för blodprover, dvs vid baseline, vid randomisering samt 
tre månader efter randomisering. 
Studieprover tas i två typer av rör: 
1. Lila 5 mL L provrör (Vacutainer): EDTA för tillvaratagande av plasma som fryses i aliqouter i -70°C.  
2. Grönt 5 mL provrör (Vacutainer). Heparin. för tillvaratagande av plasma som fryses i 
aliqouter i -70°C 
 
Provtagningsprocedur för studieprover: 
Instruktioner för provtagare 
1. Proverna tas efter 5 minuters vila. 
2. Identitetskontroll sker innan provtagning 
 
Utför identitetskontroll genom att be patienten själv uppge personnummer  
 
och namn.  
3. Tag fram två venojectrör. Ett EDTA (lila kork) och ett Heparin (grön kork) Märk rören med 
personnummer och studie ID. Etiketter från BBN 
4. Använd gärna grov kanyl i syfte att undvika hemolys, om möjligt 
5. Patienten bör om möjligt ej knyta handen vid provtagningen. Tag 5 ml blod (utan stas om möjligt) i 
EDTA-röret (lila kork) samt 5 mL blod i heparinröret (grön kork). Vid behov av stas ta gärna 
studieproverna sist. 
6. Skicka provrören omedelbart till biobank eller motsvarande. Provet bör vara biobanken tillhanda 
inom ca 15 minuter. Bifoga följesedel med namn, personnummer och studie ID. 
Instruktioner för provhantering vid biobank eller motsvarande 
7. Kontrollera provrörens ID märkning mot följesedel vid utplock från rörpost 
8. Ställ rören i provrörsstället  och låt stå i 15 minuter 
9. Ta fram 16 st frysrör med 2D kod. Märk rören med studie ID samt datum, samt B för baseline, R för 
randomisering och 3M för tre månaders kontroll. Och 2 st engångspipetter 
10. Centrifugera proverna i 15 min med 3200 varv (1500G). 
11. Använd engångspipett. Pipettera upp 8 st 0,25 ml plasmaprov ur EDTA-röret (lila kork).  
12. Använd den andra engångspipetten och upprepa proceduren med det heparin-behandlade 
blodprovet (grön kork). 8 st plasmaprov à 0,25 ml vardera i frysrören. 
13. Kontrollera att locken är förslutna väl (skruva igen ordentligt!) och placera rören i nästa lediga rad i 
infrysningskartongen som finns i frysen och återställ därefter kartongen till frysförvaring. 
14. Proverna skall vara i frysen (-800) inom 1 timme.  

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