A Monocenter Prospective No-profit Interventional Study for Lung Cancer Early Diagnosis With Tomosynthesis: Re-evaluation of Lung Nodule Detection Rate at 5 Years
Phase: PHASE3
Conditions: Lung Cancer
Sponsor: Ospedale Santa Croce-Carle Cuneo

SOS2 trial 
           Digital Tomosynthesis in Lung Cancer Screening 
OSPEDALE SANTA CROCE E CARLE - CUNEO 
 
‘SOS2’ Trial 
 
SOS2 - A monocenter prospective no-profit interventional 
study for lung cancer early diagnosis with tomosynthesis: re-
evaluation of lung nodule detection rate at 5 years 
 
 
Diagnosi precoce del tumore polmonare con  tomosintesi: 
studio interventistico, con dispositivo medico, prospettico, 
monocentrico,  no-profit 
 
 
 
 
Sponsor: 
Trial Chairman: 
Santa Croce e Carle Hospital 
Via M. Coppino 26, 12100 Cuneo, Italy 
Dr Maurizio Grosso 
 
 
 
 
 
 
 

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Contact addresses 
 
Study chairman: Dr. Maurizio Grosso 
Radiology Division 
Phone: +39 0171.64.1401 
e-mail: grosso.m@ospedale.cuneo.it 
 
Study coordinator: Dr. Stéphane Chauvie  
Medical Physics Division 
Phone: +39 0171.64.1558 
e-mail: chauvie.s@ospedale.cuneo.it 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Writing Committee and Scientific support:  
Alberto Biggi (Nuclear Medicine Division), Andrea Campione, Mirella Fortunato (Anatomical Pathology 
Division), Adriano De Maggi, Stéphane Chauvie (Medical Phisics Division), Ida Colantonio (Oncology 
Division), Maurizio Grosso (Radiology Division), Giulio Melloni, Federico Mazza, Alessia Stanzi (Thoracic 
Surgery Division), Paolo Noceti (Pneumology Division), Paolo Pellegrino (Health Management), Elvio Russi 
(Radiotherapy Division). 

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Contents 
Abbreviations..................................................................................................................................................... 5 
2. Objectives of the trial .................................................................................................................................... 9 
2.1. General objectives .................................................................................................................................. 9 
2.2. End-points ............................................................................................................................................... 9 
3. Patient selection criteria ................................................................................................................................ 9 
3.1. Patients inclusion criteria ....................................................................................................................... 9 
3.2. Exclusion criteria ................................................................................................................................... 10 
4. Trial Design .................................................................................................................................................. 10 
5. Evaluation criteria ........................................................................................................................................ 11 
5.1. Overall survival ..................................................................................................................................... 11 
5.2. Quality of life ........................................................................................................................................ 11 
5.3. Cost-effectiveness ................................................................................................................................ 12 
6. Statistical considerations ............................................................................................................................. 12 
6.1. Statistical design ................................................................................................................................... 12 
6.1.1. Sample size .................................................................................................................................... 12 
6.2. Analysis ................................................................................................................................................. 12 
6.3. End of study .......................................................................................................................................... 12 
6.4. Study duration ...................................................................................................................................... 12 
7. DTS evaluation and revision ........................................................................................................................ 12 
8. Independent data monitoring committee................................................................................................... 12 
9. Quality of life evaluation ............................................................................................................................. 13 
9.1. Rationale ............................................................................................................................................... 13 
9.2. QoL instrument ..................................................................................................................................... 13 
10. Cost-effectiveness analysis ........................................................................................................................ 13 
10.1. Methods ............................................................................................................................................. 13 
10.1.1. Type of Economic Evaluation. ..................................................................................................... 13 
10.1.2. Choice of Comparator. ................................................................................................................ 13 
10.1.3.  Patient population ...................................................................................................................... 13 
11. Pharmacokinetics ...................................................................................................................................... 13 
12. Translational research ............................................................................................................................... 13 
13. Publication policy....................................................................................................................................... 14 
14. Enrollment and randomization procedures .............................................................................................. 14 
15. Forms and procedures for collecting data ................................................................................................. 14 

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16. Reporting and evaluation of adverse events ............................................................................................. 14 
17. Quality assurance ...................................................................................................................................... 14 
17.1. Control of data consistency ................................................................................................................ 14 
18. Ethical considerations ................................................................................................................................ 14 
18.1. Patient Protection .............................................................................................................................. 14 
18.2. Subject identification .......................................................................................................................... 14 
18.3. Informed consent ............................................................................................................................... 14 
19. Administrative responsibilities .................................................................................................................. 15 
19.1. The study coordinator ........................................................................................................................ 15 
20. Trial sponsorship and financing. ................................................................................................................ 15 
21. Trial insurance ........................................................................................................................................... 15 
22. Appendix .................................................................................................................................................... 15 
22.1. Definitions .......................................................................................................................................... 15 
22.1.1. WHO performance status scale ................................................................................................... 15 
22.1.2. Fleischner’s society criteria ......................................................................................................... 16 
22.2. Technical Procedures .......................................................................................................................... 16 
22.2.1. Procedure for the pathological review of diagnosis .................................................................... 16 
22.2.2. Procedures for DTS examination ................................................................................................. 16 
22.2.3. Quality of Life evaluation............................................................................................................. 17 
22.3. References .......................................................................................................................................... 19 
23. Writing Committee and Scientific support: ........................................................................................... 21 
 
 

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Abbreviations 
DTS 
Digital Tomosynthesis 
CT  
REID 
BEIR 
QoL 
Computer Tomography 
Risk of Exposure-Induced Death 
Biologic Effects of Ionizing Radiation 
Quality of Life 
OS 
Overall Survival 
LLE 
Loss of Life Expectancy 
ROC 
Receiver Operating Characteristic  
NELSON 
The Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym) 
ICH 
International Conference On Harmonisation 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organisation for Research and Treatment of Cancer 
CRF 
Case Record Forms 

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Synopsis 
 
Sponsor 
Santa Croce e Carle Hospital founded by the Fondazione CRC di Cuneo 
Project Title 
A monocenter prospective no-profit interventional study for lung cancer early diagnosis with 
tomosynthesis: re-evaluation of lung nodule detection rate at 5 years 
Version 
July 15th, 2017 
Study Phases 
 
Phase 3  
 
Coordinators 
Maurizio Grosso (study chairman), Stéphane Chauvie (study coordinator) 
Statistician 
Paola Berchialla (University of Torino)   
Writing 
Committee 
Alberto Biggi (Nuclear Medicine Division), Andrea Campione, Mirella Fortunato (Anatomical 
Pathology Division), Adriano De Maggi, Stéphane Chauvie (Medical Phisics Division), Ida 
Colantonio (Oncology Division), Maurizio Grosso (Radiology Division), Giulio Melloni, Federico 
Mazza, Alessia Stanzi (Thoracic Surgery Division), Paolo Noceti (Pneumology Division), Paolo 
Pellegrino (Health Management), Elvio Russi (Radiotherapy Division). 
Population  
Subjects enrolled in previously closed SOS trial (high risk subjects for lung cancer) without 
confirmed lung cancer. 
Study 
Objectives 
To evaluate the lung cancer detection rate in the population of high risks subjects previously 
enrolled in lung cancer screening trial with chest digital tomosynthesis (SOS trial). 
Participating 
centers 
Single center, Santa Croce e Carle Hospital 
Overall Study 
design 
The study aims to evaluate the lung cancer detection rate. Patients that previously were 
enrolled in SOS study will be called by project assistants and booked for DTS examination. In 
case the subject refuses to perform examination a phone interview for follow-up will be 
carried out acquiring information on the status of the subject, on the variation of quality of 
life, on smoke habits and on attitude toward lung cancer screening.  
For the subject accepting the DTS examination the same questionnaire will be filled onsite just 
before examination. DTS will be then performed and blindly evaluated by two radiologists. 
DTS findings will be classified based on their dimension (large axis measurement), radiological 
characteristics (calcific, pleural, solid, partially solid and ground glass opacity) and position (in 
the 5 lobes). Findings will be then classified using LUNG-RADS [1]. The results of the DTS,in 
case of negative report, will be communicated with a letter  to the patient. 
The subjects with one or more nodules larger than 5 mm, not clearly benign, will undergo 
diagnostic contrast enhanced CT and will be followed according to Fleischner society [2] 
criteria. 
 

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Discordant and positive cases will be discussed in a consensus session among 
radiologists and thoracic surgeons. The consensus results will be used in the following 
analysis.  
Endpoints 
Primary 
Lung cancer detection rate. 
 
Secondary 
 
Percentage of lung cancer addressed to radical surgery treatment; 
 
Sensitivity of DTS evaluating the number of lung cancer occurred in the population of SOS 
study in the last 5 years; 
 
Mortality  
 
Overall survival (OS) 
 
Quality of Life (QoL) 
 
Cost-effectiveness 
Eligibility 
criteria 
Inclusion criteria: 
 
current or former smoker status; 
 
for former smokers, the maximum time since quitting smoking must be below 10 
years. 
 
smoking history of at least 20 pack-years; 
 
age 45-80 years; 
 
no previous history of cancer in the 10 years before the beginning of the study;  
 
be able to stand and hold the breath for 11 seconds during image acquisition 
 
previous participation to SOS trial 
Exclusion criteria: 
 
pregnancy 
DTS 
Acquisition 
DTS is performed with Discovery XR650 (GE Healthcare, Milwaukee, WI). Images are acquired 
with a source-to-image distance of 180 cm. The tube voltage is set to 120 kVp with 3 mm Al 
inherent and 0.2 mm additional Cu filtration. The DTS acquisition consists of 60 projection 
images along a vertical source path spanning 30° of total tube angular motion. The set of 60 
images is acquired in 10 s in breath hold condition. Images are reconstructed at 3 mm plane 
spacing in the coronal plane. Image reconstruction is done using a filtered back-projection 
algorithm and a sliding average of seven adjacent planes is taken to reduce noise and low-
contrast tomosynthesis artifacts.  
Dose 
The mean effective dose expected for DTS is 0.09±0.04 mSv. Based on organ doses the loss of 
life expectancy (LLE) and the risk of exposure-induced death (REID) are calculated for lung 
cancer for man and women and for breast cancer for women using BEIRVII[3] model. REID for 
lung cancer for men and women are 10/100.000 and 3/100.000 respectively. REID for breast 
cancer for women are 10/100.000. LLE were 0.2 h for men and 0.6 h for women. These values 
are small respect to the baseline mortality in the normal population that are 7700/100.000 
and 4.600/100.000 for lung cancer for men and women and 3.000/100.000 for breast cancer 
[3]. 
Referral 

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Two independent radiologists carry out blinded independent central reviewing for DTS. 
Discordant and positve cases are discussed in consensus.  
Treatment 
Subjects are managed in line with Fleishchner Society criteria for the management of small 
pulmonary nodules and treated using physicians’ choiche (no indication is given to treatment 
of patient from this trial).  
Radiotherapy 
Radiotherapy is performed based on physician’s choice (no indication is given to treatment of 
patient from this trial). 
Sample size 
The primary objective of this study is to calculate the detection rate on lung cancer at 5 years 
distance from the previous DTS. In the SOS study 1843 subjects were enrolled and lung cancer 
was found in 18 (0.8%) of them at baseline. 1703 subjects performed the first round DTS at 
one-year distance and lung cancer was found in 5 (0.3%) of them.  
The number of patients needed to be confident that the disease will be detected if present at 
or above the specified prevalence of 0.3% with a confidence of 5% (i.e. assuming that the true 
prevalence is at least 0.3%, then a sample consisting only of subjects without lung cancer 
would occur 5% of the time or less given a sample with the calculated size) is 998. Allowing for 
a drop out of no more than 50%, a minimum number of 1496 subjects is required. 
Timelines 
Expected accrual time: September 2017 / August  2018 
Patients with positive TC will be subjected to diagnostic investigations to identify the 
pathology according to Fleischner Society. Length of Follow-up: no follow-up is foreseen for 
these patients 
Background and 
rationale 
Lung cancer is the leading cause of cancer-related death around the world. In 2008 
there were nearly 1.6 million new cases worldwide, accounting for the 12.7% of all new 
cancer diagnoses[4]. Despite decreasing trends in smoking and resulting decrease in lung 
cancer mortality, the population at risk for lung cancer continues to be large[5]. In the past 
years several programs have been developed to screen for lung cancer using low-dose chest 
computed radiography (CT). However, only recently different studies demonstrated a clear 
reduction in mortality[5,6]. In particular,NLST low dose CT screening trial demonstrated a 
6.7% reduction in the death rate compared to chest X-ray with a positive screening test rate 
for lung cancer detection of 24.2%, compared to 6.9% for conventional X-ray[7]. The use of CT 
as a screening test has nonetheless recently prevailed over the concern for the cost and the 
radiation burden[8].  Digital tomosynthesis (DTS) is a limited angle tomography that allows 
reconstruction of multiple image planes from a set of projection data acquired over a 
relatively small angle of X-ray tube movement[9]. Santa Croce and Carle Hospital has this 
technology from March 2010, thanks to a donation of Fondazione CRC. Although it does not 
have the spatial depth resolution of computed tomography, it provides high-resolution 
images in the sagittal planes at a lower dose and cost than CT[10]. Several studies have shown 
that DTS offers advantages over conventional chest X-ray and comparable of those of CT[11–
13]. The Studio OSservazionale (SOS) was a clinical trial conducted within Santa Croce e Carle 
Hospital sponsored by Fondazione CRC analysing smokers and former smokers aged 45-80 
with no cancer diagnosis. All the subjects in whom a suspicious nodule was detected by DTS 
underwent diagnostic CT. The SOS study demonstrated that baseline DTS detected pulmonary 
abnormalities in 14.5% and lung cancer in 1.0% of the subjects[14], comparable to results 
obtained in CT screening programs. A second DTS, within the same study, executed one year 
later reported pulmonary abnormalities in 0.7% and lung cancer in 0.3% of the subjects[15]. 
 
 

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1. Background and introduction 
Lung cancer is the leading cause of cancer-related death around the world, it represents 13% of all new 
cancer diagnoses [4]. The lung cancer incidence is gradually increasing, especially among women and young 
people, but the fraction of cured patient remains low. In 80% of cases lung cancer, in early phase, is 
treatable only with surgery without chemotherapy or adjuvant radiotherapy and the survival perspective at 
five years exceeds 70% [4] .  Recently several studies [5,16] showed a relative reduction in lung cancer 
mortality of 20% in high-risk subjects enrolled in screening trials performed with low-dose Chest CT [7]. As a 
consequence, several of scientific guidelines recommended chest Computed Tomomgraphy (CT) in lung 
cancer screening. CT examination allows detection of small nodules and a good quality of the image but its 
disadvantages includes high cost and high radiation dose [8]. Digital tomosynthesis (DTS) is a limited angle 
tomography that allows reconstruction of coronal images from a set of projection acquired over a small 
angle of X-ray tube movement [9]. This technique is available in the AO Santa Croce e Carle since 2010 and 
more than 5000 have been executed with it. Several studies demonstrates that DTS is a reasonable 
alternative to the CT and allows a better evaluation of suspects nodules compared to conventional chest RX 
[11–13]. 
2. Objectives of the trial 
2.1. General objectives 
 
To evaluate the lung cancer detection rate in the population of high risks subjects previously enrolled in lung 
cancer screening trial with chest digital tomosynthesis (SOS trial). 
Repeating the DTS at 5 years from the baseline exam will permit to pursue three different tasks: 
1) find subjects with lung cancer to be addressed to radical surgery treatment; 
2) calculate the sensitivity of DTS evaluating the number of lung cancer occurred in the population of SOS 
study in the last 5 years; 
3) establish the correct timing for DTS screening. 
 
2.2. End-points 
 
 
Mortality  
 
Overall survival (OS) 
 
Quality of Life (QoL) 
 
Cost-effectiveness  
 3. Patient selection criteria 
3.1. Patients inclusion criteria 

Inclusion criteria: 
 
current or former smoker status; 
 
for former smokers, the maximum time since quitting smoking below 10 years. 
 
smoking history of at least 20 pack-years; 
 
age 45-75 years; 

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 
no previous history of cancer in the 10 years before the start of the study;  
 
be able to stand and hold the breath for 11 seconds during image acquisition 
 
 previous participation to SOS trial 
 
3.2. Exclusion criteria  
 
Exclusion criteria: 
 
pregnancy 
4. Trial Design 
 
 
During this study, about 1700 subjects, who have been enrolled in SOS Observational Study will 
undergo a DTS. The study will be presented as an observational clinical trial and registered on 
clinicaltrials.gov. Initially, all the subjects that participated in the SOS study, will be contacted by phone and 
invited to perform a DTS in Carle Hospital. When accessing the hospital the subjects will be asked to fill-in a 
form to confirm that the inclusion criteria of the SOS study are still met. DTS will be then performed and 
blindly evaluated by two radiologists. DTS findings will be classified based on their dimension (large axis 
measurement), radiological characteristics (calcific, pleural, solid, partially solid and ground glass opacity) 
and position (in the 5 lobes). Findings will be then classified using LUNG-RADS[1] schema and ROC analysis 
will be applied. Inter-observer variability will be analyzed with Krippendorff’s Alpha[17]. 
Discordant and positive cases will be discussed in a consensus session among radiologists and 
thoracic surgeons. The consensus results will be used in the following analysis. The subjects with one or 
more nodules larger than 5 mm, not clearly benign, will undergo diagnostic contrast enhanced CT and will 
be followed in line with Fleischner Society[2].  

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5. Evaluation criteria 
Lung cancer will be histologically proven, following the procedure of Pathology Division that use a double 
blinded analysis of biological material. 
5.1. Overall survival 
Overall survival (OS) defined as the time from randomization until death as a result of any cause  
(with at least five years of follow-up). 
5.2. Quality of life 
Related end-points are termed in the chapter on "Quality of life" (chapter 9). 

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5.3. Cost-effectiveness 
Related end-points are defined in the Chapter on "Economic evaluation" (chapter 10). 
6. Statistical considerations 
6.1. Statistical design 
6.1.1. Sample size 
  
The primary objective of this study is to calculate the detection rate on lung cancer at 5 years distance from 
the previous DTS. In the SOS study 1843 subjects were enrolled and lung cancer was found in 18 (0.8%) of 
them at baseline. 1703 subjects performed the first round DTS at one-year distance and lung cancer was 
found in 5 (0.3%) of them.  
Assuming a binomial model for the occurrence of the disease (Flanders WD and Kleinbaum DG. Basic 
Models for Disease Occurrence in Epidemiology, International Journal of Epidemiology, Volume 24, Issue 1, 
1 February 1995, Pages 1–7) the number of patients needed to be confident that the disease will be 
detected if present at or above the specified annual incidence of 0.3% with a confidence of 5% (i.e. that 
assuming the true incidence is at least 0.3%, then a sample consisting only of subjects without lung cancer 
would occur 5% of the time or less given a sample with the calculated size) is 998. Allowing for a drop out of 
no more than 50%, a minimum number of 1496 subjects is required. 
6.2. Analysis 
Findings will be then classified using LUNG-RADS[1] schema and ROC  analysis will be applied. Inter-
observer variability will be analysed with Krippendorff’s Alpha. 
6.3. End of study 
End of study befalls when all of the next criteria have been satisfied: 
1. One year after start-up  
2. At least 80% of the subjects enrolled in SOS trial have been contacted 
3. The database has been fully cleaned and frozen for the analysis 
 
6.4. Study duration  
The start of the study is planned for September 2017. All patients defined by inclusion criteria will  be 
included in the study. The enrollment is done by email. Patients are advised to contact the administrative 
staff to book an appointment to perform the exam. If the study is completed prematurely, the reasons 
must be documented. The last patient is expected to enter the study at the end of August 2018.  
 
7. DTS evaluation and revision 
Blinded independent central reviewing for DTS. 
8. Independent data monitoring committee  
This trial will NOT be monitored and scrutinized by an Independent Data Monitoring Committee (IDMC) 
because no toxicity is expected due to the DTS examination. 

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9. Quality of life evaluation 
Although reducing mortality and morbidity still represent the crucial issue in clinical research,  efforts to 
reduce adverse effects and control symptoms have reached a prominent role in devising therapeutic 
strategies.  
Cancer treatments may produce adverse effects and diminish the QoL even when survival is extended. 
Progress in the acceptance of new cancer therapies is sometimes critically dependent on their QoL 
consequences. 
Health-related QoL is a multidimensional concept which represents the physiological, psychological and 
social influences of the disease and the therapeutic process from the patient's perspective. It comprises 
four principal components: physical, emotional and social well-being, and daily-life functioning.  
 
9.1. Rationale 
In ‘SOS trial’, QoL is a secondary endpoint. Since no difference in QoL is expected due to physical events 
only emotional, social, and cognitive events will be analyzed. 
 
9.2. QoL instrument 
In order to understand the impact of long-term psychosocial outcomes of lung cancer screening a QoL 
questionnaire will be adopted to measures the effectiveness of a screening program of the smoking habits 
of the subjects, anxiety and decision satisfaction. The reliability and validity of the questionnaire are highly 
consistent across different language-cultural groups.  
10. Cost-effectiveness analysis 
During the study the costs associated with the DTS procedure are evaluated, comparing them to those 
incurred for the execution of the CT in the subjects positive to the DTS. 
10.1. Methods 
10.1.1. Type of Economic Evaluation. 
Since a predictable variance in effectiveness, a cost-effectiveness analysis is justified. 
10.1.2. Choice of Comparator. 
The results are compared to the data obtained from the NELSON study and the National Screen Screening 
Trial for the evaluation of the effectiveness of screening in the control of 10-year mortality due to lung 
cancer. 
10.1.3.  Patient population 
The patient population for the economic evaluation is the same as defined by the 
inclusion/exclusion criteria of the clinical trial. 
11. Pharmacokinetics 
No pharmacokinetics evaluation will be performed in this study. 
12. Translational research 
Does not apply. 

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13. Publication policy 
The final publication of the study results will be elaborated by the Study Chairman on the basis of the 
analyses completed at the Data Center.  
14. Enrollment and randomization procedures 
Patients will be registered in the study via the study website at the time of exam. 
15. Forms and procedures for collecting data 
Data will be collecting in anonymous form in a database accessible only to the study group. 
16. Reporting and evaluation of adverse events 
 
Does not apply. 
 
17. Quality assurance 
17.1. Control of data consistency 
Data forms will be entered in the database by the study assistants. 
18. Ethical considerations 
18.1. Patient Protection 
The responsible investigator will guarantee that this study is led according with either the Declaration of 
Helsinki and its amendments, and the national, regional and local laws and rules, so to provide adequate 
protection of the patient. 
The protocol has been written, and the trial will be steered according to the ICH Harmonized Guideline for 
Good Clinical Practice (http://www.ifpma.org/pdfifpma/e6.pdf). 
The protocol was approved by the Local Ethics Committees 
 
Comitato Etico Interaziendale ASO Santa Croce e Carle di Cuneo 
AA.SS.LL. Cuneo1,Cuneo2,Asti. 
Via Monte Zovetto 18-12100 Cuneo  
Comitato.etico@ospedale.cuneo.it-0171/641571 
Parere Unico n 15-16 del 14/12/2016 
Oggetto: “Studio “SOS-Tumore Polmone”: diagnosi precoce del tumore polmonare con tomosintesi-ns rif 
RX10 
Codice Protocollo:SOS2 
18.2. Subject identification 
The name of the patient will not be asked for, nor detailed and recorded in the cloud database. A serial 
identification number will be ascribed to each patient enrolled into the trial. This number will recognize the 
patient and must be contained within all the study fans. 
18.3. Informed consent 
All patients will be learned of the goals of the study, the absence of potential adverse events, the 
procedures and impending hazards to which he/she will be exposed, and the procedures and algorythm of 
treatment allocation. 

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They will be informed as to the strict privacy of their patient data, but that their medical records may be 
revised for trial purposes by authorized individuals other than their treating physician. A patient informed 
consent statement is given (in Italian) as an appendix to this protocol (See 22.3.2.). Within the informed 
consent, it is highlighted that the participation is voluntary and that the patient is permitted to refuse 
further participation in the protocol whenever he/she wants. This will not prejudice the patient’s care in 
any setting. It is the responsibility of the individual investigator to explain the enclosed informed consent 
document.  
The ‘informed consent’ form is an essential constituent of the documents and modules needed for protocol  
submission to the ethics committee for approval.   
Documented informed consent must be obtained for all patients included in the study before they are 
registered or randomized at the Data Center. This must be done in agreement with the national and local 
regulatory requirements. 
The informed consent procedure obeys the ICH guidelines on Good Clinical Practice. This implies that “the 
written informed consent form should be signed and personally dated by the patient or by the patient’s 
legally acceptable representative”. 
19. Administrative responsibilities 
19.1. The study coordinator 
The Study Chairman(in cooperation with the Data Center) will be responsible for writing the protocol, 
revising all case report forms and documenting his/her review on evaluation forms, discussing the contents 
of the reports with the Data Manager and the Statistician, and for publishing the study results. He will also, 
as a rule, be responsible for replying all clinical queries about eligibility, treatment, and the assessment of 
the patients. 
20. Trial sponsorship and financing. 
Santa Croce e Carle Hospital, thanks to a donation of Fondazione CRC, will cover costs of DTS examination, 
data organization, supervision and project assistance. 
21. Trial insurance 
Covered by Santa Croce e Carle Hospital 
 
22. Appendix  
22.1. Definitions 
22.1.1. WHO performance status scale 
 
Eastern Cooperative Oncology Group (ECOG, Zubrod, World Health Organization) performance scale  
 

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22.1.2. Fleischner’s society criteria 
 
22.2. Technical Procedures 
22.2.1. Procedure for the pathological review of diagnosis 
The diagnosis made in blinded indipendent review by the local pathologists will be accepted for the 
Registration. Disagreement will be resolved by consensus. 
22.2.2. Procedures for DTS examination  
 
Patient Preparation and Acquisition Protocol. 
DTS is performed with Discovery XR650 (GE Healthcare, Milwaukee, WI). Images are acquired with a 
source-to-image distance of 180 cm. The tube voltage is set to 120 kVp with 3 mm Al inherent and 0.2 mm 
additional Cu filtration. The DTS acquisition consists of 60 projection images along a vertical source path 
spanning 30° of total tube angular motion. The set of 60 images is acquired in 10 s in breath hold condition.  
 
Technical Requirements for DTS scanners including image reconstruction 
 

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Images are reconstructed at 3 mm plane spacing in the coronal plane. Image reconstruction is done using a 
filtered back-projection algorithm and a sliding average of seven adjacent planes is taken to reduce noise 
and low-contrast tomosynthesis artifacts.  
 
DTS analysis 
Two independent radiologists carry out blinded independent central reviewing for DTS. Discordant and 
positve cases are discussed in consensus.  
22.2.3. Quality of Life evaluation  
 
Guidelines for administration of questionnaires 
EORTC Quality of Life evaluation: guidelines for administration of questionnaires (revised 
January 2001) 
The instructions given below are intended to provide some general guidelines for collecting quality 
of life (QoL) data in EORTC studies. These instructions apply to all types of questionnaires. 
 
1. Who is the responsible person (RP) for Qol data collection? 
The overall-responsible person for QoL data collection is the study-co-ordinator of the trial. 
However, for practical reasons, it is strongly recommended that one person is responsible for the 
organization of QoL data collection in each Institution. This can be a physician, data manager, (research) 
nurse or a psychologist. Such a person should have the full protocol at his/her disposal as well as the 
questionnaire. This person would also be the intermediate contact point in case of any necessary 
clarification asked by the Data Center. 
 
2. Who should fill out the questionnaire? 
In principle, it is the patient him/herself who has to fill out QoL forms and preferably without help from 
others. If a patient is too sick to complete the questionnaire or if the patient is not able to fill out the 
questionnaire for reasons such as forgetting his/her glasses, another person could read the questions 
without making any comments and report the answers on the forms. If a patient received this type of help, 
please note this on the form. 
 
3. What instructions should be given to the patient? 
At entry into a study, the RP should give the patient an explanation of the objective of the study and 
instructions for filling out questionnaires. The patient should be informed that participation in the QoL 
protocol is voluntary and that the information provided is confidential (identification is only for 
administrative purposes and includes patient’s initials, date of birth and today’s date). 
The following issues should be explained to the patient: 
¬ The schedule of assessments. 
¬ The questionnaire is a self-administered questionnaire that should be filled out preferably by the 
patient him (her) self. 
¬ The patient should circle the choice that best corresponds to his/her situation. 
¬ There is no right or wrong answer to any of these questions. 
¬ All questions should be answered. 
The RP should make sure that the patient understands the instructions. 
At each subsequent assessment as defined by the protocol, the patient should receive the questionnaire 
from the RP or by other appropriate staff if the RP is not available. 
4. Where should the patient fill out the questionnaire? 

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The patient should complete the questionnaire in the clinic, ideally in a quiet, private room. If this is not 
possible, the waiting room is an acceptable alternative. In general, it does not take more than 5 to 10 
minutes to fill out a questionnaire, but patients should be given the time they need to answer all questions. 
5. When should the patient fill out the questionnaire? 
When a QoL assessment is planned, the questionnaire should be given to the patient preferably 
before the meeting with the physician, ensuring that the patient has enough time to complete the 
questionnaire. If the patient receives therapy, the questionnaire should be filled out before 
administration of the treatment. The questionnaire should not be taken home and/or mailed. 
6. Review of the completed questionnaire. 
After the patient has filled out the questionnaire, the person handling the questionnaire should: 
¬ Check the answers for omissions, for incorrectly completed questions and for inconsistent answers;  
If this is the case: 
- Please ask the patient for the reason for omissions or incorrect answers. If the patient 
prefers not to answer a question, this should be noted on the form; 
- Additional explanation may be provided, but the questions should not be rephrased; 
- Any additional comments could be added by the person handling the questionnaire (if 
possible in English) followed by their name and signature. 
7. Missing forms 
If for some reason the patient is unable or does not wish to complete a quality of life questionnaire the 
reason, and date of the visit should be documented on the questionnaire and returned to the person 
responsible for completing the CRF’s (case record forms). 
8. Mailing to the Data Center 
The questionnaire should be sent to the Data Center with the CRF’s. As it is not possible to 
retrospectively collect missing quality of life data, please make sure the patient completes the 
questionnaire at the time-point when he/she is supposed to fill it out. 
Thank you very much for your cooperation. If you have any remarks on this leaflet or if you need 
further information, please contact: 
 
EORTC Quality of Life evaluation: instructions for Monitors 
¬ Check if all QL questionnaires have been filled out on schedule 
¬ If not, the Monitor should inform the person in charge of data collection and explain again the 
schedule of the QL questionnaires. 
¬ Make sure the QL questionnaires are correctly completed 
¬ If not, tell the responsible person to explain again to the patient how to fill out the QL 
questionnaires at the next visit. 
 
 
 

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22.2.4. Checklists 
Logistics checklist 

 Inform the patient according to the patient briefing record and hand out the Information for 
Patients and Declaration of Consent to him/her. 
 
 Inform the patient before start of treatment about the quality of life survey and hand out the QoL 
form to him/her. 
 
 Check the inclusion and exclusion criteria and document the results on the I/E form. 
 
 Fill DTS review form after DTS is performed 
 
 Fill CT review form after CT if needed 
 
 Confirmation of the diagnosis: the primary histology report must be available 
 
 F-up eCRF  
 
 
 
 
 
 
22.3. References 
1.  
McKee, B. J.; McKee, A. B.; French, R.; Hesketh, P.; Wald, C.; Flacke, S. “Lung-rads” a proposed 
standardized reporting and data system for ct lung cancer screening. J. Thorac. Oncol. 2012, 4), 
S277–S278. 
2.  
MacMahon, H.; Austin, J. H. M.; Gamsu, G.; Herold, C. J.; Jett, J. R.; Naidich, D. P.; Patz, E. F.; 
Swensen, S. J. Guidelines for management of small pulmonary nodules detected on CT scans: a 
statement from the Fleischner Society. Radiology 2005, 237, 395–400. 
3.  
National Research Council, C. to A. H. R. from E. to L. L. of I. Health Risks from Exposure to Low Levels 
of Ionizing Radiation: BEIR VII Phase 2; The National Acedemy Press: Washington DC, 2006; ISBN 
9780309091565. 
4.  
Malvezzi, M.; Bertuccio, P.; Levi, F.; La Vecchia, C.; Negri, E. European cancer mortality predictions 
for the year 2012. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. ESMO 2012, 23, 1044–1052, 
doi:10.1093/annonc/mds024. 
5.  
Aberle, D. R.; Adams, A. M.; Berg, C. D.; Black, W. C.; Clapp, J. D.; Fagerstrom, R. M.; Gareen, I. F.; 
Gatsonis, C.; Marcus, P. M.; Sicks, J. D. Reduced lung-cancer mortality with low-dose computed 
tomographic screening. N. Engl. J. Med. 2011, 365, 395–409. 
6.  
Jung, H.; Chung, M.; Koo, J. Digital tomosynthesis of the chest: Utility for detection of lung 

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metastasis in patients with colorectal cancer. Clin. Radiol. 2011, 1–7, 
doi:10.1016/j.crad.2011.08.017. 
7.  
Goldstraw, P.; Crowley, J.; Chansky, K.; Giroux, D. J.; Groome, P. A.; Rami-Porta, R.; Postmus, P. E.; 
Rusch, V.; Sobin, L. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM 
stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant 
tumours. J. Thorac. Oncol. 2007, 2, 706–14, doi:10.1097/JTO.0b013e31812f3c1a. 
8.  
Jacobson, F. L.; Austin, J. H. M.; Field, J. K.; Jett, J. R.; Keshavjee, S.; MacMahon, H.; Mulshine, J. L.; 
Munden, R. F.; Salgia, R.; Strauss, G. M.; Sugarbaker, D. J.; Swanson, S. J.; Travis, W. D.; Jaklitsch, M. 
T. Development of The American Association for Thoracic Surgery guidelines for low-dose computed 
tomography scans to screen for lung cancer in North America: recommendations of The American 
Association for Thoracic Surgery Task Force for Lung Cancer Screenin. J. Thorac. Cardiovasc. Surg. 
2012, 144, 25–32, doi:10.1016/j.jtcvs.2012.05.059. 
9.  
Dobbins, J. T.; Mcadams, H. P. Chest tomosynthesis: technical principles and clinical update. Eur. J. 
Radiol. 2009, 72, 244–251, doi:10.1016/j.ejrad.2009.05.054. 
10.  
Terzi, A.; Bertolaccini, L.; Viti, A.; Comello, L. Lung Cancer Detection with Digital Chest 
Tomosynthesis. J. Thorac. Oncol. 2013, 8, 685–692, doi:10.1097/JTO.0b013e318292bdef. 
11.  
Dobbins, J. T.; McAdams, H. P.; Song, J.-W.; Li, C. M.; Godfrey, D. J.; DeLong, D. M.; Paik, S.-H.; 
Martinez-Jimenez, S. Digital tomosynthesis of the chest for lung nodule detection: Interim sensitivity 
results from an ongoing NIH-sponsored trial. Med. Phys. 2008, 35, 2554–2557. 
12.  
Vikgren, J.; Zachrisson, S.; Svalkvist, A.; Johnsson, A. A.; Boijsen, M.; Flinck, A.; Kheddache, S.; Båth, 
M. Comparison of chest tomosynthesis and chest radiography for detection of pulmonary nodules: 
human observer study of clinical cases. Radiology 2008, 249, 1034–1041. 
13.  
Quaia, E.; Baratella, E.; Cioffi, V.; Bregant, P.; Cernic, S.; Cuttin, R.; Cova, M. A. The value of digital 
tomosynthesis in the diagnosis of suspected pulmonary lesions on chest radiography: analysis of 
diagnostic accuracy and confidence. Acad. Radiol. 2010, 17, 1267–74, 
doi:10.1016/j.acra.2010.05.009. 
14.  
Terzi, A.; Bertolaccini, L.; Viti, A.; Comello, L.; Ghirardo, D.; Priotto, R.; Grosso, M. Lung cancer 
detection with digital chest tomosynthesis: baseline results from the observational study SOS. J. 
Thorac. Oncol. 2013, 8, 685–92, doi:10.1097/JTO.0b013e318292bdef. 
15.  
Bertolaccini, L.; Viti, A.; Tavella, C.; Priotto, R.; Ghirardo, D.; Terzi, A.; Group, S. Lung cancer 
detection with digital chest tomosynthesis : first round results from the SOS observational study. 
2015, 3, 1–6, doi:10.3978/j.issn.2305-5839.2015.03.41. 
16.  
McWilliams, A.; Tammemagi, M. C.; Mayo, J. R.; Roberts, H.; Liu, G.; Soghrati, K.; Yasufuku, K.; 
Martel, S.; Laberge, F.; Gingras, M.; Atkar-Khattra, S.; Berg, C. D.; Evans, K.; Finley, R.; Yee, J.; English, 
J.; Nasute, P.; Goffin, J.; Puksa, S.; Stewart, L.; Tsai, S.; Johnston, M. R.; Manos, D.; Nicholas, G.; Goss, 
G. D.; Seely, J. M.; Amjadi, K.; Tremblay, A.; Burrowes, P.; MacEachern, P.; Bhatia, R.; Tsao, M.-S.; 
Lam, S. Probability of Cancer in Pulmonary Nodules Detected on First Screening CT. N. Engl. J. Med. 
2013, 369, 910–919, doi:10.1056/NEJMoa1214726. 
17.  
Hayes, A.; Krippendorff, K. Answering the call for a standard reliability measure for coding data. 
Commun Methods Meas. 2007, 1, 77–89. 
 
 

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23. Writing Committee and Scientific support: 
 
Alberto Biggi (Nuclear Medicine Division), Andrea Campione, Mirella Fortunato (Anatomical Pathology 
Division), Adriano De Maggi, Stéphane Chauvie (Medical Phisics Division), Ida Colantonio (Oncology 
Division), Maurizio Grosso (Radiology Division), Giulio Melloni, Federico Mazza, Alessia Stanzi (Thoracic 
Surgery Division), Paolo Noceti (Pneumology Division), Paolo Pellegrino (Health Management), Elvio Russi 
(Radiotherapy Division).