Cost-effectiveness Evaluation of Robotic Surgery, Compared to Thoracoscopic and Open Surgery, in the Removal of Lung Lesions Based on "Real-world" Efficacy and Cost Data From the ATS of Milan
Conditions: Lung Cancer
Sponsor: Agenzia di Tutela della Salute della Città Metropolitana di Milano

STUDY PROTOCOL 
 
Cost-effectiveness evaluation of robotic surgery, compared to 
thoracoscopic and open surgery, in the removal of lung 
lesions based on "real-world" efficacy and cost data from the 
ATS of Milan 
 
 
ID trial 
2699 
Version number and date 
Version 2.0 – 2022/03/16 
Number of pages 
21 
Study type  
Observational multicenter retrospective and 
prospective 
Document state  
Definitive 
Promoter 
ATS Città Metropolitana di Milano 
 
 
 
 
 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 2 of 21 
 
Organizational structure of the study 
Promoter 
Name: Direzione Generale, ATS Città Metropolitana di 
Milano 
Address: Corso Italia 52 - 20122 Milano (MI) 
Phone: +39 02 8578 2000 – 2001 - 2007 
Email: direzionegenerale@ats-milano.it 
 
Study responsible  
Name: Antonio Giampiero Russo 
Address: Via Conca del Naviglio 45- 20122 Milano (MI) 
Phone: +39 02 8578 2111 
Email: agrusso@ats-milano.it 
 
Study coordination unit 
Antonio Giampiero Russo  
UOC Unità di Epidemiologia, ATS Città Metropolitana di Milano 
Anita Andreano 
UOC Unità di Epidemiologia, ATS Città Metropolitana di Milano 
Elena Camelia Ivanciu 
UOC Unità di Epidemiologia, ATS Città Metropolitana di Milano 
Scuola di Specializzazione in Statistica Sanitaria e Biometria, 
Dipartimento di Scienze Cliniche e di Comunità, Università degli 
Studi di Milano 
Participating Centers and Principal 
Investigators of the Centers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Center: IEO Istituto Europeo di Oncologia 
Name: Monica Casiraghi 
Address: Via Ripamonti 435, 20122 Milano (MI) 
Phone: +39 257489665 
Email: monica.casiraghi@ieo.it 
 
Center: IRCCS HUMANITAS 
Name: Marco Alloisio 
Address: Via Manzoni 56, 20089 Rozzano (MI) 
Phone: +39 236538890 
Email: marco.alloisio@hunimed.eu 
 
Center: IRCCS Istituto Nazionale dei Tumori 
Name: Ugo Pastorino 
Address: Via G. Venezian 1, 20122 Milano (MI) 
Phone: +39 223902384 
Email: ugo.pastorino@istitutotumori.mi.it 
 
Center: IRCCS Ospedale San Raffaele 
Name: Giulia Veronesi 
Address: Via Olgettina 60, 20122 Milano (MI) 
Phone: +39 291751541 
Email: veronesi.giulia@hsr.it  
 
Center: ASST Grande Ospedale Metropolitano Niguarda 
Name: Massimo Domenico Torre 
Address: Piazza Ospedale Maggiore 3, 20122 Milano (MI) 
Phone: +39 264442589 
 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 3 of 21 
 
Email: toracica@ospedaleniguarda.it 
 
Center: IRCCS Ospedale Policlinico di Milano 
Name: Davide Tosi 
Address: Via Francesco Sforza 35, 20122 Milano (MI) 
Phone: +39 255034640 
Email: davide.tosi@policlinico.mi.it 
 
Center: ASST SS Paolo e Carlo Ospedale San Paolo 
Name: Alessandro Baisi 
Address: Via A. di Rudinì 8, 20122 Milano (MI) 
Phone: +39 281844076 
Email: alessandro.baisi@asst-santipaolocarlo.it 
 
Center: ASST Ovest - Ospedale di Legnano 
Name: Fabrizio Grignani 
Address: Via Papa Giovanni Paolo II 3, 20025 Legnano (MI) 
Phone: +39 331449356 
Email: fabrizio-grignani@asst-ovestmi.it 
 
Center: IRCCS MULTIMEDICA 
Name: Matteo Incarbone 
Address: Via Milanese 300, 20122 Milano (MI) 
Phone: +39 224209288 
Email: matteo.incarbone@multimedica.it 
 
 
 
 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 4 of 21 
 
1. RATIONALE AND INTRODUCTION 
Robotic surgery in the pulmonary field: introduction and uses 
Robotic surgery is a type of minimally invasive surgery in which the surgeon sits at a console from 
which, using mechanical arms, he/she controls the instruments inserted into the patient 
endoscopically [1]. The purpose of this technology is not to replace the surgeon, but to assist him in 
carrying out increasingly precise operations [2]. Historically, the first uses of robotic surgery date 
back to the early 1990s and involved abdominal surgery. Currently, in Italy, the greatest use is in the 
urological sectors, mainly in radical prostatectomy, and in gynecology [3]. However, the use in the 
thoracic area is spreading rapidly [4]. The use in this area dates back to 2001, when a group from Pisa 
performed the first lobectomy with the use of the da Vinci® robot. The surgeons completed five 
robotic lobectomies without mortality [5]. Subsequently, the use of the robotic platform in thoracic 
surgery expanded and the publication of several studies, including a multicenter one, testifies to its 
development [6]. With regard to pulmonary pathology, it is used both in benign pathology such as 
bronchiectasis, granulomas and alveolar echinococcus [7], and in the removal of solitary pulmonary 
nodules, whose nature is to be determined and whose treatment must be minimally invasive. It is also 
used in diagnosed small cell lung tumors (SCLC) and not (NSCLC) [8]. Moreover, lung metastases 
and carcinoid tumors were also removed [9]. 
Epidemiology of lung cancer and indications for surgical treatment 
In Europe, lung cancer remains in second place among the most frequent neoplasms in men with 
14.2% in 2020, after prostate cancer, while it is in third place with 9.1% in women, after breast cancer 
and colorectal cancer. Italy reflects the European trend, with 14.1% in men and 7.3% in women [10]. 
However, in some countries, such as the United Kingdom and Northern Europe, it is now in second 
place also in women [11]. As regards mortality, lung cancer causes 20.4% of deaths from cancer, 
remaining the most frequent cause of death from cancer. In fact, five-year survival for lung cancer is 
still around 18%, respectively 15% for men and 21% for women; this is also due to the high 
percentage of advanced stage diagnoses [12]. NSCLC represents 80-90% of cases of lung cancer, 
while SCLC frequency is around 14% [13,14]. As far as Italy is concerned, in 2020 lung cancer was 
the first cause of cancer mortality in men (23.9%) and the second in women (12.5%) [10]. In the ATS 
of Milan area in the three-year period 2016-2018, only 23.4% of lung cancers for all ages were 
diagnosed in stage I and II, and 76.6% in stage III and IV [15]. When the tumor is resectable, and the 
patient can undergo surgery, the most indicated treatment for this kind of tumor is surgical removal. 
The National Institute for Clinical Excellence (NICE) recommends to offer surgical treatment to all 
patients with NSCLC up to stage IIIB. Furthermore, the NICE guidelines suggest lobectomy as a 
curative intervention when possible, not specifying a preference between the open and the 
thoracoscopic approach (NICE Guideline 2019). On the contrary, the European Society of Medical 
Oncology (ESMO) specifies that VATS is the preferable approach in stage I tumors. However, this 
recommendation has a level of evidence V (studies without control groups, case reports, and expert 
opinions) and a rating C (insufficient evidence of efficacy). 
 
 
Characteristics of robotic surgery 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 5 of 21 
 
As regards the structural characteristics, the robotic systems developed so far can have two types of 
design: a single-arm one for single-access surgery and a multi-arm one for procedures with multiple 
surgical accesses. Important advantages of the multi-arm system are the ability to cover a larger 
operating field, to insert and maneuver instruments more easily and to allow for better visibility [16]. 
Among the 22 developed robotic surgery systems: 13 are still to be refined, 7 are commercialized (da 
Vinci SI®, da Vinci SP®, da Vinci XI®, da Vinci X®, Freehand v1.2, Surgenius Beta and 
Senhance™ Surgical System), 1 is used only for research, and 1 is dedicated only to the transoral and 
transanal surgical approach [17]. The seven systems currently on the market are manufactured by 
four companies. Intuitive Surgical is the American company that produces the da Vinci® robots. It 
was founded in 1995 and represents the world leader in the sector; it has so far launched four 
generations of robots, of which three are currently on the market. The da Vinci XI® has four robotic 
arms and enjoys the most advanced instrumentation, the da Vinci X® has the same architecture as 
the XI, but uses a more economical technology that allows to reduce costs, the da Vinci SP® instead 
has a single arm architecture. All Intuitive Surgical systems are CE marked and FDA cleared. Surgica 
Robotica is an Italian company that currently offers the Surgenius Beta system, and it is developing 
the Surgenius Gamma. Surgenius Beta has the CE mark. TransEnterix is an American company that 
manufactures the Senhance™ Surgical System, an FDA-approved and CE-marked three-arm robot. 
Freehand Ltd is a British company that manufactures Freehand v1.2, a single arm robot with a camera, 
FDA cleared and CE marked [17].   
 
The platform of the most used robotic system, the da Vinci, consists of several components: the 
surgeon's console with a three-dimensional vision system and two manipulators, a surgical cart with 
one or more arms that execute the surgeon's commands, the Endowrist® instrumentation that allows 
7 degrees of movement that simulate and amplify the movements of the human hand and wrist, and 
a visualization system with 3D endoscopes that allows an enlargement of the image in real time. The 
absence of the tactile function is a significant problem that developers are trying to overcome with 
the technological innovation of haptic feedback, which allows the surgeon to "feel" the reaction of 
the tissue or organ to the force exerted [18]. Intuitive surgical, the leading manufacturer of robotic 
surgery platforms, estimates that over 5 million minimally invasive robotic procedures have been 
performed since 2000, with nearly 5000 units installed worldwide (https://www.intuitive.com/en-us). 
After the introduction of the da Vinci platform in Italy in 1999, there were 111 robots active in our 
county in 2019; of those 22 placed in Lombardy region [19]. To use the robotic platform, specific 
training is required. Usually. it is provided by the manufacturer and distributor and is addressed to 
both the surgeon and all operating room personnel, also involving anesthesiologists and sterilization 
personnel [19]. In the area served by the ATS of Milan, the Training School in Robotic Surgery of 
the Department of Health Sciences of the State University of Milan was recently established. 
The robotic lung-thoracic surgery system comes alongside open surgery and video-assisted 
thoracoscopy (VATS). VATS is a minimally invasive approach that does not require classic 
thoracotomy. VATS instrumentation includes optics in addition to classic thoracic or laparoscopic 
instruments [20]. Minimally invasive surgery (both robotic and VATS) has several benefits over open 
surgery, such as a lower risk of infection and a lower healing and recovery time, while maintaining 
overlapping efficacy outcomes [21]. Robotic surgery ensures a greater degree of flexibility compared 
to the laparoscopic approach, it allows to operate even in hard-to-reach locations, uses 
instrumentation with greater stability and allows a very precise three-dimensional view [2]. 
However, the cost of the necessary equipment is relevant; the purchase cost is about 1.7 million euros, 
while the annual maintenance represents about 10% of this sum. In addition, we have to add the costs 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 6 of 21 
 
for disposable material and equipment with limited reusability (usually ten procedures). 
Consequently, the cost of this technology is high and volume dependent [4]. The European Society 
of Medical Oncology (EMSO) also highlights the fact that the robotic approach can be more 
expensive than the commonly used VATS [22]. On the other hand, in the robotic approach other costs 
are reduced, such as those related to hospitalization, the occupation of intensive care units, and the 
treatment of complications, which are reduced. Furthermore, there are potential advantages such as 
reduction of blood loss and tissue trauma, and less need for surgery conversion to open surgery 
compared to VATS. Furthermore, from the patient's point of view, there is an improvement in the 
quality of life (less pain, faster healing with consequent rapid return to work, less burden on 
caregivers). Lastly, this method has the advantage of improving ergonomics and reduce the physical 
effort of the surgeon [23]. Previous studies have attempted to evaluate the cost-effectiveness profile 
of this method in the thoracic area. Camberlin's study [4] is an HTA report carried out by the Belgian 
agency KCE, whose economic evaluation consists of a literature review for cost evaluation and a 
budget impact analysis. This study highlights that the cost structure of the different surgical 
approaches is very different and difficult to compare and the studies are generally of low quality. 
However, the analysis of the studies points out that robotic surgery is more expensive than traditional 
approaches such as thoracotomy and VATS. The systematic review by Turchetti [24] draws the same 
conclusion, while focusing on further relevant aspects: the facilitation in the execution of complex 
and advanced operations and the different role of the assistant surgeon during robot-assisted 
thoracoscopy operations. The organizational aspect most addressed in the literature was instead the 
training course for the use of the robotic surgical platform [19]. 
 
2. OBJECTIVE 
2.1. PRIMARY OBJECTIVE 
The objective of the analysis is to compare the cost-effectiveness profile of robotic surgery with that 
of thoracotomy and VATS in the surgical treatment of operable lung cancers in the adult population 
of the ATS of Milan. 
2.2. SECONDARY OBJECTIVES 
The secondary objective of the study is to compare the cost-effectiveness profile of robotic surgery 
versus that of thoracotomy and VATS in the surgical treatment of benign lung lesions in the same 
population. 
3. METHODS  
3.1. OVERALL DESIGN AND ORGANIZATION OF THE STUDY  
Single multicenter retrospective observational study with Real World Evidence (RWE) approach 
[25], i.e. an evaluation that uses real-world data (RWD) derived from healthcare flows of the ATS of 
Milan and data provided by participating centers on the basis of medical records/ clinical databases, 
both as regards the analysis of efficacy and safety and as regards the economic evaluation of direct 
costs. For the analysis of quality of life and the calculation of QALYs (quality-adjusted life years), 
validated questionnaires will be prospectively administered to the participating subjects. The 
Epidemiology Unit of the ATS of Milan is the study promoter and it will coordinate the collection of 
data and will carry out the statistical and economic analyses. Other participating centers will be the 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 7 of 21 
 
thoracic surgeries of the ATS hospitals, which carried out in 2019 (last pre-pandemic COVID-19 
year) at least 50 lung operations with the ICD-9-CM codes shown in Table 1. 
 
Table 1 
ICD-9-CM code 
Description 
32.29 
Other local excision or destruction of lesion or tissue of lung 
32.3 
Segmental resection of lung 
32.4 
Lobectomy of lung 
32.5 
Pneumonectomy 
 
Both for the evaluation of clinical efficacy and of costs, the study will include all adult subjects (age 
equal or over 18 years of age at the time of surgery) residents in the ATS of Milan, who were 
hospitalized between 01/01/2016 and 31/12/2021  for pulmonary surgery (operation codes in any 
position of the hospital discharge summary form (SDO – Scheda di Dimissione Ospedaliera)) 
included in Table 1) and whose hospitalization is present in the SDO database of the ATS of Milan 
in one of the participating centers . For the evaluation of cost-effectiveness in malignant tumors, 
subjects with metastases at diagnosis will be excluded. 
3.2. TECHNICAL CHARACTERISTICS OF ROBOTIC SURGERY, ORGANIZATIONAL AND ETHICAL ASPECTS 
OF THE TECHNOLOGY  
The technical characteristics of the technology under evaluation will be summarized (ie type of 
device, procedure, etc.). A survey (Annex 1) will also be carried out at the participating centers to 
obtain indications on the temporal phases of acquisition of the technology in its subsequent 
developments in the territory under study. The organizational aspects will also be described, 
comparing them with those of the currently most widespread technologies according to the model 
proposed by Cacciatore et al. [26]. Finally, any problems of an ethical nature posed by the introduction 
of technology will be highlighted [27]. 
3.3. CLINICAL EFFECTIVENESS AND SAFETY 
Within the evaluation of relative efficacy, we will evaluate clinical efficacy and safety, i.e. 
undesirable or harmful effects. 
3.3.1. Design of the retrospective observational study for efficacy evaluation  
For the group of patients who have undergone pulmonary surgery, extracted from the SDOs as 
described in paragraph 3.1, the surgical modality of each surgery will be identified starting from the 
administrative databases (ICD-9-CM codes 00.31-00.39 for robotic surgery and 34.21 for VATS in 
any location, Table 2). Given that preliminary assessments state a low sensitivity of these codes in 
identifying the surgical approach, this data will be supplemented by information relating to the 
surgical technique used and not contained in the SDO provided by the participating centers as reported 
in Annex 2. 
 
Table 2 ICD-9-CM codes for the identification of interventions in VATS and robotic surgery 
Surgery 
Description 
Code 
VATS 
Transpleural thoracoscopy 
34.21 
Robotics 
Computer assisted surgery with CT/CTA 
00.31 
 
Computer assisted surgery with MR/MRA 
00.32 
 
Computer assisted surgery with fluoroscopy 
00.33 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 8 of 21 
 
 
Imageless computer assisted surgery 
00.34 
 
Computer assisted surgery with multiple datasets 
00.35 
 
Other computer assisted surgery 
00.39 
 
Following preliminary descriptive analyzes on these data, we will evaluate in which types of surgery, 
among those listed in Table 1, the three surgical methods under analysis are actually used 
(thoracotomy, video-assisted thoracoscopy (VATS) and robotic surgery). If open surgery is used, the 
approach will be further evaluated (i.e.posterolateral, muscle-sparing lateral, axillary or anterolateral, 
thoracosternotomy, or median sternotomy [28]. Instead, in case VATS method is used [29], it will be 
assessed whether a single surgical access technique (Uniportal VATS) [30], double access (Duke's 
approach) [31] or triple access (Copenhagen's approach) [32] was used. Furthermore, for ATS 
residents who underwent surgery a distinction will be made on the operations preceded by histological 
examination confirmatory of malignancy, comparing the date and the basis of diagnosis of the ATS 
cancer registry, from those performed for benign tumors and lesions with uncertain malignant 
potential. 
3.3.2. Prospective study design for the evaluation of quality of life and efficacy 
All subjects who will undergo lung surgery (Table 1) during 2022 at the participating centers and will 
give their consent to participate in the study by signing the informed consent form at the pre-
hospitalization or at hospitalization before surgery will be eligible to be enrolled. To evaluate the 
quality of life PROMs related, we will use the generic questionnaire EuroQol-5 Dimension (EQ-5D-
5L) and the specific European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Lung Cancer (EORCT QLQ-LC29), which are available and validated in Italian 
[33,34]. The pre-intervention questionnaire will be completed on paper during hospitalization before 
the intervention or at pre-admission and the data will be entered into the web application of the ATS 
of Milan by dedicated staff. The subsequent questionnaires at day 7 and 30 can be self-completed by 
patients or electronically, using the dedicated web application of the ATS of Milan or in paper form, 
by filling in the documents issued on discharge for this purpose. At the first follow-up visit after 30 
days, the patient will deliver the completed forms to the Thoracic Surgery department in charge of 
him. The Thoracic Surgery Department will forward all the documents, including pre-intervention 
documents, in a single mailing at the end of the study, to the Epidemiology Unit of ATS of Milan. 
The latter will enter the data and prepare it for subsequent analyses. The choice of how to complete 
the questionnaire will be left to the participating center. In both cases, when completing the first 
questionnaire, the study staff will enter the patient's fiscal code (patient identifier) in the application 
and a unique random ID will be generated which will be issued to the patient on paper so that he can 
enter it in the two subsequent self-compiled questionnaires. The information necessary for the 
evaluation of efficacy will be collected with the same modalities of the retrospective study. In addition 
to the evaluation of the quality of life, a questionnaire for the collection of patient experience 
(PREMs) will also be administered 30 days after the intervention or at the first follow-up visit [35,36]. 
The PREMs questionnaire will also be self-completed by patients either electronically, using the 
dedicated web application of the ATS of Milan, or in paper form, by filling in the document issued 
during hospitalization, the transmission of which to the Epidemiology Unit will take place with the 
methods indicated above. 
Definition of efficacy outcomes 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 9 of 21 
 
Efficacy and safety will be evaluated starting from the diagnosis and procedure fields of the SDO, 
from the life status derived from the ATS patient registry (NAR – Nuova Anagrafe Regionale) and 
from the data provided by the centers in terms of:  
3.3.2.1. Efficacy 
The evaluated outcomes will be related to two domains: 
-How does technology affect the course of the disease?  
Long-term survival 
-How technology affects health-related quality of life?  
Descriptive analysis of EQ-5D-5L and EORCT QLQ-LC29 questionnaire results by type of 
approach and surgical procedure 
 
3.3.2.2. Safety  
- 30-day mortality   
- Reoperation during hospitalization  
- Need for conversion to thoracotomy for VATS and robotic surgery  
- Major complications by type of surgery (Table 3)   
 
 
Secondly, differences in terms of duration of operation and hospitalization will be evaluated. This 
information will be used for the cost-effectiveness assessment. 
 
 
Table 3 Complications of interest and related ICD-9-CM codes 
COMPLICATION 
CODE 
Iatrogenic cerebrovascular infarction or hemorrhage 
Central nervous system complication  
(Brain anoxic damage, Cerebral hypoxia) 
997.02 
997.01 
Cardiac complications, not elsewhere classified  
(Cardiac: arrest, insufficiency, cardiorespiratory insufficiency, heart failure) 
997.1 
Post traumatic pulmonary insufficiency  
518.5 
Urinary complications, not elsewhere classified  
(Renal: Acute defaillance, acute failure, acute tubular necrosis specified as due to 
interventions) 
997.5 
Postoperative infection, not elsewhere classified 
998.5x 
Hemorrhage or hematoma or seroma complicating a procedure, not elsewhere classified 
998.1x 
Persistent postoperative fistula 
998.6 
 
3.3.3. Collected variables  
3.3.3.1. From administrative databases  
The staff of the Epidemiology Unit involved in the study will extract the information specified in Table 
4 from the current administrative databases of the ATS of Milan. Subsequently, it will perform the 
deterministic record linkage on a unique key (fiscal code) and will anonymize the dataset for the 
analysis, removing the tax code, deleting the dates once the time intervals necessary for the analysis 
have been calculated (age, length of hospitalization, length of post-operative stay, etc.), and assigning 
a random ID to the patient. Separate copy of correspondence between social security number and 
random id will be kept in a separate password protected file. 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 10 of 21 
 
Table 4 Variables collected from administrative databases 
Data flow 
Data relating to 
Variables 
Hospital 
Discharge 
Summary (SDO) 
Patient 
Civil status, study level 
Hospital admission  
Admission date, intervention date, discharge date, 
type of discharge, within hospital transfers 
 
Diagnoses and complications 
All ICD-9-CM diagnosis codes present in a SDO  
Procedures  
DRGs, ICD-9-CM procedure codes, procedure date 
Patient registry 
Patient 
Sex, birth date, city of residence, vital status at 
2022/12/31 
SDO, outpatient services, 
pharmaceuticals, 
exemptions 
Patient comorbidities 
Charlson comorbidity index calculated through the 
algorithm in use at the Epidemiology Unit 
Cancer registry 
Cancer 
Histology (morphological code ICDO3, margins of 
resection, number of mediastinal lymph nodes 
removed, number of positive mediastinal lymph 
nodes, stage at diagnosis) 
 
3.3.3.2. From the data provided by the centers through a dedicated platform made 
available by the ATS of Milan 
The Epidemiology Unit of the ATS of Milan has an IT platform, which can display the list of their 
patients included in the study only to clinicians who have or have had the patient in treatment. The 
same platform allows the clinicians in charge to view the information relating to the patient and 
pertinent to the study in question. Information can be derived from the administrative databases and 
from the internal databases of the center. The platform will also allow to fill in an ad hoc 
questionnaire, which will be piloted on 2 patients per center, for the collection of additional data 
necessary for the study. The information collected will form a database that will be linked via fiscal 
code to that derived from administrative flows passing through the third table of correspondence 
between random id and fiscal code. The questionnaire will collect the following information (details 
in the data collection form, Annex 2). Part of the information necessary for the study will be acquired 
by the Epidemiology Unit of the ATS of Milan directly from available internal information flows of 
the participating Centers. Specifically, this is information collected by the participating Centers in the 
context of collaboration with important projects for the construction of European and Italian registries 
(such as those of the ESTS (European Society of Thoracic Surgeons) and the Study Group and Italian 
Register of VATS Lobectomy) or which can be extracted by participating centers from computerized 
medical records. The participating centers will select the subjects included in this study and the 
variables included in the CRF of the same. 
 
 
Table 5 Variables collected at participating thoracic surgery centers 
Data relating to: 
Variables 
Intervention 
Surgical approach 
- Open 
- VATS  
• 
Need for conversion to thoracotomy 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 11 of 21 
 
• 
Equipment used (brand and model) 
- Computer-assisted 
• 
Need for conversion to thoracotomy 
• 
Equipment used (brand and model) 
Patient 
Smoking habit 
Performance status 
Complications 
See Table 3 
 
3.3.3.3. Quality of life questionnaires: PROMs and PREMs 
Through the dedicated ATS application, the answers to the EQ-5D-5L and EORCT QLQ-LC29 
questionnaires and to the PREMs questionnaire (Annex 3) will be collected in an electronic database. 
This database will have a unique ID code for the 4 questionnaires relating to each patient (generated at 
first administration and entered by the patient in the two subsequent self-administrations of the other 
three questionnaires). The database will be subject to record linkage with the administrative databases 
for data collection of the variables in Table 4. Furthermore, the variables in Table 5 will be collected 
by the referring clinicians. The collection methods will be the same used in the retrospective study. 
3.3.4. Data analysis 
3.3.4.1.  Power of the study 
 
To study the efficacy, data from the retrospective and prospective study will be analyzed jointly. For 
the retrospective part, approximately 5,000 patients operated on for lung cancer in the participating 
centers from 01/01/2016 to 12/31/2021 will be included. Based on the average of approximately 450 
subjects operated on in the participating centers over 6 months during the years 2019-2021, a sample 
of 400 subjects eligible for enrollment in 6 months during 2022 was considered in the prospective 
observational study. As regards the statistical power in the analysis of the primary efficacy outcome, 
i.e. long-term survival, the calculation was based on an assumption of non-inferiority. The following 
formula was used to calculate potency in survival studies which is based on the hazard ratio [37]. 
1−β=Φ(z−z1−α),   z=(ln(θ)−ln(θ0)) √npApBpE 
Where: 
θ0 = hazard ratio under the null hypothesis, set equal to 1 
θ 
=  observed hazard ratio 
pE =  probability of event, i.e. death, set equal to 0.8 on the basis of epidemiological data from the 
ATS cancer registry 
pA =  proportion of treated by robotic surgery equal to 0.12 on the basis of the data present in the 
SDOs for the year 2019 and of the preliminary information provided by the participating 
centers 
pB = 1-pA 
n 
= sample size, equal to 5400 
Φ  = distribution function of the standard normal  
Α =  I-type error, set equal to 0 
1−β =  statistical power  
 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 12 of 21 
 
By varying the observed HR of VATS death versus the observed control group between 1.08 and 
1.15, the statistical power ranged from 0.5 to 0.91. The power calculation was performed using R 
(v4.1.2, R Core Team 2021, Vienna, Austria.) 
As regards the analysis of quality of life, the prospective study will take into consideration patients 
undergoing three types of surgery: robot-assisted, VATS, and open surgery. Specifically, the number 
of groups enrolled is assumed starting from the average of interventions carried out in the period 
2016-2021. Therefore, for the prospective study, we estimated 48 subjects operated with robotic 
surgery, 94 with VATS, and 258 with open surgery. Literature relating to the comparison of the 
quality of life in patients operated with VATS and open surgery [38] illustrates the analysis of the 
EQ-5D questionnaire at different post-intervention time points. The data of our interest relate to the 
mean and standard deviation of the Visual Analogue Score of the EQ-5D questionnaire administered 
4 weeks after the intervention; respectively: VATS 78.1, Open 73.5. The one-way analysis of variance 
methodology was used to study the power. For robotic surgery, since the necessary data in the 
literature are not available, we assumed an average of the Visual Analogue Score EQ-5D ranging 
from 80 to 83, which allowed the calculation of the estimated power illustrated in the table below. A 
standard deviation of 17.2 was assumed for all three groups based on literature data [38]. For the 
analysis of statistical power, we used the PROC POWER procedure, statement ONEWAYANOVA 
of the SAS software (v. 9.4, SAS Institute Inc., Cary, NC, USA). 
Mean Visual Analogue Score EQ-5D 
Power  
80 
0.669 
81 
0.790 
82 
0.880 
83 
0.939 
 
3.3.4.2. Efficacy study 
Since this is an observational study, all analyses must take confounding into account. For each outcome, 
a Direct Acyclic Graph (DAG) will be prepared, discussed by surgeons and epidemiologists, i.e. a graph 
that allows hypothesizing the causal relationship between intervention and outcome taking into account 
potential confounding factors, measurable or not. On the basis of this graph, which underlies a causal 
model, the variables to be included in the multinomial regression model will be selected for estimating 
the probability of being treated with each surgical modality as a function of potential confounders 
(known as propensity score). Among the variables that will be considered to define the DAGs are age, 
gender, performance status, treatment center and tumor characteristics. The inverse of this estimated 
probability will be used as weight in the regression models (inverse probability weighted, IPW) which 
will have the outcome as the dependent variable and the treatment modality as the independent variable: 
robotics, VATS and thoracotomy (reference). Differences in the duration of surgery and hospitalization 
will be analysed using an IPW generalized linear regression model. The 30-day odds ratio (OR) of death 
for VATS and robotic surgery versus thoracotomy will be estimated by means of an IPW logistic 
regression model. Relative survival will be evaluated using a Cox IPW model and expressed both in 
terms of hazard ratio (HR) and as one and 5 year survival. For inpatient reoperation, the need for 
conversion to thoracotomy for VATS vs. robotic surgery and major complications by type of surgery, 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 13 of 21 
 
which are expected to be rare events, a we will consider a IPW zero-inflated (Poisson or negative 
binomial) approach. All estimates will be presented together with 95% confidence intervals obtained 
from a robust standard error [39]. The same analyses, if allowed by the study number, will be repeated 
in the three surgical subgroups (atypical and segmental resection, lobectomy, pneumonectomy), in 
subjects aged less than or equal to 65 years vs. superior, in patients with performance status of 0 vs. 1 
vs. 2. Sensitivity analyses will be carried out using alternative models for the probability of estimating 
the type of intervention. 
3.3.4.3. Quality of life and patient experience  
Descriptive analyses will be carried out, also using bar graphs, of the items of the EQ-5D-5L and 
EORCT QLQ-LC29 questionnaires, comparing the pre- and post-operative values for each surgical 
approach. Starting from the results of the EQ-5D, the utility index associated with the health-related 
quality of life (HRQoL) will be calculated, and will be summarized through appropriate measures of 
position and variability for the three surgical approaches. Differences between surgical approach in 
terms of utility index will be estimated using a model for longitudinal data weighted by the inverse 
of the probability of surgical approach, similarly to what is described in the previous paragraph. As 
regards the PREMs questionnaires, descriptive analyses of the individual items will be carried out 
globally and by type of treatment. 
3.4. COSTS AND ECONOMIC EVALUATION  
This is a de novo economic evaluation. The target population is the adult population undergoing lung 
surgery (atypical resection, segmentectomy, lobectomy, pneumonectomy) for benign or malignant 
pathology in the ATS of Milan, the intervention is the robotic surgical approach or computer-assisted 
surgery. This approach will be compared with both open surgery and VATS. The cost-effectiveness 
evaluation will be conducted according to the CHEERS (Consolidated Health Economic Evaluation 
Reporting Standards) guidelines [40]. 
 
3.4.1. 
Economic evaluation outcomes  
 
The results of the cost estimates for each surgical approach will be summarized in tables and presented 
graphically. The outcome of the cost-effectiveness (CEA) and cost-utility (CUA) analysis will be the 
incremental cost-effectiveness ratio (ICER); in terms of cost per year of life gained for the first case 
and in terms of cost per QALYs earned for the second. The ICER of robotic surgery and VATS versus 
open surgery and the ICER of robotic surgery versus VATS will be calculated. A cost-effectiveness 
plan will also be constructed for these comparisons. Since the ICER alone cannot answer the question 
of whether a technology is cost-effective per se, it will be compared with a value in euros that society 
is willing to pay for an additional QALY earned ("societal willingness-to -pay”). Since there are no 
Italian regulatory references for willingness-to-pay, the references of NICE (£20-30,000), those of 
the Italian Association of Health Economics (€25-40,000) and the ICER calculated for dialysis 
(€50,000) will be used. Lastly, if the technology is cost-effective in at least one subgroup, a budget 
impact analysis will be carried out. 
 
3.4.2. 
Point of view, time horizon 
 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 14 of 21 
 
The point of view of both the cost-effectiveness and cost-utility evaluation is twofold. Initially, the 
point of view of the hospital structures will be adopted, therefore the direct health costs will be 
estimated, i.e. those relating to surgery, diagnostics, length of stay, health personnel, and drugs. These 
costs will be compared with the rate reimbursed for the DRG. Subsequently, the analysis will be 
extended to the point of view of society, considering indirect healthcare costs and non-healthcare 
costs, direct and indirect and intangible costs, evaluating the VAS and the utility index of the EQ-5D. 
The time horizon of the evaluation will be limited to 5 years from the intervention and the purchase 
of the technology. The tangible investments will be discounted according to the net present value 
method (marginal cost 5%/year and payment period of 5 years). 
 
3.4.3. Model, clinical and cost input parameters  
A decision tree model will be applied to summarize the consequences of the different interventions 
with regards to their clinical outcomes and costs incurred.  
The input parameters for efficacy will be derived from the retrospective and prospective observational 
study. If further information becomes necessary, once the decision tree has been built, it will be 
calculated if possible by the court of the efficacy study. Otherwise, it will be derived from the 
literature. For the calculation of the QALYs, the utility values will be obtained starting from the 
results of the EQ-5D questionnaires prospectively administered to the patients, as described in 
paragraph 3.3.2., using the score function of van Hout et al. [41] and the Italian values of reference 
by Scalone et al [42].  
For the input parameters of the costs, the identification of the resources will take place through a 
panel of expert thoracic surgeons and epidemiologists participating in the study. The quantification 
of resource consumption will take place using the administrative databases of the ATS with regard to 
pre-operative examinations, length of stay, follow-up visits, drugs and other identified direct health 
costs, using the same court identified for the efficacy study. To estimate the indirect health costs 
(patient travel, domestic assistance) the distance between the residence and the intervention hospital 
will be calculated for each patient. We will also use the estimate of the accesses number to the 
healthcare facility by surgical modality in the 30 days preceding and in the 6 months following the 
operation, using the administrative databases. For direct and indirect non-healthcare costs, such as 
the patient's lost days of work and lost productivity or early retirement, the human capital approach 
will be used. 
For the allocation of costs strictly related to the surgical intervention with the three access modalities 
(purchase and maintenance of the instrumentation, duration of the intervention, personnel, etc.) a 
literature review will be performed. They will be compared with the rate reimbursed by the SNR per 
DRG. The determination of the unit cost for all other direct health costs (exams, visits, drugs) will be 
equal to the rate reimbursed by the regional health system, using the rates of the Lombardy region for 
hospital assistance, outpatient services and the prices of drugs agreed between AIFA and producer 
and published in the Italian Official Gazette. All costs will be expressed in euros. 
 
3.4.4. Sensitivity analysis  
Since the costs are volume-dependent, the effect of a different number of cases on the costs and 
therefore on the cost-effectiveness with respect to the measured volumes will be evaluated. 
Furthermore, to evaluate the robustness of the model, deterministic sensitivity analyzes will be 
performed to evaluate the fluctuation of the results as the parameter values vary with respect to the 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 15 of 21 
 
minimum and maximum of the confidence interval. Univariate analysis will be presented by tornado-
plot. 
4. DATA COLLECTION AND STORAGE METHODS 
The study will be conducted in accordance with EU regulation 2016/679, EU directive 2016/680 and 
its amendment. In particular, the data of the patients enrolled during the course will be kept, archived 
and processed in full compliance with the privacy regulations pursuant to art. 13 of Regulation no. 
2016/679/EU and the national privacy legislation in force and the Code of Ethics regarding data 
processing for statistical-scientific purposes. To guarantee the confidentiality of the data, the cloud 
computing service system will be used, supplied to the ATS by third parties, equipped with high security 
standards, where there are the administrative data necessary for the study and where the variables 
extracted from them will be kept and all the data will be analysed. The managers of the participating 
centers will exchange data with ATS via a web platform, published on hosting compliant with the 
GDPR, subjected to the control of appropriate perimeter protections, and created ad hoc with 
technologies and methods previously submitted to the analysis of the Data Protection Officer (DPO) 
for the verification of the standards of safety. For the definition of ownership of the data, specific 
agreements will be signed between the entities. The results of the analyses will be disseminated only in 
aggregate form through the publication of an HTA report and through articles in a scientific journal. If 
some analysis subgroups consisted of three subjects or less, the related data will not be published. 
5. CHARACTERISTICS OF THE STUDY AND INFORMED CONSENT  
As for the retrospective observational part, it provides for the analysis of administrative databases of 
the ATS of Milan managed by the staff of the Epidemiology Unit during their normal activity. The data 
sources are those normally used by the Epidemiology Unit, i.e. the pathological anatomy reports, the 
hospital discharge forms, the flow of outpatient services, territorial pharmaceuticals and the “file F” 
relating to the assisted residents of the ATS of Milan. To complete the collection of data necessary for 
the efficacy analysis, additional information is requested from the clinicians who treat or have treated 
the patient and who participate in the study via the web platform created ad hoc by the Epidemiology 
Unit of the ATS. This retrospective study will be carried out in compliance with the Provision no. 146 
of 5 June 2019 – Provision containing the provisions relating to the processing of particular categories 
of data, pursuant to art. 21, paragraph 1 of Legislative Decree 10 August 2018, n. 101 (Published in the 
Official Gazette n. 176 of 29 July 2019) which recalls the previous Authorization n. 9/2016 - General 
authorization for the processing of personal data carried out for scientific research purposes - 15 
December 2016 (Published in the Official Gazette No. 303 of 29 December 2016), which allows the 
processing of data suitable for revealing the state of health even in absence of the consent of the 
interested parties, for scientific research purposes in the medical, biomedical or epidemiological fields 
in compliance with the limits and conditions set out in the Authorization itself. 
For the prospective part of the study, informed consent will be requested from the patient (Annex 4) at 
the time of pre-admission or surgical admission before surgery. It is the responsibility of the investigator 
to provide each patient with complete and adequate verbal and written information regarding the study 
objective and procedures and the possible risks involved. The patient must be informed of his right to 
withdraw from the study at any time. Written information that will be given to the patient must be 
approved by the EC and must be provided to each patient prior to any study-related procedure. A copy 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 16 of 21 
 
of the signed and dated informed consent form (IC) must be issued to the patient, the other, signed in 
original, must be archived. 
6. FINANCIAL ASPECTS 
As this is an observational study, there are no additional costs related to patient management for the 
prospective part. The costs related to the implementation of the information network, being an activity 
of institutional interest of the ATS of Milan, will be borne by the same through the use of internal 
personnel resources. No funds are foreseen for the conduct of the study, for the participating centers, 
nor for the sending notices to the doctors participating in the study. Participation will be on a voluntary 
basis. 
7. EXPECTED RESULTS 
The expected result is the evaluation of the cost-effectiveness profile of robotic surgery for the treatment 
of lung malignant lesions based on the evaluation of both the effectiveness and the costs measured in 
patients treated in the area of the ATS of Milan in recent years. This information will make it possible 
to determine whether the technology is cost-effective in the specific healthcare context and what would 
be the impact on the budget of a greater diffusion of the technology in the coming years. 
8. PUBLICATION PLAN 
The results of the cost-effectiveness analysis are expected to be published in Italian on the ATS website 
and in international scientific journals in the sector. In addition to the staff of the Epidemiology Unit of 
the ATS directly involved in the study and in the analyses, the heads of the participating centers will be 
included among the authors. A working group will then be defined in which all the collaborators who 
have directly participated in the study for each center will be present, defined at the beginning of the 
study itself. 
 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 17 of 21 
 
9. ANNEXES LIST 
Annex 1 Initial questionnaire for participating centers 
Annex 2 Electronic data collection form for retrospective and prospective study (effectiveness 
analysis) 
Annex 3 Electronic data collection form for prospective study (quality of life, PROMs, PREMs) 
Annex 4 Informed consent for prospective study 
Annex 5 Information for the attending physician 
 
 
 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 18 of 21 
 
REFERENCES 
1  
Hazey JW, Melvin WS. Robot-assisted general surgery. Semin Laparosc Surg 2004;11:107–12. 
doi:10.1177/107155170401100207 
2  
Ryan M. Health technology assessment of robot-assisted surgery in selected  surgical procedures. 
2011;Health 
Information 
and 
Quality 
Authority, 
Ministry 
for 
Health, 
Ireland.https://www.hiqa.ie/sites/default/files/2017-01/HTA-robot-assisted-surgery.pdf (accessed 16 Sep 
2021). 
3  
Jefferson 
TO, 
Abraha 
J, 
Chiarolla 
E, 
et 
al. 
Chirurgia 
robotica. 
2017.https://www.agenas.gov.it/images/agenas/hta/report_hta/nuovi/4_Robot_Assisted_Surgery_HTA%
20report.pdf (accessed 16 Sep 2021). 
4  
Camberlin C, Arnaud S, Mark L, et al. Robot-assisted surgery: health technology assessment. KCE reports 
104C. 2009;Health Services Research (HSR). Brussels: Belgian Health Care Knowledge Centre 
(KCE).https://kce.fgov.be/sites/default/files/atoms/files/d20091027309.pdf 
5  
Melfi FMA, Menconi GF, Mariani AM, et al. Early experience with robotic technology for thoracoscopic 
surgery. Eur J Cardiothorac Surg 2002;21:864–8. doi:10.1016/s1010-7940(02)00102-1 
6  
Park BJ, Melfi F, Mussi A, et al. Robotic lobectomy for non-small cell lung cancer (NSCLC): long-term 
oncologic results. J Thorac Cardiovasc Surg 2012;143:383–9. doi:10.1016/j.jtcvs.2011.10.055 
7  
Toker A, Ayalp K, Uyumaz E, et al. Robotic lung segmentectomy for malignant and benign lesions. J 
Thorac Dis 2014;6:937–42. doi:10.3978/j.issn.2072-1439.2014.06.40 
8  
Dylewski MR, Ohaeto AC, Pereira JF. Pulmonary resection using a total endoscopic robotic video-assisted 
approach. Semin Thorac Cardiovasc Surg 2011;23:36–42. doi:10.1053/j.semtcvs.2011.01.005 
9  
Pardolesi A, Park B, Petrella F, et al. Robotic anatomic segmentectomy of the lung: technical aspects and 
initial results. Ann Thorac Surg 2012;94:929–34. doi:10.1016/j.athoracsur.2012.04.086 
10  AIOM Associazione Italiana di oncologia medica. I Numeri del Cancro in Italia 2020. 2020;AIOM, AIRTUM, 
SIAPEC-IAP.https://www.aiom.it/wp-content/uploads/2020/10/2020_Numeri_Cancro-operatori_web.pdf 
(accessed 16 Sep 2021). 
11  Cancer 
Research 
UK. 
Lung 
cancer 
statistics. 
2021.https://www.cancerresearchuk.org/health-
professional/cancer-statistics/statistics-by-cancer-type/lung-cancer (accessed 28 May 2021). 
12  JRC. 
Lung 
Cancer 
Burden 
in 
Europe. 
2020;Joint 
Research 
Center, 
European 
Commission.https://ecis.jrc.ec.europa.eu/pdf/factsheets/Lung_cancer_en-July_2021.pdf (accessed 16 
Sep 2021). 
13  Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice 
Guidelines 
for 
diagnosis, 
treatment 
and 
follow-up. 
Ann 
Oncol 
2018;29:iv192–237. 
doi:10.1093/annonc/mdy275 
14  Barta JA, Powell CA, Wisnivesky JP. Global Epidemiology of Lung Cancer. Ann Glob Health;85:8. 
doi:10.5334/aogh.2419 
15  Andreano A, Russo AG, Bergamaschi W. Tumore del polmone: indicatori di percorso di cura e valutazione 
dei 
farmaci 
innovativi. 
2021.https://www.ats-
milano.it/Portale/Portals/0/AtsMilano_Documenti/Tumore%20del%20polmone_938686ca-876c-4fcb-
9b17-c9807576cb59.pdf 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 19 of 21 
 
16  Turchetti G, Pierotti F, Palla I, et al. Comparative health technology assessment of robotic-assisted, direct 
manual laparoscopic and open surgery: a prospective study. Surg Endosc 2017;31:543–51. 
doi:10.1007/s00464-016-4991-x 
17  Schmidt L, Lohr P, Prenner A, et al. Robot-assisted surgery in thoracic and visceral indications. 
Collaborative 
assessment. 
Diemen 
(The 
Netherlands) 
Project 
ID: 
OTCA14. 
2019;EUnetHTA.https://www.eunethta.eu/wp-content/uploads/2019/05/Robot-assisted-surgery-in-
thoracic-and-visceral-indications_v1.4_final.pdf (accessed 16 Sep 2021). 
18  Ballini L, Minozzi S, Negro A, et al. La Chirurgia Robotica: il robot da Vinci. 2008;Agenzia sanitaria e 
sociale 
regionale-Regio 
Emilia-Romagna.https://assr.regione.emilia-
romagna.it/pubblicazioni/dossier/doss167-abs 
19  Jefferson 
T. 
HTA 
Report 
Chirurgia 
Robotica. 
2017;AGENAS.https://www.salute.gov.it/imgs/C_17_ReportDispositivi_6_0_documentoITA.pdf 
(accessed 16 Sep 2021). 
20  Emmert A, Straube C, Buentzel J, et al. Robotic versus thoracoscopic lung resection: A systematic review 
and meta-analysis. Medicine (Baltimore) 2017;96:e7633. doi:10.1097/MD.0000000000007633 
21  Park JS, Choi G-S, Park SY, et al. Randomized clinical trial of robot-assisted versus standard laparoscopic 
right colectomy. Br J Surg 2012;99:1219–26. doi:10.1002/bjs.8841 
22  Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv238–55. doi:10.1093/annonc/mdy308 
23  Freschi C, Ferrari V, Melfi F, et al. Technical review of the da Vinci surgical telemanipulator. Int J Med 
Robot 2013;9:396–406. doi:10.1002/rcs.1468 
24  Turchetti G, Palla I, Pierotti F, et al. Economic evaluation of da Vinci-assisted robotic surgery: a systematic 
review. Surg Endosc 2012;26:598–606. doi:10.1007/s00464-011-1936-2 
25  Pongiglione B, Torbica A, Blommestein H, et al. Do existing real-world data sources generate suitable 
evidence for the HTA of medical devices in Europe? Mapping and critical appraisal. International Journal 
of Technology Assessment in Health Care 2021;37. doi:10.1017/S0266462321000301 
26  Cacciatore P, Specchia ML, Solinas MG, et al. The organizational domain in HTA reports: towards a 
technology-oriented assessment. Eur J Public Health 2020;30:219–23. doi:10.1093/eurpub/ckz173 
27  Lysdahl KB, Oortwijn W, van der Wilt GJ, et al. Ethical analysis in HTA of complex health interventions. 
BMC Med Ethics 2016;17:16. doi:10.1186/s12910-016-0099-z 
28  Chikwe J, Cooke D, Weiss A. Cardiothoracic Surgery (Oxford Specialist Handbooks in Surgery). Oxford, 
UK: : Oxford University Press 2013. doi:10.1093/med/9780199642830.001.0001 
29  Magouliotis DE, Fergadi MP, Spiliopoulos K, et al. Uniportal Versus Multiportal Video-Assisted 
Thoracoscopic Lobectomy for Lung Cancer: An Updated Meta-analysis. Lung 2021;199:43–53. 
doi:10.1007/s00408-020-00411-9 
30  Galvez C, Sesma J, Bolufer S, et al. The techniques of uniportal video-assisted thoracoscopic surgery: 
lower lobectomies and lymphadenectomy. J Thorac Dis 2019;11:S2095–107. doi:10.21037/jtd.2019.02.67 
31  Kara HV, Balderson SS, D’Amico TA. Modified uniportal video-assisted thoracoscopic lobectomy: Duke 
approach. Ann Thorac Surg 2014;98:2239–41. doi:10.1016/j.athoracsur.2014.06.086 
32  Hansen HJ, Petersen RH. Video-assisted thoracoscopic lobectomy using a standardized three-port 
anterior 
approach 
- 
The 
Copenhagen 
experience. 
Ann 
Cardiothorac 
Surg 
2012;1:70–6. 
doi:10.3978/j.issn.2225-319X.2012.04.15 

Cost-effectiveness of robotic thoracic surgery 
 
Observational multicenter study
 
Version 2.0 – 2022/03/16                                                                                                       Page 20 of 21 
 
33  Bertolaccini L, Giani M, Ruffini E, et al. Health-related quality of life in lung cancer patients: validation of a 
national version of EORTC QLQ-LC29 questionnaire. European Respiratory Journal 2019;54. 
doi:10.1183/13993003.congress-2019.OA3789 
34  Savoia E, Fantini MP, Pandolfi PP, et al. Assessing the construct validity of the Italian version of the EQ-
5D: preliminary results from a cross-sectional study in North Italy. Health Qual Life Outcomes 2006;4:47. 
doi:10.1186/1477-7525-4-47 
35  De Rosis S, Cerasuolo D, Nuti S. Using patient-reported measures to drive change in healthcare: the 
experience of the digital, continuous and systematic PREMs observatory in Italy. BMC Health Services 
Research 2020;20:315. doi:10.1186/s12913-020-05099-4 
36  Lungu DA, Pennucci F, De Rosis S, et al. Implementing successful systematic Patient Reported Outcome 
and Experience Measures (PROMs and PREMs) in robotic oncological surgery-The role of physicians. Int 
J Health Plann Manage 2020;35:773–87. doi:10.1002/hpm.2959 
37  Chow S-C, Wang H, Shao J. Sample Size Calculations in Clinical Research. 2nd ed. New York: : Chapman 
and Hall/CRC 2007. doi:10.1201/9781584889830 
38  Bendixen M, Jørgensen OD, Kronborg C, et al. Postoperative pain and quality of life after lobectomy via 
video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung cancer: a 
randomised controlled trial. Lancet Oncol 2016;17:836–44. doi:10.1016/S1470-2045(16)00173-X 
39  Shu D, Yoshida K, Fireman BH, et al. Inverse probability weighted Cox model in multi-site studies without 
sharing individual-level data. Stat Methods Med Res 2020;29:1668–81. doi:10.1177/0962280219869742 
40  Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting 
Standards (CHEERS)—Explanation and Elaboration: A Report of the ISPOR Health Economic Evaluation 
Publication Guidelines Good Reporting Practices Task Force. Value in Health 2013;16:231–50. 
doi:10.1016/j.jval.2013.02.002 
41  van Hout B, Janssen MF, Feng Y-S, et al. Interim Scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to 
EQ-5D-3L Value Sets. Value in Health 2012;15:708–15. doi:10.1016/j.jval.2012.02.008 
42  Scalone L, Cortesi PA, Ciampichini R, et al. Health Related Quality of Life norm data of the Italian general 
population: results using the EQ-5D-3L and EQ-5D-5L instruments. Epidemiology, Biostatistics and Public 
Health Published Online First: 8 September 2015. doi:10.2427/11457