Introduction

Since 2008 KRAS mutational status has become the main tissue biomarker of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (CRC). Large phase III and randomized phase II studies have demonstrated that mutation of KRAS gene predicts resistance to treatment with an anti-EGFR antibody either alone or in combination with chemotherapy [1], [2]. The effect of combination of anti-EGFR antibody and chemotherapy seems particularly relevant in patients with liver limited initially not resectable disease [3], [4]. Furthermore, in palliative setting the addition of anti-EGFR monoclonal antibodies to chemotherapy regimens increases the progression free survival and overall survival [5]. Only in few studies biased by selection and methodological issues the predictive role of KRAS has not clearly emerged; however, also in one of these studies response rate was significantly higher in wild-type (wt) tumors [6], [7].

The most accepted guidelines now consider KRAS mutation status a central step of decision-making process in the therapy of metastatic CRC, both in potentially resectable and palliative treatment settings. Access to the advantage provided by this test, however, may be limited by some practical difficulties that may hinder the therapeutic opportunities resulting from anti-EGFR targeting therapy. Mutational analysis, in fact, needs technical and expertise resources that may be not everywhere available [8]. Both complexity of the test and different access to molecular biology laboratory may cause delays, which often conflict with the urgency of clinical decision. This means that an unknown, but not irrelevant, percentage of patients is excluded from a potential therapeutic advantage with negative consequences either on symptom control or resection rate and survival.

The peculiarity of the Italian situation can be clearly seen from the data collected with the KRAS aKtive system, a network aimed to facilitate KRAS testing in Italy. In the period from 1 January 2011 to 31 December 2011, this project has involved 407 oncologists and 125 pathologists, and 24 reference laboratories in 16 of the 21 Italian regions [9]. The times to the diagnosis in most of involved regions result more than 15 days: with the exception of the only region of Puglia, all other times are longer than 10 days and, except Lazio and Tuscany, all are over 15 days (Figure 1). This value is similar to that found in a retrospective study including 160 French centers, where the median time between prescription and result of the K-RAS testing was 19 months [10].

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Figure 1. KRAS aKtive program in Italy – Requested time (days) to diagnosis –2011.

https://doi.org/10.1371/journal.pone.0085897.g001

In addition to differences in reaching the needed resources for KRAS test, economic concerns may have the potential to constrain the use of anti-EGFR antibodies, despite the large evidence resulting from clinical trials. Recently, a health technology assessment report has evaluated the clinical and economic profile of cetuximab in first-line metastatic colorectal cancer (mCRC) in Italy on a specific population (KRAS wt liver limited disease patients). The economic analysis of cetuximab in the treatment of metastatic colorectal cancer shows that this therapy, in combination with FOLFOX and FOLFIRI, is more cost-effective than the alternatives currently available in first line (bevacizumab+FOLFOX, FOLFOX, FOLFIRI); therefore cetuximab can be considered as a sustainable alternative for the NHS [11].

Among the possible strategies, aimed to equalize patients opportunity of access to the potential advantage of anti-EGFR strategy, the anticipation of KRAS testing might be of value. In the present study we have analyzed the opinion and the attitude of a representative group of Italian specialists, mainly oncologists and pathologists, on the implication of KRAS testing in order to optimize overall therapeutic approach to patients with metastatic CRC. The economic supportability of a different strategy of KRAS testing was assessed by a specifically modeled cost-effectiveness analysis.

Methods

Delphi Technique

The Delphi technique is a validated consensus-building process to develop consensus and make group-based decisions in a variety of fields [12], [13]. It was conceived and developed in the mid-1950s by researchers at the Rand Corporation as a way to predict the impact of technologies or interventions on complex systems, which has often been used in the social and health care context [14]–[16].

The Delphi method (Figure 2) is traditionally based on three fundamental concepts. The first is anonymity. The participants never meet each other during the process. Each participant submits his or her opinion independently, by completing a specially designed questionnaire. The replies are then disclosed to all participants, without identifying the particular respondent. The second concept is controlled feedback. The process consists of several rounds; during each of them the respondents are asked to judge all the opinions expressed in the previous rounds, often presented in the form of statistics. The last concept is statistical group response. The Delphi method reaches a collective decision and expresses it in terms of a statistical score. In addition to these basic characteristics, the Delphi method can be described as follows:

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Figure 2. Phases of the Delphi method.

https://doi.org/10.1371/journal.pone.0085897.g002

• It requires individual effort for the expression of an opinion.
• It requires written answers to questionnaires.
• The individual opinions (questionnaire responses) are collected and assembled by the project coordinator.
• The respondents have enough time to come up with and evaluate opinions (unlike task force meeting, in which, quite often, not enough time is allowed to assess other people’s opinions).

Delphi method was used specifically in the field of oncology and diagnostic test assessment for epidemiological, inhabitant awareness and behavior, and to set up and define healthcare protocols and procedures and treatment guidelines [17]–[27].

For the purpose of this specific project, a small group of specialists, the board of experts (comprised of six major specialists selected from Italian universities and public hospitals and one pharmacoeconomist) examined the scientific literature and developed a 22-item questionnaire (Q1; see Table 1), including 4 demographic initial questions. The questionnaire was designed for an expert panel consisting of 108 oncologists, pathologists, molecular biologists, surgeons, quite all of them persons in charge of hospital departments, randomly selected from different Italian regions.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Questionnaire 1.

https://doi.org/10.1371/journal.pone.0085897.t001

Q1 was written in order to avoid possible bias caused by inadvertently influencing replies, so the sequence of questions was ordered within a framework of three mains chapters (Management of patients with metastatic colorectal cancer; Definition of operated patient at high risk of relapse; Anticipation of KRAS testing at the diagnosis of primary tumor). For each question, space was provided for comments.

The majority of Q1 questions (11 out of 18) allowed a classified answer on a scale of 0 (total disagreement) to 9 (complete agreement) while other asked the responders either to rank a set of provided options in order of relevance following their clinical opinion, or to fill in open-ended questions.

To better analyze the replies, two categories of answers were defined for the questions with a 0–9 range:

• Score 0–4: negative answer;
• Score 5–9: positive answer.

After the replies to Q1 were processed, a second questionnaire (Q2) was developed (Table 2). Q2 was presented to the same expert panel and replies were collected and processed in the same way, as done with Q1.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Questionnaire 2.

https://doi.org/10.1371/journal.pone.0085897.t002

After both rounds, the level of agreement was evaluated based on the percentage of positive answers to each question. To reach consensus, a cut-off level of two-thirds (67%) of agreement (for positive or negative answers) was required for the first (Q1) and the second round (Q2). These arbitrary but standard consensus levels were agreed on by all members of the board before beginning the study.

Results

Q1 was sent to 160 specialists involved in diagnosis and treatment process in the oncology field: 17 molecular biologists (10.7%), 21 surgeons (13.1%), 85 oncologists (53.1%), 37 pathologists (23.1%). These 160 specialists define a representative sample of the different Italian regions. The 108 respondents (67.5% of those initially selected) were from northern (43%), central (28%) and southern (29%) Italy. Q2 was sent to the 108 responders to Q1, and 96 (88.8% of them) returned an answer.

The percentage of respondents choosing each reply is presented in tables 1 and 2. By analyzing and evaluating the replies to both questionnaires, the board identified the following statements about different issues on KRAS testing that attained expert agreement of 67% or more:

Anticipation of KRAS Testing at the Diagnosis of Primary Tumor

1. In patients at high risk of relapse anticipating KRAS testing before the onset of metastatic disease may allow the timely use of the most appropriate therapy when the patients metastasizes (Q1–14; Q2–6b; Q2–8)
2. In patients at high risk of relapse, the best time for KRAS testing is after radical resection of CRC in order to have the information when it should be necessary (Q1–9)
3. Anticipating KRAS testing before the onset of metastatic disease in patients at high risk does not affect the sustainability of cetuximab in first-line mCRC regardless of the level of risk of developing metastases (Q1–14; Q2–8)

Cost effectiveness results of early KRAS testing in high risk patients that would have no access to well-timed KRAS testing if they develop metastatic disease are summarized in Table 3.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 3. Cost effectiveness results of Early KRAS testing in high risk patients that would have no access to well-timed KRAS testing if they develop metastatic disease.

https://doi.org/10.1371/journal.pone.0085897.t003

In this table the treatment with cetuximab+FOLFOX-4 is compared to FOLFOX-4 and bevacizumab+FOLFOX-4, while cetuximab+FOLFIRI is compared to FOLFIRI. Anticipating the KRAS testing has as consequence an increase of the costs for the metastatic population represented by the cost of KRAS tests of those patients that will not develop metastases and for which the test would not be necessary. In order to simulate the incremental cost effectiveness that would be generated by early KRAS testing in high risk patients and to test the robustness of results, we conducted several analyses under different assumptions, by setting the level of risk of developing metastatic disease at the level of 1 patients out of 2 (i.e. 50% chance), 1/3, 1/4, 1/5 and 1/10, i.e. including very low risk. The range of ICER generated is between 9,948.51 Euro/QALY (ICER1) and 10,903.73 Euro/QALY (ICER5), far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy.

Discussion

The Delphi method used in the present analysis has advantages and drawbacks. The methodology can overcome many of the limitations intrinsic to traditional group decision-making processes, it keeps attention directly on the issue, and it is flexible and inexpensive compared to focus group. Depending on the nature of the problem, the method can be adjusted for improved overall efficacy. Since the use of strict statistical methods for setting guidelines is rather problematic, due to the quantitative nature of the expected results, the use of modified classification procedures makes easier monitoring and expression of the process by which a consensus is developed. On the other hand, there are some disadvantages: information comes from a selected group of people and may be not representative; it tends to eliminate extreme positions and to force a middle-of-the-road consensus; it is more time-consuming than group process methods; it requires skills in written communication; finally, it requires adequate time and participant commitment.

At the end, the consensus process has become part of the technology for solving problems in health service and medicine by putting the knowledge and experience of practitioners and other experts in touch with scientific literature [30].

In advanced CRC the treatment strategy based on KRAS status is related to clinical outcome of patients [3], [5]. Determining the tumor K-RAS status is now part of clinical practice in most countries; for example, in France the prescription rate in first line therapy is estimated around 81% [10]. In the present study most of experts come from centers certified by the national quality program for KRAS testing or participating to the KRAS aKtive program, so their opinion reflects both the clinical attitude and the real situation in treatment of CRC cancer in Italy. They strongly agree on the relevance of KRAS mutational status in the decision process in metastatic CRC because it allows both the choice of the most appropriate treatment and the proper use of resources. Although other mutations in KRAS, BRAF and PIK3CA genes have been evaluated in relation to resistance to anti-EGFR antibodies, only the most frequent seven KRAS mutations of exons 12 and 13 (Gly12Ala, Gly12Asp, Gly12Arg, Gly12Cys,Gly12Ser, Gly12Val, Gly13Asp) have been investigated in phase III clinical trials and have a proven relation to clinical efficacy of anti-EGFR antibodies [5], [31]. Accordingly, most panelists in our analysis believe that only these mutations should be considered in the practice and that accuracy in the determination of the test is not affected by the source of the sample, either the primary tumor or metastases.

Despite about 40% of experts think that time required to obtain the result of KRAS test do not affect treatment choice in first-line treatment of metastatic CRC, based on their experience, most of them doubt that presently an alternative therapeutic choice might have the same level of effectiveness when the possibility of personalizing treatment were deemed. In addition, large percentage of panelists agree that in first-line chemotherapy a time interval longer than 15 days for obtaining the result actually could limit the therapeutic choices. In support of this view, an interval of 10 days has been considered an optimal time, suggesting that waiting longer is not rare. As a matter of fact, in the previously mentioned KRAS aKtive system it has been shown that delay in obtaining KRAS testing is more than 15 days in most of Italian regions [9].

The clinical situation, however, seems to influence the relevance of shortening the time needed for having test results. In fact, a very large percentage of panelists agree that, in conversion therapy of liver metastases, waiting time for KRAS test must allow the use of a monoclonal anti-EGFR antibody in combination with chemotherapy. This partial divergence may be the consequence of two different aspects: on the one hand, response and tumor shrinkage is largely perceived as important in conversion therapy, as it results in several clinical studies. On the other hand, Italian regulatory rules allow to use cetuximab later whether it was not used in first-line. Therefore, some oncologists might conceive that, when response does not seem to have a crucial role, the activity of cetuximab might be recovered in a subsequent line of treatment. However, this thinking does not consider that a number of KRAS positive patients not responding to an alternative treatment might be definitively excluded from EGFR targeting therapy due to progressive disease, deterioration of performance status and eventually death.

In the metastatic CRC, only when the mutational status of KRAS is known, a proper therapeutic decision may be reached. Panelists agree that in patients with metachronous metastases this may be undoubtedly realized by anticipating KRAS test before the onset of metastatic disease, meeting the need of improving decision making in clinical practice, as it has been recently underlined [10]. In the opinion of most experts the right time for KRAS test is after radical resection of CRC. This implies the need of identifying which group of patients should be considered at high risk of relapse. Panelists largely shared that conditions as surgically removed limited peritoneal carcinomatosis and/or positive peritoneal washing and/or removed ovarian metastases have a very high risk of relapse and require an immediate assessment of KRAS mutational status. In radically resected patients, according to existing evidence, other unfavorable prognostic factors have been recognized including: pT4, high tumor grade, intestinal occlusion-perforation at presentation in N- patients, and pN2 followed by pT4 in N+.

Contrary to what happens in other European countries, such as Spain where a network do exist but all tests are referred to only five laboratories [32], in Italy the system is more scattered in the national territory [9] and the perception of relevance of the timing of KRAS testing is diffuse. Therefore, the convergence of panelists opinion toward the anticipation of KRAS testing in order to ensure the timely use of the most appropriate and personalized therapy in metastatic disease means that an anti-EGFR therapy should be extensively considered in metastatic KRAS wt tumors. As a consequence, the economic impact and sustainability of such a strategy has been evaluated.

KRAS testing to limit use of EGFR inhibitors to patients with KRAS wild-type tumors resulted in net savings of $7,500 to $1,200 and of €3,900 to €9,600 per patient in the United States and Germany, respectively, and was shown cost-effective in patients with KRAS wild-type liver limited disease [33], [34]. It has been estimated that KRAS testing to all metastatic CRCs may realize annual savings ranging from $740 to $103 million in the United States depending on parameters and alternative treatment included in the analysis, that result in different outcomes in terms of cost-effectiveness [35], [36].

Our analysis was aimed to evaluate the different scenery of KRAS early testing not in metastatic CRCs but in patients with CRC at risk of relapse and/or metastases. Not all patients at high risk will eventually develop metastases and will therefore be eligible for treatment with cetuximab. The cost effectiveness of early KRAS testing mimics the situation in which part of KRAS test will be performed in vain (i.e. for those patients who will not eventually develop metastases), and part will only be anticipated (i.e. for those who will subsequently develop metastases). Computationally, this is equivalent to adding to the population of patients eventually developing metastatic disease and being treated, the cost of KRAS tests of the population of patients that will not develop metastases and for which the test will not be necessary. The results of this economic analysis on early KRAS testing in CRC patients, including those at high as well those at very low risk, show that the incremental cost-effectiveness ratio remains within the range of 6,000 to 15,000 Euro per quality adjusted life year (QALY) gained, regardless of the level of risk of developing metastases and far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy (Table 3). In our analysis, we hypothesized that the cost of promptly treating patients developing metastases will include the cost of those KRAS tests performed in patients that would not develop metastases. In case of absence of timely knowledge on KRAS status, patients may receive alternative treatments, which may be highly variable from area to area, but it will essentially include a mix of FOLFOX/FOLFIRI with or without bevacizumab. Therefore, in order to allow the decision maker to judge based on the actual practice in any relevant area, we assessed early KRAS testing against any single alternative therapeutic strategy that may take place in absence of adequate knowledge on KRAS status. In this way, every decision maker can find information on each possible relevant comparator assessed one by one against early KRAS test. In other words, rather than assessing the “mix” of treatments that patients may receive as a whole, we assessed each single part of the mix, one by one against KRAS testing.

This study shows that anticipating KRAS testing in patients with high risk of relapse is a strategy accepted and perceived as useful by Italian specialists in the field of diagnosis and treatment of CRC. A specifically modeled cost-effectiveness analysis suggests that this clinical attitude is economically sustainable.

Taken together, the economic sustainability and the convergence of panelists toward the anticipation of KRAS testing support the inclusion of early KRAS testing in the joined recommendations of societies of Medical Oncology and Pathology in Italy. This might represent the necessary condition for a larger national program of guidelines in molecular diagnosis of cancer.

Acknowledgments

We wish to thank the 160 specialists who participated in the panel of experts: Massimo Aglietta, Istituto di Ricerca e Cura del Cancro di Candiolo, Torino; Giuseppe Antinolfi, Ospedale Monaldi, Napoli; Adelmo Antonucci, Ospedale Policlinico, Monza; Alessandro Apollo, Ospedale Universitario Santa Chiara, Pisa; Giuseppe Maria Aprile, A.O.U. Santa Maria della Misericordia, Udine; Maria Astorino, Ospedale Misericordia e Dolce, Grosseto; Antonio Avallone, Istituto dei Tumori Pascale, Napoli; Caterina Battaglia, A.O. Pugliese-Ciaccio, Catanzaro; Emilio Bertani, Istituto Europeo di Oncologia, Milano; Renato Bisonni, Ospedale Civile Augusto Murri, Fermo; Anna Maria Bochicchio, IRCCS CROB Rionero in Vulture, (PZ); Roberto Bordonaro, Azienda Ospedaliera Garibaldi Nesima, Catania; Giovanni Brandi, A.O.U. Policlinico S.Orsola-Malpighi, Bologna; Sergio Bretti, ASL Torino 4, Ivrea; Ugo Buonocore, Ospedale Cardarelli, Napoli; Fulvio Calise, Ospedale Cardarelli, Napoli; Francesca Capelli, Ospedale Cesare Zonchello, Nuoro; Francesca Caputo, Ospedale Cotugno, Napoli; Laura Caramanico, Azienda USL Vale d’Aosta, Aosta; Stefania Casazza, E.O. Ospedali Galliera, Genova; Francesca Castiglione, A.O.U. Careggi, Firenze; Vincenzo Catalano, A.O. Ospedali Riuniti Marche Nord, Presidio S. Salvatore, Pesaro; Massimiliano Cergnul, Casa di Cura Privata Accreditata MultiMedica, Castellanza; Andrea Ciarlo, Ospedale Misericordia e Dolce, Prato; Mario Clerico, Ospedale degli Infermi, Biella; Domenico Corsi, Ospedale San Giovanni Calibita-Fatebenefratelli-Isola Tiberina, Roma; Bruno Daniele, A.O. Gaetano Rummo, Benevento; Federica De Galitiis, Istituto Dermopatico Immacolata-IRCCS, Roma; Carlo De Sangro, Ospedale San Gennaro dei Poveri, Napoli; Alfonso De Stefano, A.O.U. Federico II, Napoli; Michele De Tursi, Ospedale “SS. Annunziata”, Chieti; Annarita Destro, Istituto Clinico Humanitas, Milano; Francesco Di Costanzo, Ospedale Careggi, Firenze; Francesca Di Fabio, Policlinico S.Orsola-Malpighi, Bologna; Katia Dotti, Fondazione IRCCS - Istituto Nazonale dei Tumori, Milano; Giorgio Ercolani, Policlinico S.Orsola-Malpighi, Bologna; Giovanni Esposito, Istituto Oncologico Veneto - IRCCS, Padova; Giuseppe Maria Ettorre, A.O. San Camillo-Forlanini, Roma; Antonio Febbraro, Ospedale Fatebenefratelli, Benevento; Gianfranco Filippelli, Ospedale San Francesco di Paola, Paola (CS); Franco Filipponi, Centro A.O.U. Pisana, Pisa; Michelangelo Fiorentino, Istituto Oncologico “Addarii”, Bologna; Roberto Fiorentino, Ospedale S. Maria delle Grazie-Pozzuoli, Napoli; Mario Franchini, ASL CN2 Alba - Bra, Alba; Franco Francomano, Policlinico “SS Annunziata” Chieti, Chieti; Michela Frisinghelli, Presidio Ospedaliero S. Chiara - Ospedale di Trento, Trento; Gennaro Galizia, A.O.U. Federico II, Napoli; Marco Galliano, Ospedale Monsignor Giovanni Galliano, Acqui Terme; Silvia Gasperoni, A.O.U. Careggi, Firenze; Andrea Gianatti, A.O. Ospedali Riuniti, Bergamo; Linda Giol, A.O. Santa Maria degli Angeli, Pordenone; Giuseppe Giuffrè, A.O.U. Policlinico “G. Martino”, Messina; Alfredo Guglielmi, A.O.U. Integrata, Verona; Michela Iacobellis, Ospedale “Umberto I”, Altamura; Alessandro Inno, Policlinico Gemelli, Roma; Roberta Invernizzi, A.O. Ospedale di Circolo, Busto Arsizio; Laura La Paglia, A.O.U. Policlinico “P. Giaccone”, Palermo; Eugenio Leonardo, A.O.U. “Ospedali Riuniti”, Trieste; Luciano Leonetti, A.O. “Pugliese-Ciaccio”, Catanzaro; Roberta Libener, A.O. S.S. Antonio e Biagio, Alessandria; Loredana Lo Giudice, A.O. Provincia di Lodi, Lodi; Sara Lonardi, Istituto Oncologico Veneto, Padova; Raffaele Longo, A.C.O. San Filippo Neri, Roma; Vito Lorusso, P.O. “Vito Fazzi”, Lecce; Giovanna Luchena, A.O. Ospedale Sant’Anna, Como; Vienna Ludovini, A.O. Ospedale Renato Silvestrini, Perugia; Gabriele Luppi, A.O.U. Policlinico, Modena; Antonio Maestri, A.U.S.L. di Imola, Imola; Alessandra Mandolesi, Università Politecnica delle Marche, Ancona; Michela Manzotti, Istituto Europeo di Oncologia, Milano; Pierenrico Marchesa, Fondazione Istituto San Raffaele Giglio di Cefalù, Palermo; Marzia Mare, Istituto Oncologico del Mediterraneo, Viagrande; Laura Mariuzzi, A.O.U. Santa Maria della Misericordia, Udine; Gianluca Masi, A.O.U. Pisana, Pisa; Luca Mastracci, A.O.U. San Martino, Genova; Vincenzo Memeo, Policlinico Giovanni XXIII, Bari; Piergiorgio Mezzatesta, La Maddalena - CDC di Alta Specialità - Dipartimento Oncologico, Palermo; Umberto Miglio, A.O.U. Ospedale Maggiore della Carità, Novara; Mauro Minelli, Ospedale S. Eugenio, Roma; Gianmaria Miolo, Centro di Riferimento Oncologico, Aviano; Vincenzo Montesarchio, A.O. Cotugno, Napoli; Oscar Nappi, A.O. Antonio Cardarelli, Napoli; Francesca Negri, A.O.U. di Parma, Parma; Maria Emanuela Negru, A.O.U. Maggiore della Carità, Novara; Gloria Pessina, Ospedale Belcolle, Viterbo; Vincenzo Petrozza, Università La Sapienza, Polo Pontino, I.C.O.T., Latina; Antonio Daniele Pinna, Policlinico S.Orsola-Malpighi, Bologna; Maria Adalgisa Police, A.O. R.N. San Giuseppe Moscati, Avellino; Angelo Pomillo, P.O. “Nicola Giannettasio”, Rossano; Francesca Pucci, A.O.U. di Parma, Parma; Patrizia Racca, Ospedale Molinette, Torino; Manuela Riccardi, Ospedale SS. Giovanni e Paolo, Venezia; Enrico Ricevuto, Ospedale S. Salvatore, L’Aquila; Fabiola Lorena Rojas Llimpe, Policlinico S.Orsola-Malpighi, Bologna; Adriana Romiti, A.O. Sant’Andrea, Roma; Gerardo Rosati, A.O.R. San Carlo, Potenza; Mario Roselli, Fondazione PTV - Policlinico Tor Vergata, Roma; Luigi Ruco, A.O. Sant’Andrea, Roma; Solidea Saltarelli, Ospedale S. Salvatore, L’Aquila; Roberto Santoro, A.O. San Camillo-Forlanini, Roma; Mario Scartozzi, A.O.U. Ospedali Riuniti - Torrette, Ancona; Anna Sebastio, P.O. S. Giuseppe Moscati, Taranto; Angelo Sidoni, A.O. “S. Maria”, Terni; Emiliano Tamburini, P.O. “Infermi”, Rimini; Marco Tampellini, A.O.U. San Luigi Gonzaga, Orbassano; Francesco Tata, A.O. Villa Scassi, Genova; Anna Tomezzòli, Ospedale Civile Maggiore Borgo Trento, Verona; Laura Troiani, IRCCS CROB Rionero in Vulture, Rionero; Paola Ulivi, I.R.S.T., Meldola (FC); Luigi Veneroni, P.O. “Infermi”, Rimini; Franco Verderame, A.O. Ospedali Civili Riuniti, Sciacca (AG); William Vermi, A.O. Spedali Civili, Brescia.

We wish to thank also ThinkTank, a Milan-based Delphi Method consultant agency, for its methodological and logistic support.