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Original article
Appropriateness of endoscopic surveillance recommendations in organised colorectal cancer screening programmes based on the faecal immunochemical test
  1. Manuel Zorzi1,
  2. Carlo Senore2,
  3. Anna Turrin3,
  4. Paola Mantellini4,
  5. Carmen Beatriz Visioli4,
  6. Carlo Naldoni5,
  7. Priscilla Sassoli de’ Bianchi5,
  8. Chiara Fedato3,
  9. Emanuela Anghinoni6,
  10. Marco Zappa4,
  11. Cesare Hassan7,
  12. the Italian colorectal cancer screening survey group
    1. 1Registro Tumori del Veneto, Regione Veneto, Padova, Italy
    2. 2AOU Città della Salute e della Scienza, CPO Piemonte, Torino, Italy
    3. 3Settore promozione e sviluppo igiene e sanità pubblica, Regione Veneto, Venezia, Italy
    4. 4Istituto per lo Studio e la Prevenzione Oncologica, Firenze, Italy
    5. 5Assessorato alle politiche per la salute, Regione Emilia-Romagna, Bologna, Italy
    6. 6Servizio Medicina Preventiva nelle Comunità—AUSL Mantova, Mantova, Italy
    7. 7Unità di Gastroenterologia, Ospedale Nuovo Regina Margherita, Roma, Italy
    1. Correspondence to Dr Manuel Zorzi, Registro Tumori del Veneto, Regione del Veneto, Passaggio Gaudenzio 1, Padova 35131, Italy; manuel.zorzi{at}regione.veneto.it

    Abstract

    Objectives To assess the appropriateness of recommendations for endoscopic surveillance in organised colorectal cancer (CRC) screening programmes based on the faecal immunochemical test (FIT).

    Design 74 Italian CRC screening programmes provided aggregated data on the recommendations given after FIT-positive colonoscopies in 2011 and 2013. Index colonoscopies were divided into negative/no adenoma and low- risk, intermediate-risk and high-risk adenomas. Postcolonoscopy recommendations included a return to screening (FIT after 2 years or 5 years), an endoscopic surveillance after 6 months or after 1 year, 3 years or 5 years, surgery or other. We assessed the deviation from the postcolonoscopy recommendations of the European Guidelines in 2011 and 2013 and the correlation between overuse of endoscopic surveillance in 2011 and the process indicators associated with the endoscopic workload in 2013.

    Results 49 704 postcolonoscopy recommendations were analysed. High-risk, intermediate-risk and low-risk adenomas, and no adenomas were reported in 5.9%, 19.3%, 15.3% and 51.5% of the cases, respectively. Endoscopic surveillance was inappropriately recommended in 67.4% and 7%, respectively, of cases with low-risk and no adenoma. Overall, 37% of all endoscopic surveillance recommendations were inappropriate (6696/17 860). Overuse of endoscopic surveillance was positively correlated with the extension of invitations (correlation coefficient (cc) 0.29; p value 0.03) and with compliance with post-FIT+ colonoscopy (cc 0.25; p value 0.05), while it was negatively correlated with total colonoscopy waiting times longer than 60 days (cc −0.26; p value 0.05).

    Conclusions In organised screening programmes, a high rate of inappropriate recommendations for patients with low risk or no adenomas occurs, affecting the demand for endoscopic surveillance by a third.

    • COLORECTAL CANCER SCREENING
    • COLONOSCOPY
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    Significance of this study

    What is already known on this subject?

    • Organised colorectal cancer screening programmes with immunochemical faecal test have been implemented in Europe.

    • A high rate of inappropriateness in the postpolypectomy recommendations for endoscopic surveillance has been reported in community-based endoscopy.

    • European guidelines on postcolonoscopy/polypectomy surveillance have been implemented in organised screening programmes.

    What are the new findings?

    • In the Italian screening programme using the immunochemical faecal test, the overall level of inappropriateness of postcolonoscopy recommendations was relevant, accounting for a third of all endoscopic surveillance recommendations.

    • The inappropriateness rate was markedly higher in the low-risk group, where only a minority of patients were recommended to return for screening.

    • Underuse of surveillance in the intermediate-risk and high-risk groups was marginal.

    How might it impact on clinical practice in the foreseeable future?

    • Educational interventions aiming at improving the application of current guidelines may reduce by a third the endoscopic workload for endoscopic surveillance within organised screening programmes.

    Introduction

    Colorectal cancer (CRC) is a major cause of morbidity and mortality.1 ,2 CRC screenings with a biannual faecal occult blood test (FOBT) have been shown to reduce CRC mortality;3 ,4 the faecal immunochemical test (FIT) has been shown to be more accurate than the guaiac-FOBT for advanced neoplasia.5 ,6 An organised screening programme using FIT has been implemented in Italy,7 as well as in other European countries and Australia.8

    FIT-based screening programmes are characterised by very high detection rates of neoplasia and advanced neoplasia at colonoscopy. In 75 569 FIT+ colonoscopies, adenoma detection and advanced adenoma detection rates were 45% and 29%, respectively. When considering the magnitude of the population invited, the absolute number of postpolypectomy patients is substantial.9

    Following the initial polypectomy, it is assumed that patients entering a surveillance programme will have metachronous or recurrent adenomatous lesions and cancer detected at an earlier stage.10 ,11 Despite the lack of randomised trials, it has also been suggested that stratification according to endoscopic findings allow patients at greater risk to benefit from endoscopic surveillance.12–14 In a recent cohort study without endoscopic surveillance, patients with low-risk adenomas at the index colonoscopy still presented with a reduced risk of CRC mortality as compared with the general population, while the risk was substantially increased in those with high-risk adenomas.15

    When considering the very high detection rate of neoplasia at colonoscopy in the FIT-based screening programmes and the lack of definitive evidence to support postpolypectomy surveillance, a conservative approach in organised screening programmes has been recommended recently.16 The European guidelines for quality assurance in colorectal cancer screening and diagnosis (EuGL) limited endoscopic surveillance only to patients with intermediate-risk or high-risk adenomas, referring to screening those with low-risk lesions.16 Although such an approach may be expected to minimise the burden of surveillance colonoscopies, previous studies have shown a substantial rate of overuse of endoscopic surveillance.17–25 Inappropriateness rates between 76% and 89% were recently reported in a large community-based series on 2997 postpolypectomy patients in the Netherlands.26

    In theory, organised screening programmes represent an ideal setting for postpolypectomy surveillance. All health operators are expected to follow predefined protocols based on the available evidence. An integrated endoscopic-pathological database allows continuous monitoring of the individual steps of the programme, including adherence to surveillance guidelines. The interaction between epidemiologists and endoscopists is expected to facilitate a conservative approach, when considering the need of FIT+ subjects for endoscopic resources in the first place. Organised screening programmes also allow monitoring the potential use of endoscopic surveillance in patients with no adenomas at a baseline endoscopy, despite these patients being expected to be referred to a subsequent round of screening.

    The aim of this nationwide survey was to assess the adherence to current guidelines on postpolypectomy endoscopic surveillance and rescreening in negative subjects, and the impact of the inappropriateness of recommendations with regards to the additional endoscopic workload.

    Methods

    The CRC screening programmes in Italy

    Within the Italian National Health System, each Regional Health Service is committed to implement organised population-based CRC screening programmes, involving active invitation of the whole target population. Within each region screening activity is generally organised at the local level, with programmes covering municipalities of local health units. Overall, during the period considered for this analysis, we had 120 established local programmes.

    The majority of the Italian CRC screening programmes employ FIT (apart from some—nearly all restricted to the Piedmont region—that employ a one-time flexible sigmoidoscopy and FIT for non-responders to flexible sigmoidoscopy) for subjects aged from 50 to 69–70 years. All FIT programmes invite their target population by mail every 2 years to undergo a one-time FIT. Quantitative haemoglobin analysis is performed by automated instruments using the 100 ng Hb/mL threshold to determine positivity. People with a negative FIT are notified of their results by mail and are advised to repeat the screening in 2 years. Subjects with a positive screening test are contacted to undergo a total colonoscopy (TC) that is usually performed at an endoscopic referral centre. Patients with screen-detected neoplasms are treated during endoscopy or referred to surgery or for an additional endoscopy, and then enrolled in a surveillance programme.

    In 2011, the European Commission published the EuGL, which have been promoted by the Italian group for CRC screening and have increasingly been adopted by most Italian screening programmes.16

    The national survey on screening programme activities

    Since 2005, the National Centre for Screening Monitoring (Osservatorio nazionale screening) on behalf of the Ministry of Health, has carried out an annual national survey regarding the activities performed by Italian CRC screening programmes.27 Programmes fill out a questionnaire with aggregated data regarding the entire screening process, including the number of invitations and of subjects screened, the results of the diagnostic workup, as well as the treatment and stage at diagnosis of screen-detected cancers. Since 2011, specific items on postcolonoscopy surveillance have been included in the survey. Information is collected on the distribution by type (ie, second level assessments, repetition, endoscopic surveillance) of colonoscopies carried out by the screening programmes and on the recommendations given at the end of the diagnostic workup (after a clean colon) by type of diagnosis. According to the EuGL, information on three risk categories for adenomas (high, intermediate and low) is systematically reported. Thus, patients are categorised within the annual national survey as follows:

    • negative/non-adenomatous polyps

    • low risk: patients with one to two tubular adenomas <10 mm, with low-grade dysplasia

    • intermediate risk: patients with three to four adenomas or at least one adenoma ≥10 mm and <20 mm or at least one adenoma with villous histology or high-grade dysplasia

    • high risk: patients with ≥five adenomas or one adenoma ≥20mm

    • adenoma with invasive cancer (ie, submucosal invasion)

    • non-retrieved polyps

    • other

    According to EUGL, for surveillance purposes, serrated adenomas are dealt with like any other adenoma.16

    The systematically collected recommendations included return to screening (FIT after 2 years or 5 years) TCs after 6 months or after 1 year, 3 years or 5 years, surgery or other.16

    Analysis

    We used the data from the 2013 national survey and selected only those programmes that had already introduced the EuGL for the classification of adenomas. For patients with a negative diagnosis or with a diagnosis of adenoma (any category), we evaluated the agreement between the reported recommendations and the EuGL (table 3) and then computed the impact of those recommendations not in line with the EuGL in the programmes’ entire endoscopic workload.

    We also accessed the data from the 2011 national survey and selected those programmes that completed the items regarding postcolonoscopy follow-up in 2011 and 2013. We compared the distribution of recommendations reported in those 2 years with a χ2 test after a negative TC or a diagnosis of adenoma. Cohen's κ28 with 95% CI was used to evaluate the agreement between the 2011 and 2013 recommendations and the EuGL.

    Finally, in order to evaluate the impact of disagreement with the EuGL on programme performance, we computed the correlation coefficient between overprescription of TC in 2011 and the process indicators associated with the endoscopic workload in 2013 (ie, extension of invitations, compliance with TCs and TC waiting times) within screening programmes.20 The SAS V.9.3 statistical package (Cary, North Carolina, USA) was used.

    Results

    In 2013, there were 120 colorectal screening programmes in Italy. Of these, 74 reported data on postcolonoscopy rescreenings or endoscopic surveillance and had already introduced the EuGL for the classification of adenomas. Table 1 shows the main data reported by these programmes. Overall, 51 320 TCs were performed by the study programmes. 19% of these TCs (n=9751) were performed as postcolonoscopy surveillance.

    Table 1

    Main results of the 2013 study programmes

    Data on 49 704 recommendations given after a FIT+ colonoscopy in 2013 were provided (table 2). In detail, more than half of the cases dealt with patients with no adenoma (51.5%, n=25 581), while high-risk, intermediate-risk and low-risk adenomas occurred in 5.9%, 19.3% and 15.3%, respectively, cumulatively corresponding to 20 198 postpolypectomy patients. There were 713 adenomas with invasive cancer (1.4%) and 3056 cases with other diagnoses (mainly haemorrhoids, diverticula and IBD, (6.1%)).

    Table 2

    Distribution by diagnosis type of the diagnostic workups whose recommendation was reported

    The agreement between observed recommendations and the EuGL was evaluated only for those patients with a negative TC or a diagnosis of adenoma.

    Recommendations after a negative FIT+ colonoscopy

    Most subjects with a negative colonoscopy were invited to perform a new FIT screening round after 5 years (76.6%), in line with the EuGL, while another 6.5% were recalled for FIT after 2 years. On the other hand, patients were recommended to undergo a surveillance colonoscopy (figure 1) in 1818/25 581 (7.1%) of the cases. The majority of these inappropriate procedures were recommended to be performed after 3 years or 5 years from the negative colonoscopy.

    Figure 1

    Distribution of recommendations given at the end of the diagnostic workup, by type of diagnosis. Year 2013. FIT, faecal immunochemical test; TC, total colonoscopy.

    Recommendations after a low-risk adenoma

    The EuGL recommend returning to screening (ie, FIT) also in the case of a low-risk adenoma diagnosis. This recommendation was respected only in 16.6% cases (1268/7629), while the indication in the vast majority of cases was a surveillance colonoscopy after different time intervals. In 46.8% of the cases, a surveillance TC was recommended after 5 years, in 15% of the cases after 3 years.

    Recommendations after an intermediate-risk or high-risk adenoma

    About two-thirds of the cases with an intermediate-risk adenoma (6121/9612) were correctly recommended to undergo a surveillance TC after 3 years, while 16.6% were recalled after a shorter interval and 7.6% after 5 years.

    According to the EuGL, high-risk adenomas should be recalled for a surveillance TC after 1 year. This recommendation was given in only 43.3% cases (1281/2957), while in 13.8% of the cases, a colonoscopy was recommended after 6 months and in 25.8% cases it was delayed at 3 years or 5 years.

    The recommendation of a routine FIT in the case of intermediate-risk or high-risk adenomas was rare (2.6% and 0.6% of the cases, respectively).

    Compared with the EuGL, the reported recommendations were mainly in the direction of overprescribing an endoscopic follow-up (TCs after a negative colonoscopy or a low-risk adenoma), while underprescribing (routine FITs after an intermediate-risk or high-risk adenoma) were very few. The largest deviation from the EuGL regarded the cases with a negative diagnosis and those with a low-risk adenoma.

    Difference in recommendations between 2011 and 2013

    Overall, 18 programmes had already introduced the EuGL for the adenoma classification s in 2011. The 2013 distribution of recommendations in these programmes was different from 2011, with an increase in the proportion of cases whose recommendation was in line with the EuGL in all diagnostic categories (table 3): return to routine FIT screening increased from 87.2% to 92.1% and from 7.1% to 19.8% for negative colonoscopies and patients with low-risk adenoma, respectively; TC after 3 years from 58.7% to 70.4% for cases with intermediate-risk adenoma; TC after 1 year from 57.5% to 68.3% for cases with high-risk adenoma. The agreement with the EuGL of the 2013 recommendations was higher than in 2011 (Cohen's κ 0.53 with 95% CI 0.52 to 0.55, and 0.43 with 95% CI 0.41 to 0.46, respectively).

    Table 3

    Distribution of 2011 and 2013 recommendations, by type of diagnosis

    Impact of inappropriateness of recommendations on endoscopic workload

    Table 4 compares the number of expected recommendations of endoscopic surveillance according to the EuGL with the number of observed recommendations, by type of diagnosis. In the case of a negative diagnosis or a low-risk adenoma, the EuGL recommend returning to FIT, thus no TC is expected. We estimated the expected number of TCs after an intermediate-risk or high-risk adenoma, counting one TC for each case (table 2). This did not include those who received a recommendation of ‘other’, probably because findings or reasons for deviating from the guidelines were not reported (respectively 9.6% and 16.5%, figure 1).

    Table 4

    Comparison of the number of observed recommendations for a TC and of expected recommendations according to the EuGL, by type of diagnosis

    Overall, there have been almost 6700 more TC recommendations than expected, accounting for 35.7% of all the TCs recommended in 2013 by the study programmes (table 4).

    Finally, overprescription of TCs in 2011 was positively correlated with the extension of invitations in 2013 (correlation coefficient 0.29; p value 0.03) and with TC compliance in 2013 (correlation coefficient 0.25; p value 0.05), while it was negatively correlated with TC waiting times longer than 60 days (correlation coefficient −0.26; p value 0.05).

    Discussion

    According to our study, there is a substantial rate of inappropriateness in the postcolonoscopy recommendations for endoscopic surveillance within organised screening programmes, accounting for over a third of all endoscopic surveillance recommendations. The main finding is the substantial rate of inappropriateness in the recommendations concerning rescreening after a negative FIT or the removal of low-risk adenoma. Our findings are relevant for several reasons. First, our analysis is based on nearly 50 000 TCs. Of these, nearly half for postpolypectomy surveillance were derived from 74 different screening programmes, assuring the generalisability of our analysis. Second, it shows that the most critical postcolonoscopy group is represented by patients with low-risk adenomas, where the 3–5 year endoscopic surveillance is inappropriate, yet largely preferred to a referral for a new round of FIT screenings, as recommended by the EuGL.16 Of note, this is also the group where international postpolypectomy surveillance guidelines mainly differ, since the current US-based guidelines still recommend a 5–10 year endoscopic surveillance for patients with low-risk adenomas.29 Third, it shows that, despite the rate of inappropriateness for the post-TC recommendation in the non-adenoma group being relatively modest (ie, less than 10%), it accounts for 27% of the inappropriate recommendations after a post-FIT+ TC. This is mainly related to the fact that patients with no adenoma still represent more than half of the FIT+ colonoscopy population. Thus, even a small fraction of inappropriateness results in a substantial number of undesired recommendations and the impact on the endoscopic workload of indicating an endoscopic follow-up to these patients is larger than of recommending an endoscopic surveillance after 1 year in the case of a high-risk adenoma. Therefore, full application of the EuGL would reduce the overall endoscopic workload. Fourth, it shows that there is marginal underuse of endoscopic surveillance in the intermediate-risk and high-risk groups, as shown by the very low rate of FIT rescreenings recommended to these patients. Moreover, the EuGL-recommended surveillance interval was the one most adopted in both categories. Fifth, it shows that the impact of the 1-year EuGL-surveillance recommendation for the high-risk group—not present in other international endoscopic surveillance guidelines29 ,30—is relatively modest, accounting for 14% of all recommended surveillance examinations. Sixth, by comparing two different time periods (ie, 2011 and 2013) we showed an increased rate of adherence to the EuGL, underlining the progressive penetration of these recommendations within organised screening programmes. Seventh, we unexpectedly showed that the level of inappropriateness of the post-FIT+ TC recommendations is positively associated with the extension of the invitations within a programme (ie, the number of invited subjects/number of eligible subjects) and the compliance to FIT invitation, worsening the absolute number of undesired recommendations within the screening programmes. Of note, the inappropriateness rate was also inversely associated with the post-FIT+ colonoscopy waiting list among the programmes, suggesting that a larger availability of endoscopic resources may indirectly favour the overuse of endoscopic surveillance. However, this should not be seen as a justification for the inappropriate use of endoscopic surveillance, especially after the very low risk of incident CRC and CRC-mortality in those with no-risk or low-risk-adenomas was recently confirmed.15 ,31 Eighth, we showed that the potential impact of educational interventions may be large, since inappropriate recommendations account for a third of all the post-FIT+ surveillance TCs.

    The high degree of disagreement between the reported and the theoretical recommendations in the low-risk group deserves additional comment. The survey is reflecting ongoing practice before the publication of the results of the recent Norway study, showing reduced CRC mortality in this group as compared with the general population.15 At that time, the only two population studies completed showed a similar—but not a decreased—risk of incident CRC in the low-risk group, when compared with the general population.11 ,32 Moreover, the risk of metachronous advanced neoplasia appeared to be higher in the low-risk group, as compared with the no-adenoma groups,33 creating some uncertainty on the correct management of these patients. In addition, as explained earlier, pre-EuGL international endoscopic guidelines recommended endoscopic surveillance, rather than rescreening for the low-risk group.34

    The following reasons for the high rate of inappropriateness in our study may be put forward. Before the publication of the EuGL guidelines, clinical recommendations were mainly based on US guidelines on postpolypectomy surveillance, as shown by previous publications on this topic in Italy.23 ,34 ,35 According to such US guidelines, 5–10 years endoscopic surveillance was required in the low-risk group, generating a dissociation between the clinical and the organised screening recommendations. This may have delayed the penetration of the EuGL in this low-risk group, as also shown by a similar experience in the Netherlands.26 Of note, the new clinical guidelines released by the European Society of Gastrointestinal Endoscopy recommend the same no-surveillance policy for the low-risk group, removing any discrepancy between clinical and screening guidelines.30 Despite our study being based in an organised screening setting, we cannot exclude that other factors shown to be associated with an inappropriate recommendation in community-based endoscopy may still be applicable to our series. For instance, a recent Canadian survey showed that deviation from recommended intervals was not due to ignorance of current guidelines, and to deviations dictated by clinical experience.36 Based on a nationwide survey in the USA, Saini et al suggested as a reason for deviation the concern about missed synchronous or metachronous lesions, and the associated medicolegal consequences. Our findings within organised screening programmes are in line with previous series based in community-based or non-organised screening settings performed in European or American countries, disappointingly showing a high rate of inappropriateness in postpolypectomy recommendations.20 ,37–41 Thus, our finding indicates that the simple shift of the same endoscopists from a community-based or non-organised screening to an organised programme does not result in an automatic improvement of the adherence or awareness of postpolypectomy recommendations. This should be generalised to other countries implementing organised programmes, warranting the development of specific policies to reduce such deviation, especially when a high rate of inappropriateness has been shown in community-based setting. Our data also trigger the need for policies aiming to improve the adherence to current recommendations. When considering the burden related with overuse of surveillance, such a variable should be periodically audited, in order to implement quality assurance programmes.42 ,43 Second, active interventions, especially based on information technology, may be considered.44 These web-based technologies should be quite simple to be applied in an organised programme, when considering that health operators, including endoscopists, are expected to include all the data in a dedicated software that may embed active suggestions.

    There are limitations to the present analysis. The ‘negative’ category includes a (not specified) proportion of hyperplastic polyps, whose surveillance protocols have not been homogeneous in the past: this could partly explain a persisting variability in the observed recommendations. We also limited our analysis to aggregated data, so that we could not identify potentially endoscopist-related or patient-related predictors of inappropriateness, such as an inadequate rate of bowel preparation or an incomplete endoscopic resection. However, the magnitude of the main finding of our study—that is, the degree of disagreement in the low-risk group—is unlikely to be affected by confounding variables. Second, we measured the inappropriateness rate of post-TC recommendations, but we could not analyse the actual compliance with the recommended surveillance indications, so that an additional discrepancy between what we measured and what really occurred in real life cannot be excluded. However, as the information concerning the recommendations and the classification of the patient's level of risk, used for this analysis, were directly extracted from the computerised screening databases, adopting common standardised coding systems, the quality of available data was high. Finally, in our survey data concerning the detection rates of (advanced) neoplasia at endoscopic surveillance was not collected. However, while this kind of information might be useful to further assess the impact of different surveillance intervals, it does not seem to be relevant when evaluating endoscopists’ compliance with guidelines recommendations concerning the management of patients following index TC.

    In conclusion, a high rate of inappropriate recommendations for patients with low-risk adenomas—and to a lesser extent, those with no adenomas—occurs in organised screening programmes, making up about a third of the surveillance-related endoscopic workload.

    References

    View Abstract

    Footnotes

    • Collaborators Italian colorectal cancer screening survey group: Manuela Di Giacomo (Direzione Politiche della Salute, Regione Abruzzo, Pescara), Angelo Sigillito (Azienda Ospedaliera San Carlo, Potenza), Liliana Rizzo (Dipartimento Tutela della salute e politiche sanitarie, Regione Calabria, Catanzaro), Giovanna Luciano (Osservatorio epidemiologico regionale, Assessorato alla Sanità, Regione Campania, Napoli), Carlo Naldoni (Assessorato alle politiche per la salute, Regione Emilia-Romagna, Bologna), Nora Coppola (Direzione Centrale salute, integrazione socio sanitaria, politiche sociali e famiglia, Regione Friuli Venezia Giulia, Trieste), Alessandra Barca (Regione Lazio, Roma), Gabriella Paoli (Settore comunicazione, ricerca, sistema informativo e coordinamento progetti in sanità, Regione Liguria, Genova), Luigina Bonelli (S.S. Prevenzione secondaria e screening, Istituto nazionale per la ricerca sul cancro, Genova), Liliana Coppola (Direzione generale salute, Regione Lombardia, Milano), Lucia Di Furia (Servizio Salute, Regione Marche, Ancona), Giuseppe Cecere (Ospedale Cardarelli, Regione Molise, Campobasso), Nereo Segnan (Centro per la Prevenzione Oncologica—CPO Piemonte, Torino), Antonio Fanolla (Osservatorio epidemiologico provinciale, assessorato alla Sanità, Provincia Autonoma di Bolzano, Bolzano), Silvano Piffer (Osservatorio epidemiologico, Azienda provinciale per i servizi sanitari, Provincia Autonoma di Trento, Trento), Cinzia Annatea Germinario (Università degli studi di Bari e Osservatorio Epidemiologico della Regione Puglia, Bari), Pierina Tanchis (Assessorato dell'Igiene e sanità e dell'assistenza sociale, Regione Sardegna, Cagliari), Gabriella Dardanoni (Dipartimento Attività sanitarie e Osservatorio epidemiologico dell'Assessorato alla salute, Regione Sicilia, Palermo), Paola Mantellini (Istituto per lo Studio e la Prevenzione Oncologica—ISPO, Firenze), Mariadonata Giaimo (Direzione Regionale Salute, Coesione sociale e Società della Conoscenza, Regione Umbria, Perugia), Gabriella Furfaro (Servizio promozione della salute, assessorato alla Sanità, salute e politiche sociali, Regione Valle d'Aosta, Aosta), Manuel Zorzi (Registro Tumori del Veneto, Padova)

    • Contributors AT, MZo, CH, CS: study concept and design and drafting of the manuscript; AT, MZo: acquisition of data, statistical analysis. All the authors: interpretation of data and critical revision of the article for important intellectual content and final approval of the article.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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