- Email: [email protected]
Colonoscopic surveillance of first-degree relatives of colorectal cancer patients in a faecal occult blood screening programme
Cancer Epidemiology 37 (2013) 469–473
Contents lists available at SciVerse ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Colonoscopic surveillance of first-degree relatives of colorectal cancer patients in a faecal occult blood screening programme Priscilla Sassoli de Bianchi a, Cinzia Campari b, Silvia Mancini c, Orietta Giuliani c, Patrizia Landi a, Luisa Paterlini b, Carlo Naldoni a, Alba C. Finarelli a, Fabio Falcini c, Maurizio Ponz de Leon d, Romano Sassatelli e, Elisabetta Borciani f, Fabio Fornari f, Giorgio Gatti f, Marella Zatelli f, Corrado Zurlini f, Federica Rossi f, Rossella Corradini f, Rossella Olivetti f, Marilena Manfredi f, Paola Baldazzi f, Roberto Nannini f, Stefano Zanarini f, Vincenzo G. Matarese f, Caterina Palmonari f, Omero Triossi f, Sonia Gordini f, Rosa Vattiato f, Americo Colamartini f, Mauro Palazzi f, Mirna Severi f, Laura Briganti f, Mauro Giovanardi f, Coralba Casale f, Lauro Bucchi c,* a
Department of Health, Emilia-Romagna Region, 40127 Bologna, Italy Department of Planning and Control, Reggio Emilia Health Care District, 42122 Reggio Emilia, Italy Romagna Cancer Registry, IRST, 47014 Meldola, Forlı`, Italy d Department of Internal Medicine and Specialty Medicine, Medicine I, Policlinico, 41124 Modena, Italy e Unit of Gastroenterology and Digestive Endoscopy, Arcispedale Santa Maria Nuova, 42100 Reggio Emilia, Italy f Regional Colorectal Cancer Screening Programme Centres, Department of Health, Emilia-Romagna Region, 40127 Bologna, Italy b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 January 2013 Received in revised form 13 April 2013 Accepted 15 April 2013 Available online 14 May 2013
Background: In some Italian areas, colonoscopic surveillance of first-degree relatives (FDRs) of colorectal cancer (CRC) patients is provided as a part of local population-based faecal occult blood test (FOBT) screening programmes. The objective of the present study was to assess the feasibility and early results of this surveillance model. Methods: Data from district screening centres were used to evaluate the process of identification and selection of eligible FDRs (residence in the Emilia-Romagna Region, age 40– 75 years, no recent colonoscopy) of screen-detected CRC patients and the detected prevalence of disease. The probability for an FDR to undergo colonoscopy and to be diagnosed with CRC and advanced adenoma was estimated using the Kaplan–Meier method. The sex- and age-standardised ratio of detected prevalence to that expected based on results from a colonoscopy screening study of the Italian general population was estimated. Results: Between 2005 and 2011, 9319 FDRs of 2437 screen-detected CRC patients (3.8 per patient) were identified and contacted. Their likelihood of being eligible for, and accepting, colonoscopy was 0.11 (95% confidence interval: 0.11–0.12). Among the 926 subjects undergoing colonoscopy, the prevalence of previous negative screening FOBT was 63%. Eleven CRCs (1.2%) and 100 advanced adenomas (10.8%) were detected. The standardised ratio of detected prevalence to that expected was 0.91 (95% confidence interval: 0.19–2.66) for CRC and 1.48 (1.04–2.05) for advanced adenoma. Conclusions: The procedure of selection of FDRs was extremely ineffective. Due to previous negative screening tests, the prevalence of disease was less than expected. A population-based FOBT screening programme is a highly unsuitable setting for the provision of surveillance to FDRs of CRC patients. ß 2013 Elsevier Ltd. All rights reserved.
Keywords: Colorectal neoplasm Colonoscopy Family history Mass screening Faecal occult blood test
1. Introduction People with a family history of sporadic colorectal cancer (CRC) are 2–2.5-fold more likely to develop the disease [1,2]. Many organisations recommend that first-degree relatives (FDRs) of CRC patients undergo regular colonoscopic surveillance, although optimal strategies are not established [3]. In Europe, the most common approach to identify the individuals at risk of familial CRC * Corresponding author. Tel.: +39 0543 739455; fax: +39 0543 739459. E-mail address: [email protected] (L. Bucchi). 1877-7821/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canep.2013.04.004
is case finding [4]. Persons are interviewed for their family history when they attend primary health care providers, and are referred to specialised reference centres [5–8] if the collected information is suspicious. The European guidelines for CRC screening recommend that FDRs be excluded from faecal occult blood test (FOBT) screening programmes only if alternative surveillance models are in place [9]. In general, those participants reporting a specific family history are referred for specialist care [4]. A different model is being explored in Italy. Several regional health authorities have implemented surveillance schemes that
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P. Sassoli de Bianchi et al. / Cancer Epidemiology 37 (2013) 469–473
are nested within local FOBT screening programmes, and where colonoscopy is directly delivered by screening centres. The effects of such an innovative approach to the management of familial CRC, however, have never been documented. The objectives of this study from the Emilia-Romagna Region (northern Italy) were to assess the results of selection of FDRs and to evaluate the detected prevalence of disease.
2. Patients and methods 2.1. Setting The CRC screening programme of the regional Department of Health is divided into three intervention arms: (A) residents aged 50–69 (N = 1,105,000) are offered two-yearly, single-sample
Fig. 1. Design and results of the intervention. The procedure of identification and selection of first-degree relatives of screen-detected colorectal cancer patients is illustrated step by step. At each step, three numbers are given, namely: the number of subjects with incomplete procedure and thus not evaluable; the number of subjects successfully selected for the next step; and the number of subjects who were not selected. In the right-hand column of the figure, the proportion of evaluable subjects successfully selected for the next step is shown.
P. Sassoli de Bianchi et al. / Cancer Epidemiology 37 (2013) 469–473
immunochemical FOBT; (B) residents aged 70–74 years attending family physicians are offered one-time colonoscopy; and (C) FDRs of CRC patients are offered five-yearly colonoscopy. The intervention arm A uses a one-day immunochemical FOBT without dietary restrictions (OC-Sensor Micro, Eiken Chemical, Tokyo, Japan) which is distributed and collected, within 3 days of stool sampling, through primary care facilities. A positive FOBT result is defined as 100 ng/ml faecal haemoglobin. The intervention arm C, according to the original planning, had to include three phases respectively targeted at: (C1) FDRs aged 40–74 years of CRC patients diagnosed by FOBT screening; (C2) FDRs of patients aged 69 years diagnosed in the routine health care setting after the start of FOBT screening; and (C3) FDRs of prevalent patients aged 69 years and diagnosed with CRC before the start of FOBT screening. The intervention arm A was initiated in early 2005, and phase C1 six months later. Phase C2 has been implemented in 6/11 health care districts. Phase C3 has been postponed. This study focuses on phase C1. 2.2. Design In Fig. 1, the procedure for identification and selection of FDRs of screen-detected CRC patients is illustrated (along with the results) in the form of a flow chart. After surgical treatment, the screening centre informs the index screen-detected CRC patient that his (or her) FDRs are at increased risk of disease, and asks his consent to offer them a colonoscopy (step 1). If the index patient gives his consent, he is asked to provide name, birth date, address, and telephone number of his FDRs (step 2). At step 4, a check for demographic eligibility of FDRs is done (exclusion criteria: death, age <40 years or 75 years, and residence elsewhere than in the Emilia-Romagna Region). FDRs aged <40 years, temporarily not eligible, are recorded in a dedicated file and later contacted. At step 5, FDRs are contacted by telephone and a second eligibility check is done (exclusion criteria: the same as above plus previous diagnosis of CRC and of colorectal polyp with follow-up still in progress, severe illness contraindicating colonoscopy, and colonoscopy within 5 years). Eligible FDRs are invited for a face-to-face consultation and, if they attend (step 7), they are offered colonoscopy unless they report having undergone it after phone contact (step 8). 2.3. Data For this study, two anonymous datasets were created using data from screening centres (N = 11): one containing information on selection of FDRs of CRC patients detected by FOBT screening between 2005 and 2010, and the other composed of information on the results of colonoscopy. FDRs were followed-up until 31 December 2011. FDRs who had previously had a negative screening FOBT were identified from the regional, anonymous database of screening tests using their personal identification number. 2.4. Statistical methods Patient subgroups were compared for proportions using the Pearson chi-square test. Trends in proportions were evaluated using the chi-square test for linear-by-linear association. Group comparisons for continuous variables were performed using the Mann–Whitney test. All tests were two-tailed with the alpha value set at 0.05. The probability, with 95% confidence interval (CI), for a registered FDR to undergo colonoscopy and to be diagnosed with CRC and advanced adenoma was estimated using the Kaplan– Meier method with censoring for incomplete follow-up.
471
Sex- and age-standardised prevalence rate ratios were calculated to compare the prevalence of disease among FDRs with that expected based on findings from (a) the colonoscopy arm of the SCORE3 screening trial targeting the general population of northern Italy [10], and (b) the subjects undergoing colonoscopy for a positive FOBT in the regional screening programme. The estimate of complete prevalence of CRC on 1 January 2005 was obtained from a national Working Group [11]. The number of incident CRC cases 2005–2010 was obtained from the regional CRC Registry. This observational study had institutional review board approval. 3. Results 3.1. Identification and selection of FDRs In the right-hand part of Fig. 1, the proportion of evaluable subjects successfully selected at each step of the procedure is shown. The study included 9319 FDRs. At steps 4 and 5, a total of 7475 subjects were excluded because of demographic reasons (death, age, and residence status) (N = 6811), previous diagnosis of CRC (N = 70), recent colonoscopy (N = 450), and other and unspecified reasons (N = 144). After steps 4 and 5, the proportion of FDRs still eligible was 0.19 (95% CI: 0.18– 0.20). At step 9, FDRs still eligible were offered colonoscopy and 30% did not accept it. Refusal was more frequent among younger subjects (median age, 58 years vs. 61 years for refusers vs. acceptors; P < 0.0001), and among subjects without previous negative screening FOBT (39.6% vs. 23.7%; P < 0.0001). Conversely, it was independent of sex and calendar year (test for trend). The probability of a registered FDR (step 3) undergoing colonoscopy was 0.11 (95% CI: 0.11–0.12). The prevalence of previous negative screening FOBT among FDRs undergoing colonoscopy was 62.6% on average, and increased from 5.0% at age 40–49 to 82.7% at age 70. Subjects who had had a negative FOBT during the last two years were 53.3%. 3.2. Detected prevalence of disease This is shown in Table 1. The probability of a registered FDR being diagnosed with CRC and advanced adenoma was 1.4 (95% CI: 0.7–2.4) per 1000 and 12.3 (10.1–14.9) per 1000, respectively. 3.3. Ratio of detected to expected prevalence of disease This is shown in Table 2. Compared with the general population enrolled in the SCORE3 trial, FDRs had an almost equal prevalence of CRC and a 40–50% greater prevalence of adenoma. The Table 1 Number and prevalence rate (%) of colorectal cancer and adenoma among firstdegree relatives undergoing surveillance colonoscopy. Age (years)
Total FDRs
40–49 50–59 60–69 70
98 303 446 79
Totala
926
CRC 0 2 7 2
(0.0) (0.7) (1.6) (2.5)
11 (1.2)
Advanced adenoma 6 29 58 7
(6.1) (9.6) (13.0) (8.9)
100 (10.8)
Non-advanced adenoma 14 60 89 23
(14.3) (19.8) (20.0) (29.1)
186 (20.1)
Abbreviations: FDRs, first-degree relatives; CRC, colorectal cancer. Advanced adenoma was defined as a polyp size of 10 mm or as a polyp containing >20% villous features or high-grade dysplasia. a Twelve of the total number of 938 patients indicated in Fig. 1 were excluded from the table because they were aged <40 years.
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Table 2 Ratio between the prevalence of colorectal cancer and adenoma among first-degree relatives undergoing surveillance colonoscopy and that expected based on reference data from different colonoscopic studies. Referent Source
Patients
SCORE3 triala Emilia-Romagna Regionb Emilia-Romagna Regionc
General population With positive FOBT (1st) With positive FOBT (2nd+)
Age
CRC
Advanced adenoma
Non-advanced adenoma
55–64 50–69 50–69
0.91 (0.19–2.66) 0.19 (0.10–0.35) 0.42 (0.21–0.75)
1.48 (1.04–2.05) 0.35 (0.28–0.42) 0.48 (0.39–0.59)
1.41 (1.09–1.79) 1.46 (1.25–1.70) 0.99 (0.85–1.16)
Abbreviations: CRC, colorectal cancer; FOBT, faecal occult blood test; 2nd+, second and subsequent. Prevalence rate ratios are standardised for age (5-year groups) and sex; numbers in parentheses are 95% confidence intervals. a Italian multicentre randomised trial of CRC screening (colonoscopy arm), 2002–2004 [10] (unpublished data courtesy of the Authors). b Local population-based FOBT screening programme, 2005–2009 (unpublished data). c Local population-based FOBT screening programme, 2007–2009 (unpublished data).
prevalence of CRC was 19% and 42% of that expected based on findings from subjects testing positive on their first and, respectively, second and subsequent screening FOBT. The corresponding figures for advanced adenoma were 35% and 48%. 3.4. Public health impact of the intervention Screen-detected CRC patients reported to the regional CRC Registry in 2005–2010 (N = 3790) were 2.45-fold less than patients aged 69 years with prevalent CRC to be targeted in phase C3 (N = 9283), and 1.85-fold less than incident CRC patients aged 69 years diagnosed in the routine health care setting (N = 6997) who were only partially targeted in phase C2. The nine cancers detected among FDRs aged 50–69 years (Table 1) accounted for 0.1% of total patients of the same age reported to the CRC Registry over the same period (N = 9672). 4. Discussion The rationale of this intervention was the idea that the effectiveness of FOBT screening can be maximised if the preventive strategy is expanded to include the colonoscopic surveillance of FDRs of screen-detected CRC patients. The results contrast greatly with expectations. The probability for a registered FDR to be eligible for, and accept, colonoscopy was as low as 11%, and the detected prevalence of disease was less than expected because of the high proportion of subjects with recent negative FOBT results. The population of prevalent CRC patients in a given geographic area is almost impossible to identify in its entirety, since cancer registries are not ubiquitous and most of them cannot provide long-term incidence data. If this is the problem, however, targeting the FDRs of screen-detected CRC patients is not a solution. This approach suffers from poor sensitivity, because screen-detected patients are a minority of total CRC patients in a population, and poor specificity, because they provide a list of FDRs who have a very low likelihood of being eligible for, and accepting, colonoscopy. Moreover, the process of eligibility verification is laborious and time-consuming, which caused phase C2 of the regional programme to be incompletely implemented, and phase C3 to be postponed. Total nursing time expenditure for each patient undergoing colonoscopy averaged 3 h and 50 min according to a rough estimate from 3 district screening centres with administrative data of sufficient quality. This is the first point of weakness of this surveillance model. The prevalence of disease among FDRs was less than expected. A first-degree family history of CRC increases the risk of disease by 2–2.5-fold [1,2], whereas the yield of CRC in our data was similar to the general population [10], and the yield of adenoma was only 40– 50% greater. The reason for these modest findings was a 63% prevalence of previous negative FOBT. Noteworthy, a previous
negative screening FOBT was a strong predictor of acceptance of colonoscopy. This is the second point of weakness in this surveillance model. The risk decrease resulting from a recent negative FOBT is larger than the increase associated with a first-degree family history of CRC. Italian studies have reported an incidence decrease by 6.5 times during the first year after a negative FOBT and 2.5–3.2 times during the second year [12,13]. Under these conditions, the positive predictive value of a screening FOBT in an average-risk subject is greater than that of a first-degree family history. It clearly appears that FDRs with a recent negative FOBT should not receive colonoscopy. If they were excluded from the intervention, however, this would further reduce the already marginal proportion of subjects undergoing colonoscopy. Due to this marginal proportion, coupled with a low prevalence of disease, the public health impact of the intervention was nil. The detected number of cancers at age 50–69 years was 0.1% of total incidence over the study period. Given these extreme levels of ineffectiveness, it appears that a population-based FOBT screening programme is a highly unsuitable setting for the provision of surveillance to FDRs of CRC patients. Conflict of interest statement The authors have no conflict of interest to declare. Funding source The authors did not receive any external funding. References [1] Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001;96(10):2992–3003. [2] Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 2006;42(2):216–27. [3] Wilschut JA, Steyerberg EW, van Leerdam ME, Lansdorp-Vogelaar I, Habbema JD, van Ballegooijen M. How much colonoscopy screening should be recommended to individuals with various degrees of family history of colorectal cancer? Cancer 2011;117(18):4166–74. [4] Vasen HF, Mo¨slein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe. Fam Cancer 2010;9(2):109–15. [5] Hunt LM, Rooney PS, Hardcastle JD, Armitage NC. Endoscopic screening of relatives of patients with colorectal cancer. Gut 1998;42(1):71–5. [6] Dove-Edwin I, Sasieni P, Adams J, Thomas HJ. Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study. BMJ 2005;331(7524): 1047–9. [7] Puente Gutie´rrez JJ, Marı´n Moreno MA, Domı´nguez Jime´nez JL, Bernal Blanco E, Dı´az Iglesias JM. Effectiveness of a colonoscopic screening programme in firstdegree relatives of patients with colorectal cancer. Colorectal Dis 2011; 13(6):145–53.
P. Sassoli de Bianchi et al. / Cancer Epidemiology 37 (2013) 469–473 [8] van der Meulen-de Jong AE, Morreau H, Becx MC, Crobach LF, van Haastert M, ten Hove WR, et al. High detection rate of adenomas in familial colorectal cancer. Gut 2011;60(1):73–6. [9] Malila N, Senore C, Armaroli P. Organisation. In: Segnan N, Patnick J, von Karsa L, eds. European guidelines for quality assurance in colorectal cancer screening and diagnosis. first ed., Luxembourg: Publications Office of the European Union, 2010: 33–69. [10] Segnan N, Senore C, Andreoni B, Azzoni A, Bisanti L, Cardelli A, et al. Comparing attendance and detection rate of colonoscopy with sigmoidoscopy and FIT for colorectal cancer screening. Gastroenterology 2007;132(7):2304–12.
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[11] AIRTUM Working Group. Italian cancer figures, report 2010: cancer prevalence in Italy. Patients living with cancer, long-term survivors and cured patients. Epidemiol Prev 2010;34(5–6 (Suppl. 2)):1–188. [12] Campari C, Sassatelli R, Paterlini L, Camellini L, Menozzi P, Cattani A. Test and programme sensitivities of screening for colorectal cancer in Reggio Emilia. Epidemiol Prev 2011;35(2):118–24. [13] Zorzi M, Fedato C, Grazzini G, Stocco FC, Banovich F, Bortoli A, et al. High sensitivity of five colorectal screening programmes with faecal immunochemical test in the Veneto Region, Italy. Gut 2011;60(7):944–9.
Contents lists available at SciVerse ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Colonoscopic surveillance of first-degree relatives of colorectal cancer patients in a faecal occult blood screening programme Priscilla Sassoli de Bianchi a, Cinzia Campari b, Silvia Mancini c, Orietta Giuliani c, Patrizia Landi a, Luisa Paterlini b, Carlo Naldoni a, Alba C. Finarelli a, Fabio Falcini c, Maurizio Ponz de Leon d, Romano Sassatelli e, Elisabetta Borciani f, Fabio Fornari f, Giorgio Gatti f, Marella Zatelli f, Corrado Zurlini f, Federica Rossi f, Rossella Corradini f, Rossella Olivetti f, Marilena Manfredi f, Paola Baldazzi f, Roberto Nannini f, Stefano Zanarini f, Vincenzo G. Matarese f, Caterina Palmonari f, Omero Triossi f, Sonia Gordini f, Rosa Vattiato f, Americo Colamartini f, Mauro Palazzi f, Mirna Severi f, Laura Briganti f, Mauro Giovanardi f, Coralba Casale f, Lauro Bucchi c,* a
Department of Health, Emilia-Romagna Region, 40127 Bologna, Italy Department of Planning and Control, Reggio Emilia Health Care District, 42122 Reggio Emilia, Italy Romagna Cancer Registry, IRST, 47014 Meldola, Forlı`, Italy d Department of Internal Medicine and Specialty Medicine, Medicine I, Policlinico, 41124 Modena, Italy e Unit of Gastroenterology and Digestive Endoscopy, Arcispedale Santa Maria Nuova, 42100 Reggio Emilia, Italy f Regional Colorectal Cancer Screening Programme Centres, Department of Health, Emilia-Romagna Region, 40127 Bologna, Italy b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 January 2013 Received in revised form 13 April 2013 Accepted 15 April 2013 Available online 14 May 2013
Background: In some Italian areas, colonoscopic surveillance of first-degree relatives (FDRs) of colorectal cancer (CRC) patients is provided as a part of local population-based faecal occult blood test (FOBT) screening programmes. The objective of the present study was to assess the feasibility and early results of this surveillance model. Methods: Data from district screening centres were used to evaluate the process of identification and selection of eligible FDRs (residence in the Emilia-Romagna Region, age 40– 75 years, no recent colonoscopy) of screen-detected CRC patients and the detected prevalence of disease. The probability for an FDR to undergo colonoscopy and to be diagnosed with CRC and advanced adenoma was estimated using the Kaplan–Meier method. The sex- and age-standardised ratio of detected prevalence to that expected based on results from a colonoscopy screening study of the Italian general population was estimated. Results: Between 2005 and 2011, 9319 FDRs of 2437 screen-detected CRC patients (3.8 per patient) were identified and contacted. Their likelihood of being eligible for, and accepting, colonoscopy was 0.11 (95% confidence interval: 0.11–0.12). Among the 926 subjects undergoing colonoscopy, the prevalence of previous negative screening FOBT was 63%. Eleven CRCs (1.2%) and 100 advanced adenomas (10.8%) were detected. The standardised ratio of detected prevalence to that expected was 0.91 (95% confidence interval: 0.19–2.66) for CRC and 1.48 (1.04–2.05) for advanced adenoma. Conclusions: The procedure of selection of FDRs was extremely ineffective. Due to previous negative screening tests, the prevalence of disease was less than expected. A population-based FOBT screening programme is a highly unsuitable setting for the provision of surveillance to FDRs of CRC patients. ß 2013 Elsevier Ltd. All rights reserved.
Keywords: Colorectal neoplasm Colonoscopy Family history Mass screening Faecal occult blood test
1. Introduction People with a family history of sporadic colorectal cancer (CRC) are 2–2.5-fold more likely to develop the disease [1,2]. Many organisations recommend that first-degree relatives (FDRs) of CRC patients undergo regular colonoscopic surveillance, although optimal strategies are not established [3]. In Europe, the most common approach to identify the individuals at risk of familial CRC * Corresponding author. Tel.: +39 0543 739455; fax: +39 0543 739459. E-mail address: [email protected] (L. Bucchi). 1877-7821/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.canep.2013.04.004
is case finding [4]. Persons are interviewed for their family history when they attend primary health care providers, and are referred to specialised reference centres [5–8] if the collected information is suspicious. The European guidelines for CRC screening recommend that FDRs be excluded from faecal occult blood test (FOBT) screening programmes only if alternative surveillance models are in place [9]. In general, those participants reporting a specific family history are referred for specialist care [4]. A different model is being explored in Italy. Several regional health authorities have implemented surveillance schemes that
470
P. Sassoli de Bianchi et al. / Cancer Epidemiology 37 (2013) 469–473
are nested within local FOBT screening programmes, and where colonoscopy is directly delivered by screening centres. The effects of such an innovative approach to the management of familial CRC, however, have never been documented. The objectives of this study from the Emilia-Romagna Region (northern Italy) were to assess the results of selection of FDRs and to evaluate the detected prevalence of disease.
2. Patients and methods 2.1. Setting The CRC screening programme of the regional Department of Health is divided into three intervention arms: (A) residents aged 50–69 (N = 1,105,000) are offered two-yearly, single-sample
Fig. 1. Design and results of the intervention. The procedure of identification and selection of first-degree relatives of screen-detected colorectal cancer patients is illustrated step by step. At each step, three numbers are given, namely: the number of subjects with incomplete procedure and thus not evaluable; the number of subjects successfully selected for the next step; and the number of subjects who were not selected. In the right-hand column of the figure, the proportion of evaluable subjects successfully selected for the next step is shown.
P. Sassoli de Bianchi et al. / Cancer Epidemiology 37 (2013) 469–473
immunochemical FOBT; (B) residents aged 70–74 years attending family physicians are offered one-time colonoscopy; and (C) FDRs of CRC patients are offered five-yearly colonoscopy. The intervention arm A uses a one-day immunochemical FOBT without dietary restrictions (OC-Sensor Micro, Eiken Chemical, Tokyo, Japan) which is distributed and collected, within 3 days of stool sampling, through primary care facilities. A positive FOBT result is defined as 100 ng/ml faecal haemoglobin. The intervention arm C, according to the original planning, had to include three phases respectively targeted at: (C1) FDRs aged 40–74 years of CRC patients diagnosed by FOBT screening; (C2) FDRs of patients aged 69 years diagnosed in the routine health care setting after the start of FOBT screening; and (C3) FDRs of prevalent patients aged 69 years and diagnosed with CRC before the start of FOBT screening. The intervention arm A was initiated in early 2005, and phase C1 six months later. Phase C2 has been implemented in 6/11 health care districts. Phase C3 has been postponed. This study focuses on phase C1. 2.2. Design In Fig. 1, the procedure for identification and selection of FDRs of screen-detected CRC patients is illustrated (along with the results) in the form of a flow chart. After surgical treatment, the screening centre informs the index screen-detected CRC patient that his (or her) FDRs are at increased risk of disease, and asks his consent to offer them a colonoscopy (step 1). If the index patient gives his consent, he is asked to provide name, birth date, address, and telephone number of his FDRs (step 2). At step 4, a check for demographic eligibility of FDRs is done (exclusion criteria: death, age <40 years or 75 years, and residence elsewhere than in the Emilia-Romagna Region). FDRs aged <40 years, temporarily not eligible, are recorded in a dedicated file and later contacted. At step 5, FDRs are contacted by telephone and a second eligibility check is done (exclusion criteria: the same as above plus previous diagnosis of CRC and of colorectal polyp with follow-up still in progress, severe illness contraindicating colonoscopy, and colonoscopy within 5 years). Eligible FDRs are invited for a face-to-face consultation and, if they attend (step 7), they are offered colonoscopy unless they report having undergone it after phone contact (step 8). 2.3. Data For this study, two anonymous datasets were created using data from screening centres (N = 11): one containing information on selection of FDRs of CRC patients detected by FOBT screening between 2005 and 2010, and the other composed of information on the results of colonoscopy. FDRs were followed-up until 31 December 2011. FDRs who had previously had a negative screening FOBT were identified from the regional, anonymous database of screening tests using their personal identification number. 2.4. Statistical methods Patient subgroups were compared for proportions using the Pearson chi-square test. Trends in proportions were evaluated using the chi-square test for linear-by-linear association. Group comparisons for continuous variables were performed using the Mann–Whitney test. All tests were two-tailed with the alpha value set at 0.05. The probability, with 95% confidence interval (CI), for a registered FDR to undergo colonoscopy and to be diagnosed with CRC and advanced adenoma was estimated using the Kaplan– Meier method with censoring for incomplete follow-up.
471
Sex- and age-standardised prevalence rate ratios were calculated to compare the prevalence of disease among FDRs with that expected based on findings from (a) the colonoscopy arm of the SCORE3 screening trial targeting the general population of northern Italy [10], and (b) the subjects undergoing colonoscopy for a positive FOBT in the regional screening programme. The estimate of complete prevalence of CRC on 1 January 2005 was obtained from a national Working Group [11]. The number of incident CRC cases 2005–2010 was obtained from the regional CRC Registry. This observational study had institutional review board approval. 3. Results 3.1. Identification and selection of FDRs In the right-hand part of Fig. 1, the proportion of evaluable subjects successfully selected at each step of the procedure is shown. The study included 9319 FDRs. At steps 4 and 5, a total of 7475 subjects were excluded because of demographic reasons (death, age, and residence status) (N = 6811), previous diagnosis of CRC (N = 70), recent colonoscopy (N = 450), and other and unspecified reasons (N = 144). After steps 4 and 5, the proportion of FDRs still eligible was 0.19 (95% CI: 0.18– 0.20). At step 9, FDRs still eligible were offered colonoscopy and 30% did not accept it. Refusal was more frequent among younger subjects (median age, 58 years vs. 61 years for refusers vs. acceptors; P < 0.0001), and among subjects without previous negative screening FOBT (39.6% vs. 23.7%; P < 0.0001). Conversely, it was independent of sex and calendar year (test for trend). The probability of a registered FDR (step 3) undergoing colonoscopy was 0.11 (95% CI: 0.11–0.12). The prevalence of previous negative screening FOBT among FDRs undergoing colonoscopy was 62.6% on average, and increased from 5.0% at age 40–49 to 82.7% at age 70. Subjects who had had a negative FOBT during the last two years were 53.3%. 3.2. Detected prevalence of disease This is shown in Table 1. The probability of a registered FDR being diagnosed with CRC and advanced adenoma was 1.4 (95% CI: 0.7–2.4) per 1000 and 12.3 (10.1–14.9) per 1000, respectively. 3.3. Ratio of detected to expected prevalence of disease This is shown in Table 2. Compared with the general population enrolled in the SCORE3 trial, FDRs had an almost equal prevalence of CRC and a 40–50% greater prevalence of adenoma. The Table 1 Number and prevalence rate (%) of colorectal cancer and adenoma among firstdegree relatives undergoing surveillance colonoscopy. Age (years)
Total FDRs
40–49 50–59 60–69 70
98 303 446 79
Totala
926
CRC 0 2 7 2
(0.0) (0.7) (1.6) (2.5)
11 (1.2)
Advanced adenoma 6 29 58 7
(6.1) (9.6) (13.0) (8.9)
100 (10.8)
Non-advanced adenoma 14 60 89 23
(14.3) (19.8) (20.0) (29.1)
186 (20.1)
Abbreviations: FDRs, first-degree relatives; CRC, colorectal cancer. Advanced adenoma was defined as a polyp size of 10 mm or as a polyp containing >20% villous features or high-grade dysplasia. a Twelve of the total number of 938 patients indicated in Fig. 1 were excluded from the table because they were aged <40 years.
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Table 2 Ratio between the prevalence of colorectal cancer and adenoma among first-degree relatives undergoing surveillance colonoscopy and that expected based on reference data from different colonoscopic studies. Referent Source
Patients
SCORE3 triala Emilia-Romagna Regionb Emilia-Romagna Regionc
General population With positive FOBT (1st) With positive FOBT (2nd+)
Age
CRC
Advanced adenoma
Non-advanced adenoma
55–64 50–69 50–69
0.91 (0.19–2.66) 0.19 (0.10–0.35) 0.42 (0.21–0.75)
1.48 (1.04–2.05) 0.35 (0.28–0.42) 0.48 (0.39–0.59)
1.41 (1.09–1.79) 1.46 (1.25–1.70) 0.99 (0.85–1.16)
Abbreviations: CRC, colorectal cancer; FOBT, faecal occult blood test; 2nd+, second and subsequent. Prevalence rate ratios are standardised for age (5-year groups) and sex; numbers in parentheses are 95% confidence intervals. a Italian multicentre randomised trial of CRC screening (colonoscopy arm), 2002–2004 [10] (unpublished data courtesy of the Authors). b Local population-based FOBT screening programme, 2005–2009 (unpublished data). c Local population-based FOBT screening programme, 2007–2009 (unpublished data).
prevalence of CRC was 19% and 42% of that expected based on findings from subjects testing positive on their first and, respectively, second and subsequent screening FOBT. The corresponding figures for advanced adenoma were 35% and 48%. 3.4. Public health impact of the intervention Screen-detected CRC patients reported to the regional CRC Registry in 2005–2010 (N = 3790) were 2.45-fold less than patients aged 69 years with prevalent CRC to be targeted in phase C3 (N = 9283), and 1.85-fold less than incident CRC patients aged 69 years diagnosed in the routine health care setting (N = 6997) who were only partially targeted in phase C2. The nine cancers detected among FDRs aged 50–69 years (Table 1) accounted for 0.1% of total patients of the same age reported to the CRC Registry over the same period (N = 9672). 4. Discussion The rationale of this intervention was the idea that the effectiveness of FOBT screening can be maximised if the preventive strategy is expanded to include the colonoscopic surveillance of FDRs of screen-detected CRC patients. The results contrast greatly with expectations. The probability for a registered FDR to be eligible for, and accept, colonoscopy was as low as 11%, and the detected prevalence of disease was less than expected because of the high proportion of subjects with recent negative FOBT results. The population of prevalent CRC patients in a given geographic area is almost impossible to identify in its entirety, since cancer registries are not ubiquitous and most of them cannot provide long-term incidence data. If this is the problem, however, targeting the FDRs of screen-detected CRC patients is not a solution. This approach suffers from poor sensitivity, because screen-detected patients are a minority of total CRC patients in a population, and poor specificity, because they provide a list of FDRs who have a very low likelihood of being eligible for, and accepting, colonoscopy. Moreover, the process of eligibility verification is laborious and time-consuming, which caused phase C2 of the regional programme to be incompletely implemented, and phase C3 to be postponed. Total nursing time expenditure for each patient undergoing colonoscopy averaged 3 h and 50 min according to a rough estimate from 3 district screening centres with administrative data of sufficient quality. This is the first point of weakness of this surveillance model. The prevalence of disease among FDRs was less than expected. A first-degree family history of CRC increases the risk of disease by 2–2.5-fold [1,2], whereas the yield of CRC in our data was similar to the general population [10], and the yield of adenoma was only 40– 50% greater. The reason for these modest findings was a 63% prevalence of previous negative FOBT. Noteworthy, a previous
negative screening FOBT was a strong predictor of acceptance of colonoscopy. This is the second point of weakness in this surveillance model. The risk decrease resulting from a recent negative FOBT is larger than the increase associated with a first-degree family history of CRC. Italian studies have reported an incidence decrease by 6.5 times during the first year after a negative FOBT and 2.5–3.2 times during the second year [12,13]. Under these conditions, the positive predictive value of a screening FOBT in an average-risk subject is greater than that of a first-degree family history. It clearly appears that FDRs with a recent negative FOBT should not receive colonoscopy. If they were excluded from the intervention, however, this would further reduce the already marginal proportion of subjects undergoing colonoscopy. Due to this marginal proportion, coupled with a low prevalence of disease, the public health impact of the intervention was nil. The detected number of cancers at age 50–69 years was 0.1% of total incidence over the study period. Given these extreme levels of ineffectiveness, it appears that a population-based FOBT screening programme is a highly unsuitable setting for the provision of surveillance to FDRs of CRC patients. Conflict of interest statement The authors have no conflict of interest to declare. Funding source The authors did not receive any external funding. References [1] Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001;96(10):2992–3003. [2] Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 2006;42(2):216–27. [3] Wilschut JA, Steyerberg EW, van Leerdam ME, Lansdorp-Vogelaar I, Habbema JD, van Ballegooijen M. How much colonoscopy screening should be recommended to individuals with various degrees of family history of colorectal cancer? Cancer 2011;117(18):4166–74. [4] Vasen HF, Mo¨slein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe. Fam Cancer 2010;9(2):109–15. [5] Hunt LM, Rooney PS, Hardcastle JD, Armitage NC. Endoscopic screening of relatives of patients with colorectal cancer. Gut 1998;42(1):71–5. [6] Dove-Edwin I, Sasieni P, Adams J, Thomas HJ. Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study. BMJ 2005;331(7524): 1047–9. [7] Puente Gutie´rrez JJ, Marı´n Moreno MA, Domı´nguez Jime´nez JL, Bernal Blanco E, Dı´az Iglesias JM. Effectiveness of a colonoscopic screening programme in firstdegree relatives of patients with colorectal cancer. Colorectal Dis 2011; 13(6):145–53.
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