Invitation to Screening Colonoscopy in the Population at Familial Risk for Colorectal Cancer
A cluster-randomized study aimed at increasing participation rates
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Background: Screening colonoscopy can lower the incidence of colorectal cancer (CRC), yet participation rates are low even in groups at high risk. The goal of this study was to double the rate of participation in screening colonoscopy among persons at familial risk and then to determine the frequency of neoplasia in this risk group.
Methods: In a nationwide, cluster-randomized, multicenter study, first-degree relatives (FDR) of patients with CRC across Germany received written informational materials concerning the familial risk of CRC, along with an invitation to undergo colonoscopy. Participants in the intervention group were additionally counseled by nurses over the telephone. The primary endpoint of the study was colonoscopy uptake within 30 days.
Results: The participants’ mean age was 50.8 years. The colonoscopy uptake rates were 99/125 (79%) in the intervention group and 97/136 (71%) in the control group (RR = 1.11; 95% confidence interval [0.97; 1.28]). A polypectomy was performed in 72 of 196 asymptomatic persons (37%). In 13 cases (7%), an advanced neoplasia was detected; two of these persons had colon cancer (stages T0 and T1). 42% of the participants expressed barriers against colonoscopy. 22 reported mild side effects; there were no serious side effects.
Conclusion: Additional counseling by nurses over the telephone does not increase the participation rate. Approaching patients who have CRC is an opportunity to increase the participation of their first-degree relatives in screening colonoscopy. The frequency of neoplasia that was found in this study underscores the need to screen relatives even before they reach the usual age threshold for screening.
Colorectal cancer (CRC) is the third most frequently occurring malignant disease in the world, with more than 1.2 million new cases annually (1), and it also ranks third in cancer deaths worldwide, at over 600 000 per year. First-degree relatives (FDR) of persons with CRC are 2 to 4 times more likely to develop CRC themselves (2, 3). The need for a more intense screening of this population is thus supported by empirical data (4, 5).
Colonoscopy is considered the gold standard for early detection of CRC. It enables highly sensitive identification and simultaneous excision of precursor lesions (6, 7). A German case–control study showed that colonoscopy lowers the risk of CRC by 90% (8). Since 2002, residents of Germany aged 55 or over have the right to screening colonoscopy. However, no invitations are issued; the participation is opportunistic. The 10-year colonoscopy uptake rate in Germany is currently only 20 to 25% (9). A German study showed that participation was higher (29%) among those with a known family history of CRC (10).
In other countries too, the colonoscopy rates among those with a familial risk of CRC are less than ideal, at 14 to 69 % (11–13). The reasons for the low uptake are the invasive nature of the procedure, with severe complications in around two of every 1000 colonoscopies (14, 15), and the need for extensive bowel preparation in advance of the examination. Other factors repeatedly shown to hold patients back from making an appointment for screening colonoscopy include lack of awareness of the options for screening (16), unawareness of the familial risk (17–19), incorrect assumptions regarding the procedure (20, 21), inadequate communication within the family (22), and socioeconomic factors (23, 24).
The explicit recommendation by a physician (25, 26) and individual counseling with regard to existing barriers and concerns (17, 27, 28) have been shown to increase the rate of uptake of colonoscopy, by 33% and 27% respectively. We therefore set out to lay the groundwork for active invitation and individual counseling of persons at familial risk of CRC within the framework of a nationwide screening colonoscopy program and in accordance with current data protection laws. The study on transdisciplinary promotion of participation in screening among persons with familial increased risk of CRC (FAMKOL) was carried out to establish whether active invitation and individual counseling by non-physicians raises the uptake rate of screening colonoscopy appreciably in comparison with purely written invitation. Moreover, we also sought to determine the incidence of malignancies in this population, describe the barriers to colonoscopy, and ascertain the complication rates.
Patients with a first diagnosis of CRC (index patients, IP) were recruited at 61 certified German colorectal cancer centers and three independent gastroenterological practices between December 2012 and August 2015. Based on a written training manual, all nursing staff at the respective sites attended a 2-day training course. No incentives were offered to the IP, FDR, and gastroenterologists to encourage them to participate in the study. The inclusion criteria for IP were a histologically confirmed diagnosis of CRC and the existence of one or more FDR in the age range 40 to 75 years. IP with FDR under 40 were also included if the age of the FDR was no more than 10 years less than that of the IP at first diagnosis. IP were excluded if they had not given written consent for their FDR to be contacted or if they had insufficient command of the German language.
Randomization was carried out at the Institute of Medical Epidemiology, Biometry, and Informatics (IMEBI) at the University of Halle, an external and independent facility, by means of computer-generated block lists with random block sizes. Individual randomization to the intervention group or the control group took place at index patient level. The IP formed the cluster criterion for the group allocation of the FDR. A cluster-randomized design was selected to avoid contamination of the study intervention by FDR in different study arms.
FDR with colonoscopy or CT colonography (CT, computed tomography) within the previous 5 years, diagnosed bowel cancer, familial adenomatous polyposis, or chronic inflammatory bowel disease were excluded. Assessment of the exclusion criteria was carried out by telephone interview after the FDR had received the study materials from the IP and given their written consent.
The IP were blinded as to their group allocation. They passed all written information to their FDR in opaque sealed envelopes. The independent gastroenterological practices were blinded as to the group allocation of the IP. However, blinding of the FDR was not possible owing to the counseling.
The study had two levels. At the level of the IP in the colorectal cancer centers, specifically trained nursing staff informed the patients of both groups about the elevated familial risk for their FDR and about the goals of the study. IP of both groups were advised to talk to their relatives specifically about bowel cancer and to encourage eligible FDR to join the study. All IP were asked to pass on, in person or by post, a study leaflet with information about the elevated familial risk and the availability of CRC screening to their FDR.
FDR of the intervention group received telephone counseling from specifically trained nursing staff at the study coordination center. The aim of these conversations was to identify barriers to screening colonoscopy and then to overcome them by counseling. Furthermore, information was provided about the sensivity, specificity, and complications of colonoscopy and other screening methods. If required, help was given in arranging appointments with an office-based gastroenterological practice. By contrast, the FDR in the control group received only the study documents and an information leaflet.
Both groups were sent written questionnaires 3 and 6 months after the beginning of the study. Neither group had any restriction on their choice of gastroenterologist for colonoscopy.
The primary endpoint of the study was the physician-confirmed colonoscopy uptake rate within 30 days of enrollment. This period was kept short to ensure that only colonoscopies connected with the study were recorded. We also included physician-confirmed cases where an appointment for colonoscopy had been made but the examination had not yet been conducted. In these cases the colonoscopy findings were recorded later. All macroscopic and histologic findings were communicated by fax to the study coordination center. The advice given by telephone was documented and categorized on standardized forms. At the 6-month follow-up we asked the FDR for whom no colonoscopy was documented why they had not participated.
The secondary endpoints were the carcinoma/adenoma detection rate, barriers to uptake of screening colonoscopy, and the spectrum of complications up to 30 days after colonoscopy.
It was calculated that 77 FDR per group would be needed to detect an absolute and clinically meaningful difference of 25% in the primary endpoint between the intervention group and the control group (17, 27, 28) with an α error of 0.05 and power (1-β) of 0.90. To take account of possible intracluster effects, we used a conservative intracluster correlation coefficient (ICC) of 0.10 (29) and an estimate of three FDR per IP. With a design effect for cluster randomization of 1.2 (30), the effective sample size rose to 93 FDR per group. On the assumption of a 50% drop-out rate, the required sample size was 186 per group.
The analysis took the form of a logistic regression model with group allocation as random effect according to the intention-to-treat principle. Because FDR of the same IP represented correlated observations, the final model was adjusted for the number of family members. We adjusted for the distance between the residence of the FDR and the recruitment site of the IP to minimize intrafamily distortions through personal contact. Chi-square tests were used for the secondary endpoints to compare the number of events in each treatment group. All hypothesis tests were two-sided with the level of significance set at 0.05. Analyses were carried out using SAS (version 9.4) and SPSS (version 23.0).
Overall, 2360 IP were screened. Of these, 1251 were excluded because they did not meet the inclusion criteria. Thus 1109 IP aged 31 to 91 years (mean 68.4, SD 10.8) were included (Figure 1). A total of 556 FDR submitted their signed agreement to participate in the study. Of these, 261 FDR aged 28 to 75 years (mean 50.8, SD 8.1) fulfilled the inclusion criteria and gave information regarding the primary endpoint. The characteristics of the FDR in the two groups were comparable at the beginning of the study, except that the control group had a significantly higher number of FDR and the age of the FDR was significantly higher in the intervention group (Table 1). The FDR in the intervention group received one episode of telephone counseling with a mean duration of 26.6 min (range 5 to 50, SD 9.7).
Altogether, 196 of the 261 FDR (75%) underwent a screening colonoscopy. The uptake rates were 99 out of 125 (79%, including 57 women) in the intervention group and 97 out of 136 (71%, including 66 women) in the control group (relative risk [RR] = 1.11; 95% confidence interval [0.97; 1.28]; p = 0.16). The RR decreased to 1.09 ([0.95; −1.25]; p = 0.22) after adjustment for cluster size and the distance between recruitment center and residence of FDR. In neither case were there any significant differences between the intervention group and the control group.
CRC and advanced adenoma
Polypectomy was carried out in 72 of 196 asymptomatic persons (37%), with no significant difference between the intervention group and the control group (RR = 1.05 [0.59; 1.88]). A total of 75 adenomas were detected in 45 persons. Twelve adenomas in 11 patients were classified advanced (size >1 cm, villous components, or high-grade dysplasia). Two cases of CRC stage T0 and T1 in patients aged 55 and 67 years were reported to the cancer registry. The detection rate of advanced neoplasia of the colon was therefore 6.6% (13 of 196 FDR; RR = 2.21 [0.70; 6.92]).
Barriers to colonoscopy
Barriers to colonoscopy were discussed during the telephone counseling, so these data refer only to the 125 FDR of the intervention group. Serious concerns about colonoscopy were found in 54 of these FDR (43%), who were allowed to give multiple answers when asked about their concerns (Table 2). At 6-month follow-up, 61 FDR across the two groups stated their reasons for not having had a colonoscopy (Table 3).
Information on complications of colonoscopy was available for 176 of the 196 patients. Altogether, 22 of 176 FDR (13%) experienced minor complications within 30 days (intervention 14/89 versus control 8/87; RR = 1.31 [0.92; 1.86]). The most frequently reported events were flatulence in the first 3 days after the intervention (12/176) and mild pain for up to 7 days (11/176). No major complications occurred (Table 4).
Our study, carried out in a large number of colorectal cancer centers, showed the efficacy of the invitation of first-degree relatives to undergo screening colonoscopy. The colonoscopy uptake rate of 75% is 2.7 times higher than achieved with the standard opportunistic screening in Germany (9, 10), where all members of public health insurance schemes are eligible for colonoscopy from the age of 55 years. Additional personal counseling increased the uptake nonsignificantly by just under 8%, whereby almost half of the FDR expressed barriers to colonoscopy. The absence of major complications in a 30-day period following the procedure confirms the low risk profile of screening colonoscopy (14, 15, 31). Aversion to the necessary bowel preparation and fear of pain were named significantly more often as reasons for not having a colonoscopy in the group that was counseled by nurses. In contrast, there were no clinically meaningful or statistically significant differences with regard to the adenoma detection rate. Future efforts should therefore be directed towards reducing unfounded anxiety about the bowel cleansing process and pain in connection with colonoscopy.
Advanced malignancies were detected in 7% of our study population with an average age of 50.8 years. The corresponding detection rate in a USA population with a similar average age but no familial risk of CRC was 2.1% (2). This contrast underlines the importance of screening colonoscopy for persons at familial risk—including those under the hitherto applicable age limits (32–35).
The unadjusted odds ratio (OR) of 1.53 [0.97; 2.71] in our study is consistent with the findings of previous investigations in which FDR were approached via IP and the effect of individual counseling was evaluated (Figure 2). However, the interventions, study populations, and relevant laws are comparable to only a limited extent. Ingrand et al. found that individual counseling increased the colonoscopy uptake rate by 21% (to 56.3%) compared with provision of information material alone (36). In contrast to our study, their intervention also included standardized counseling of the patients by independently practicing gastroenterologists. Studies of other screening procedures (fecal occult blood test, flexible sigmoidoscopy) also found that individual counseling increased the uptake rate by 11 to 12% (17, 37). On the other hand, some studies found no or only slight effects for the provision of individualized information (12, 38). A possible explanation for the wide variation in results emerged from a study on information preferences that showed contrasting effects of sending one or two standardized newsletters by e-mail (39). In comparison with standardized information, individualized information clearly increased colonoscopy uptake among those probands who preferred to weigh up the advantages and disadvantages of various screening options themselves (26% versus 17%; p<0.05). In contrast, the group of probands with a preference for a directive style of communication showed lower colonoscopy uptake when provided with individualized information materials (18% versus 24%; p>0.05).
The inclusion of 64 centers from all over the country ensures that the results are representative for Germany and simultaneously confirms that such a program is practicable. Despite the complex nature of the study, colonoscopy of the FDR who opted for screening took place on average as soon as around 70 days after the initial approach to the IP. The requirement for confirmation of colonoscopy by a physician permits precise assessment of the primary endpoint. Nevertheless, there are limitations with regard to the generalizability of our findings. Due to data protection regulations, we could not approach the FDR directly. The advice that therefore had to be given to the IP about passing on the information to their relatives very probably acted as an unintended intervention itself and also contributed to the failure to attain the planned number of cases. For this reason, the observed nonsignificant difference between the the intervention group and the control group is of only limited generalizability. However, a study arm without any intervention would have been questionable from an ethical perspective.
Moreover, we restricted ourselves to colonoscopy uptake as endpoint, not recording alternative forms of screening. The efficacy of the intervention in increasing the uptake of screening measures may therefore have been underestimated (40). Furthermore, it is probable that intrafamily effects moderate the uptake (22). It is not clear whether adjustment for the number of eligible family members helped to reduce this effect sufficiently.
Active invitation of first-degree relatives resulted in a higher rate of colonoscopy than the conventional opportunistic screening. Judging from the findings of earlier studies (25, 26), additional counseling by physicians might have increased the colonoscopy uptake rate further still. Although the result did not achieve statistical significance, the high rate of barriers to colonoscopy suggests that it may be necessary to offer individual counseling to members of risk groups.
The probands included persons under 50 years of age who would not have been eligible for the existing screening colonoscopy program. The observed rate of advanced neoplasia confirms the need for screening the relatives of CRC patients—including those outside the current age limits. Funding bodies and the health care system should take steps to tailor CRC screening to risk groups, which will involve individualization.
Future research should examine the effect of the FAMKOL intervention on the uptake of other screening methods. Moreover, to optimize the efficacy of the screening program, the follow-up of patients with advanced adenoma should also be included (e1).
We thank Dr. Thomas Ettrich (Department of Internal Medicine, Ulm University Hospital) for evaluation and classification of the histological materials, Dr. Katharina Hirsch (Institute for Medical Epidemiology, Biometrics, and Information Science, Faculty of Medicine, University of Halle-Wittenberg) for the statistical analyses, and all of the families, nursing staff, and physicians who took part in the study.
The study was approved before the beginning of recruitment by the ethics committee of the Faculty of Medicine, University of Halle-Wittenberg (no. 2012-47) and the ethics committees of the medical associations of all 16 federal states of Germany under the title “Transdisziplinäre Förderung der Screeningteilnahme bei Personen mit familiär erhöhtem Risiko für kolorektale Karzinome. Eine prospektive clusterrandomisierte kontrollierte Multi-Center-Studie (FAMKOL)” [Transdisciplinary promotion of participation in screening among persons with familial increased risk of colorectal cancer. A prospective cluster-randomized controlled multicenter study (FAMKOL)].
Clinicaltrials.gov registration number: NCT01903395
The study was financed by grant FKz NKP 332–031 from the German Federal Ministry for Health as part of the National Cancer Plan.
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript submitted on 19 January 2018, revised version accepted on
30 May 2018
Translated from the original German by David Roseveare
Dr. rer. medic. Alexander Bauer
Institut für Allgemeinmedizin
Magdeburger Str. 8
06112 Halle, Germany
For eReferences please refer to:
Dr. Alexander Bauer, Prof. Thomas Frese
Institute for Health and Nursing Sciences, Faculty of Medicine, University of Halle-Wittenberg, Halle:
Dr. Stephanie Boese, Prof. Margarete Landenberger
Director Emeritus, Department of Medicine C, Ludwigshafen Hospital, c/o LebensBlicke Foundation, Ludwigshafen:
Prof. Jürgen F. Riemann
Department of Internal Medicine I, Ulm University Hospital, Ulm: Prof. Thomas Seufferlein
Department of Medicine I, Braunschweig Municipal Hospital, Braunschweig: Prof. Max Reinshagen
Department of Gastroenterology, Celle General Hospital, Celle: Prof. Stephan Hollerbach
Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen:
Prof. Ulrike Haug
Faculty of Human and Health Sciences, University of Bremen: Prof. Ulrike Haug
Institute for Medical Epidemiology, Biometrics, and Information Science, Faculty of Medicine, University of Halle-Wittenberg, Halle:
PD Dr. Susanne Unverzagt
Nursing Research Unit, Halle University Hospital, Halle: Madeleine Ritter-Herschbach, MScN, RN; Dr. Patrick Jahn
Department for Health, University of Bath, Claverton Down, Bath, UK : Prof. Michael Harris
|1.||Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017; 66: 683–91 CrossRef MEDLINE|
|2.||Samadder NJ, Curtin K, Tuohy TMF, et al.: Increased risk of colorectal neoplasia among family members of patients with colorectal cancer: a population-based study in Utah. Gastroenterology 2014; 147: 814–U169 CrossRef MEDLINE|
|3.||Schoen RE, Razzak A, Yu KJ, et al.: Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer. Gastroenterology 2015; 149: 1438–45.e1 CrossRef MEDLINE PubMed Central|
|4.||Ait Ouakrim D, Lockett T, Boussioutas A, Hopper JL, Jenkins MA: Screening participation for people at increased risk of colorectal cancer due to family history: a systematic review and meta-analysis. Fam Cancer 2013; 12: 459–72 CrossRefMEDLINE|
|5.||Sulz MC, Meyenberger C, Sawatzki M: How is the increased risk of colorectal cancer in first-degree relatives of patients communicated? Eur J Gastroenterol Hepatol 2014; 26: 222–8 CrossRef MEDLINE|
|6.||Scalise P, Mantarro A, Pancrazi F, Neri E: Computed tomography colonography for the practicing radiologist: a review of current recommendations on methodology and clinical indications. World J Radiol 2016; 8: 472–83 CrossRef MEDLINE PubMed Central|
|7.||Strum WB: Colorectal adenomas. New Eng J Med 2016; 374: 1065–75 CrossRef MEDLINE|
|8.||Brenner H, Chang-Claude J, Jansen L, Knebel P, Stock C, Hoffmeister M: Reduced risk of colorectal cancer up to 10 years after screening, surveillance, or diagnostic colonoscopy. Gastroenterology 2014; 146: 709–17 CrossRef MEDLINE|
|9.||Brenner H, Altenhofen L, Stock C, Hoffmeister M: Expected long-term impact of the German screening colonoscopy programme on colorectal cancer prevention: analysis based on 4,407,971 screening colonoscopies. Eur J Cancer 2015; 51: 1346–53 CrossRef MEDLINE|
|10.||Ruthotto F, Papendorf F, Wegener G, et al.: Participation in screening colonoscopy in first-degree relatives from patients with colorectal cancer. Ann Oncol 2007; 18: 1518–22 CrossRef MEDLINE|
|11.||Rees G, Martin PR, Macrae FA: Screening participation in individuals with a family history of colorectal cancer: a review. Eur J Cancer Care 2008; 17: 221–32 CrossRef MEDLINE|
|12.||Rawl SM, Champion VL, Scott LL, et al.: A randomized trial of two print interventions to increase colon cancer screening among first-degree relatives. Patient Educ Couns 2008; 71: 215–27 CrossRef MEDLINE PubMed Central|
|13.||Senore C, Inadomi J, Segnan N, Bellisario C, Hassan C: Optimising colorectal cancer screening acceptance: a review. Gut 2015; 64: 1158–77 CrossRef MEDLINE|
|14.||Castro G, Azrak MF, Seeff LC, Royalty J: Outpatient colonoscopy complications in the CDC‘s Colorectal Cancer Screening Demonstration Program: a prospective analysis. Cancer 2013; 15: 2849–54 CrossRef MEDLINE|
|15.||Ko CW, Riffle S, Michaels L, et al.: Serious complications within 30 days of screening and surveillance colonoscopy are uncommon. Clin Gastroenterol Hepatol 2010; 8: 166–73 CrossRef MEDLINE PubMed Central|
|16.||Basch CH, Basch CE, Zybert P, Wolf RL: Failure of colonoscopy knowledge to predict colonoscopy uptake. J Community Health 2016; 41: 1094–9 CrossRef MEDLINE|
|17.||Glanz K, Steffen AD, Taglialatela LA: Effects of colon cancer risk counseling for first-degree relatives. Cancer Epidemiol Biomarkers Prev 2007; 16: 1485–91 CrossRef MEDLINE|
|18.||Cameron E, Rose S, Carey M: Assessment of family history of colorectal cancer in primary care: perceptions of first degree relatives of people with colorectal cancer. Patient Educ Couns 2014; 94: 427–31 CrossRef MEDLINE|
|19.||Kinney AY, Boonyasiriwat W, Walters ST, et al.: Telehealth personalized cancer risk communication to motivate colonoscopy in relatives of patients with colorectal cancer: the family CARE randomized controlled trial. J Clin Oncol 2014; 32: 654–62 CrossRef MEDLINE PubMed Central|
|20.||Bhise V, Modi V, Kalavar A, et al.: Patient-reported attributions for missed colonoscopy appointments in two large healthcare systems. Dig Dis Sci 2016; 61: 1853–61 CrossRef MEDLINE|
|21.||Basch CH, Basch CE, Zybert P, Wolf RL: Fear as a barrier to asymptomatic colonoscopy screening in an urban minority population with health insurance. J Community Health 2016; 41: 818–24 CrossRef MEDLINE|
|22.||Lowery JT, Ahnen DJ, Schroy PC, 3rd, et al.: Understanding the contribution of family history to colorectal cancer risk and its clinical implications: a state-of-the-science review. Cancer 2016; 122: 2633–45 CrossRef MEDLINE PubMed Central|
|23.||Wardle J, von Wagner C, Kralj-Hans I, et al.: Effects of evidence-based strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme (ASCEND): four cluster-randomised controlled trials. Lancet 2016; 387: 751–9 CrossRef|
|24.||Steffen LE, Boucher KM, Damron BH, et al.: Efficacy of a telehealth intervention on colonoscopy uptake when cost is a barrier: the family CARE cluster randomized controlled trial. Cancer Epidemiol Biomarkers Prev 2015; 24: 1311–8 CrossRef MEDLINE PubMed Central|
|25.||Boguradzka A, Wiszniewski M, Kaminski MF, et al.: The effect of primary care physician counseling on participation rate and use of sedation in colonoscopy-based colorectal cancer screening program—a randomized controlled study. Scand J Gastroenterol 2014; 49: 878–84 CrossRef MEDLINE|
|26.||Dignan M, Shelton B, Slone SA, et al.: Effectiveness of a primary care practice intervention for increasing colorectal cancer screening in Appalachian Kentucky. Prev Med 2014; 58: 70–4 CrossRef MEDLINE PubMed Central|
|27.||Meng W, Bi XW, Bai XY, et al.: Barrier-focused intervention to increase colonoscopy attendance among nonadherent high-risk populations. World J Gastroenterol 2009; 15: 3920–5 CrossRef MEDLINE PubMed Central|
|28.||Sriphanlop P, Hennelly MO, Sperling D, Villagra C, Jandorf L: Increasing referral rate for screening colonoscopy through patient education and activation at a primary care clinic in New York City. Patient Educ Couns 2016; 99: 1427–31 CrossRef MEDLINE|
|29.||Lapointe J, Abdous B, Camden S, et al.: Influence of the family cluster effect on psychosocial variables in families undergoing BRCA1/2 genetic testing for cancer susceptibility. Psychooncology 2012; 21: 515–23 CrossRef MEDLINE|
|30.||Coupland C, DiGuiseppi C: The design and use of cluster randomised controlled trials in evaluating injury prevention interventions: part 2. Design effect, sample size calculations and methods for analysis. Injury Prev 2010; 16: 132–6 CrossRef MEDLINE|
|31.||Zwink N, Holleczek B, Stegmaier C, Hoffmeister M, Brenner H: Complication rates in colonoscopy screening for cancer. Dtsch Arztebl Int 2017; 114: 321–7 VOLLTEXT|
|32.||Menges M, Fischinger J, Gartner B, et al.: Screening colonoscopy in 40- to 50-year-old first-degree relatives of patients with colorectal cancer is efficient: a controlled multicentre study. Int J Colorectal Dis 2006; 21: 301–7 CrossRef CrossRef MEDLINE|
|33.||Armelao F, Orlandi PG, Tasini E, et al.: High uptake of colonoscopy in first-degree relatives of patients with colorectal cancer in a healthcare region: a population-based, prospective study. Endoscopy 2010; 42: 15–21 CrossRef MEDLINE|
|34.||Del Vecchio Blanco G, Cretella M, Paoluzi OA, et al.: Adenoma, advanced adenoma and colorectal cancer prevalence in asymptomatic 40- to 49-year-old subjects with a first-degree family history of colorectal cancer. Colorectal Dis 2013; 15: 1093–9 MEDLINE|
|35.||Brenner H, Zwink N, Ludwig L, Hoffmeister M: Should screening colonoscopy be offered from age 50? Dtsch Arztebl Int 2017; 114: 94–100 CrossRef|
|36.||Ingrand I, Defossez G, Richer JP, et al.: Colonoscopy uptake for high-risk individuals with a family history of colorectal neoplasia: a multicenter, randomized trial of tailored counseling versus standard information. Medicine (Baltimore) 2016; 95: e4303 CrossRef MEDLINE PubMed Central|
|37.||Manne SL, Coups EJ, Markowitz A, et al.: A randomized trial of generic versus tailored interventions to increase colorectal cancer screening among intermediate risk siblings. Ann Behav Med 2009; 37: 207–17 CrossRef MEDLINE PubMed Central|
|38.||Hoffmeister M, Holleczek B, Zwink N, Stock C, Stegmaier C, Brenner H: Screening for bowel cancer: increasing participation via personal invitation. Dtsch Arztebl Int 2017; 114: 87–93 VOLLTEXT|
|39.||Resnicow K, Zhou Y, Hawley S, et al.: Communication preference moderates the effect of a tailored intervention to increase colorectal cancer screening among African Americans. Patient Educ Couns 2014; 97: 370–5 CrossRef MEDLINE|
|40.||Aubin-Auger I, Laouenan C, Le Bel J, et al.: Efficacy of communication skills training on colorectal cancer screening by GPs: a cluster randomised controlled trial. Eur J Cancer Care 2016; 25: 18–26 CrossRef MEDLINE|
|e1.||Lin JS, Piper MA, Perdue LA, et al.: Screening for colorectal cancer: Updated evidence report and systematic review for the US preventive services task force. JAMA 2016; 315: 2576–94 CrossRef MEDLINE|