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Are Colorectal Cancer Screening Recommendations for First-Degree Relatives of Patients With Adenomas Too Aggressive?
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:308 –313
PERSPECTIVE Are Colorectal Cancer Screening Recommendations for First-Degree Relatives of Patients With Adenomas Too Aggressive? GREGORY L. AUSTIN,* JONATHAN I. GOLDSTEIN,* STEVANY L. PETERS,‡ and DENNIS J. AHNEN* *Division of Gastroenterology and Hepatology, University of Colorado Denver, Aurora, Colorado; and ‡Huron Gastroenterology Center for Digestive Care, Ypsilanti, Michigan
Consensus guidelines of the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommend first-degree relatives of individuals diagnosed with an adenoma before age 60 should be screened every 5 years with colonoscopy starting at age 40. This is the identical recommendation for those with a first-degree relative diagnosed with colorectal cancer (CRC) before age 60. There is good evidence that first-degree relatives of individuals diagnosed with CRC before age 60 are at substantially increased risk for developing cancer at a young age. However, it is unclear whether an individual with a first-degree relative with an adenoma diagnosed before age 60 is at increased risk of CRC. Because not all adenomas portend the same cancer risk in the individual who has the adenoma, they would not be expected to portend the same risk in their first-degree relatives. Because of these uncertainties, the US Preventive Services Task Force does not recommend more aggressive screening of first-degree relatives of individuals with an adenoma. The adenoma detection rate for individuals 50 to 59 years old without a first-degree relative with CRC is sufficiently high (approximately 25%–30%) that almost half the population would be high risk on the basis of one first-degree relative having an adenoma. Given the weakness of evidence supporting the guidelines, suboptimal levels of screening in the general population, and lack of resources to comply with the recommendation, first-degree relatives of individuals with adenomas should be screened as average-risk persons until more compelling data are available to justify more aggressive screening. Keywords: Colorectal Cancer; Screening Guidelines; Adenoma.
initial colonoscopy was reduced by 76%–90% with polypectomy.2 Although CRC screening is generally accepted as an effective way to reduce both the incidence and mortality of CRC, the optimal screening strategy for specific populations is unclear.3 Experts agree that screening for individuals at average risk for CRC should begin at age 50, although recently both the American College of Gastroenterology and the American Society of Gastrointestinal Endoscopy have recommended that African Americans start being screened at age 45.4,5 Some groups have been identified who are at a greatly increased risk for CRC, such as individuals with inflammatory bowel disease and those with a family history of familial adenomatous polyposis or hereditary non-polyposis colon cancer (Lynch syndrome). There is a general consensus that these high-risk groups require earlier and more frequent CRC screening. Other higher-risk subgroups represent areas of considerable uncertainty. Individuals with a first-degree relative (FDR) with CRC have been shown to be at increased risk for CRC themselves, and the risk varies with both the number of FDRs with CRC and the age of the CRC in the FDRs.6,7 Screening guidelines generally recommend earlier (age 40 or 10 years younger than the earliest cancer in the family) and more frequent CRC screening if the CRC in the FDR was diagnosed before the age of 60, or if there is more than 1 FDR with CRC.8,9 However, the consensus guidelines from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (ACSMSTF-ACR) also recommend the same earlier (starting at age 40) and more frequent CRC screening for FDRs of patients with adenomatous polyps (adenomas) of the colon diagnosed before age 60.10 We review the evidence for and implications of recommending this more intensive colonoscopic screening for the FDRs of patients with colorectal adenomas.
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Review of Current Recommendations Rationale for Colorectal Cancer Screening
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olorectal cancer (CRC) is the second leading cause of cancer death in the United States. For 2009, it was estimated that 146,970 individuals were diagnosed and that 49,920 died of CRC.1 CRC is also one of the few cancers for which effective screening strategies are available both for early detection of existent cancers and also for prevention of CRC by adenoma detection and removal. As such, screening for CRC has important public health implications. In the National Polyp Study, the incidence of CRC in individuals with an adenoma on
In 2008, the American Cancer Society, the US MultiSociety Task Force on Colorectal Cancer (composed primarily of gastroenterologists), and the American College of Radiology Abbreviations used in this paper: ACS-MSTF-ACR, American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology; CI, confidence interval; CRC, colorectal cancer; FDR, first-degree relative; OR, odds ratio; RR, relative risk; USPSTF, United States Preventive Services Task Force. © 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.01.004
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published consensus guidelines for CRC screening.10 The ACSMSTF-ACR guidelines specifically recommended that patients with either CRC or adenomatous polyps (adenomas) in an FDR before age 60 should begin screening for CRC at 40 years of age with colonoscopy at 5-year intervals. The other major set of CRC screening guidelines from the United States Preventive Services Task Force (USPSTF) do not recommend earlier screening for those with a family history of CRC or adenomas, although they do state that earlier screening might be reasonable for those with an FDR who developed CRC at a younger age or had multiple FDRs affected with CRC.11
Rationale for More Intensive Screening The increased risk of CRC in FDRs of patients with CRC is well-characterized,6,12,13 but the evidence for more aggressive screening is best supported by the prospective study of more than 119,000 individuals by Fuchs et al.7 In this study, they showed that individuals 30 to 44 years old with an FDR with CRC were 5.37 times as likely to be diagnosed with CRC (compared with those without an FDR with CRC), and that individuals 45 to 49 years old with an FDR with CRC were 3.85 times as likely to be diagnosed with CRC during the follow-up period. They demonstrated that the cumulative incidence of CRC at age 40 in those with an FDR with CRC was similar to the cumulative incidence of CRC at age 50 of those without an FDR with CRC. This provides the evidence base for justifying starting CRC screening at age 40 for those with an FDR with CRC. The increased risk of CRC in FDRs of patients with adenomas is less well-defined. The PubMed database was systematically searched independently by 3 of the authors (G.A., J.G., S.P.). The following keywords were used to identify relevant articles published between September 1966 and April 2010: (1) colon, rectal, or colorectal cancer, adenoma, polyp, adenomatous polyp, or tumor; (2) family history; familial; relative(s); first-degree. This search strategy yielded all articles cited in the ACS-MSTF-ACR guidelines and a previous meta-analysis. All articles that cited the identified articles were also identified. The results of keyword searches were combined by using the terms “and/or.” To date, there are not any prospective studies to assess the risk of developing CRC in FDRs of patients with adenomas. The association of CRC in FDRs of those with adenomas is largely based on case-control studies in which adenoma cases (detected during colonoscopy) were surveyed as to whether any of their FDRs had CRC. A majority of the published studies support the finding that patients with 1 or more adenomas are more likely to have an FDR with CRC.14 –20 A previous meta-analysis found a pooled relative risk (RR) of 1.99 (95% confidence interval [CI], 1.55– 2.55).13 These studies are the evidence for the recommendation for earlier and more frequent screening in FDRs of patients with adenomas. However, the basic design of these studies did not address the prospective incident risk of being diagnosed with CRC for an FDR of an individual with an adenoma. In addition, the index adenoma cases would be considered high risk because they had a family member with CRC. Furthermore, these studies were largely performed on symptomatic patients (eg, blood in stool) before the era of performing screening colonoscopy on average-risk, asymptomatic individuals starting at age 50. In a majority of studies, more than half of the adenoma cases were individuals older than the age of 60.
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Of the published studies evaluating the association between having an adenoma and having at least 1 FDR with CRC, only 4 (Table 1) have addressed the question of whether the age at which the adenoma was diagnosed influenced the patient’s odds of having an FDR with CRC, and the results are mixed. Specifically, the study by Ahsan et al14 showed that the FDRs of patients who were diagnosed with an adenoma between 51 and 60 years of age were not at increased risk for having CRC (RR, 1.22; 95% CI, 0.67–2.23) compared with the FDRs of adenomafree controls. Similarly, Lynch et al20 found that individuals who were diagnosed with an adenoma between 50 and 59 years of age were not at increased risk for having an FDR with CRC (odds ratio [OR], 1.27; 95% CI, 0.86 –1.87). In the study by Cottet et al,21 the FDRs of patients who had large adenomas (ⱖ10 mm) underwent colonoscopy. There was a nonsignificant increased risk (OR, 3.81; 95% CI, 0.92–15.87) of having an incident CRC in these FDRs if the adenoma was diagnosed in the index case before the age of 60. The study by Winawer et al15 is the only one to demonstrate a significant increase in the odds of CRC in FDRs of patients diagnosed with an adenoma between ages 50 and 59. The increased odds were specific for siblings (RR, 2.49; 95% CI, 1.37– 4.52) of the index adenoma cases, although primarily in patients who had a parent with CRC. In addition to the lack of strong evidence supporting an increased risk of CRC in FDRs of patients diagnosed with an adenoma before the age of 60, these studies have several limitations related to the recommendation that these FDRs should start screening for CRC at age 40 with colonoscopy every 5 years. The most important unanswered question is whether the FDRs of an individual with an adenoma (but without an FDR with CRC) are at greater risk for CRC compared with the FDRs of an individual without adenomas. Second, if the risk of CRC is increased, the next unanswered question is whether these FDRs are specifically at risk before the age of 50. This is a critically important question and separates the family history of adenoma recommendation from the family history of CRC recommendation. Unlike the evidence for earlier CRC risk in FDRs of those with CRC, there are limited data on the age distribution at which CRC was diagnosed in the FDRs of the adenoma cases. The study by Winawer et al15 does report an increased risk of CRC in siblings (and adjusts for the year of birth of the sibling) of those with an adenoma diagnosed between 50 and 59 years of age. However, the average age of the siblings with CRC was reported as 62.3 years, similar to the age of CRC in FDRs of the spouse controls (63.7 years), and both groups were substantially younger than the average age of CRC in the parents of adenoma subjects (73.2 years). Furthermore, the risk was greatly increased (and potentially fully attributable) if the sibling and index adenoma case had a parent who had been diagnosed with CRC. In this scenario, the index adenoma case and the sibling would have already been considered high risk because the parent had already been diagnosed with CRC. The study does not address the future risk of CRC in FDRs of a patient with an adenoma who does not have an FDR with CRC. Finally, several of the studies have evaluated other highrisk features that might increase the odds of patients with adenomas having FDRs with CRC, including size, histology, and number of adenomas. Whereas Lynch et al20 and Boutron et al22 showed that only adenomas at least 10 mm in
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Table 1. Summary of Studies Evaluating the Association of CRC in FDRs of Those With an Adenoma Study Ahsan et al,14 1998
Winawer et al,15 1996
Lynch et al,20 2003
Cottet et al,21 2007
Study populations 1554 FDRs of 244 adenoma cases, 2173 FDRs of 362 controls
Overall OR or RR for CRC
Increased CRC risk based on diagnosis of adenoma in FDR
RR, 1.7; 95% CI, 1.2–2.4
Increased CRC risk if adenoma diagnosed in FDR ⬍50 y (RR, 4.36; 95% CI, 2.24–8.51). No increased risk if adenoma detected in FDR 51–60 y (RR, 1.22; 95% CI, 0.67–2.23) 4246 FDRs of 1031 RR, 1.78; 95% CI, Increased CRC risk in siblings adenoma cases, 1.18–2.67 (but not parents) if 1411 spouse adenoma diagnosed in FDR controls 50–59 y (RR, 2.49; 95% CI, 1.37–4.52) or in FDR ⬍50 y (RR, 4.08; 95% CI, 1.56– 10.68) 1141 FDRs of adenoma OR, 1.35 (95% CI, 50- to 59-y group with cases, 1559 FDRs of 1.08–1.68) in adenoma: OR, 1.27 (95% polyp-free controls those with 1 CI, 0.86–1.87) of having an adenoma FDR with CRC. 70- to 75-y having an FDR group with adenoma: OR, with CRC 2.18 (95% CI, 1.33–3.55) of having an FDR with CRC 168 FDRs of 306 cases OR, 3.90; 95% CI, OR of large adenoma or with adenomas ⱖ10 0.89–17.01 cancer, 3.81 (95% CI, mm, 307 controls 0.92–15.87) if FDR had without family history large adenoma diagnosed of CRC/adenoma before age 60; OR, 1.82 (95% CI, 0.66–4.99) if FDR was 60 y or older
size are associated with an increased risk of having an FDR with CRC, Ahsan et al14 found increased risk for adenomas both more and less than 5 mm. Conversely, Aitken et al23 did not find an association of having an FDR with CRC for adenomas that were either more or less than 10 mm. Equivocal results have also been reported on the basis of the histology of the adenoma, with the majority of studies demonstrating nonsignificant differences in the odds of having an FDR even if the histology revealed moderate to severe dysplasia.16,20 –23 Similarly conflicting reports have been published on whether the number of adenomas detected influences the risk of having an FDR with CRC. Lynch et al reported that only individuals with ⱖ2 adenomas were more likely to have an FDR with CRC, whereas other studies did not find that the number of adenomas influenced their reported risk association.14,16,22 Again, none of these studies answered the question of whether the FDRs of an individual with any of these high-risk features are at greater risk for CRC compared with the FDRs of individuals without these high-risk features. In summary, the evidence that FDRs of individuals with an adenoma diagnosed before the age of 60 are at increased risk for CRC is weak and inconsistent. Furthermore, there is no evidence that these FDRs are more likely to be diagnosed with CRC at an earlier age in the absence of a parent who had CRC. There are no studies that prospectively assess the incidence of CRC in FDRs of patients with adenomas (where neither the patient nor the FDRs have an FDR with CRC).
Increased risk based Age characteristics of on size? adenoma cases No heterogeneity of 68.4% were ⱖ61 y RR comparing adenomas ⬎5 mm with those ⱕ5 mm
Not reported
60.9% were ⱖ60 y
Nonsignificant OR, 1.26 (95% CI, 0.99–1.61) if adenoma ⬍10 mm
69.9% were 60–75 y
Only evaluated if adenomas ⱖ10 mm
Average age of FDRs undergoing colonoscopy was 55.3 y, with 60.3% younger than 60 y
This would be especially useful for asymptomatic, averagerisk individuals who undergo a colonoscopy for CRC screening and who represent the largest proportion of individuals being diagnosed with adenomas. Furthermore, there are not any studies to support that earlier and more frequent screening decreases the incidence, morbidity, or mortality from CRC in this group.
Impact of More Intensive Screening on Colonoscopy Use Recommendations from the ACS-MSTF-ACR guidelines state that individuals with an FDR who had an adenoma before age 60 should begin their own screening for CRC at the age of 40 with colonoscopy at 5-year intervals. Given the equivocal nature of the evidence showing an increased risk of CRC in these FDRs, is such an aggressive regimen justified? By using our own data at the University of Colorado, we sought to model these recommendations and estimate the impact that their implementation would have on our endoscopy workload.24 We focused specifically on individuals 50 to 59 years old at average risk for CRC undergoing a screening colonoscopy. It is these patients whose FDRs would be impacted by the finding of 1 or more adenomas at colonoscopy. We identified 2145 screening colonoscopies between April 2005 and April 2007 that were performed on men and women between 50 and 59 years of age at average risk for CRC (asymptomatic without a family history of CRC or adenoma). The adenoma detection rate for patients
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Figure 1. Implications of beginning CRC screening at age 40 in FDRs of patients diagnosed with an adenoma before the age of 60.
aged 50 –59 was 25.9% (555/2145), which is comparable to previously published rates for this age group.25,26 Gender-specific adenoma detection rates were 21.1% for women aged 50 –59 and 31.7% for men in this age group, again comparable with previously published detection rates. On the basis of these adenoma detection rates, we estimate that 46.1% of adults (Figure 1) would have at least 1 parent who had an adenoma found on screening colonoscopy (assuming both parents underwent screening colonoscopy between the ages of 50 and 59). Out of a hypothetical sample of 1000 individuals, this would result in a change in screening recommendations for 461 of them if the ACS-MSTF-ACR guidelines were followed. This would result in an additional 922 colonoscopies performed (461 ⫻ 2) for these 1000 FDRs before they turn 50 and twice as many subsequent surveillance examinations in those not found to have adenomas (5-year interval instead of 10-year interval). This model is a straightforward presentation of the impact of the guidelines on the population that we currently serve by using our own data. The exact impact of the guidelines will vary depending on the population being served. To calculate the impact for a different population, it is only necessary to calculate the gender-specific adenoma detection rates for those younger than the age of 60 who are undergoing average-risk screening with colonoscopy. This model does not take into account potential younger siblings (younger than the age of 50) of the index adenoma cases. For example, the guidelines would recommend that an asymptomatic 40-year-old woman would be instructed to start screening immediately with colonoscopy and then every 5 years because her 50-year-old brother (who was considered average risk for CRC before his initial colonoscopy) was just found to have a tubular adenoma. The model also does not take into account increased adenoma detection rates that might result with use of new technologies (eg, high-definition colonoscopy). These would further increase the number of additional colonoscopies needed to comply with the screening recommendation. Finally, it does not address the additional recommendation that any individual with an FDR who has an adenoma detected at any age (including older than age 60) should start routine screening at age 40, although colonoscopy is not specifically recommended and the intervals for screening are not more frequent. Adenomas are very common in the general population, as seen in our database and in previous studies. Thus, the ACSMSTF-ACR guidelines for earlier and more intensive screening
for FDRs of individuals with an adenoma detected before the age of 60 impact a large proportion of the population. The ramifications of this more intensive screening recommendation must be considered. From a financial perspective, the implications are enormous. In our proposed example, every 1000 average-risk patients screened would result in a minimum of 922 additional colonoscopies for their FDRs before the age of 50. Given that the median total cost of colonoscopy is $923,27 these additional recommended colonoscopies would cost an additional $851,006 to screen the 461 individuals at age 40 and again at age 45. With an estimated 43,600,000 individuals between the ages of 40 and 49, this would result in a change in screening recommendations for up to 20 million people.28 A major consideration is whether we even have the capacity to increase rates of colonoscopy to meet these guidelines with the current resources. We currently perform about 14.2 million total colonoscopies a year in the United States, and it is estimated that this could be increased up to 22.4 million with our current resources.29,30 However, another study estimates that our demand already greatly exceeds our current supply, even without implementing these recommendations for FDRs of individuals with adenomas.31 They estimated that on the basis of current practice patterns, demand exceeds current supply regardless of screening strategy. They estimated that an increase of at least 1360 gastroenterologists would be necessary even if we waited to start screening everyone until age 65.31 In addition to the financial implications of these additional colonoscopies, one must also consider other burdens such as iatrogenic complications, loss of time from work, and the potential anxiety of being labeled at increased risk for CRC. Implementing this recommendation would label half of the population as belonging to a high-risk group for CRC. Significant potential iatrogenic complications include bleeding, perforation, and cardiopulmonary complications related to sedation. Perforation rates are estimated at 1 in 2600.11 Overall serious complications, defined as deaths attributable to colonoscopy or adverse events requiring hospital admission including perforation, major bleeding, severe abdominal pain, and cardiovascular events, are estimated to occur in 25 per 10,000 procedures.32 An important related question is whether we should be focusing on trying to pursue this more intensive screening recommendation, given our low levels of overall compliance with CRC screening in general. Although levels of CRC screen-
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ing in the United States are slowly increasing, they still lag behind those of other effective cancer screening tests such as Pap smears, mammography, and prostate-specific antigen testing. It has been estimated that fully screening a cohort of 4 million average-risk patients at age 50 would prevent an additional 31,500 deaths a year compared with current screening rates.33 A recently published study by the Centers for Disease Control and Prevention of more than 190,000 individuals reported only 54.7% of patients aged 50 – 64 years had undergone a fecal occult blood test within the last year or had a lower endoscopy (either colonoscopy or flexible sigmoidoscopy) within the last 10 years.34 The annual incidence of CRC in patients aged 50 –54 years is 54.5/100,000 and is only 15.2/ 100,000 in 40- to 44-year-olds.35 Even if we double this incidence to 30.4 cases/100,000, it is still far lower than for an average-risk individual in the 50- to 54-year-old age group. Therefore, we would find and prevent more CRC by simply increasing screening compliance in these individuals starting at age 50.
Conclusions The risk of CRC in FDRs of individuals with adenomas is not well-defined, and incidence and mortality reduction studies looking at screening these FDRs are not available. There is also no evidence to date regarding which screening strategies are the most cost-effective. The prevalence of adenomas in average-risk men and women 50 –59 years old is sufficiently high that the implication of providing the more intensive screening to their FDRs as recommended in the ACS-MSTFACR guidelines is daunting. Adenoma size and histology might play a role in CRC risk, but this is not addressed by the current guidelines. Restricting the recommendation to the FDRs of those with advanced adenomas would certainly decrease the overall impact on colonoscopy use and might increase the yield in the FDRs whose screening guidelines would be impacted. However, there is still insufficient evidence to support the earlier and more frequent guidelines even in this more selective population. As the field of genetic and molecular epidemiology grows, we might be able to further define higher-risk individuals who would benefit from an aggressive screening strategy, but these data are not currently available. We conclude that the implications of recommending more intensive screening of FDRs of patients diagnosed with an adenoma before the age of 60 are enormous, especially given the relative lack of evidence for this recommendation. A study examining the age incidence of CRC in the FDRs of patients with adenomas and appropriate controls is needed to support this recommendation. Before adopting any guidelines, we need to further define whether there is a subgroup of FDRs of patients with adenomas that is truly at increased risk of CRC and focus our more intensive screening efforts on this high-risk subset. Until these subgroups are defined, FDRs of individuals with adenomas should be screened as average-risk persons.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at doi:10.1016/ j.cgh.2011.01.004.
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Reprint requests Address requests for reprints to: Gregory L. Austin, MD, MPH, 12631 E 17th Avenue, Room 7609, University of Colorado Denver, Aurora, Colorado 80045. e-mail: [email protected]; fax: (303) 7241891. Conflicts of interest The authors disclose no conflicts.
PERSPECTIVE Are Colorectal Cancer Screening Recommendations for First-Degree Relatives of Patients With Adenomas Too Aggressive? GREGORY L. AUSTIN,* JONATHAN I. GOLDSTEIN,* STEVANY L. PETERS,‡ and DENNIS J. AHNEN* *Division of Gastroenterology and Hepatology, University of Colorado Denver, Aurora, Colorado; and ‡Huron Gastroenterology Center for Digestive Care, Ypsilanti, Michigan
Consensus guidelines of the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommend first-degree relatives of individuals diagnosed with an adenoma before age 60 should be screened every 5 years with colonoscopy starting at age 40. This is the identical recommendation for those with a first-degree relative diagnosed with colorectal cancer (CRC) before age 60. There is good evidence that first-degree relatives of individuals diagnosed with CRC before age 60 are at substantially increased risk for developing cancer at a young age. However, it is unclear whether an individual with a first-degree relative with an adenoma diagnosed before age 60 is at increased risk of CRC. Because not all adenomas portend the same cancer risk in the individual who has the adenoma, they would not be expected to portend the same risk in their first-degree relatives. Because of these uncertainties, the US Preventive Services Task Force does not recommend more aggressive screening of first-degree relatives of individuals with an adenoma. The adenoma detection rate for individuals 50 to 59 years old without a first-degree relative with CRC is sufficiently high (approximately 25%–30%) that almost half the population would be high risk on the basis of one first-degree relative having an adenoma. Given the weakness of evidence supporting the guidelines, suboptimal levels of screening in the general population, and lack of resources to comply with the recommendation, first-degree relatives of individuals with adenomas should be screened as average-risk persons until more compelling data are available to justify more aggressive screening. Keywords: Colorectal Cancer; Screening Guidelines; Adenoma.
initial colonoscopy was reduced by 76%–90% with polypectomy.2 Although CRC screening is generally accepted as an effective way to reduce both the incidence and mortality of CRC, the optimal screening strategy for specific populations is unclear.3 Experts agree that screening for individuals at average risk for CRC should begin at age 50, although recently both the American College of Gastroenterology and the American Society of Gastrointestinal Endoscopy have recommended that African Americans start being screened at age 45.4,5 Some groups have been identified who are at a greatly increased risk for CRC, such as individuals with inflammatory bowel disease and those with a family history of familial adenomatous polyposis or hereditary non-polyposis colon cancer (Lynch syndrome). There is a general consensus that these high-risk groups require earlier and more frequent CRC screening. Other higher-risk subgroups represent areas of considerable uncertainty. Individuals with a first-degree relative (FDR) with CRC have been shown to be at increased risk for CRC themselves, and the risk varies with both the number of FDRs with CRC and the age of the CRC in the FDRs.6,7 Screening guidelines generally recommend earlier (age 40 or 10 years younger than the earliest cancer in the family) and more frequent CRC screening if the CRC in the FDR was diagnosed before the age of 60, or if there is more than 1 FDR with CRC.8,9 However, the consensus guidelines from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (ACSMSTF-ACR) also recommend the same earlier (starting at age 40) and more frequent CRC screening for FDRs of patients with adenomatous polyps (adenomas) of the colon diagnosed before age 60.10 We review the evidence for and implications of recommending this more intensive colonoscopic screening for the FDRs of patients with colorectal adenomas.
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Review of Current Recommendations Rationale for Colorectal Cancer Screening
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olorectal cancer (CRC) is the second leading cause of cancer death in the United States. For 2009, it was estimated that 146,970 individuals were diagnosed and that 49,920 died of CRC.1 CRC is also one of the few cancers for which effective screening strategies are available both for early detection of existent cancers and also for prevention of CRC by adenoma detection and removal. As such, screening for CRC has important public health implications. In the National Polyp Study, the incidence of CRC in individuals with an adenoma on
In 2008, the American Cancer Society, the US MultiSociety Task Force on Colorectal Cancer (composed primarily of gastroenterologists), and the American College of Radiology Abbreviations used in this paper: ACS-MSTF-ACR, American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology; CI, confidence interval; CRC, colorectal cancer; FDR, first-degree relative; OR, odds ratio; RR, relative risk; USPSTF, United States Preventive Services Task Force. © 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.01.004
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published consensus guidelines for CRC screening.10 The ACSMSTF-ACR guidelines specifically recommended that patients with either CRC or adenomatous polyps (adenomas) in an FDR before age 60 should begin screening for CRC at 40 years of age with colonoscopy at 5-year intervals. The other major set of CRC screening guidelines from the United States Preventive Services Task Force (USPSTF) do not recommend earlier screening for those with a family history of CRC or adenomas, although they do state that earlier screening might be reasonable for those with an FDR who developed CRC at a younger age or had multiple FDRs affected with CRC.11
Rationale for More Intensive Screening The increased risk of CRC in FDRs of patients with CRC is well-characterized,6,12,13 but the evidence for more aggressive screening is best supported by the prospective study of more than 119,000 individuals by Fuchs et al.7 In this study, they showed that individuals 30 to 44 years old with an FDR with CRC were 5.37 times as likely to be diagnosed with CRC (compared with those without an FDR with CRC), and that individuals 45 to 49 years old with an FDR with CRC were 3.85 times as likely to be diagnosed with CRC during the follow-up period. They demonstrated that the cumulative incidence of CRC at age 40 in those with an FDR with CRC was similar to the cumulative incidence of CRC at age 50 of those without an FDR with CRC. This provides the evidence base for justifying starting CRC screening at age 40 for those with an FDR with CRC. The increased risk of CRC in FDRs of patients with adenomas is less well-defined. The PubMed database was systematically searched independently by 3 of the authors (G.A., J.G., S.P.). The following keywords were used to identify relevant articles published between September 1966 and April 2010: (1) colon, rectal, or colorectal cancer, adenoma, polyp, adenomatous polyp, or tumor; (2) family history; familial; relative(s); first-degree. This search strategy yielded all articles cited in the ACS-MSTF-ACR guidelines and a previous meta-analysis. All articles that cited the identified articles were also identified. The results of keyword searches were combined by using the terms “and/or.” To date, there are not any prospective studies to assess the risk of developing CRC in FDRs of patients with adenomas. The association of CRC in FDRs of those with adenomas is largely based on case-control studies in which adenoma cases (detected during colonoscopy) were surveyed as to whether any of their FDRs had CRC. A majority of the published studies support the finding that patients with 1 or more adenomas are more likely to have an FDR with CRC.14 –20 A previous meta-analysis found a pooled relative risk (RR) of 1.99 (95% confidence interval [CI], 1.55– 2.55).13 These studies are the evidence for the recommendation for earlier and more frequent screening in FDRs of patients with adenomas. However, the basic design of these studies did not address the prospective incident risk of being diagnosed with CRC for an FDR of an individual with an adenoma. In addition, the index adenoma cases would be considered high risk because they had a family member with CRC. Furthermore, these studies were largely performed on symptomatic patients (eg, blood in stool) before the era of performing screening colonoscopy on average-risk, asymptomatic individuals starting at age 50. In a majority of studies, more than half of the adenoma cases were individuals older than the age of 60.
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Of the published studies evaluating the association between having an adenoma and having at least 1 FDR with CRC, only 4 (Table 1) have addressed the question of whether the age at which the adenoma was diagnosed influenced the patient’s odds of having an FDR with CRC, and the results are mixed. Specifically, the study by Ahsan et al14 showed that the FDRs of patients who were diagnosed with an adenoma between 51 and 60 years of age were not at increased risk for having CRC (RR, 1.22; 95% CI, 0.67–2.23) compared with the FDRs of adenomafree controls. Similarly, Lynch et al20 found that individuals who were diagnosed with an adenoma between 50 and 59 years of age were not at increased risk for having an FDR with CRC (odds ratio [OR], 1.27; 95% CI, 0.86 –1.87). In the study by Cottet et al,21 the FDRs of patients who had large adenomas (ⱖ10 mm) underwent colonoscopy. There was a nonsignificant increased risk (OR, 3.81; 95% CI, 0.92–15.87) of having an incident CRC in these FDRs if the adenoma was diagnosed in the index case before the age of 60. The study by Winawer et al15 is the only one to demonstrate a significant increase in the odds of CRC in FDRs of patients diagnosed with an adenoma between ages 50 and 59. The increased odds were specific for siblings (RR, 2.49; 95% CI, 1.37– 4.52) of the index adenoma cases, although primarily in patients who had a parent with CRC. In addition to the lack of strong evidence supporting an increased risk of CRC in FDRs of patients diagnosed with an adenoma before the age of 60, these studies have several limitations related to the recommendation that these FDRs should start screening for CRC at age 40 with colonoscopy every 5 years. The most important unanswered question is whether the FDRs of an individual with an adenoma (but without an FDR with CRC) are at greater risk for CRC compared with the FDRs of an individual without adenomas. Second, if the risk of CRC is increased, the next unanswered question is whether these FDRs are specifically at risk before the age of 50. This is a critically important question and separates the family history of adenoma recommendation from the family history of CRC recommendation. Unlike the evidence for earlier CRC risk in FDRs of those with CRC, there are limited data on the age distribution at which CRC was diagnosed in the FDRs of the adenoma cases. The study by Winawer et al15 does report an increased risk of CRC in siblings (and adjusts for the year of birth of the sibling) of those with an adenoma diagnosed between 50 and 59 years of age. However, the average age of the siblings with CRC was reported as 62.3 years, similar to the age of CRC in FDRs of the spouse controls (63.7 years), and both groups were substantially younger than the average age of CRC in the parents of adenoma subjects (73.2 years). Furthermore, the risk was greatly increased (and potentially fully attributable) if the sibling and index adenoma case had a parent who had been diagnosed with CRC. In this scenario, the index adenoma case and the sibling would have already been considered high risk because the parent had already been diagnosed with CRC. The study does not address the future risk of CRC in FDRs of a patient with an adenoma who does not have an FDR with CRC. Finally, several of the studies have evaluated other highrisk features that might increase the odds of patients with adenomas having FDRs with CRC, including size, histology, and number of adenomas. Whereas Lynch et al20 and Boutron et al22 showed that only adenomas at least 10 mm in
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Table 1. Summary of Studies Evaluating the Association of CRC in FDRs of Those With an Adenoma Study Ahsan et al,14 1998
Winawer et al,15 1996
Lynch et al,20 2003
Cottet et al,21 2007
Study populations 1554 FDRs of 244 adenoma cases, 2173 FDRs of 362 controls
Overall OR or RR for CRC
Increased CRC risk based on diagnosis of adenoma in FDR
RR, 1.7; 95% CI, 1.2–2.4
Increased CRC risk if adenoma diagnosed in FDR ⬍50 y (RR, 4.36; 95% CI, 2.24–8.51). No increased risk if adenoma detected in FDR 51–60 y (RR, 1.22; 95% CI, 0.67–2.23) 4246 FDRs of 1031 RR, 1.78; 95% CI, Increased CRC risk in siblings adenoma cases, 1.18–2.67 (but not parents) if 1411 spouse adenoma diagnosed in FDR controls 50–59 y (RR, 2.49; 95% CI, 1.37–4.52) or in FDR ⬍50 y (RR, 4.08; 95% CI, 1.56– 10.68) 1141 FDRs of adenoma OR, 1.35 (95% CI, 50- to 59-y group with cases, 1559 FDRs of 1.08–1.68) in adenoma: OR, 1.27 (95% polyp-free controls those with 1 CI, 0.86–1.87) of having an adenoma FDR with CRC. 70- to 75-y having an FDR group with adenoma: OR, with CRC 2.18 (95% CI, 1.33–3.55) of having an FDR with CRC 168 FDRs of 306 cases OR, 3.90; 95% CI, OR of large adenoma or with adenomas ⱖ10 0.89–17.01 cancer, 3.81 (95% CI, mm, 307 controls 0.92–15.87) if FDR had without family history large adenoma diagnosed of CRC/adenoma before age 60; OR, 1.82 (95% CI, 0.66–4.99) if FDR was 60 y or older
size are associated with an increased risk of having an FDR with CRC, Ahsan et al14 found increased risk for adenomas both more and less than 5 mm. Conversely, Aitken et al23 did not find an association of having an FDR with CRC for adenomas that were either more or less than 10 mm. Equivocal results have also been reported on the basis of the histology of the adenoma, with the majority of studies demonstrating nonsignificant differences in the odds of having an FDR even if the histology revealed moderate to severe dysplasia.16,20 –23 Similarly conflicting reports have been published on whether the number of adenomas detected influences the risk of having an FDR with CRC. Lynch et al reported that only individuals with ⱖ2 adenomas were more likely to have an FDR with CRC, whereas other studies did not find that the number of adenomas influenced their reported risk association.14,16,22 Again, none of these studies answered the question of whether the FDRs of an individual with any of these high-risk features are at greater risk for CRC compared with the FDRs of individuals without these high-risk features. In summary, the evidence that FDRs of individuals with an adenoma diagnosed before the age of 60 are at increased risk for CRC is weak and inconsistent. Furthermore, there is no evidence that these FDRs are more likely to be diagnosed with CRC at an earlier age in the absence of a parent who had CRC. There are no studies that prospectively assess the incidence of CRC in FDRs of patients with adenomas (where neither the patient nor the FDRs have an FDR with CRC).
Increased risk based Age characteristics of on size? adenoma cases No heterogeneity of 68.4% were ⱖ61 y RR comparing adenomas ⬎5 mm with those ⱕ5 mm
Not reported
60.9% were ⱖ60 y
Nonsignificant OR, 1.26 (95% CI, 0.99–1.61) if adenoma ⬍10 mm
69.9% were 60–75 y
Only evaluated if adenomas ⱖ10 mm
Average age of FDRs undergoing colonoscopy was 55.3 y, with 60.3% younger than 60 y
This would be especially useful for asymptomatic, averagerisk individuals who undergo a colonoscopy for CRC screening and who represent the largest proportion of individuals being diagnosed with adenomas. Furthermore, there are not any studies to support that earlier and more frequent screening decreases the incidence, morbidity, or mortality from CRC in this group.
Impact of More Intensive Screening on Colonoscopy Use Recommendations from the ACS-MSTF-ACR guidelines state that individuals with an FDR who had an adenoma before age 60 should begin their own screening for CRC at the age of 40 with colonoscopy at 5-year intervals. Given the equivocal nature of the evidence showing an increased risk of CRC in these FDRs, is such an aggressive regimen justified? By using our own data at the University of Colorado, we sought to model these recommendations and estimate the impact that their implementation would have on our endoscopy workload.24 We focused specifically on individuals 50 to 59 years old at average risk for CRC undergoing a screening colonoscopy. It is these patients whose FDRs would be impacted by the finding of 1 or more adenomas at colonoscopy. We identified 2145 screening colonoscopies between April 2005 and April 2007 that were performed on men and women between 50 and 59 years of age at average risk for CRC (asymptomatic without a family history of CRC or adenoma). The adenoma detection rate for patients
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Figure 1. Implications of beginning CRC screening at age 40 in FDRs of patients diagnosed with an adenoma before the age of 60.
aged 50 –59 was 25.9% (555/2145), which is comparable to previously published rates for this age group.25,26 Gender-specific adenoma detection rates were 21.1% for women aged 50 –59 and 31.7% for men in this age group, again comparable with previously published detection rates. On the basis of these adenoma detection rates, we estimate that 46.1% of adults (Figure 1) would have at least 1 parent who had an adenoma found on screening colonoscopy (assuming both parents underwent screening colonoscopy between the ages of 50 and 59). Out of a hypothetical sample of 1000 individuals, this would result in a change in screening recommendations for 461 of them if the ACS-MSTF-ACR guidelines were followed. This would result in an additional 922 colonoscopies performed (461 ⫻ 2) for these 1000 FDRs before they turn 50 and twice as many subsequent surveillance examinations in those not found to have adenomas (5-year interval instead of 10-year interval). This model is a straightforward presentation of the impact of the guidelines on the population that we currently serve by using our own data. The exact impact of the guidelines will vary depending on the population being served. To calculate the impact for a different population, it is only necessary to calculate the gender-specific adenoma detection rates for those younger than the age of 60 who are undergoing average-risk screening with colonoscopy. This model does not take into account potential younger siblings (younger than the age of 50) of the index adenoma cases. For example, the guidelines would recommend that an asymptomatic 40-year-old woman would be instructed to start screening immediately with colonoscopy and then every 5 years because her 50-year-old brother (who was considered average risk for CRC before his initial colonoscopy) was just found to have a tubular adenoma. The model also does not take into account increased adenoma detection rates that might result with use of new technologies (eg, high-definition colonoscopy). These would further increase the number of additional colonoscopies needed to comply with the screening recommendation. Finally, it does not address the additional recommendation that any individual with an FDR who has an adenoma detected at any age (including older than age 60) should start routine screening at age 40, although colonoscopy is not specifically recommended and the intervals for screening are not more frequent. Adenomas are very common in the general population, as seen in our database and in previous studies. Thus, the ACSMSTF-ACR guidelines for earlier and more intensive screening
for FDRs of individuals with an adenoma detected before the age of 60 impact a large proportion of the population. The ramifications of this more intensive screening recommendation must be considered. From a financial perspective, the implications are enormous. In our proposed example, every 1000 average-risk patients screened would result in a minimum of 922 additional colonoscopies for their FDRs before the age of 50. Given that the median total cost of colonoscopy is $923,27 these additional recommended colonoscopies would cost an additional $851,006 to screen the 461 individuals at age 40 and again at age 45. With an estimated 43,600,000 individuals between the ages of 40 and 49, this would result in a change in screening recommendations for up to 20 million people.28 A major consideration is whether we even have the capacity to increase rates of colonoscopy to meet these guidelines with the current resources. We currently perform about 14.2 million total colonoscopies a year in the United States, and it is estimated that this could be increased up to 22.4 million with our current resources.29,30 However, another study estimates that our demand already greatly exceeds our current supply, even without implementing these recommendations for FDRs of individuals with adenomas.31 They estimated that on the basis of current practice patterns, demand exceeds current supply regardless of screening strategy. They estimated that an increase of at least 1360 gastroenterologists would be necessary even if we waited to start screening everyone until age 65.31 In addition to the financial implications of these additional colonoscopies, one must also consider other burdens such as iatrogenic complications, loss of time from work, and the potential anxiety of being labeled at increased risk for CRC. Implementing this recommendation would label half of the population as belonging to a high-risk group for CRC. Significant potential iatrogenic complications include bleeding, perforation, and cardiopulmonary complications related to sedation. Perforation rates are estimated at 1 in 2600.11 Overall serious complications, defined as deaths attributable to colonoscopy or adverse events requiring hospital admission including perforation, major bleeding, severe abdominal pain, and cardiovascular events, are estimated to occur in 25 per 10,000 procedures.32 An important related question is whether we should be focusing on trying to pursue this more intensive screening recommendation, given our low levels of overall compliance with CRC screening in general. Although levels of CRC screen-
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ing in the United States are slowly increasing, they still lag behind those of other effective cancer screening tests such as Pap smears, mammography, and prostate-specific antigen testing. It has been estimated that fully screening a cohort of 4 million average-risk patients at age 50 would prevent an additional 31,500 deaths a year compared with current screening rates.33 A recently published study by the Centers for Disease Control and Prevention of more than 190,000 individuals reported only 54.7% of patients aged 50 – 64 years had undergone a fecal occult blood test within the last year or had a lower endoscopy (either colonoscopy or flexible sigmoidoscopy) within the last 10 years.34 The annual incidence of CRC in patients aged 50 –54 years is 54.5/100,000 and is only 15.2/ 100,000 in 40- to 44-year-olds.35 Even if we double this incidence to 30.4 cases/100,000, it is still far lower than for an average-risk individual in the 50- to 54-year-old age group. Therefore, we would find and prevent more CRC by simply increasing screening compliance in these individuals starting at age 50.
Conclusions The risk of CRC in FDRs of individuals with adenomas is not well-defined, and incidence and mortality reduction studies looking at screening these FDRs are not available. There is also no evidence to date regarding which screening strategies are the most cost-effective. The prevalence of adenomas in average-risk men and women 50 –59 years old is sufficiently high that the implication of providing the more intensive screening to their FDRs as recommended in the ACS-MSTFACR guidelines is daunting. Adenoma size and histology might play a role in CRC risk, but this is not addressed by the current guidelines. Restricting the recommendation to the FDRs of those with advanced adenomas would certainly decrease the overall impact on colonoscopy use and might increase the yield in the FDRs whose screening guidelines would be impacted. However, there is still insufficient evidence to support the earlier and more frequent guidelines even in this more selective population. As the field of genetic and molecular epidemiology grows, we might be able to further define higher-risk individuals who would benefit from an aggressive screening strategy, but these data are not currently available. We conclude that the implications of recommending more intensive screening of FDRs of patients diagnosed with an adenoma before the age of 60 are enormous, especially given the relative lack of evidence for this recommendation. A study examining the age incidence of CRC in the FDRs of patients with adenomas and appropriate controls is needed to support this recommendation. Before adopting any guidelines, we need to further define whether there is a subgroup of FDRs of patients with adenomas that is truly at increased risk of CRC and focus our more intensive screening efforts on this high-risk subset. Until these subgroups are defined, FDRs of individuals with adenomas should be screened as average-risk persons.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at doi:10.1016/ j.cgh.2011.01.004.
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Reprint requests Address requests for reprints to: Gregory L. Austin, MD, MPH, 12631 E 17th Avenue, Room 7609, University of Colorado Denver, Aurora, Colorado 80045. e-mail: [email protected]; fax: (303) 7241891. Conflicts of interest The authors disclose no conflicts.