Computed tomographic colonography for colorectal cancer screening

Risk factors for the detection of advanced neoplasia

Authors


  • All authors were involved in the conception and design or the analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. The first two authors had full access to all data in the study, and the last author had final responsibility for the decision to submit for publication.

Abstract

BACKGROUND

The objective of this study was to determine whether age, sex, a positive family history of colorectal cancer, and body mass index (BMI) are important predictors of advanced neoplasia in the setting of screening computed tomographic colonography (CTC).

METHODS

Consecutive patients who were referred for first-time screening CTC from 2004 to 2011 at a single medical center were enrolled. Results at pathology were recorded for all patients who underwent polypectomy. Logistic regression was used to identify significant predictor variables for advanced neoplasia (any adenoma ≥10 mm or with villous component, high-grade dysplasia, or adenocarcinoma). Odds ratios (ORs) were used to express associations between the study variables (age, sex, BMI, and a positive family history of colorectal cancer) and advanced neoplasia.

RESULTS

In total, 7620 patients underwent CTC screening. Of these, 276 patients (3.6%; 95% confidence interval [CI], 3.2%-4.1%) ultimately were diagnosed with advanced neoplasia. At multivariate analysis, age (mean OR per 10-year increase, 1.8; 95% CI, 1.6-2.0) and being a man (OR, 1.7; 95% CI, 1.3-2.2) were independent predictors of advanced neoplasia, whereas BMI and a positive family history of colorectal cancer were not. The number needed to screen to detect 1 case of advanced neoplasia varied from 51 among women aged ≤55 years to 10 among men aged >65 years. The number of post-CTC colonoscopies needed to detect 1 case of advanced neoplasia varied from 2 to 4.

CONCLUSIONS

Age and sex were identified as important independent predictors of advanced neoplasia risk in individuals undergoing screening CTC, whereas BMI and a positive family history of colorectal cancer were not. These results have implications for appropriate patient selection. Cancer 2013;119:2549–2554. © 2013 American Cancer Society.

INTRODUCTION

Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries.[1] Evidence suggests that screening asymptomatic populations can reduce CRC mortality[2] and that the removal of precursor adenomas may reduce the incidence of CRC.[3] Computed tomographic (CT) colonography (CTC) has been well studied and identified as a valid screening test for CRC and other advanced neoplasias,[4] and it has demonstrated both cost-effectiveness[10, 11] and a high degree of acceptance among patients.[12, 13]

Advanced neoplasia has been considered a valid target for CRC screening tests, including CTC.[4, 9, 14] The identification of important risk factors for advanced colonic neoplasia may have an impact on both risk stratification and the development of risk-reduction strategies.[15] It has been demonstrated that both age and sex are strictly associated with the detection of advanced neoplasia at colonoscopy screening,[16, 17] whereas the role of body mass index (BMI) remains controversial.[17] A positive family history of CRC also has been identified as predictive of the risk of advanced neoplasia at screening colonoscopy.[16, 17] The role of these risk factors in the stratification of patients for screening CTC is currently unclear.

The primary objective of this study was to derive and validate a model for the detection of advanced colorectal neoplasia during screening CTC using age, sex, a positive family history of CRC, and BMI as predictive variables. Our secondary objectives were to determine the number needed to screen (NNS) at CTC and the number of post-CTC colonoscopies needed to detect 1 case of advanced neoplasia for those variables identified as predictive of advanced neoplasia risk. This information may be useful in refining future screening recommendations.

MATERIALS AND METHODS

Study Design

The study protocol was in compliance with the Health Insurance Portability and Accountability Act of 1996 and was approved by our institutional review board. The need for signed informed consent was waived. We prospectively enrolled 8321 consecutive, asymptomatic individuals for first-time CTC examination for the purpose of CRC screening. We excluded patients who had a prior history of CRC, inflammatory bowel disease, polyposis syndromes, or colorectal surgery as well as those who were referred after an incomplete optical colonoscopy. After appropriate exclusions, in total, 7620 asymptomatic individuals comprised the screening CTC study population (Table 1). Patient age, sex, a positive family history of CRC, and BMI were recorded. A positive family history of CRC was strictly defined according to American Cancer Society criteria as having 1 first-degree relative diagnosed by age 60 years or 2 first-degree relatives diagnosed at any age.

Table 1. Characteristics of the Study Population
 No. Screened (%)
CharacteristicAll, N = 7620Women, N = 4093Men, N = 3527
  1. Abbreviations: BMI, body mass index; CTC, computed tomographic colonography; SD, standard deviation.
Age   
Mean ± SD, y56.7 ± 7.356.5 ± 7.357.0 ± 7.5
Age group, y   
<50294 (3.9)162 (4.0)132 (3.7)
50-543123 (41)1720 (42)1403 (39.8)
55-592024 (26.5)1103 (26.9)921 (26.1)
60-641266 (16.6)660 (16.2)606 (17.2)
≥65913 (12)448 (10.9)465 (13.2)
Positive family history200 (2.6)119 (2.9)81 (2.3)
BMI, kg/m2   
Mean ± SD, kg/m228.1 ± 7.127.8 ± 8.528.4 ± 5.1
≥25 kg/m25,125 (67.3)2,411 (58.9)2,714 (76.9)
Positive CTC1,087 (14.3)480 (11.7)607 (17.2)
Underwent polypectomy735 (9.6)341 (8.3)394 (11.2)

A positive CTC examination was defined as any examination in which any polyp that measured ≥6 mm was identified. In accordance with the CT Colonography Reporting and Data System (C-RADS), positive patients who had any large polyp (≥10 mm) or >2 small polyps (6-9 mm) identified at CTC were referred for colonoscopy with polypectomy.[23] Patients who had 1 or 2 small polyps were given the option of either colonoscopy with polypectomy or CTC polyp surveillance. Patients who had a negative examination result at CTC received a recommendation to undergo routine screening in 5 years.

The results of colonoscopy and polypectomy, as well as the final histologic result at pathology, were recorded for all patients who underwent colonoscopy. Concordance was recorded for the CTC findings in patients who underwent colonoscopy with polypectomy using colonoscopy findings as the reference standard. For discordant cases in which the CTC findings were not confirmed, the finding was considered a false-positive CTC unless additional imaging or repeat colonoscopy demonstrated that the lesion was missed at initial colonoscopy.

The findings at colonoscopy were categorized on the basis of the most advanced lesion identified.[16] Advanced neoplasia was defined as any adenoma ≥10 mm in greatest dimension, any adenoma with a villous component or high-grade dysplasia at histology, or any adenocarcinoma.[16, 17]

Computed Tomographic Colonography Technique

The CTC technique used in our screening program has been described elsewhere.[24] Briefly, patients underwent a bowel-preparation protocol beginning 1 day before CTC, consisting of a cathartic cleansing agent. Residual fluid and fecal material was tagged using 2.1% weight/volume barium and diatrizoate. Colonic insufflation was achieved and maintained throughout image acquisition using automated, continuous carbon dioxide delivered through a rectal catheter. Patients were routinely scanned in both supine and prone positions with decubitus positioning used as needed.[25] Images were acquired with 8-to-64-section multidetector CT scanners using 1.25-mm collimation; 1-mm reconstruction interval; 120 peak kilovoltage; and either a fixed-tube, current-time product (50-75 mega-amperes [mA]) or tube-current modulation (range, 30-300 mA). Interpretation of CT examinations by the radiologists was performed using both 3-dimensional reconstructions for initial polyp detection and 2-dimensional cross-sectional images for secondary detection and polyp confirmation.[6, 7, 26]

Statistical Analysis

Stepwise multiple logistic regression analysis was used to identify significant predictor variables for advanced neoplasia on a per-patient basis. The prediction model was built using the JMP 98.0 software package (version 8.0; SAS Institute, Inc., Cary, NC) for stepwise logistic regression analysis with an entry criteria of P < .05. Odds ratio (ORs) were used to express the association between study variables (age, sex, and BMI) and the selected outcome. To test the accuracy of the multivariate model in predicting the selected outcome, the study population was randomly divided into a derivation group and a validation group of equal size. Once the model was established using the exploratory group, the parameter estimates were tested in the validation group to check goodness-of-fit (Hosmer-Lemeshow test). The procedure was repeated 20 times. Point estimates for NNS were derived from the inverse of the point estimates for prevalence. We derived the confidence intervals (CIs) for the NNS by inverting the values for the 95% CIs for risk proportions. Patients who had 1 or 2 small polyps (6-9 mm) identified at CTC were given the option of either colonoscopy with polypectomy or CTC polyp surveillance, as noted above, presumably resulting in an underestimation of the advanced neoplasia rate. Consequently, in a secondary analysis, we adopted the same regression model to predict the rate of advanced neoplasia for small polyps in patients undergoing CTC surveillance and generated an adjusted advanced neoplasia detection rate.

RESULTS

In total, 7620 individuals underwent first-time CTC screening during the study period (Table 1). The mean age (±standard deviation) in years for the entire population was 56.7 ± 7.3 years. Men accounted for 46.3% of this cohort. A positive family history of CRC was reported by 200 individuals (3%). The mean BMI was 28.1 ± 7.1 kg/m2, and 5062 individuals (66.4%) presented with a BMI ≥25 kg/m2. CTC examination was positive (at least 1 polyp ≥6 mm) in 1087 individuals (14.3%; 95% CI, 13.5%-15.1%). Of these, 735 (67.6%) underwent colonoscopy, and the remaining 352 (32.4%) entered CTC surveillance for small polyps. Overall, 480 of 7620 individuals (6.3%) had at least 1 adenoma. Of these, 276 of 7620 (3.6%; 95% CI, 3.2%-4.1%) had at least 1 advanced neoplastic lesion. Table 2 reports the distribution of colorectal lesions according to histology and risk factors as well as the association between the study variables and the risk of advanced neoplasia at univariate analysis.

Table 2. Colonoscopy Findings After Computed Tomographic Colonography According to Histology and Risk Factorsa
 No. Screened (%)
  WomenMenBMIFH
CharacteristicAll, N = 7620Aged <55 y, N = 1882Aged ≥55 y, N = 2211Aged <55 y, N = 1535Aged ≥55 y, N = 1992<25 kg/m2, N = 2495≥25 kg/m2, N = 5125Positive, N = 200Negative, N = 7420
  1. Abbreviations: BMI, body mass index; FH, family history of colorectal carcinoma.
  2. Associations between study variables and (advanced) neoplasia at univariate analysis also are reported.
  3. aP < .05 (chi-square test).
Advanced neoplasia276 (3.6)37 (2)75 (3.4)a48 (3.1)116 (5.8)a69 (2.8)207 (4)a9 (4.5)267 (3.6)
Any adenoma ≥6 mm480 (6.3)75 (4)126 (5.7)a96 (6.3)183 (9.2)a119 (4.8)361 (7)a18 (9)462 (6.2)
Non-neoplastic polyp ≥6 mm152 (2)24 (1.3)44 (2)38 (2.5)46 (2.3)50 (2)102 (2)a7 (3.5)145 (2)

Multivariate modeling indicated that age (mean OR per 10-year increase: 1.8; 95% CI, 1.6-2.0) and male sex (OR, 1.7; 95% CI, 1.3-2.2) were independent predictors of advanced neoplasia risk, whereas a positive family history of CRC (OR, 1.2; 95% CI, 0.6-2.4) and BMI (OR, 1.0; 95% CI, 0.9-1.1) were not. When dividing the study population into derivation and validation samples, the Hosmer-Lemeshow test confirmed the goodness-of-fit of the model with a mean P value (among 20 iterations) of .3 for the validation data set (in which P < .05 would indicate a lack of fit). Figure 1 (top) and Table 3 indicate the NNS to detect advanced neoplasia according to age and sex, and Figure 1 (bottom) depicts the same analysis after adjustment, with the multivariate model predicting the advanced neoplasia rate for the positive patients with small detected lesions (6-9 mm) entering CTC polyp surveillance. Table 3 lists the number of post-CTC colonoscopies needed to detect 1 case of advanced neoplasia according to age and sex.

Figure 1.

(Top) The number needed to screen (NNS) to detect advanced neoplasia is illustrated according to age and sex. (Bottom) The same data are reported after simulation to predict advanced neoplasia in individuals undergoing computed tomographic colonography surveillance for small polyps. Dotted lines represent the yearly NNS values estimated by the multivariate model.

Table 3. The Number Needed to Screen With Computed Tomographic Colonography (CTC) to Detect 1 Case of Advanced Neoplasia and the Number of Post-CTC Colonoscopies Needed to Detect 1 Case of Advanced Neoplasia According to Age and Sex
Age/SexNo. Needed to Screen to Detect Advanced Neoplasia (95% CI)No. of Post-CTC Colonoscopies Needed to Detect Advanced Neoplasia (95% CI)
  1. Abbreviations: CI, confidence interval.
Aged <55 y  
Men32 (25-44)3.1 (2.5-4.0)
Women51 (39-75)3.4 (2.6-4.6)
Ages 55-59 y  
Men26 (19-38)2.4 (2-3.3)
Women48 (34-81)4.0 (2.9-6.1)
Ages 60-64 y  
Men18 (13-25)2.2 (1.8-3)
Women33 (23-58)3.1 (2.2-4.8)
Aged ≥65 y  
Men10 (8-14)1.8 (1.5-2.2)
Women14 (10-21)2 (1.6-2.7)

DISCUSSION

According to our study, age and sex are associated significantly with the detection of advanced neoplasia in a large cohort of individuals undergoing first-time CTC screening, allowing for clinically relevant risk stratification of the study population. The wide interval in the estimates of the NNS with CTC to detect 1 case of advanced neoplasia, ranging from 10 to 51 (or from 7 to 37 when adjusting for 6-9 mm polyps still in surveillance) closely approximates the 10 to 36 NNS interval reported by Regula et al in a large cohort of individuals who underwent primary screening colonoscopy.[16] This suggests equivalence in the role of age and sex in stratifying average-risk individuals between CTC and colonoscopy. The greater than 4-fold variation in NNS to detect advanced neoplasia according to age and sex may be informative when planning for general population screening. In cases of limited resources, which are likely to occur when CRC screening is recommended for all adults aged >50 years, it makes sense for health systems to target patients with a greater expected benefit to best use the available economic and medical resources. This would not be new in the field of CRC screening, as indicated by the adoption of a selective cutoff value for the exploitation of colonoscopy resources after sigmoidoscopy or immunochemical fecal testing.[2, 3, 14] Our observation of an exponential reduction in the NNS according to increasing age also would be consistent with the adoption of a higher cutoff age for initial population screening, as in the recently recommended 55-year to 65-year age interval for sigmoidoscopy screening.[3] Although sex has not been explicitly included in any guidelines, our analysis confirms a substantial difference in the prevalence of advanced neoplasia between men and women, as outlined previously by Regula et al.[16] For example, as illustrated by the prediction model in Figure 1, women appear to reach the same NNS as men with an approximate 10-year delay. Thus, it would seem reasonable to propose different age recommendations for CTC screening according to sex, whereas perhaps a less costly strategy, such as fecal occult blood testing, could be used earlier. Specifically, women aged <65 years and men aged <55 years have an NNS below the study-wide mean NNS of 28, suggesting that screening these patients represents a somewhat less efficient use of CTC.

The adoption of noninvasive CRC screening approaches, including CTC, necessitates post-test referral to colonoscopy after positive examinations. The ultimate efficiency of any noninvasive approach would depend greatly on the number of post-test colonoscopies needed to detect 1 case of advanced neoplasia as a matter of avoiding unnecessarily redundant procedures. When stratifying our study population according to age and sex, there was a 2-fold difference in the efficiency of post-CTC colonoscopy exploitation, ranging from 2 to 4 procedures to detect 1 case of advanced neoplasia. In instances of limited endoscopic capacity, this information could trigger more conservative nonendoscopic surveillance policies for those CTC-positive individuals who have a lower risk of advanced neoplasia or the adoption of a more selective post-CTC dimensional cutoff for referring patients to polypectomy.

Despite an apparent association at univariate analysis, our study failed to confirm any association between BMI and the detection of advanced neoplasia in multivariate analysis, casting doubt on the relevance of this factor in stratifying the average-risk population for CRC screening with CTC. It is noteworthy that approximately 66% of the study population reported a BMI ≥25 kg/m2, so any eventual impact of this variable would have been substantial. Our result supports a previous predictive model for advanced neoplasia at colonoscopy.[17] The lack of an association between BMI and advanced neoplasia also was confirmed in a recent meta-analysis, which included 168,201 individuals and failed to demonstrate any statistically significant association between these 2 variables.[18, 19] It is worth noting that the same meta-analysis demonstrated a slight, but statistically significant, increase in the prevalence of colorectal adenomas (ie, also including nonadvanced adenomas) when comparing individuals who had a BMI ≥25 kg/m2 with those who had a BMI <25 kg/m2.[18, 19] This is also in line with a previous report from our group in a separate CTC screening series, in which we also demonstrated an association between higher visceral adiposity measurements on CTC and the presence of adenomas (including nonadvanced adenomas).[20] Therefore, as suggested by the authors of the meta-analysis, obesity appears to be involved in tumor initiation (ie, adenoma formation) rather than tumor progression (ie, advanced neoplasia).[18]

We could not confirm the role of a positive family history of CRC in stratifying for the risk of advanced neoplasia. When considering the relatively low prevalence of a positive family history of CRC—3% in our cohort compared with 13.3% in a previous endoscopic series16—we cannot exclude the possibility that the lack of an association simply may be attributed to a sample size bias. In a recent well designed endoscopic study, a moderate association between a positive family history of CRC and the risk of advanced neoplasia was demonstrated in a Chinese population.[21] Thus, further studies that specifically examine the siblings of patients with CRC are needed to clarify the role of CTC in these high-risk individuals.

We acknowledge limitations to our study. Approximately 33% of our positive patients entered noninvasive CTC surveillance of their 6-mm to 9-mm polyps, potentially underestimating the prevalence of advanced neoplasia in our population. We attempted to address this bias by calculating the adjusted advanced neoplasia rate at multivariate analysis. In addition, although our CTC screening cohort was among the largest ever reported, the CIs for our 5-year age groups were quite large. However, the 4-fold difference among point-estimates for NNS, as well as the linear model prediction according to age and sex, are likely to be informative for policy makers.

In conclusion, age and sex appear to be useful variables for predicting the risk of advanced neoplasia at screening CTC, whereas BMI and a positive family history of CRC do not appear to have a major impact. These findings could be useful in stratifying patients who undergo CTC screening.

FUNDING SOURCES

This work was supported in part by National Institutes of Health (National Cancer Institute) grant 1R01CA144835-01.

CONFLICT OF INTEREST DISCLOSURES

Dr. Kim received consultancy fees from Viatronix and Digital Artforms, and is cofounder of VirtuoCTC. Dr. Pickhardt received consultancy fees from Viatronix, Check-Cap, Bracco, and iCAD, and is cofounder of VirtuoCTC.

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