Incremental benefits of screening colonoscopy over sigmoidoscopy in average-risk populations: a model-driven analysis

Abstract

Purpose: Screening colonoscopy and flexible sigmoidoscopy (FSG) reduce the risk of colorectal cancer (CRC), but the magnitude and duration of protection, particularly against right-sided cancer, remain uncertain. We computed the incremental benefit of colonoscopy over FSG using a validated mathematical model, which reflects colorectal neoplasia growth characteristics while allowing uncertainty in endoscopic detection and removal of adenomas.

Methods: We calibrated models of CRC incidence within a multistage clonal expansion framework to data from: (1) San Francisco-Oakland SEER registry (reference population) and (2) FSG long-term follow-up data from 50,757 individuals after a negative FSG in the Kaiser Permanente system. We compared the residual CRC risks after FSG with full-length colonoscopy.

Results: Our model mirrors trial data with 10-year CRC risk reductions after FSG screening at age 50 years of approximately one-third; the optimal age for a 'once-only' FSG exam was between ages 50 and 60 years; and the greater benefit was for men compared with women. There were considerable incremental gains in reduction in CRC risk by colonoscopy compared with FSG with the greatest benefit for screening colonoscopy at age 50 years. These results held up against lowering the right-sided adenoma detection sensitivity by 30%, as well as reducing the curative efficacy of polypectomy throughout the colon.

Conclusions: Mathematical modeling of CRC screening, which takes account of important aspects of tumor biology, demonstrates superior risk reductions by colonoscopy over FSG. Our predictions provide further rationale for recommending screening colonoscopy in average-risk populations before the age of 60.

Fig. 1

Scaling method. P=proximal cancer, D=distal cancer (descending colon and sigmoid colon separately), R=rectal cancer. KP distal and rectal cancer model parameters are estimated by taking a KP proximal model parameter and multiplying it by the corresponding SEER-SFO ratio.

Fig. 2

(a),(b) Proximal colon cancer incidence in the KP negative-FSG cohort (grey line: empirical distribution vs black line: prediction by the MSCE-CRC model). (c)–(f) Empirical distribution vs simulation results (detection thresholds: 10³ and 10⁴ stem cells for distal colon and rectum, respectively); (c), (d) Distal colon cancer incidence (combined descending and sigmoid colon) in the KP negative-FSG cohort, (e), (f) Rectal cancer incidence in the KP-negative FSG cohort. KM curve: Kaplan Meier curve with 95 % confidence intervals. Black dashed lines: model prediction for cancer incidence in SEER-SFO.

Fig. 3

Predicted age-specific incidence (hazard) of CRC for people who had screening exam at age 50 (left), 60 (middle), and 70 (right); (1) dotted lines: predicted age-specific incidence of CRC for unscreened reference population. (2) dashed lines: incidence for individuals who had FSG. A positive FSG is assumed to trigger a follow-up colonoscopy. (3) solid lines: incidence for individuals who had ‘once-only’ colonoscopy. Upon detection, adenomas are assumed to be completely resected. These results are based on 100,000 simulated people. The sensitivity rate for colonoscopy in right-sided colon is assumed the same as the left-sided colon.

Fig. 4

Relative risk of CRC to unscreened reference population for two screening modality: (1) FSG (dashed lines); (2) Colonoscopy (solid lines). The results are based on 100,000 simulated people who had screening exam at age 50 (left), 60 (middle), and 70 (right). Upon detection, adenomas are assumed to be completely resected. The sensitivity rate for colonoscopy in right-sided colon is assumed the same as the left-sided colon.