Affiliations of authors: I. Shureiqi (Departments of Clinical Cancer Prevention and Gastrointestinal Medical Oncology), C. D. Cooksley (Department of Health Services Research), J. Morris (Department of Biostatistics), A. S. Soliman (Department of Epidemiology), B. Levin (Division of Cancer Prevention), S. M. Lippman (Department of Clinical Cancer Prevention), The University of Texas M. D. Anderson Cancer Center, Houston.
Correspondence to: Scott M. Lippman, M.D., Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 236, Houston, TX 770304095 (e-mail: slippman{at}mdanderson.org).
Patients with a history of colorectal cancer are considered to be at a high risk of colorectal second primary tumors (SPTs), for which they usually receive intensive surveillance (13). Actual data on risk of SPTs (all from retrospective analyses) are not consistent, however, and even when increased relative to the risk of a first colorectal cancer in the general population, the risk of an SPT was modest (49). Reported incidences of colorectal SPTs also vary widely, ranging from 0.3% to 3.6% (based on variable mean follow-ups ranging from approximately 3 to >10 years) (410). Limited data suggest that the risk of a colorectal SPT is higher in younger than in older patients (4,6). A better understanding of the risk faced by patients with a history of colorectal cancer will help to determine whether all colorectal cancer patients or identifiable subpopulations of patients require targeted approaches for colorectal cancer early detection and prevention, both of which have improved substantially in recent years (1,11,12).
We assessed the overall and age-specific risks of colorectal SPTs within the national Surveillance, Epidemiology, and End Results (SEER)1 Program database population. We defined colorectal SPTs as epithelial carcinomas of the colon and rectum that occurred 2 or more months from the diagnosis of the first cancer (8). We expressed the overall and age-specific risks of colorectal SPTs as standardized incidence ratios (SIRs), calculated as the ratio of the observed rate of colorectal SPTs among patients with a history of colorectal cancer to the expected rate of first colorectal cancers among individuals matched by decade of age from the general population. Both rates were adjusted for sex and person-years of follow-up. The person-years of follow-up for colorectal SPTs began with the diagnosis of the first colorectal cancer. The expected rates of first colorectal cancer in the general population were calculated from a public-use file (SEER Program PublicUse CD-ROM [19731996], Surveillance Program, Cancer Statistics Branch, Division of Cancer Control and Population Sciences, National Cancer Institute, released April 1999; based on the August 1998 submission), which included SEER colorectal cancer cases and 1970 U.S. census data.
A total of 217 705 SEER database patients had a first colorectal cancer diagnosed from 1979 through 1996, of which 4202, or 1.9%, developed colorectal SPTs during a median follow-up period of 4.2 years. Eighty percent of the SPTs developed 1 or more years from the first cancer diagnosis. The overall SIR for a colorectal SPT was 1.9 (95% confidence interval [CI] = 1.8 to 1.9). Our age-stratified analyses showed a strong inverse relationship between the SIRs and decade of age (Fig. 1). Among patients experiencing an SPT, the overall mean and median times between the diagnoses of the first and second colorectal cancers were 45.6 and 32 months, respectively. We examined the potential effect of the colorectal cancer patients (who were grouped according to age at first-cancer diagnosis) moving between 10-year age groups. This moving between groups was not a major factor because of the relatively short time to SPT development (median, 32 months). Most SPT patients did not develop the SPT in the next age group, and no patients with an SPT moved through more than one age group. The inverse correlation between age and SIR remained in an ultraconservative analysis using the next older age group for standardizing the SIRs (data not shown).
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A potential limitation of our study was the unavailability of data from SEER on surveillance patterns in the different age strata. It is very unlikely, however, that the increased risk that we found in younger patients was because of differences in the frequency of screening and clinical follow-up (compared with in older patients), since the increase was extremely large, the annual age-specific SPT hazard rates were constant over time, and the guidelines for screening and clinical follow-up after a colorectal cancer diagnosis are not age specific (13).
Although colorectal cancer risk generally increases with age, the SIR of colorectal SPT, which is an age-matched risk measure, was greatly increased for younger patients in our study. The great increase in this younger-age SIR was likely because of a biologic predisposition rather than a longer follow-up in younger patients compared with older patients. The limited influence of follow-up is suggested by our findings that the annual hazard rate of colorectal SPTs was constant overall, which is consistent with the findings of Cali et al. (7), and constant over time for each age stratum. Furthermore, our SIRs included age-matched groups in the U.S. population and were adjusted for follow-up. There is evidence to suggest that younger patients have a biologic predisposition to develop SPTs that show microsatellite instability (MSI) and that are associated with hereditary defects in mismatch repair genes, such as those that occur in hereditary nonpolyposis colon cancer (HNPCC) (16,17), which is associated with both an increased risk of colorectal SPTs and younger age (17). HNPCC, however, is found in only 15% of younger colorectal SPT patients, suggesting that acquired mismatch repair defects also may be involved (18). The involvement of these defects is supported by two small studies (19,20) that excluded patients with a family history of colorectal cancer and found higher rates of MSI in colorectal cancer patients who developed SPTs than in those who did not. Familial adenomatous polyposis (FAP) probably does not contribute appreciably to our increased-risk findings in younger patients because the rigorous standard management of FAP (e.g., prophylactic proctocolectomy) virtually eliminates the risk of SPTs. Targeted colorectal cancer screening and prevention strategies will benefit from further epidemiologic and biologic studies of increased colorectal SPT risk.
NOTES
1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
Supported in part by Public Health Service grants CA86970 and CA16672 from the NCI, National Institutes of Health, Department of Health and Human Services. S. M. Lippman holds the Margaret and Ben Love Professorship in Clinical Cancer Care.
We thank Martin L. Brown, Ph.D. (NCI), for his valuable scientific advice and Kendall Morse (M. D. Anderson Cancer Center) for his editorial assistance during the preparation of this manuscript.
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Manuscript received January 23, 2001; revised June 4, 2001; accepted June 15, 2001.
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