Cancer Epidemiology Unit and Registre Vaudois des Tumeurs, Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Biopôle 2, Route de la Corniche 10, Lausanne, Switzerland
Registre Neuchâtelois des Tumeurs, Av. des Cadolles 7, Neuchâtel, Switzerland
Cancer Epidemiology Unit and Registre Vaudois des Tumeurs, Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Biopôle 2, Route de la Corniche 10, 1010 Lausanne, Switzerland
Patients who had a colorectal cancer have a 1.5- to 2-fold excess risk of a second colorectal cancer as compared to the general population, the excess being higher at younger age at diagnosis. To further investigate the risk and the age-relation of the incidence of second primary colorectal cancer, we considered 9,389 first colon and rectal cancers registered in the Vaud Cancer Registry, Switzerland, between 1974 and 2008, and followed-up to the end of 2008 for a total of 44,113 person-years. There were 136 second colorectal cancers versus 90.5 expected, corresponding to a standardized incidence ratio (SIR) of 1.5 (95% confidence interval, CI, 1.3–1.8). The SIRs were not heterogeneous between men and women, and in strata of calendar year at diagnosis, duration of follow-up, and subsite. However, the SIR was 7.5 (95% CI 4.2–12.4) for subjects diagnosed below age 50 and declined thereafter to reach 1.0 (95% CI 0.6–1.6) at age 80 or over. Consequently, the incidence of second primary colorectal cancer was stable, and exceedingly high, around 300–400/100,000 between age 30–39 and 70 or over. This age pattern is consistent with the existence of a single mutational event in a population of highly susceptible individuals.
Patients who had a colorectal cancer have an excess risk of selected cancers, and in particular a 1.5- to 2-fold excess of a second colorectal cancer in the same organ, as compared to the general population.1–4
More important, the relative risk (RR) of second colorectal cancer declines from over 40 before age 40 to about 1.5 at age 70–79, and is close to unity at age 80 or over.2, 4, 5 This pattern of risk may reflect a high constant incidence of second colorectal cancers at subsequent ages.5
To further investigate the RR and age-relation of the incidence of second primary colorectal cancer, we analyzed the data from the Cancer Registry of the Swiss canton of Vaud,2 updated to the end of 2008.
Material and Methods
The data considered in the present analysis were derived from the Vaud Cancer Registry dataset, which includes information concerning incident cases of malignant neoplasms occurring in the Canton of Vaud (about 690,000 inhabitants in 2005).6 Population-based data have been available since 1974. The main information available comprises demographic characteristics of the patient (i.e., age and sex), primary site and histological type of the tumor according to the standard international classification of diseases for oncology (ICD-O-1 and ICD-O-3).7, 8 Passive and active follow-up is recorded and information from the death certificate is added to the registration file.
The registry is tumor-based, and multiple primary cancers in the same person are registered separately. Within colon, separate primary sites in the same patient were considered for left colon (ICD-O-1 topography codes 153.1-.3, 153.7) and right colon (ICD-O-1 153.0, 153.4-153.6). Thus, in the same patient, up to three colorectal primaries could be registered, two for colon and one for rectum (ICD-O-1 154.0-154.1). Second primary tumors occurring in the same site were not registered. Further, only one second primary was considered.
After the exclusion of 245 cases diagnosed at death and of those with a second primary occurring 2 or less months since the first primary (n = 120), a total of 9,389 first colon and rectal cancers (4,953 males, 4,436 females) were registered and followed over the period 1974–2008 for the occurrence of a second colon or rectal primary, emigration or death, contributing to a total of 44,113 person-years (mean follow-up 4.7 years).
We computed the age-specific incidence rates of first colorectal cancers in the general population6 as well as those of second colon or rectal cancer in subjects with a first primary. Calculation of expected numbers of second primary colon or rectal cancer was based on site-, sex-, 5-year age group- and calendar year (single years, 1974–2008)-specific number of person-years at risk. From the observed and expected number of events, we computed the standardized incidence ratio (SIR) of second colon or rectal cancer, and the corresponding 95% confidence interval (CI), based on the Poisson distribution.
Table 1 gives the observed and expected numbers of second primary colorectal cancer, and the corresponding SIR and 95% CI, in strata of sex, age at diagnosis, calendar period, time since diagnosis, and subsite of second primary cancer. Among 9,389 incident colorectal cancers, a total of 136 second colorectal cancers were registered, versus 90.5 expected, corresponding to a SIR of 1.5 (95% CI, 1.3–1.8). The SIR was 1.4 (95% CI, 1.1–1.8) for men and 1.7 (95% CI, 1.3–2.2) for women. The SIR was 7.5 (95% CI, 4.2–12.4) below age 50 and declined thereafter, reaching 1.0 (95% CI, 0.6–1.6) at age 80 or more. The SIRs were somewhat higher in subjects with a first diagnosis between 1974 and 1988 (SIR = 1.8; 95% CI, 1.4–2.3) and in those with a diagnosis of second primary cancer after 10 years from the first diagnosis (SIR = 2.1; 95% CI, 1.5–1.8). With reference to subsite of second primary cancer, the SIRs were 1.2 (95% CI, 1.0–1.4) for colon and 1.6 (95% CI, 1.1–2.3) for rectal cancer.
Table 1. Observed and expected numbers of second primary colorectal cancer, and corresponding standardized incidence ratios (SIR) and 95% confidence intervals (CI), following 9,389 first colorectal cancers, by sex, age at diagnosis, calendar period at diagnosis, years since diagnosis, and subsite of second primary. Vaud, Switzerland, 1974–2008
Figure 1 shows the age distribution of first and second colorectal cancer. While the incidence of first primary cancers increased with increasing age from 0.5/100,000 at age 20–24 to 265/100,000 at age 80–84, that of second cancer did not increase, but, if anything, tended to decline with age, being around 300 to 400/100,000 at age 30 to 39 and 80.
The present updated analysis of second primary colorectal cancer in the Vaud Cancer Registry confirms the existence of an excess risk. This is comparable across subsequent calendar periods at diagnosis—despite the likely improved surveillance over more recent calendar periods—'persists up to 10 years or longer after diagnosis of first primary cancer, and is exceedingly high for neoplasms diagnosed under age 50, with SIRs levelling off toward unity for primary neoplasms diagnosed at subsequent age. This reflects an approximately constant incidence rate of second primary colorectal cancer between age 30 and 80, whereas the incidence of first colorectal cancer increases by over 100-fold. Such a constant rate is over 300/100,000, i.e., higher than that of primary colorectal cancer above age 80 in the general population. This pattern of incidence of second primary cancer with age was observed for colorectal cancer in the surveillance, epidemiology and end results (SEER) dataset,4, 9 and for other digestive tract cancers,5, 10–12 breast5, 13–18 and skin5, 18–20 cancers in other cancer registration areas.
In the SEER program, colorectal cancer patients had elevated SIRs of second primary colon cancer (SIR = 1.49 for men and 1.60 for women), which appeared to increase over recent calendar periods,21, 22 but the age-specific rates of second primary colorectal cancer showed no apparent rise between age 50 and 80.23 In the Swedish Cancer Registry dataset24 between 1960 and 1981 the SIRs of rectal cancer following colorectal cancer and colon cancer following colorectal cancer ranged between 2.6 and 3.3. In the Osaka Cancer Registry dataset,25 excess risks following colon cancer were observed for cancers of the rectum (SIR = 2.0 in men and 4.3 in women). In the Swiss Vaud Cancer Registry dataset up to 1999,2 the SIRs for second primary colorectal cancer were 1.9 in men and 1.5 in women. In the Swedish Family-Cancer Database,26 the SIRs for all cancers combined following colon and rectal cancer ranged between 1.2 and 1.5 in both sexes, with a 2.7 excess risk for second primary colorectal cancer. In the Thames Cancer Registry database,27 excess risks after colorectal cancer were observed for cancer of the colon (SIR = 2.33 in men and 1.28 in women). In a French cancer registry the SIR of second colorectal cancer was 1.6.28 Likewise, in the Australian New South Wales Central Cancer Registry the SIR of second colorectal cancer was 1.5.29 The SIRs in the California cancer registry were 1.4 for colon and 1.1 for rectal cancer.30
In a historical cohort study based on 3,278 patients with resected stages II–III colon cancer, 42 cases of second primary invasive colon cancer were observed after a median follow-up of 7 years, and the SIR was 1.6, despite intensive surveillance.31 A study based on 5,447 Korean colorectal cancer patients found an over sixfold excess relative risk (RR) of second cancer in patients diagnosed below 40 years as compared to those over 40 years, in the absence, however, of absolute or relative risk estimates at a population level.9 Several other studies reported high (cumulative) incidence of metachronous colorectal cancers in various populations, in the absence, however, of population-based and age-specific estimates of risk.32–38
The excess risk of second colorectal cancers reported is indeed likely to be underestimated in our as previous studies, since in several cancer registration areas second colorectal cancer was considered as a new primary only when occurring at a different site (right colon, left colon, rectum including recto-sigmoid junction).2, 5 However, this is unlikely to influence the shape of the age curves of second neoplasms.
The power function of age observed in most primary epithelial cancers has been interpreted within the multistage theory of carcinogenesis,39 in terms of accumulation of several stochastic somatic changes in the process of carcinogenesis. This is also consistent with mechanistic data indication that several pathways need to be disrupted for a cancer to develop.40 In contrast, the constant rate of incidence with age of second primary cancer is consistent with the occurrence of a single mutational event in a population of susceptible individuals, as observed for retinoblastoma and other childhood cancers, or for breast cancers in BRCA1 women.14, 16, 41
The work of C.B., C.L.V. and V.R. was supported by the Italian Association for Cancer Research (AIRC), Italy (Grant N. 10068).