SEARCH

SEARCH BY CITATION

Keywords:

  • colorectal cancer;
  • second cancer;
  • metachronous cancer;
  • standardized incidence ratio;
  • tumor subsite

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

Individuals with a history of colorectal cancer (CRC) have an increased risk of subsequent cancer. In this study, the authors used cancer registry data to evaluate whether this increased risk of cancer after CRC differed by anatomic subsite of a first CRC.

METHODS

Individuals diagnosed with a first primary CRC between 1992 and 2009 were identified from 12 Surveillance, Epidemiology, and End Results (SEER) cancer registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing the incidence of subsequent cancers in these patients who had an index CRC versus the cancer incidence rates in the general population. SIRs were calculated for cancers at anatomic sites within and outside the colorectum in analyses stratified by subsite of the index CRC.

RESULTS

Cancer incidence rates were significantly higher in individuals who had a previous CRC than in the general population (SIR, 1.15; 95% CI, 1.13-1.16). Individuals with an index CRC located between the transverse and descending colon experienced the greatest increased risk both overall (SIR, 1.29-1.33) and particularly with respect to the risk of a second CRC (SIR, 2.53-3.35). The incidence of small intestinal cancer was elevated significantly regardless of the index CRC subsite (SIR, 4.31; 95% CI, 3.70-4.77), and the incidence of endometrial cancer was elevated in those who had an index CRC in the proximal colon (SIR, 1.37-1.79).

CONCLUSIONS

The risk of second cancer after CRC differs by anatomic site of the first tumor and is particularly pronounced for those with prior CRC located in the transverse to descending colon. The mechanisms underlying this pattern of second cancer risk remain unknown. Cancer 2013;119:3140–3147. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Advances in the early detection and treatment of colorectal cancer (CRC) have contributed to improvements in CRC prognosis over recent decades, such that the population of CRC survivors is growing.[1] However, as the short-term prognosis for CRC improves, longer term health concerns facing CRC survivors will likely become more prominent.[2-4] One such concern is the increased risk of second primary cancers in CRC survivors.[5-10] This increased risk may reflect shared genetic or environmental risk factors for different malignancies or the effect of treatment for primary CRC.

Previous studies have reported an increased risk (up to 1.4-fold) of a second cancer after an initial CRC.[5, 7, 8, 11] This elevated risk is observed most consistently for the risk of a second primary CRC.[6-8, 10-12] Less consistent evidence suggests an increased risk of cancer of the stomach,[9] small intestine,[5-7, 9] breast,[5-7] ovaries,[6, 7] prostate,[6, 7] bladder,[7] kidney,[6, 7, 9] and endometrium[5-7, 9] after CRC. On the basis of these prior observations and the finding that the biologic characteristics of cancer may reflect, to some extent, the embryologic origin of tissue, we hypothesized that the excess risk of second primary cancer after CRC may be high for organs that are developmentally related with endoderm-derived epithelia, particularly tissues in close proximity to the colorectum.

Recent studies have suggested that the risk of second primary cancer after CRC also differs by anatomic site of the first CRC.[10, 11, 13] In particular, it has been suggested that the risk of second primary CRC is greater in individuals with a first primary CRC located in the proximal colon compared with individuals with a first primary CRC in the distal colon or rectum.[10, 11, 13] In light of differences in tumor biology and potential differences in tumor etiology across the colorectal continuum,[14, 15] it is plausible that the distribution and risk of second primary cancer may differ according to the site of the first primary CRC. Thus, we tested the hypothesis that the risk of a second primary CRC in bowel subsites may change as a continuum in relation to the subsite of the first primary CRC. We used data from Surveillance, Epidemiology, and End Results (SEER) cancer registries[16] to estimate the risk of second primary cancer after CRC according to the site of the first and the second primary cancers.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

We used data from the 12 SEER cancer registries, which have contributed cancer incidence data since 1992 to the linked multiple-primary SEER*Stat query database: Hawaii; Iowa; Connecticut; New Mexico; Utah; Atlanta, Georgia; Rural Georgia; Detroit, Michigan; San Francisco-Oakland, California; San Jose-Monterey, California; Los Angeles, California; and Seattle-Puget Sound, Washington.[16] Information is collected by SEER on all incident cancers, excluding basal or squamous skin cancer, occurring within these ascertainment regions. SEER also collects follow-up information on deaths and diagnoses of new cancers in individuals with a history of cancer.

To ensure that recurrences and metastases are not recorded as new primary cancers, SEER registrars adhere to a series of coding rules.[17] To be classified as a primary cancer, a tumor subsequent to an invasive CRC cannot be described as a metastasis in the clinical record and must be located in a site with different International Classification of Diseases for Oncology third edition (ICD-O-3) topography or histology codes; or, if codes are the same, a tumor must be diagnosed more than 1 year after the prior primary CRC. Hereinafter, we refer to the first primary CRC as the index CRC.

Index Colorectal Cancers Cases

For the current study, patients with an index CRC (index cases) included individuals who were diagnosed with an invasive index CRC between 1992 and 2009 within the catchment area for the aforementioned SEER registries. We restricted inclusion to individuals who were diagnosed at ages 40 to 79 years with no history of cancer before the index CRC. We excluded individuals with an index CRC that was identified by death certificate or autopsy only, those with cancers located in the appendix, and those with an index CRC of unknown anatomic subsite. In total, 170,159 index cases met these criteria.

Second Primary Case Criteria

All second primary cancers were diagnosed among index CRC cases between 1992 and 2009 within the ascertainment area of the included SEER registries. Definitions for second primary cancer were based on established SEER criteria.[17] Tumors diagnosed during a 2-month period after the index CRC diagnosis were excluded as likely synchronous tumors. We also conducted sensitivity analyses to further exclude tumors that were diagnosed within 6 months of the index CRC. We restricted our evaluation to second primary cancers that were diagnosed within 10 years of the index CRC; approximately 89% of second cancers were diagnosed within this timeframe. Some individuals were diagnosed with multiple primary cancers within this timeframe; all invasive cancers subsequent to the index CRC were included in calculations of standardized incidence ratios (SIRs), as described below. In situ second cancers were excluded. In total, 16,697 second primary cancers in 14,880 index CRC cases met these inclusion criteria.

Statistical Analyses

We calculated SIRs by comparing the observed occurrence of second primary cancers after an index CRC versus the occurrence that would have been expected based on cancer incidence rates in the general population of the SEER ascertainment areas. Expected incidence rates were stratified by sex, age (5-year intervals), calendar year (5-year intervals), and race (white, black, other); person-years at risk for second cancer were stratified in the same manner. Numbers of expected cancers were calculated by multiplying stratum-specific person-years at risk and corresponding stratum-specific incidence rates and then summing these products across strata. Thus, SIRs represent the ratio of observed-to-expected second primary cancers with adjustment for sex, age, calendar year, and race.

SIRs were calculated separately for the following index CRC subsites: cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, rectosigmoid junction, and rectum. For each case group defined by index CRC subsite, we calculated SIRs for second primary cancers at all anatomic sites combined, at all non-CRC sites combined, for each of the most common non-CRC cancer sites, and for each cancer subsite within the colorectum. SIRs based on fewer than 5 observed second primary cases are not presented. We conducted exploratory analyses stratified by race and by stage at index diagnosis. We restricted SIR calculations to diagnoses and person-years at risk accrued in the 10 years after the index CRC diagnosis. A determination of statistical significance was based on a 2-sided P value < .05.

We also estimated the absolute excess risk for second CRC and for non-CRC second primary cancers with SIRs that were statistically significantly different from the null. Excess risk was calculated as the number of observed cases minus the number of expected cases divided by person-years at risk. Estimates of excess risk are presented per 10,000 person-years at risk. All analyses were conducted using SEER*Stat software (version 7.1.0; SEER Program, National Cancer Institute, Bethesda, Md).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Population Characteristics

Characteristics of the index case population are presented in Table 1. The majority of index cases were ages 60 to 79 years (67%), men (54%), and non-Hispanic whites (69%); the proportion of cases exhibiting these attributes was greater among those who subsequently developed a second primary cancer.

Table 1. Characteristics of First Primary Colorectal Cancer Cases According to the Occurrence and Site of Second Primary Cancers: Surveillance, Epidemiology, and End Results 13 Registries, 1992 to 2009
 All First Primary No. Who Developed a Second Primary Cancer (Column %)
CharacteristicCRC Cases: No. (Column %)All Second Primary SitesSecond Primary CRC
  1. Abbreviations: CRC, colorectal cancer; SEER, Surveillance, Epidemiology, and End Results Program.

  2. a

    Excludes Alaska Native Tumor Registry, which is not included in SEER multiple primary data files.

Age at first CRC diagnosis, y   
40-4916,834 (10)675 (5)206 (7)
50-5938,679 (23)2359 (16)499 (17)
60-6953,089 (31)5163 (35)904 (32)
70-7961,557 (36)6683 (45)1245 (44)
Sex   
Men92,299 (54)9029 (61)1594 (56)
Women77,860 (46)5851 (39)1260 (44)
Race   
White non-Hispanic117,125 (69)10,923 (73)1984 (70)
Black18,493 (11)1618 (11)369 (13)
White Hispanic14,600 (9)998 (7)246 (9)
American Indian/Alaska Native778 (0.5)67 (0.5)10 (0.4)
Asian or Pacific Islander18,032 (11)1263 (8)240 (8)
Other/unspecified1131 (1)11 (0.1)5 (0.2)
Stage at first CRC diagnosis   
Localized71,436 (42)8000 (54)1349 (47)
Regional64,925 (38)5764 (39)1183 (41)
Distant29,837 (18)801 (5)216 (8)
Unstaged3961 (2)315 (2)106 (4)
Site of first CRC   
Cecum25,856 (15)2231 (15)380 (13)
Ascending colon18,615 (11)1743 (12)267 (9)
Hepatic flexure5923 (3)549 (4)103 (4)
Transverse colon9757 (6)945 (6)218 (8)
Splenic flexure4365 (3)432 (3)130 (5)
Descending colon7624 (4)784 (5)185 (6)
Sigmoid colon41,829 (25)3880 (23)761 (27)
Rectosigmoid junction16,952 (10)1418 (10)275 (10)
Rectum39,238 (23)2898 (19)535 (19)
SEER registrya   
San Francisco-Oakland18,826 (11)1553 (10)283 (10)
Connecticut19,001 (11)1812 (12)300 (11)
Detroit20,429 (12)2106 (14)425 (15)
Hawaii7033 (4)536 (4)95 (3)
Iowa17,390 (10)1672 (11)314 (11)
New Mexico7491 (4)539 (4)96 (3)
Seattle-Puget Sound17,277 (10)1579 (11)245 (9)
Utah6472 (4)500 (3)100 (4)
Atlanta10,250 (6)731 (5)138 (5)
San Jose-Monterey9119 (5)706 (5)117 (4)
Los Angeles36,203 (21)3093 (21)731 (26)
Rural Georgia668 (0.4)53 (0.4)10 (0.4)

Standard Incidence Ratios for Second Primary Cancer

Regardless of the subsite of the index CRC, the risk of second primary cancer was significantly elevated (Table 2). Among those with index cancers in the cecum, ascending colon, transverse colon, or descending colon, SIRs remained significantly elevated after excluding second primary CRC from SIR calculations. However, among individuals with an index rectal cancer, the risk of second primary non-CRC was significantly lower relative to the general population (SIR, 0.96; 95% confidence interval [CI], 0.92-1.00). The most consistent and markedly elevated SIRs for non-CRC were for cancer of the small intestine, with statistically significant SIRs ranging from 2.24 (95% CI, 1.47-3.26) for index rectal cancer cases to 7.06 (95% CI, 5.19-9.39) for index ascending colon cancer cases. There was also a significantly elevated incidence of second primary lung cancer (SIR, 1.14; 95% CI, 1.10-1.18), bladder cancer (SIR, 1.11; 95% CI, 1.04-1.18), kidney cancer (SIR, 1.42; 95% CI, 1.30-1.54), stomach cancer (SIR, 1.28; 95% CI, 1.16-1.42), and endometrial cancer (SIR, 1.26; 95% CI, 1.14-1.40) after an index CRC. Associations with the elevated incidence of these second primary cancers were consistent by race and stage, with the exception that the elevated SIR for stomach cancer after CRC was largely limited to patients with a localized index CRC (SIR: 1.44 [95% CI, 1.26-1.64] vs 1.09 [95% CI, 0.90-1.29] for a regional index CRC; results not shown). Associations were not consistent across anatomic subsites of index CRC. In particular, the elevated SIR for second primary endometrial cancers was most pronounced among individuals with an index CRC in the proximal colon. A lower than expected incidence of prostate cancer was observed (SIR, 0.91; 95% CI, 0.88-0.95), particularly among those who had an index cancer in the rectosigmoid junction (SIR, 0.82; 95% CI, 0.73-0.92) or the rectum (SIR, 0.65; 95% CI, 0.59-0.71). However, in analyses stratified by race, this lower incidence of prostate cancer was only evident in among whites (SIR, 0.87; 95% CI, 0.84-0.91), whereas the incidence of second primary prostate cancer was significantly elevated among blacks (SIR, 1.13; 95% CI, 1.02-1.24; results not shown).

Table 2. Cancer Site-Specific Standardized Incidence Ratios for Second Primary Cancer by Site of First Primary Cancer Within the Colon or Rectum: Surveillance, Epidemiology, and End Results 13 Registries, 1992 to 2009
 Cancer Site-Specific Standardized Incidence Ratio
Second Cancer SiteAll First Primary SubsitesCecumAscending ColonHepatic FlexureTransverse ColonSplenic FlexureDescending ColonSigmoid ColonRectosigmoid JunctionRectum
  1. Abbreviations: CRC, colorectal cancer.

  2. a

    P < .05

  3. b

    This standard incidence ratio was based on <5 second primary cases.

All sites1.15a1.14a1.22a1.20a1.29a1.30a1.33a1.14a1.08a1.04a
All non-CRC sites1.04a1.07a1.15a1.091.13a1.041.14a1.030.980.96a
Prostate0.91a1.021.090.941.061.011.110.970.82a0.65a
Lung/bronchus1.14a1.091.23a1.061.24a1.041.141.10a1.071.21a
Female breast0.980.991.061.31a0.970.920.980.980.970.87a
Urinary bladder1.11a1.20a0.881.081.040.651.291.101.34a1.11
Non-Hodgkin lymphoma0.971.031.161.090.781.130.830.850.941.05
Pancreas1.040.881.36a2.02a1.021.231.080.930.970.91
Kidney1.42a1.59a1.251.371.151.461.84a1.46a0.951.53a
Melanoma0.931.050.791.491.030.951.120.860.950.85
Stomach1.28a1.191.261.571.80a2.06a1.081.27a1.231.16
Endometrium1.26a1.57a1.37a1.491.79a1.371.251.240.960.89
Nonlymphocytic leukemia1.081.141.140.841.331.010.811.071.280.96
Esophagus1.121.251.040.991.47-b1.281.180.951.01
Small intestine4.21a5.64a7.06a5.60a4.67a4.47a3.69a3.48a4.05a2.24a
Lymphocytic Leukemia0.78a0.62a0.75-b1.10-b0.600.870.600.91
Larynx1.101.011.46-b0.86-b1.691.171.000.98
Liver0.79a0.45a1.23-b1.001.201.410.790.600.71

SIRs for second primary CRC were significantly elevated regardless of index CRC subsite (Fig. 1). The SIR for a second CRC was highest among those who had an index CRC in the splenic flexure (SIR, 3.35; 95% CI, 2.83-3.94). SIRs were slightly lower in cases with index CRC in the descending (SIR, 2.81; 95% CI, 2.44-3.20) and transverse colon (SIR, 2.53; 95% CI, 2.22-2.86); SIRs declined with increasing anatomic distance from the splenic flexure. Cases with index cecal or ascending colon cancer experienced significantly lower incidence rates of second cancers in the cecum and ascending colon; however, all other significant SIRs for index/second CRC subsite combinations indicated elevated incidence of second cancer. In analyses of all index cases combined, SIRs were most elevated with respect to incidence of second primary CRC located in the transverse colon (SIR, 3.78; 95% CI, 3.44-4.15), descending colon (SIR, 3.30; 95% CI, 2.90-3.75), and splenic flexure (SIR, 2.72; 95% CI, 2.26-3.25). Similar patterns of elevated risk were evident across strata defined by race and by stage (Fig. 2a,b); however, the SIR for a second primary CRC was higher in black index cases than in white or Asian/Pacific-Islander cases, regardless of the index CRC subsite.

image

Figure 1. Subsite-specific standardized incidence ratios (SIRs) are shown for second primary colorectal cancer (CRC) by anatomic site of index CRC (from the Surveillance, Epidemiology, and End Results [SEER] 13 registries, 1992-2009). Second CRC diagnosis dates ranged from 2 months to 10 years after the index CRC diagnosis in patients ages 40 to 79 years.

Download figure to PowerPoint

image

Figure 2. Standardized incidence ratios (SIRs) for second primary colorectal cancer (CRC) are illustrated according to anatomic site of index CRC and (a) race or (b) stage at index diagnosis (from the Surveillance, Epidemiology, and End Results [SEER] 13 registries, 1992-2009). Second CRC diagnosis dates ranged from 2 months to 10 years after the index CRC diagnosis in patients ages 40 to 79 years.

Download figure to PowerPoint

Excess Risk for Second Primary Cancer

In addition to having the highest SIRs for second primary cancer, cases with an index CRC located in the transverse to descending colon had the highest absolute excess risk of second primary cancer: An estimated 52.9 to 58.2 excess cancers per 10,000 person-years were diagnosed in individuals with these index cancers relative to the general population (Table 3). The magnitude of excess risk in all index cases was driven by the excess risk of a second primary CRC. Overall, 19.7 excess CRCs were diagnosed per 10,000 person-years in individuals with a prior CRC; estimates of excess risk ranged from 13.8 to 49.2 per 10,000 person-years in individuals with index rectal cancer and splenic flexure cancer, respectively.

Table 3. Cancer Site-Specific Absolute Excess Risk for Second Primary Cancer per 10,000 Person-Years by Site of First Primary Cancer Within the Colon or Rectum: Surveillance, Epidemiology, and End Results 13 Registries, 1992 to 2009
 Cancer Site-Specific Absolute Excess Risk for Second Primary Cancer
Second Cancer SiteAll First Primary SubsitesCecumAscending ColonHepatic FlexureTransverse ColonSplenic FlexureDescending ColonSigmoid ColonRectosigmoid JunctionRectum
  1. Abbreviations: CRC, colorectal cancer.

  2. a

    This calculation was based on <5 second primary cases.

All second primary sites26.227.041.338.652.956.058.225.213.57.2
Prostate−6.21.47.4−5.04.80.58.1−1.8−12.5−23.2
Lung/bronchus3.82.86.71.76.81.13.92.72.05.1
Urinary bladder1.12.1−1.30.90.4−3.62.81.03.31.0
Kidney1.82.71.11.70.72.13.72.0−0.22.3
Stomach1.00.71.02.23.03.90.31.00.80.5
Endometrium2.14.73.04.06.42.92.01.9−0.3−0.9
Small intestine2.33.54.63.52.72.61.91.72.00.8
Lymphocytic leukemia−0.5−0.9−0.6a0.2a−0.9−0.3−0.9−0.2
Liver−0.5−1.20.5a0.00.51.0−0.5−0.9−0.7
CRC19.715.615.322.932.849.236.620.816.813.8
Cecum1.7−2.8−0.9−0.46.76.44.43.41.71.6
Ascending colon2.2−0.1−1.51.55.213.09.72.90.91.7
Hepatic flexure0.70.10.0−0.21.23.42.61.00.40.6
Transverse colon3.95.58.49.01.97.18.33.11.01.5
Splenic flexure0.91.61.82.61.40.41.60.60.30.3
Descending colon2.01.12.42.95.75.31.72.51.60.8
Sigmoid colon2.35.53.45.05.97.64.40.0−0.51.2
Rectosigmoid junction0.91.40.91.51.21.30.51.3−0.20.5
Rectum4.93.41.11.33.04.82.36.111.04.9

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

In this analysis of cancer registry data, the risk of a second primary cancer after CRC was significantly greater than expected risk based on cancer incidence rates in the general population. The magnitude of this increased risk differed according to the location of the index CRC and was most pronounced for cases with an index CRC of the transverse colon, splenic flexure, and descending colon. These subsites were also the locations at which there was the greatest absolute excess risk of a second primary CRC, indicating a generally greater susceptibility to second primary cancer in patients with index cancers in these colonic segments.

Several prior studies have observed an increased risk of second primary cancers after CRC.[5-11] In particular, studies have noted an increased risk of bladder,[5, 7] kidney,[5-7] stomach,[5, 7, 9] small intestine,[5-7, 9] and endometrial[5-9] cancer after CRC. In a previous SEER analysis of second primary noncolonic cancers after CRC, Ahmed et al observed that SIRs were most pronounced with respect to the risk of small intestinal cancer.[9] We also observed that increased SIRs for second primaries were most pronounced for small intestinal cancer, regardless of the anatomic location of the index CRC.

In considering possible mechanisms responsible for the observed increased risk of noncolonic second primary cancers, it is plausible that some of this increased risk reflects the contribution of genetic predisposition in patients with familial cancer syndromes, such as hereditary nonpolyposis colorectal cancer.[18] However, hereditary nonpolyposis colorectal cancer and other familial syndromes are rare[19] and are unlikely to fully account for our findings. It is also possible that the increased risk of some cancers reflects misclassification of metastases as new primary cancers and/or reflects the contribution of shared risk factors. For example, findings of an increased risk of lung cancer after an index CRC may reflect the shared contribution of smoking to the risk of both malignancies.[20, 21] Our data also support the hypothesis that the elevated risk of second primary small intestinal, stomach, bladder, and lung cancer reflects the shared origin of the endoderm-derived epithelia at these sites. These embryologically related tissues may be expected to respond in a similar fashion to environmental exposures and carcinogens, and they may be similarly susceptible to aberrant epigenetic changes; such epigenetic changes, in turn, may form a field effect, making these tissues similarly susceptible to the development of primary tumors. This hypothesis also may explain why we observed no elevated risk of leukemia or lymphoma after CRC, because such cancers arise in cells with different embryologic origins.

Similar mechanisms may be responsible for the observed increased risk of second primary CRC. Most prior studies of second primary cancer in CRC survivors have focused on the risk of second primary CRC and have consistently demonstrated significantly elevated incidence rates.[5-8, 10-13] In a recent registry-based analysis, Ringland et al reported a cumulative incidence of second primary CRC of 2.1% at 5 years after index diagnosis.[10] Estimated SIRs for second primary CRC in previous studies have ranged from 1.4 to 2.2, consistent with our SIR of 2.1.

Few prior studies have considered possible differences in the risk of second primary cancer according to the location of the first primary CRC.[6, 10, 11, 13] However, at least 3 studies have suggested that the risk of second primary CRC is greater after an index proximal colon cancer than after an index distal colon or rectal cancer.[10, 11, 13] In contrast, we observed that the excess risk of second primary cancer, particularly second primary CRC, was greatest among individuals who had an index CRC located in the splenic flexure, and that risk declined with distance from the splenic flexure. The basis for this pattern is unclear but may be related to differences in index CRC biology across the CRC continuum.[14] Yamauchi et al recently demonstrated a clear pattern of increasing frequency of CpG island methylation, microsatellite instability, and somatic BRAF mutations across CRC subsites from the rectum to the ascending colon, suggesting that classification of CRC into tumors of the proximal colon, distal colon, or rectal cancer is an oversimplification.[14] It is plausible that other molecular or pathologic attributes may follow a pattern of distribution similar to what we observed for the distribution of second primary cancer risk, with the highest risk for patients with index CRC in the transverse to descending colon and lowest for patients with index CRC at either end of the colorectum. However, to our knowledge, such a pattern of distribution has not been described for common molecular alterations or clinical characteristics of CRC.

Patterns of risk for second primary CRC by index CRC subsite also are probably related, at least in part, to patterns of surgical procedures for the treatment of index CRC. Less than 14% of first primary CRCs are located in the transverse colon, splenic flexure, or descending colon; and these portions of the colon are likely to be preserved, at least in part, in surgical treatment for index CRC. Right hemicolectomy, for the treatment of proximal colon cancer, generally involves the removal of the cecum, ascending colon, hepatic flexure, and a small portion of the transverse colon; consequently, the SIR for second primary cecal, ascending colon, or hepatic flexure cancer was ≤1.0 for individuals who had index CRCs at these sites. Sigmoid resection for the treatment of sigmoid colon cancer generally involves the removal of the sigmoid colon and a portion of the descending colon; consequently, the SIR for a second primary sigmoid colon cancer after an index sigmoid colon cancer is 0.99. Thus, the finding that individuals who have a history of index CRC experience the greatest increased risk for second primary CRC located in the transverse colon, splenic flexure, or descending colon may reflect the reality that these portions of the colon are preserved most frequently in the surgical treatment of index CRC.

The results presented here should be interpreted in the context of study limitations. In particular, individual-level information was limited. We lacked data on tumor markers, genetic factors, family history, treatment, and lifestyle characteristics. In addition, we cannot rule out the possibility that second cancers, particularly second primary CRCs, are recurrences or metastases rather than true second primary cancers; however, we conducted sensitivity analyses excluding all second cancers diagnosed ≤6 months after an index CRC and observed no change in the conclusions drawn from our primary analyses excluding all second cancers diagnosed ≤2 months after an index CRC. Some misclassification of CRC subsite is also possible; however, it is unlikely that such misclassification would be differential according to second primary cancer risk. Finally, despite the very large population of patients with index CRC overall within SEER, the numbers were limited for SIR calculations specific to less common second primary cancer sites, particularly when stratified by index CRC subsite.

The results presented here confirm previous reports of an elevated cancer risk in CRC survivors relative to the general population and provide added evidence that this elevated risk differs by location of the index CRC. Although the precise mechanisms underlying this pattern of increased risk are unclear, the current results suggest that strategies for cancer surveillance after an index CRC may need to be individualized according to subsite of the index CRC.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

This work was supported by the National Cancer Institute, National Institutes of Health (R25-CA94880 and K05-CA152715 to Dr. Phipps; R01-CA151993 to Dr. Ogino). The National Institutes of Health had no role in the design or conduct of the study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
  • 1
    Siegel R, Desantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220-241.
  • 2
    Reeve BB, Potosky AL, Smith AW, et al. Impact of cancer on health-related quality of life of older Americans. J Natl Cancer Inst. 2009;101:860-868.
  • 3
    Carmack CL, Basen-Engquist K, Gritz ER. Survivors at higher risk for adverse late outcomes due to psychosocial and behavioral risk factors. Cancer Epidemiol Biomarkers Prev. 2011;20:2068-2077.
  • 4
    Khan NF, Mant D, Carpenter L, Forman D, Rose PW. Long-term health outcomes in a British cohort of breast, colorectal and prostate cancer survivors: a database study. Br J Cancer. 2011;105(suppl 1):S29-S37.
  • 5
    Enblad P, Adami HO, Glimelius B, Krusemo U, Pahlman L. The risk of subsequent primary malignant diseases after cancers of the colon and rectum. A nationwide cohort study. Cancer. 1990;65:2091-2100.
  • 6
    McCredie M, Macfarlane GJ, Bell J, Coates M. Second primary cancers after cancers of the colon and rectum in New South Wales, Australia, 1972-1991. Cancer Epidemiol Biomarkers Prev. 1997;6:155-160.
  • 7
    Hemminki K, Li X, Dong C. Second primary cancers after sporadic and familial colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2001;10:793-798.
  • 8
    Evans HS, Moller H, Robinson D, Lewis CM, Bell CM, Hodgson SV. The risk of subsequent primary cancers after colorectal cancer in southeast England. Gut. 2002;50:647-652.
  • 9
    Ahmed F, Goodman MT, Kosary C, et al. Excess risk of subsequent primary cancers among colorectal carcinoma survivors, 1975-2001. Cancer. 2006;107:1162-1171.
  • 10
    Ringland CL, Arkenau HT, O'Connell DL, Ward RL. Second primary colorectal cancers (SPCRCs): experiences from a large Australian cancer registry. Ann Oncol. 2010;21:92-97.
  • 11
    Raj KP, Taylor TH, Wray C, Stamos MJ, Zell JA. Risk of second primary colorectal cancer among colorectal cancer cases: a population-based analysis [serial online]. J Carcinog. 2011;10:6.
  • 12
    Shureiqi I, Cooksley CD, Morris J, Soliman AS, Levin B, Lippman SM. Effect of age on risk of second primary colorectal cancer. J Natl Cancer Inst. 2001;93:1264-1266.
  • 13
    Gervaz P, Bucher P, Neyroud-Caspar I, Soravia C, Morel P. Proximal location of colon cancer is a risk factor for development of metachronous colorectal cancer: a population-based study. Dis Colon Rectum. 2005;48:227-232.
  • 14
    Yamauchi M, Morikawa T, Kuchiba A, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012;61:847-854.
  • 15
    Yamauchi M, Lochhead P, Morikawa T, et al. Colorectal cancer: a tale of 2 sides or a continuum? Gut. 2012;61:794-797.
  • 16
    Surveillance, Epidemiology, and End Results (SEER) Program. SEER*Stat Database: Incidence—SEER 13 Regs Research Data, November 2011 submission, Vintage 2009 Populations (1992-2009) <Katrina/Rita Population Adjustment> Linked to County Attributes—Total US, 1969-2010 Counties. Bethesda, MD: National Cancer Institute, Surveillance Research Program, Cancer Statistics Branch; released April 2012, based on the November 2011 submission. Available at: www.seer.cancer.gov. [Accessed April 2012.]
  • 17
    Johnson CH, Peace S, Adamo P, Fritz A, Percy-Laurry A, Edwards BK. The 2007 Multiple Primary and Histology Coding Rules. Bethesda, MD: National Cancer Institute Surveillance, Epidemiology, and End Results Program; 2007.
  • 18
    StatBite. Lynch syndrome increases the risk of various cancers [serial online]. J Natl Cancer Inst. 2010;102:1383.
  • 19
    Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81:214-218.
  • 20
    Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels AB, Maisonneuve P. Smoking and colorectal cancer: a meta-analysis. JAMA. 2008;300:2765-2778.
  • 21
    Liang PS, Chen TY, Giovannucci E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer. 2009;124:2406-2415.