Excess risk of subsequent primary cancers among colorectal carcinoma survivors, 1975–2001

Descriptive Epidemiology of Colorectal Cancerin the United States, 1998–2001, Utilizing Data

from the NPCR and SEER ProgramsSupplement to Cancer

Excess Risk of Subsequent Primary Cancers AmongColorectal Carcinoma Survivors, 1975–2001

Faruque Ahmed, PhD1

Marc T. Goodman, PhD, MPH2

Carol Kosary, MA3

Bernardo Ruiz, MD, PhD4

Xiao-Cheng Wu, MD, MPH4

Vivien W. Chen, PhD4

Catherine N. Correa, PhD, MPH4

1 Cancer Surveillance Branch, Division of CancerPrevention and Control, Centers for DiseaseControl and Prevention (CDC), Atlanta, Georgia.

2 Cancer Research Center, University of Hawaii,Honolulu, Hawaii.

3 Cancer Statistics Branch, Surveillance ResearchProgram, Division of Cancer Control and PopulationSciences, National Cancer Institute (NCI), Rockville,Maryland.

4 Louisiana Tumor Registry, Epidemiology Program,School of Public Health, Louisiana State UniversityHealth Sciences Center, New Orleans, Louisiana.

BACKGROUND. Studies of persons with colorectal cancer have reported increased

risk of subsequent primary cancers. Results have not been consistent, however,

and there is little information about such risk in specific races and ethnic popu-

lations.

METHODS. Using 1975–2001 data from the Surveillance, Epidemiology, and End

Results (SEER) Program, we assembled 262,600 index cases of colorectal carci-

noma to assess the occurrence of subsequent primary cancers in 13 noncolonic

sites. Observed (O) subsequent cancers were compared with those expected (E)

based on age-/sex-/race-/year-/site-specific rates in the SEER population. The

standardized incidence ratio (SIR) and the absolute excess risk (AER) represent

‘O 7 E’ and ‘O – E,’ respectively.

RESULTS. Colorectal carcinoma patients had significantly elevated SIRs for small

gut, stomach (males), kidney, and corpus uteri cancers, ranging from 1.13 for sto-

mach cancer in males to 3.45 for small gut cancer in females. Elevated SIRs for

additional sites were seen in certain population subgroups: pancreas and ovary

in persons aged <50 years, and prostate in black males. The excess burden, as

assessed by AER, was notable for prostate cancer in black males and for corpus

uteri cancer in females aged <50 years (26.5 and 9.5 cancers per 10,000 person-

years, respectively), and it persisted beyond 5 years of follow-up.

CONCLUSIONS. Although significantly elevated SIRs were found for several cancers,

the excess burden was notable only for cancer of the prostate in black males and of

the corpus uteri in females under age 50. Cancer 2006;107(5 Suppl):1162–71.

� 2006 American Cancer Society.

KEYWORDS: colorectal neoplasms, second primary neoplasms, uterine neoplasms,ovarian neoplasms, stomach neoplasms, gastrointestinal neoplasms, pancreaticneoplasms, prostatic neoplasms, kidney neoplasms, breast neoplasms.

M ore effective screening and treatment regimens, coupled with

more cancer diagnoses because of an aging population, have

resulted in increasing numbers of cancer survivors who are at risk

for subsequent cancers.1 In 2002, there were an estimated 1.1 mil-

lion colorectal cancer survivors in the United States.2 The increased

risk of a second primary cancer among colorectal cancer patients,

when compared with the risk of persons without colorectal cancer,

may result from environmental or genetic factors shared between

the two cancers or from treatment effects.3,4 However, it is possible

that the intensive medical follow-up of colorectal cancer patients

may produce an artifactual association.3,4 A unidirectional altered

risk of a given cancer following colorectal cancer suggests a treat-

The findings and conclusions in this report arethose of the authors and do not necessarilyrepresent the views of the Centers for DiseaseControl and Prevention.

Address for reprints: Faruque Ahmed, PhD, Divi-sion of Cancer Prevention and Control, Centersfor Disease Control and Prevention, 4770 BufordHwy NE, MS K-53, Atlanta, GA 30341; Fax: (770)488-4759; E-mail: [email protected]

We appreciate the in-kind support from all the con-tributors to this monograph and also are grateful forthe contributions of Jessica King for the preparationof analytic files and to Faruque Ahmed for his lea-dership of the colorectal cancer monograph project.

Supported in part by the Centers for DiseaseControl and Prevention’s National Program ofCancer Registries.

Received March 2, 2006; accepted March 21,2006.

ª 2006 American Cancer SocietyDOI 10.1002/cncr.22013Published online 12 July 2006 in Wiley InterScience (www.interscience.wiley.com).

1162

ment effect or an artifactual association. A bidirec-

tional, mutually increased risk between two cancers

following each other suggests shared environmental

or genetic risk factors.4 Assessment of the risk of sub-

sequent primary cancers can facilitate strategies for

the prevention or early detection of second cancers.

Previous population-based studies on persons

with colorectal cancer, including those based on data

from one or more Surveillance, Epidemiology, and

End Results (SEER) cancer registries, have reported

increased risks of subsequent noncolonic primary

cancers of the stomach, small gut, gallbladder, pan-

creas, kidney, urinary bladder, brain, thyroid, pros-

tate, breast, corpus uteri, cervix uteri, and ovary.5–19

However, results have not been consistent, and there

is little information specific to race and ethnicity.

Most investigations have been small, and it is diffi-

cult to reconcile disparate findings because of differ-

ences in population characteristics, environmental

factors, and cancer management practices across

countries; differences in case-ascertainment, report-

ing, follow-up, and coding practices; and differences

in the criteria for defining and including multiple

primary cancers. Some studies have included all

multiple primary cancers regardless of the time-lapse

between diagnoses, whereas others have excluded

cancers diagnosed on the same day or within 1, 2, 6

months, or 1 year of the index cancer. For this study,

we analyzed data from nine SEER cancer registries,

which consistently use SEER rules for reporting and

coding multiple primary cancers.20 Our objectives

were 1) to ascertain the effect of using various inclu-

sion criteria on the excess risk of subsequent nonco-

lonic primary cancers among persons with colorectal

carcinoma and 2) to assess the excess risk of subse-

quent cancers among population subgroups.

MATERIALS AND METHODSDataThe SEER Program collects data on age, year of

diagnosis, sex, race, tumor characteristics, and other

variables among cancer cases diagnosed in the geo-

graphic areas it covers.21 Nine registries have contrib-

uted data to the National Cancer Institute’s SEER

database since 1975: Connecticut, Hawaii, Iowa, New

Mexico, Utah, Atlanta, Detroit, San Francisco-Oak-

land, and Seattle-Puget Sound.22 These SEER regis-

tries cover about 9% of the U.S. white population and

8% of the black population.23 As described previously,

all cancer patients in the SEER Program are actively

followed according to standard methods.24 Lympho-

mas of the colorectum and other sites, which are

categorized separately according to the SEER site

recodes, were excluded from our study.25 Multiple pri-

mary cancers are defined by the SEER Program as

tumors diagnosed �2 months apart, regardless of his-

tology or site, and tumors diagnosed within 2 months

of each other if they are of different histologies or if

they arise at different sites. The detailed guidelines on

identifying multiple primaries, including the excep-

tions to these general rules, are provided in the SEER

Program code manual.20 Extensions, recurrences, or

metastases of a single primary are not considered

new primaries. For comparability of stage at diagnosis

over time, we used SEER historic stage.26

Index CasesA total of 279,313 first primary invasive colorectal

cancer cases were recorded between 1975 and 2001

in the nine SEER registries. These cases did not have

prior in situ or invasive reported cancers of any site.

We excluded 16,713 (6%) cases that were a) identified

by death certificate or autopsy only, b) not microsco-

pically confirmed, c) not classified as carcinomas,27

or d) categorized as carcinoids (International Classifi-

cation of Diseases for Oncology, third edition, ICD-

O-3, histology codes 8240–8246, 8249).28 Thus, there

were 262,600 eligible index cases of colorectal carci-

noma.

Subsequent Primary CancersOn the basis of significant associations reported in

�1 previous studies (see earlier-mentioned text), we

assessed the excess risk of subsequent invasive pri-

mary cancers at 13 noncolonic sites. Because pre-

vious studies have shown no association between

colorectal and esophageal cancer, we included eso-

phagus as a control site. The subsequent cancers

included death certificate- and autopsy-only cases,

nonmicroscopically confirmed cases, and cancers of

any histologic type. Death certificate-only cases

accounted for �1% of cancers at each site. Autopsy-

only cases represented 14% of thyroid cancers, 4% of

kidney cancers, 3% of gallbladder cancers, 2% of

prostate and pancreatic cancers, and �1% of the

other cancers. Microscopic confirmation rates were

�95% for cancer sites other than kidney (87%), brain

(78%), and pancreas (72%). Carcinoids accounted for

45% of small gut cancers and �1% of cancers at the

other sites. We conducted sensitivity analysis by vary-

ing the definitions of subsequent primary and index

cancers to assess the robustness of our findings.

Statistical AnalysisDetection of a second primary for a given individual

did not preclude the counting of a subsequent pri-

mary cancer at another site. However, repeated pri-

Multiple Primary Cancers/Ahmed et al. 1163

mary cancers of the same noncolonic site were

excluded. Person-years (PY) at risk for subsequent

development of cancers were computed for each

noncolonic site from the date of diagnosis of colorec-

tal carcinoma to the date of diagnosis of the nonco-

lonic cancer, date of death, date of loss to follow-up,

or end of the study period (December 31, 2001),

whichever was earlier. The expected number of each

noncolonic cancer among index cases was calculated

by multiplying PY (stratified by sex, race, and 5-year

intervals of age and calendar year) by the strata-spe-

cific cancer incidence rates of the corresponding

sites for the population covered by the nine SEER

registries and then summing. The ratio of the

observed (O) to the expected (E) number denotes the

standardized incidence ratio (SIR). The SIR is an esti-

mate of the relative risk—adjusted for age, sex, race,

and calendar year—of developing cancer in colorec-

tal carcinoma patients when compared with that of

persons without colorectal carcinoma.

For assessing the effect of various inclusion cri-

teria, we chose the cutoffs of 0, 1, 2, 6, and 12

months that were used in previous studies.5–19 SIRs

by time since diagnosis of the index cancer were

based on the appropriate PY. Subsequent cancers

that were reported within the first 2 months of diag-

nosis of the index cancer were termed synchronous,

whereas cancers reported �2 months after the index

diagnosis date were termed metachronous. For sensi-

tivity analysis, the expected number of subsequent

cancers was computed using the same case defini-

tion as that of the observed subsequent cancer. For

determining whether SIRs differed from 1, statistical

significance was assessed with an a level of 0.05 (2-

sided) on the basis of the assumption that O fol-

lowed a Poisson random distribution.29 Because a

high SIR for a rare noncolonic cancer may not trans-

late into a high cancer burden, we also computed

the absolute excess risk per 10,000 PY (AER) using

the formula ‘[(O – E) 7 PY] � 10,000.’ SEER*Stat

software was used for the analysis.30

RESULTSIndex Case CharacteristicsAmong the 262,600 eligible index cases of colorectal

carcinoma, 51% involved males and 86% involved

whites (Table 1). Male and female index cases were

similar with respect to race, year of diagnosis, histo-

logic type, and stage at diagnosis (Table 1). However,

female index cases were more likely to be older and

to have tumors in the colon than males. The average

age at diagnosis of colorectal carcinoma was 68 years

for males and 71 years for females. The average PYs

of follow-up were 5.2 for males and 5.5 for females,

with 36% of males and 38% of females followed for

�5 years.

Excess Risk by Follow-Up PeriodThe excess risk of subsequent cancers was substan-

tially higher within the first 2 months of follow-up

than in later periods (Tables 2 and 3). For metachro-

nous cancers, small gut cancer showed significantly

elevated SIRs for all follow-up intervals (Tables 2 and

3). The SIR for stomach cancer was significantly ele-

vated after an interval of 60 months. Cancers of the

prostate and female breast showed significantly ele-

vated SIRs during the follow-up period of 2–5

months, whereas corpus uteri cancer showed signifi-

cantly elevated SIRs for the follow-up intervals 12–59

and �60 months.

Effect of Using Various Cutoffs for IncludingSubsequent CancersCancer sites some showed significantly increased SIRs

only when cancers reported during the first 1 or 2

TABLE 1Features of Index Cases of Colorectal Carcinoma,SEER Program, 1975–2001

VariableMale, %(n = 133,004)

Female, %(n = 129,596)

Race

White 85.8 86.2

Black 7.3 8.4

Other 6.7 5.2

Unknown 0.3 0.2

Age at diagnosis (yr)

<50 7.5 6.8

50–64 29.5 22.9

�65 63.0 70.3

Year of diagnosis

1975–1987 46.1 46.7

1988–2001 53.9 53.3

Subsite

Colon 67.3 74.1

Rectum 32.7 25.9

Histology*

Adenocarcinoma 98.2 97.9

Epidermoid carcinoma 0.2 0.4

Other specified carcinomas 0.2 0.2

Carcinoma, not otherwise specified 1.4 1.5

Stage at diagnosisy

Localized 37.9 36.6

Regional 38.1 40.2

Distant 19.6 19.0

Unstaged 4.4 4.3

Average person-years of follow-up 5.2 5.5

SEER: Surveillance, Epidemiology, and End Results.

* Classified using Berg’s principal histologic grouping for digestive cancers.27

y SEER Historic Stage.26

1164 CANCER Supplement September 1, 2006 / Volume 107 / Number 5

months of follow-up were included; the sites were

urinary bladder, thyroid, prostate, female breast, cer-

vix, and ovary (Table 4). Kidney cancer showed no

increased risk when cancers occurring during the

first year of follow-up were excluded. Cancer sites

with significantly increased SIRs regardless of the in-

clusion criteria were stomach (males), small gut, and

corpus uteri. Cancer sites that showed no elevated

risk, regardless of the criteria used, were esophagus,

gallbladder, pancreas, and brain. A significant protec-

tive association was found for gallbladder cancer

when synchronous cancers were excluded. The effect

of using various cutoffs (Table 4) was marked when

synchronous cancers, particularly those reported

during the first month of follow-up, were included.

Relative Excess Risk of Metachronous CancerSIRs for metachronous cancers were significantly ele-

vated for stomach (males), small gut, kidney, and

corpus uteri (Table 4). For small gut cancers, SIRs

were substantially higher for noncarcinoids (4.18 for

males and 4.91 for females) than carcinoids (1.52 for

males and 1.54 for females) (data not shown); approx-

imately 92% of the noncarcinoid small gut cancers

were adenocarcinomas.

SIRs for selected cancers by race, age at diagno-

sis, colon and rectum subsite, and year of diagnosis

of the index case are shown in Figures 1–4. Blacks,

but not whites, were at a significantly elevated risk of

prostate cancer (SIR, 1.26; P < .05). Among persons

aged <50 years, SIRs were significantly elevated for

cancers of the stomach (males), small gut, pancreas,

kidney (males), corpus uteri, and ovary. Prostate can-

cer showed a significantly elevated association with

colon cancer but a protective association with rectal

cancer. The results were generally similar for the

1975–1987 and 1988–2001 diagnosis years. For meta-

chronous breast cancer, no significant associations

were seen in any of the subgroup analyses (data not

shown). For urinary bladder cancer, a significantly

elevated risk was found only among black males

TABLE 2Subsequent Primary Cancers among Colorectal Carcinoma Patientsby Time since Initial Diagnosis, Males, SEER Program, 1975–2001

Subsequent

primary

cancer

Follow-up period (mo)

Synchronous Metachronous

<1 1 2–5 6–11 12–59 �60

Esophagus SIR 4.57* 2.40 0.73 0.74 0.95 0.98

O 14 7 8 11 78 101

Stomach SIR 8.30* 3.04* 1.04 1.06 1.06 1.20*

O 52 18 23 32 175 242

Small gut SIR 161.56* 57.16* 6.76* 3.70* 3.17* 2.38*

O 107 36 16 12 58 58

Gallbladder SIR 18.92* 13.38* 3.58* –y – 0.44*

O 9 6 6 – – 7

Pancreas SIR 7.79* 2.86* 0.76 0.53* 1.01 0.93

O 46 16 16 15 159 184

Urinary bladder SIR 4.74* 2.79* 1.27 1.00 1.03 0.96

O 79 44 75 81 474 578

Kidney SIR 23.43* 10.85* 3.71* 1.42 1.20* 1.00

O 111 49 63 33 156 167

Brain SIR – – – 0.70 0.82 0.78

O – – – 7 45 52

Thyroid SIR 8.42* – 2.34 1.72 1.11 1.01

O 6 – 6 6 21 22

Prostate SIR 5.39* 3.88* 1.36* 0.89* 0.95* 1.00

O 382 260 341 308 1861 2522

SEER: Surveillance, Epidemiology, and End Results; SIR: standardized incidence ratio; O: number of

observed cancers.

* SIR differs significantly from 1 (P < 0.05).y Dashes indicate that data are suppressed if there are <6 observed cancers.

TABLE 3Subsequent Primary Cancers among Colorectal Carcinoma Patientsby Time since Initial Diagnosis, Females, SEER Program, 1975–2001

Subsequent

primary

cancer


Synchronous Metachronous

<1 1 2–5 6–11 12–59 �60

Esophagus SIR –* – – 1.67 1.15 1.02

O – – – 8 31 38

Stomach SIR 14.88y 1.97 0.79 0.78 1.07 1.24y

O 48 6 9 12 91 140

Small gut SIR 151.30y 39.12y 5.80y 2.98y 4.61y 2.51y

O 73 18 10 7 62 50

Gallbladder SIR 32.45y 9.13y – – 0.57y 0.71

O 30 8 – – 14 22

Pancreas SIR 5.76y 1.88 1.06 0.87 0.96 0.92

O 29 9 19 21 132 177

Urinary Bladder SIR 5.71y 2.78y 1.05 0.78 1.10 1.06

O 26 12 17 17 137 185

Kidney SIR 25.38y 14.71y 3.67y 1.02 1.21 0.98

O 56 31 29 11 74 85

Brain SIR – – 1.26 0.93 0.93 1.20

O – – 6 6 33 56

Thyroid SIR – 5.84y 1.82 – 1.07 1.25

O – 6 7 – 30 43

Breast SIR 4.97y 1.79y 1.18y 0.78y 1.01 0.97

O 192 66 164 147 1043 1313

Cervix uteri SIR 11.82y – 1.01 1.52 0.97 0.96

O 23 – 7 14 46 49

Corpus uteri SIR 6.31y 2.47y 0.91 0.95 1.16y 1.27y

O 56 21 29 41 267 357

Ovary SIR 23.32y 4.24y 0.51y 1.38 1.11 0.83y

O 115 20 9 33 146 141

SEER: Surveillance, Epidemiology, and End Results; SIR: standardized incidence ratio; O: number of

observed cancers.

* Data are suppressed if there are < 6 observed cancers.y SIR differs significantly from 1 (P < 0.05).


(SIR, 1.37; P < .05) (data not shown). Metachronous

cancers of the gallbladder, brain, thyroid, and cervix

were too few to conduct meaningful subgroup analysis.

Absolute Excess Risk of Metachronous CancerThe AER of metachronous cancer was greatest for

small gut in males (1.44) and corpus uteri in females

(1.58) (Fig. 5). Substantially higher AERs were ob-

served for certain population subgroups (Figs. 1,2).

The highest AERs were for prostate cancer among

black males (26.48) and for corpus uteri cancer

among females aged <50 years (9.53). Among black

males, the AER of prostate cancer was elevated for

both colon and rectal index cancers (AERs of 30.43

TABLE 4Standardized Incidence Ratio (SIR) of Subsequent Primary Cancers Reported after Diagnosis of Colorectal Carcinomaby Follow-Up Interval, SEER Program, 1975–2001

Subsequent

primary cancer


Male Female

�0 �1 �2 �6 �12 �0 �1 �2 �6 �12

Esophagus 1.01 0.96 0.94 0.95 0.96 1.10 1.10 1.10 1.12 1.08

Stomach 1.26* 1.15* 1.13* 1.13* 1.14* 1.32* 1.13 1.12 1.14 1.16*

Small gut 5.79* 3.68* 2.98* 2.79* 2.72* 5.73* 3.88* 3.45* 3.33* 3.36*

Gallbladder 0.99 0.73 0.56* 0.39* 0.42* 1.20 0.75* 0.64* 0.64* 0.65*

Pancreas 1.04 0.95 0.92 0.93 0.96 1.01 0.95 0.94 0.93 0.93

Urinary bladder 1.08* 1.03 1.00 0.99 0.99 1.14* 1.08 1.06 1.06 1.08

Kidney 1.67* 1.37* 1.24* 1.11* 1.09 1.68* 1.37* 1.20* 1.07 1.08

Brain 0.78* 0.77* 0.78* 0.79* 0.80* 1.06 1.06 1.08 1.07 1.08

Thyroid 1.36* 1.25 1.18 1.11 1.06 1.29* 1.26* 1.19 1.16 1.17

Prostate 1.09* 1.03 0.99 0.97* 0.98 – – – – –

Breast – – – – – 1.05* 0.99 0.98 0.97 0.99

Cervix uteri – – – – – 1.22* 1.04 1.01 1.01 0.97

Corpus uteri – – – – – 1.28* 1.20* 1.19* 1.20* 1.22*

Ovary – – – – – 1.31a 1.00 0.96 0.98 0.95


* SIR differs significantly from 1 (P < 0.05).

FIGURE 1. Standardized incidenceratio (SIR) and absolute excess risk

(AER) of selected metachronous can-

cers by race, SEER Program, 1975--

2001. SIR represents the ratio of the

observed (O) to the expected (E) num-

ber of subsequent cancers, adjusted

simultaneously for age, sex, race, and

calendar year. AER denotes O � E

per 10,000 person-years of follow-up.


and 14.38, respectively), as well as for all age groups

(11.26, 26.00, and 32.52 for the <50, 50–64, and �65

age groups, respectively) and for the 1975–1987 and

1988–2001 diagnosis years (29.30 and 23.06, respec-

tively) (data not shown).

The substantial burden of prostate cancer among

black males and corpus uteri cancer in younger (aged

<50 years) females persisted beyond 5 years of the

index diagnosis date; AERs for the follow-up period of

�60 months were 36.15 and 11.22 for cancers of the

prostate and corpus uteri, respectively (data not

shown). Analysis by attained age (i.e., age at diagnosis

of the subsequent cancer) showed that the elevated

AER of corpus uteri cancer among females aged <50

years was found up to the attained age of 60 years (for

the attained age categories of<45, 45–49, 50–54, 55–59,

and �60 years, AERs were 11.57, 10.42, 11.81, 13.31,

and�3.86, respectively) (data not shown).



cers by age at diagnosis of colorectal

carcinoma, SEER Program, 1975--2001.

SIR represents the ratio of the observed

(O) to the expected (E) number of sub-

sequent cancers. AER denotes O � E

per 10,000 person-years.



cers by subsite, SEER Program, 1975--

2001. SIR represents the ratio of the

observed (O) to the expected (E) number

of subsequent cancers. AER denotes O

� E per 10,000 person-years.


Sensitivity AnalysisRepeating the analysis after expanding the index case

definition to include all colorectal cancers (n ¼279,313) did not change the results (data not shown).

For subsequent cancers, excluding cancers diagnosed

by death certificate and autopsy only, or excluding non-

microscopically confirmed cancers, yielded similar

results with the exception that the risk of metachro-

nous stomach cancer among females was significantly

elevated in both sets of analysis (SIRs of 1.14 and 1.20,

respectively; P<.05) (data not shown).

Bidirectional AssociationFor assessing possible mechanisms of carcinogenesis,

we ascertained whether the associations were present

in the reverse direction (Table 5). There was a signifi-

cant association between corpus uteri cancer and

subsequent colorectal cancer, which was more pro-

nounced among persons aged <50 years (SIR, 3.06;

P < .05). For prostate cancer, there was a significantly

elevated risk of subsequent colorectal cancer among

black males. Among persons aged <50 years, an ele-

vated risk was found with ovarian cancer (SIR, 2.52;

P < .05); it was not possible to assess the association

with pancreatic cancer because of poor survival of

pancreatic cancer patients. For small gut cancer,

there appeared to be an excess risk of colorectal can-

cer for the noncarcinoid subgroup only. For stomach

or kidney cancer, no excess risks were found.

DISCUSSIONThe excess risk of synchronous cancers (i.e., cancers

reported within the first 2 months of follow-up) in

colorectal carcinoma patients was elevated for all

sites other than brain. For metachronous cancers,

increased excess risks were observed for stomach,



cers by year of diagnosis of colorectal

carcinoma, SEER Program, 1975–2001.

SIRs represent the ratio of the observed

(O) to expected (E) numbers of sub-

sequent cancers. AERs denote O � E

per 10,000 person-years.

FIGURE 5. Absolute excess risk of selected metachronous cancers, SEERProgram, 1975–2001.


small gut (particularly noncarcinoid tumors), kidney,

and corpus uteri cancers. Elevated excess risks for

additional sites were seen in certain population sub-

groups: pancreas and ovary in persons aged <50

years and prostate in black males. A protective asso-

ciation was found for gallbladder cancer. A bidirec-

tional association was seen for noncarcinoid small

gut cancer (males) and for cancers of the corpus

uteri, ovary, and prostate (black males). A substantial

excess burden was found for subsequent cancers of

the corpus uteri in younger females and prostate in

black males.

It is well documented that intensive medical scru-

tiny can result in an apparent increase in risk of subse-

quent cancers followed by a deficit.3,31 The elevated

risk of synchronous cancers among persons with col-

orectal carcinoma might have resulted from ‘lead time

bias’: through increased medical scrutiny, second

tumors were detected before they would normally

have become clinically apparent. Although the occur-

rence of multifocal cancers is biologically plausible, it

is more likely that direct extension of the index cancer

to adjacent organs was sometimes misclassified as a

new primary.2–34 This misclassification is probably

unlikely in our study because of the experienced staff

and high quality data of the SEER registries. Also, for

the two cancers diagnosed at the same time, it may be

arbitrary which is designated as the index cancer.29 To

reduce the possibility of artifactual association, some

investigators have excluded cancers diagnosed during

the first 6 or 12 months of follow-up. Excluding can-

cers detected during the early follow-up period may

bias the study towards the null.3 Our results were very

similar (with the exception of kidney cancer) for the 2-

month comparable to the 12-month cutoff.

There are certain potential limitations to our

study. First, possible underreporting of subsequent

cancers among index cases who moved outside of the

SEER areas could result in underestimation of excess

risks, particularly with increasing time since diagnosis

of the index cancer. However, the fact that SIRs for the

esophageal cancer control group were close to unity

suggests that such underreporting was likely minimal.

Second, it is plausible that persons with advanced col-

orectal carcinoma may have incomplete reporting of

subsequent cancers. Still, similar results were obtained

when the analysis was restricted to localized or regio-

nal stage index cancers (data not shown). Finally,

because of the large number of comparisons per-

formed, associations that have not been previously

reported should be considered suggestive.35

Previous population-based studies have typically

reported the relative excess risk (i.e., the SIR) of

developing subsequent primary cancers but have not

assessed the absolute excess risk.5–19 Some of these

studies have not differentiated between synchronous

and metachronous cancers. We believe that synchro-

nous cancers should be excluded to avoid possible

bias. For corpus uteri and small gut cancers, previous

studies have consistently reported elevated excess

risks.6,7,12,15,16,18 We extend these finding by reporting

that the association is stronger for noncarcinoid

small gut cancers and that younger female colorectal

carcinoma patients have a substantial excess burden

of corpus uteri cancer. For prostate cancer, certain

studies have reported an increased risk whereas

others have not; for studies reporting an increased

risk, a bidirectional association was not found or

reported.5,6,10,12,13,15,18 To our knowledge, our study is

the first to report that black colorectal carcinoma

patients have a higher excess risk of prostate cancer

and that the association is bidirectional. For ovarian

cancer,5,6,14,15,18 an increased excess risk has been

reported. For pancreatic cancer, some studies have

found an increased risk, but others have not.6,7,15,18

We found increased excess risks for ovarian and pan-

creatic cancers only among younger persons. An ear-

lier study reported a protective association with

gallbladder cancer, which is in accord with our find-

ing.7 Results have not been consistent for cancers of

the stomach,5,6,12,15,18 kidney,7,12,15,18 breast,5,12,15,18

cervix uteri,6,7,15,18 urinary bladder,5,6,12,15,18 brain,7,18,19

and thyroid.6,7,15 We found an elevated excess risk for

stomach cancer after a lag of 5 years and for kidney

cancer only during the early follow-up period. We

did not find elevated risks for cancers of the breast,

cervix uteri, urinary bladder, brain, and thyroid.

The elevated risk of metachronous cancers of the

corpus uteri, ovary, small gut, and pancreas may be

TABLE 5Standardized Incidence Ratio (SIR) of Metachronous ColorectalCancer by Site of First Cancer, SEER Program, 1975–2001

First cancer site Male Female

All ages

Stomach 1.01 1.04

Small gut 1.20 1.19

Carcinoid 0.60 1.08

Noncarcinoid 2.07* 1.35

Kidney 1.00 0.97

Corpus uteri – 1.05*

Age <50

Corpus uteri – 3.06*

Ovary – 2.52*

Blacks

Prostate 1.09* –


* SIR differs significantly from 1 (P < 0.05).


attributed, in part, to genetic conditions such as her-

editary nonpolyposis colorectal cancer syndrome and

familial adenomatous polyposis, which are asso-

ciated with both multiple cancers and younger age.36

Acquired defects in mismatch repair genes may also

be involved.37 Hormonal factors may contribute to

the association between colorectal and corpus uteri

cancer.7 Similarly, dietary risk factors and obesity

may also account for the association of these two

malignancies.38 For prostate cancer, the elevated risk

in black men could be an artifact if black colorectal

carcinoma patients undergo more testing for prostate

cancer, which often remains asymptomatic, than do

black men in the general population. However, the

elevated risk was observed even before 1987, a time

when prostate-specific antigen screening for prostate

cancer was uncommon.39 Similar genetic mutations

have been reported in colorectal and prostate can-

cers, and saturated fat intake has been reported to

be a risk factor for both cancers.13 For kidney cancer,

the fact that the association was unidirectional and

that an elevated risk was found for the early follow-

up period only suggests that the elevated risk may be

an artifact. For stomach cancer, the finding of an ele-

vated risk after a lag of 5 years suggests that a treat-

ment-related effect may have a role.3 The risk of

gallbladder cancer could be reduced because gall-

bladders, particularly those containing gallstones, are

often removed at the time of colon cancer surgery.4

Our study has several implications. First, many

synchronous cancers were observed. Further research

is needed on the effect of early detection of concur-

rent cancers on survivorship. Second, increased risks

for metachronous cancers of the pancreas, ovary,

and prostate were seen in certain population sub-

groups only. This finding underscores the fact that

the composition of the study population can affect

the results. Third, the risks for metachronous cancers

of the female breast and cervix uteri were similar to

those risk levels in the general female population.

This observation emphasizes the importance of con-

tinued breast and cervical cancer screening in

women with colorectal carcinoma. Finally, although

significantly elevated relative excess risks were found

for several subsequent cancers, the absolute excess

risk was notable only for cancers of the prostate

among black males and the corpus uteri among

younger females. Our findings may be useful in the

formulation of strategies to improve survivorship.

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Excess risk of subsequent primary cancers among colorectal carcinoma survivors, 1975–2001