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ORIGINAL PAPER
Risk of colorectal cancer among long-term cervical cancer survivors
Ana M. Rodriguez • Yong-Fang Kuo •
James S. Goodwin
Received: 1 February 2014 / Accepted: 25 March 2014 / Published online: 3 April 2014 ! Springer Science+Business Media New York 2014
Abstract Because advances in therapy have increased long-term survival for women with cervical cancer, it is
important to study the risk of secondary primary malig-
nancies in high-dose organ areas. From the 1973–2009 National Cancer Institute Surveillance, Epidemiology, and
End Results (SEER) program, we studied the risk of
developing cancer of the colon and rectum in 64,507 cer- vical cancer patients over 35 years after initial radiation
treatment. We also assessed change in risk over time.
Kaplan–Meier estimator for survival curve and Cox pro- portional hazards models was used. More than half (52.6 %)
of the cervical cancer patients received radiation treatment.
In the analyses adjusted for race/ethnicity, age, marital status, surgery status, stage and grade, the risk of colon
cancer between those both with and without XRT diverged
beginning at approximately 8 years. After 8 years, the hazard ratio for developing colon cancer was 2.00 (95 % CI
1.43–2.80) for women with radiation versus those without
radiation treatment. The risk of rectal cancer diverged after 15 years of follow-up (HR 4.04, 95 % CI 2.08–7.86). After
35 years of follow-up, the absolute risk of developing colon cancer was 6.5 % for those who received radiation versus
2.5 % for those without, and 3.7 versus 0.8 % for rectum.
The risk of colon and rectum cancer over 20 years of fol- low-up after radiation remained the same across three eras
(1973–1980, 1981–1990, and 1991–2000). Radiation- induced second cancers of the colon and rectum may occur
8 years after radiation treatment for cervical cancer.
Keywords Cervical cancer ! SEER ! Second primary cancer ! Radiotherapy ! Colon cancer ! Rectal cancer
Introduction
The incidence and mortality for cervical cancer has decreased in the United States [1, 2]. As of 2012, of the
245,022 women surviving cervical cancer, 83 % have
already lived 5 years or more after the diagnosis [3, 4]. With the growing number of people surviving cancer in
general, it is vital to study the health complications that
might develop during the months or years following the completion of the given treatment to treat the primary
tumor [5]. Developing a second cancer is one of the most
serious complications of cancer treatment [6, 7]. An esti- mated 18 % of the incident malignancies in the United
States are a second (subsequent) cancer [8]. Patients with cervical cancer provide an excellent
opportunity to study the lasting effects of radiotherapy [6].
There is a sufficient number of patients available to study, including non-irradiated patients available for comparison.
In addition, radiation doses received by other organs while
treating cervical cancer can be estimated accurately [6, 9]. These doses range from tens of grays (thousands of rads)
for those organs nearest to the cervix to tens of grays (tens
of rads) for those farthest away [6]. Organs located in the pelvis including the rectum have been determined to
receive very high doses of radiation ([30 Gy) while colon was found to receive varied doses, ranging from 4 Gy for the transverse colon to 24 Gy for the sigmoid colon [6].
A. M. Rodriguez (&) Department of Obstetrics and Gynecology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0587, USA e-mail: [email protected]
Y.-F. Kuo ! J. S. Goodwin Department of Internal Medicine, Sealy Center on Aging, The University of Texas Medical Branch at Galveston, Galveston, TX, USA
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Med Oncol (2014) 31:943
DOI 10.1007/s12032-014-0943-2
The choice of radiotherapy is dependent on the stage of
disease [10]. Radiation treatment consists of external beam radiotherapy, brachytherapy using an intracavitary radia-
tion source, such as radium or cesium or a combination of
both modalities [10]. Previous studies have established that cervical cancer
survivors treated with radiation have an increased risk for
the development of second primary malignancies of the colon, rectum/anus, bladder and ovary [11–14]. However,
no recommendations have been established in terms of which specific screening strategies should be implemented
in this group of women or how those findings can be
applied to women currently surviving cervical cancer. The aim of this study was to assess the risk of devel-
oping SPMs of colon and rectum over 35 years of follow-
up after radiation treatment for cervical cancer and whether this risk has decreased over time as methodologies for
radiation therapy have evolved.
Materials and methods
Data source
Data for this study came from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) pro-
gram. The SEER program has been collecting data on cancer
incidence and survival since 1973 and publishes cancer statistics for approximately 28 % of the United States pop-
ulation [15]. This program currently has 18 population-based
cancer registries across the United States and covers 25 % of non-Hispanic Whites, 26 % of African Americans, 38 % of
Hispanics, 110.3 % American Indian/Alaskan Native/Paci-
fic Islander and 50.4 % other groups [15]. The SEER Program is an excellent resource to study
cancer incidence and second malignancies in the United
States with case ascertainment rate at 97.5 % [16]. All cancer sites are categorized using the International Clas-
sification of Diseases for Oncology, 3rd Edition (ICD-0-3).
Institutional review board approval for analyses was deemed not necessary because all identifying information
had been removed.
Study cohort
Initially, a total of 68,563 women with stage I–IV cervical cancer (C530–C539) were identified from 1973 to 2009 in
the SEER database. Patients were excluded if they had been
diagnosed by autopsy or death certificate only (n = 28), were younger than 20 years of age or older than 85 years of
age (n = 1,430) and had unknown radiation (n = 886) or
unknown surgical status (n = 1,712). After applying all the exclusion criteria, the final sample included 64,507 females.
Study variables
The study variables included race/ethnicity, age at diag- nosis, marital status, radiation status (yes/no), surgery sta-
tus (yes/no), tumor stage (SEER historic stage A), tumor
grade, SPMs in colon and rectum, and time to develop SPMs on colon and rectum. Racial/ethnic groups were
defined as non-Hispanic (NH) White, NH Black, Hispanic,
American Indian/Alaskan Native/Pacific Islander and other. Age at diagnosis is the age (in years) that the patient
was diagnosed with cervical cancer and was categorized
into six categories (20–30, 31–40, 41–50, 51–60, 61–70, [71). Marital status was dichotomized into married and not married (single (never married), separated, divorced or
widowed). Tumor stage was categorized as localized, regional or distant. Tumor grade is based on the Interna-
tional Classification of Diseases for Oncology, 2nd Edition
(ICD-0-2) and categorized as well differentiated, moder- ately differentiated, poorly differentiated, undifferentiated
or cell type not determined, not stated or not applicable.
Cancers of the colon (C180–C189, C260) and the rectum (C199, C209) were identified by linking registry records
based on subject numbers. The study outcome, time to
develop cancers of the colon and/or rectum, was calculated from the time of initial diagnosis of cervical cancer to
when the malignancy developed on the colon and rectum.
Patients were censored at death or at the end of the follow- up period (December 31, 2009).
Statistical analysis
Chi-square tests were used to compare patient and tumor
characteristics between patients who did or did not receive radiation treatment for cervical cancer. Risk of
subsequent colon and rectal cancer was estimated by the
Kaplan–Meier method and compared by log-rank test for patients with and without radiation treatment. Cox pro-
portional hazards models were developed to estimate the
risk, and proportional hazards assumption was examined by hazard plot and Sheffield residuals [17]. When the
proportional hazards assumption was violated—that is, the
hazards were not proportional over the 35 years of fol- low-up—the time-dependent effect of radiation up to a
specific year and after that year was included in the
model. The location of the knot point at the specific year of follow-up was estimated by nonlinear least squares
regression on the differences of hazard between two
groups over time. To assess whether the risk associated with radiation changed over the past three decades, we
limited the follow-up time to 20 years and grouped patients diagnosed with colorectal cancer into four groups
(1973–1980, 1981–1990, and 1991–2000). We tested the
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interaction between diagnosed year group and radiation in
the Cox proportional hazards model. We also explored
whether the risk of colorectal cancer associated with radiation varied by patient and cancer characteristics by
testing their interactions in the Cox proportional hazards
models. All statistical analyses were performed using SAS software (Version 9.3, SAS Institute, and Cary, NC,
USA). All p values are two-tailed with p value B 0.05
considered statistically significant.
Results
Demographics, clinical and tumor characteristics
From 1973 to 2009, there were 64,507 incident cases of
cervical cancer. A summary of demographics, tumor characteristics and treatment is shown in Table 1. More
than half (52.6 %) of the cohort received radiation therapy
as treatment. There were significant differences in race/ ethnicity, age, marital status, surgery status, stage and
grade between the radiation and no radiation groups.
Compared to the radiation group, the no radiation group had more localized stage disease, was younger and had a
higher percentage of surgeries. The no radiation group also
had a higher percentage of not being married (51.5 vs 44.3 %) and unknown tumor grade (49.2 vs 29.4 %).
Figure 1 shows the proportion of women who received
radiation treatment by year. The percent receiving radiation therapy initially decreased, from 1973 to 1999. It increased
from 2000 to 2005. Since 2006, the proportion of women
receiving radiation therapy has slightly decreased.
Second primary malignancies of colon and rectum
after radiation treatment for cervical cancer
Figures 2 and 3 demonstrated the risk of a second cancer at
the colon or rectum over time estimated by the Kaplan– Meier method. The overall risk at 35 years of follow-up for
cervical cancer patients receiving radiation therapy was
6.5 % for colon cancer and 3.7 % for rectal cancer. In comparison, cervical cancer patients without radiation
therapy had a 2.5 % risk for colon and 0.8 % risk for rectal
cancer. Table 2 shows results from the Cox proportional haz-
ards models to further assess the effect of radiation
adjusted for age, race/ethnicity, marital status, year of diagnosis, surgical treatment and tumor characteristics. We
found that the hazards of colon and rectal cancer associated
with radiation were not proportional over time (p \ 0.001).
Fig. 1 Proportion of cervical cancer patients receiving radiation after diagnosis by study year, SEER 1973–2009 (n = 64,507)
Table 1 Demographics, pathologic and surgical treatment charac- teristics between patients with cervical cancer who received radiation and patients who did not receive radiation, SEER 1973–2009 (n = 64,507)
Variables Radiation (n = 33,961)
No radiation (n = 30,546)
p value
n % n %
Race/ethnicity \0.0001 Non-Hispanic white 19,106 56.3 18,668 61.1
Non-Hispanic black 5,459 16.1 3,445 11.3
Hispanic 6,099 18.0 5,379 17.6
AAPI 2,836 8.4 2,425 7.9
Other 461 1.4 629 2.1
Age at diagnosis \0.0001 20–30 1,443 4.2 4,215 13.8
31–40 5,782 17.0 9,392 30.7
41–50 8,418 24.8 7,573 24.8
51–60 7,517 22.1 4,217 13.8
61–70 5,860 17.3 2,924 9.6
C71 4,941 14.5 2,225 7.3
Mean age at cervical cancer diagnosis (years ± SD)
53.3 ± 14.5 45.3 ± 14.4
Marital status \0.0001 Married 17,831 52.5 13,131 43.0
Not married 15,050 44.3 15,740 51.5
Unknown 1,080 3.2 1,675 5.5
Surgery \0.0001 Yes 13,545 39.9 26,809 87.8
No 20,416 60.1 3,737 12.2
Stage \0.0001 Localized 9,729 28.6 25,611 83.8
Regional 19,889 58.6 3,035 9.9
Distant 4,343 12.8 1,900 6.2
Grade \0.0001 Well differentiated 1,963 5.8 3,220 10.5
Moderately differentiated
9,445 27.8 6,392 20.9
Poorly differentiated 11,489 33.8 5,331 17.5
Undifferentiated 1,090 3.2 587 1.9
Not determined 9,974 29.4 15,016 49.2
Med Oncol (2014) 31:943 Page 3 of 7 943
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Therefore, we performed nonlinear least square regression to find the optimal cutoff on the follow-up time associated
with change of hazard. For colon cancer, there were no
statistically significant differences seen between women with and without radiation within 8 years of follow-up.
However, at more than 8 years of follow-up, the hazard
ratio for colon cancer was 2.00 (95 % CI 1.43–2.80) for women with radiation compared to those who did not
receive radiation treatment. The risk of rectal cancer
became significant at more than 15 years of follow-up (HR 4.04, 95 % CI 2.08–7.86).
There was no significant interaction between year of diagnosis and radiation treatment on the risk of malig-
nancies at colon and rectum (p = 0.5123, 0.3769, respec-
tively). We also did not find any interactions between age, ethnicity or tumor characteristics, with an increased risk of
colorectal cancer associated with radiation (all p val- ues [0.19 for interactions of colon cancer and [0.23 for interactions of rectal cancer).
Discussion
The primary purpose for conducting this study was to
evaluate the risk of second cancer in the colon and rectum
among long-term survivors of cervical cancer who received radiation therapy. Our study results show that tumors of the
colon, rectum and anus are 2–4 times more frequent in the radiation group than in the no radiation group among cer-
vical cancer survivors. The relationship between thera-
peutic radiation and the risk of SPMs has long been recognized [13].
Fig. 2 Kaplan–Meier estimates for colon cancer for patients with cervical cancer who did or did not receive radiation treatment
Fig. 3 Kaplan–Meier estimates for rectal and anal cancer for patients with cervical cancer who did or did not receive radiation treatment
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Previous research has shown that the risk of developing
cancer in organs close to the cervix (i.e., bladder, rectum,
uterine corpus, ovary, small intestine, bone and connective tissue) that had high radiation exposures since treatment
increased with time [18]. The results of this study are
consistent with past studies which have shown a positive dose–response relationship for second cancers of the
bladder, rectum, bone and stomach following radiation
treatment for cervical cancer [13, 19]. Based on our findings, we believe that a woman who
developed cervical cancer and received radiation at a young
age should not wait to start screening for colorectal cancer at the age currently recommended for low-risk women. Such
women should start screening at approximately 8 years after
treatment if cervical cancer occurs before the woman reaches the age of 50, the usual age to initiate screening in average-
risk individuals. Also, the higher rates of colorectal cancer
among these women indicate that more frequent screening for colorectal cancer should be considered.
The results should be interpreted with the recognition of
the strengths and weaknesses of cancer registry-based data.
One is the lack of information regarding lifestyle choices, such as smoking. Although radiotherapy is commonly
noted as a major causative factor in the development of
SPMs,\10 % of SPMs are due to radiotherapy, with most attributable to lifestyle and genetics [13]. Smoking can
exert variable effects on the risk of gynecologic cancer
[20–23]. Specifically, cigarette smoking can increase the risk of SPMs in cervical cancer survivors [6, 18]. Cigarette
smoking is also a risk factor for colorectal cancer [24].
Since information on lifetime active smoking is not available in this dataset, we are unable to determine the
effect modification between colorectal cancer risk and
smoking in patients with cervical cancer. A recent study by Hoffmeister et al. [24] found that the efficacy of colorectal
screening by endoscopy changes when smoking is dis-
continued. This suggests that smoking status should be taken into consideration when looking at factors affecting
Table 2 Proportional hazards to colon, rectal and anal cancer for cervical cancer patients (n = 64,507)
a Unknown was not reported
* None of interactions between radiation and covariates were significant (all p value [0.19) ** None of interactions between radiation and covariates were significant (all p value [0.23)
Characteristic Category Colon cancer* Rectum**
HR 95 % CI HR 95 % CI
Radiation
B8 years No 1.00
Yes 1.13 0.81 1.56
[8 years No 1.00 Yes 2.00 1.43 2.80
B15 years No 1.00
Yes 1.37 0.90 2.10
[15 years No 1.00 Yes 4.04 2.08 7.86
Age (every 5 years) 1.38 1.33 1.43 1.34 1.25 1.43
Race/ethnicity White 1.00 1.00
Black 1.23 0.94 1.62 1.31 0.86 1.99
Hispanic 0.60 0.41 0.89 0.81 0.48 1.36
Others 0.68 0.47 0.98 1.14 0.72 1.81
Marital statusa No 1.00 1.00
Yes 1.22 0.99 1.51 1.08 0.79 1.48
Stage Local 1.00 1.00
Regional 0.96 0.76 1.22 1.08 0.75 1.55
Distant 1.11 0.65 1.92 0.54 0.17 1.75
Grade Well differentiated 1.00 1.00
Moderately differentiated 1.29 0.85 1.95 0.98 0.57 1.70
Poorly differentiated 1.17 0.77 1.78 0.62 0.34 1.13
Undifferentiated 1.43 0.73 2.8 0.43 0.10 1.85
Not determined 0.98 0.66 1.46 0.80 0.48 1.35
Year of diagnosis 0.99 0.98 1.01 1.02 0.99 1.04
Surgery No 1.00 1.00
Yes 0.94 0.74 1.20 1.35 0.92 1.96
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screening and surveillance for colorectal cancer [24, 25].
Another limitation of this study is that second cancers diagnosed among patients who migrate out of their SEER
registry area are not reportable, and migration status is not
recorded in SEER [15]. This would affect the estimation of absolute risk, but probably not relative risk. Treatment
information recorded in cancer registries is not always
accurate, and radiation status may have been misclassified, though this is thought to be small [18]. Also, registries focus
on documenting treatment initiated within 4–6 months of diagnosis. Subsequent radiation treatment would not be
captured [18]. We also could not take into account differ-
ences in radiation doses across treatment modalities. An unavoidable limitation of studying the late effects of
radiotherapy is that the most recent changes in practice
cannot be studied. And lastly, these tumors might not represent second primary malignancies but recurrence or
metastasis of the primary cervical tumor.
Despite these limitations, there were strengths to this study. This study included a large cohort size that included
all women with cervical cancer since SEER started col-
lecting data in 1973. There was a long follow-up interval, up to 35 years. Patients with cervical cancer provide an
excellent opportunity to study the late effects of radio-
therapy because of the sufficiently large numbers of patients available for study, patients survive for long
periods of time, non-irradiated patients are available for
comparison and radiation doses to organs other than the cervix can be estimated accurately [6, 10].
Future endeavors should focus on the creation and
implementation of surveillance strategies aimed to the early detection of colorectal tumors among cervical cancer
survivors.
Acknowledgments Sarah Toombs Smith, PhD, Science Editor and Assistant Professor in the Sealy Center on Aging, University of Texas Medical Branch at Galveston, provided editorial assistance in man- uscript preparation. Dr. Toombs Smith received no compensation for her assistance apart from her employment at the institution where the study was conducted. Comparative Effectiveness Research on Cancer in Texas (CERCIT) is a statewide resource for outcomes and com- parative effectiveness research funded by The Cancer Prevention Research Institute of Texas (CPRIT), RP101207.
Conflict of interest None.
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