Med Oncol (2014) 31:943 DOI 10.1007/s12032-014-0943-2
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 Ó 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 malignancies 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 cervical 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 proportional 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 follow-up after radiation remained the same across three eras
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
(1973–1980, 1981–1990, and 1991–2000). Radiationinduced 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 estimated 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].
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The choice of radiotherapy is dependent on the stage of disease [10]. Radiation treatment consists of external beam radiotherapy, brachytherapy using an intracavitary radiation 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 developing SPMs of colon and rectum over 35 years of followup 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) program. 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 population [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/Pacific 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 Classification 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.
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Study variables The study variables included race/ethnicity, age at diagnosis, marital status, radiation status (yes/no), surgery status (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 International Classification of Diseases for Oncology, 2nd Edition (ICD-0-2) and categorized as well differentiated, moderately 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 followup 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 proportional 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 follow-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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Table 1 Demographics, pathologic and surgical treatment characteristics 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)
n
%
n
%
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
461
1.4
629
2.1
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
\0.0001
Race/ethnicity
Other Age at diagnosis
Mean age at cervical cancer diagnosis (years ± SD)
Fig. 1 Proportion of cervical cancer patients receiving radiation after diagnosis by study year, SEER 1973–2009 (n = 64,507)
\0.0001
53.3 ± 14.5
45.3 ± 14.4
17,831
13,131
52.5
43.0
Not married
15,050
44.3
15,740
51.5
Unknown
1,080
3.2
1,675
5.5 \0.0001
Surgery Yes
13,545
39.9
26,809
87.8
No
20,416
60.1
3,737
12.2
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
Well differentiated
1,963
5.8
3,220
10.5
Moderately differentiated
9,445
27.8
6,392
20.9
\0.0001
Stage
\0.0001
Grade
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
Results Demographics, clinical and tumor characteristics
\0.0001
Marital status Married
p value
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.
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 hazards 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).
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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
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 malignancies at colon and rectum (p = 0.5123, 0.3769, respectively). We also did not find any interactions between age, ethnicity or tumor characteristics, with an increased risk of
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colorectal cancer associated with radiation (all p values [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 cervical cancer survivors. The relationship between therapeutic radiation and the risk of SPMs has long been recognized [13].
Med Oncol (2014) 31:943 Table 2 Proportional hazards to colon, rectal and anal cancer for cervical cancer patients (n = 64,507)
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Characteristic
Category
Colon cancer* HR
Rectum**
95 %
CI
0.81
1.56
1.43
2.80
HR
95 %
CI
0.90
2.10
Radiation B8 years [8 years B15 years [15 years
No
1.00
Yes
1.13
No
1.00
Yes
2.00
No
1.00
Yes
1.37
No
1.00
Yes
4.04
2.08
7.86
1.38
1.33
1.43
1.34
1.25
1.43
White Black
1.00 1.23
0.94
1.62
1.00 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
No
1.00
Yes
1.22
0.79
1.48
Local
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
Well differentiated
1.00
Age (every 5 years) Race/ethnicity
Marital statusa Stage
Grade 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)
0.99
1.51
1.08 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
0.99
0.98
1.01
1.02
0.99
1.04
0.92
1.96
Year of diagnosis Surgery
1.00
No
1.00
Yes
0.94
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 averagerisk individuals. Also, the higher rates of colorectal cancer among these women indicate that more frequent screening for colorectal cancer should be considered.
1.00 0.74
1.20
1.35
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 discontinued. This suggests that smoking status should be taken into consideration when looking at factors affecting
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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 differences 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 collecting 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 radiotherapy 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 manuscript 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 comparative effectiveness research funded by The Cancer Prevention Research Institute of Texas (CPRIT), RP101207. Conflict of interest
None.
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3. de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomark Prev. 2013;22(4):561–70. 4. Maher EJ, Denton A. Survivorship, late effects and cancer of the cervix. Clin Oncol (R Coll Radiol). 2008;20(6):479–87. 5. Elena JW, Travis LB, Simonds NI, et al. Leveraging epidemiology and clinical studies of cancer outcomes: recommendations and opportunities for translational research. J Natl Cancer Inst. 2013;105(2):85–94. 6. Kleinerman RA, Boice JD Jr, Storm HH, et al. Second primary cancer after treatment for cervical cancer: an international cancer registries study. Cancer. 1995;76(3):442–52. 7. Tubiana M. Can we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review. Radiother Oncol. 2009;91(1):4–15 discussion 11–13. 8. Howlader NNA, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (2013) (eds) SEER cancer statistics review, 1975–2010. http://seer.cancer.gov/csr/ 1975_2010/. 15 Jan 2014. 9. Stovall M, Smith SA, Rosenstein M. Tissue doses from radiotherapy of cancer of the uterine cervix. Med Phys. 1989;16(5): 726–33. 10. Marcial VA, Marcial LV. Radiation therapy of cervical cancer: new developments. Cancer. 1993;71(4 Suppl):1438–45. 11. Chaturvedi AK, Engels EA, Gilbert ES, et al. Second cancers among 104,760 survivors of cervical cancer: evaluation of longterm risk. J Natl Cancer Inst. 2007;99(21):1634–43. 12. Chaturvedi AK, Kleinerman RA, Hildesheim A, et al. Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix. J Clin Oncol. 2009;27(6):967–73. 13. Berrington de Gonzalez A, Curtis RE, Kry SF, et al. Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol. 2011;12(4):353–60. 14. Oeffinger KC, Baxi SS, Novetsky Friedman D, Moskowitz CS. Solid tumor second primary neoplasms: who is at risk, what can we do? Semin Oncol. 2013;40(6):676–89. 15. Overview of the SEER Program. http://www.seer.cancer.gov/ about/overview.html. 14 June 2013. 16. Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst. 2005;97(6): 419–24. 17. Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. 2nd ed. New York: Springer; 2003. 18. Boice JD Jr, Engholm G, Kleinerman RA, et al. Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res. 1988;116(1):3–55. 19. Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000;88(2):398–406. 20. Williams RR, Horm JW. Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: interview study from the third national cancer survey. J Natl Cancer Inst. 1977;58(3):525–47. 21. Zhou B, Yang L, Sun Q, et al. Cigarette smoking and the risk of endometrial cancer: a meta-analysis. Am J Med. 2008;121(6):501–8 e503. 22. Terry PD, Rohan TE, Franceschi S, Weiderpass E. Cigarette smoking and the risk of endometrial cancer. Lancet Oncol. 2002;3(8):470–80. 23. Michnovicz JJ, Hershcopf RJ, Naganuma H, Bradlow HL, Fishman J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. N Engl J Med. 1986;315(21):1305–9.
Med Oncol (2014) 31:943 24. Hoffmeister M, Jansen L, Stock C, Chang-Claude J, Brenner H. Smoking, lower gastrointestinal endoscopy, and risk for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2014;23(3): 525–33.
Page 7 of 7 943 25. Hoffmeister M, Schmitz S, Karmrodt E, et al. Male sex and smoking have a larger impact on the prevalence of colorectal neoplasia than family history of colorectal cancer. Clin Gastroenterol Hepatol. 2010;8(10):870–6.
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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 Ó 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 malignancies 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 cervical 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 proportional 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 follow-up after radiation remained the same across three eras
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
(1973–1980, 1981–1990, and 1991–2000). Radiationinduced 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 estimated 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].
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The choice of radiotherapy is dependent on the stage of disease [10]. Radiation treatment consists of external beam radiotherapy, brachytherapy using an intracavitary radiation 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 developing SPMs of colon and rectum over 35 years of followup 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) program. 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 population [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/Pacific 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 Classification 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.
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Study variables The study variables included race/ethnicity, age at diagnosis, marital status, radiation status (yes/no), surgery status (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 International Classification of Diseases for Oncology, 2nd Edition (ICD-0-2) and categorized as well differentiated, moderately 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 followup 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 proportional 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 follow-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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Table 1 Demographics, pathologic and surgical treatment characteristics 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)
n
%
n
%
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
461
1.4
629
2.1
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
\0.0001
Race/ethnicity
Other Age at diagnosis
Mean age at cervical cancer diagnosis (years ± SD)
Fig. 1 Proportion of cervical cancer patients receiving radiation after diagnosis by study year, SEER 1973–2009 (n = 64,507)
\0.0001
53.3 ± 14.5
45.3 ± 14.4
17,831
13,131
52.5
43.0
Not married
15,050
44.3
15,740
51.5
Unknown
1,080
3.2
1,675
5.5 \0.0001
Surgery Yes
13,545
39.9
26,809
87.8
No
20,416
60.1
3,737
12.2
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
Well differentiated
1,963
5.8
3,220
10.5
Moderately differentiated
9,445
27.8
6,392
20.9
\0.0001
Stage
\0.0001
Grade
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
Results Demographics, clinical and tumor characteristics
\0.0001
Marital status Married
p value
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.
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 hazards 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).
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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
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 malignancies at colon and rectum (p = 0.5123, 0.3769, respectively). We also did not find any interactions between age, ethnicity or tumor characteristics, with an increased risk of
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colorectal cancer associated with radiation (all p values [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 cervical cancer survivors. The relationship between therapeutic radiation and the risk of SPMs has long been recognized [13].
Med Oncol (2014) 31:943 Table 2 Proportional hazards to colon, rectal and anal cancer for cervical cancer patients (n = 64,507)
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Characteristic
Category
Colon cancer* HR
Rectum**
95 %
CI
0.81
1.56
1.43
2.80
HR
95 %
CI
0.90
2.10
Radiation B8 years [8 years B15 years [15 years
No
1.00
Yes
1.13
No
1.00
Yes
2.00
No
1.00
Yes
1.37
No
1.00
Yes
4.04
2.08
7.86
1.38
1.33
1.43
1.34
1.25
1.43
White Black
1.00 1.23
0.94
1.62
1.00 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
No
1.00
Yes
1.22
0.79
1.48
Local
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
Well differentiated
1.00
Age (every 5 years) Race/ethnicity
Marital statusa Stage
Grade 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)
0.99
1.51
1.08 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
0.99
0.98
1.01
1.02
0.99
1.04
0.92
1.96
Year of diagnosis Surgery
1.00
No
1.00
Yes
0.94
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 averagerisk individuals. Also, the higher rates of colorectal cancer among these women indicate that more frequent screening for colorectal cancer should be considered.
1.00 0.74
1.20
1.35
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 discontinued. This suggests that smoking status should be taken into consideration when looking at factors affecting
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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 differences 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 collecting 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 radiotherapy 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 manuscript 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 comparative effectiveness research funded by The Cancer Prevention Research Institute of Texas (CPRIT), RP101207. Conflict of interest
None.
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