Increased risk of rectal cancer after prostate radiation: A population-based study
2005; Elsevier BV; Volume: 128; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2004.12.038
ISSN1528-0012
AutoresNancy N. Baxter, Joel E. Tepper, Sara Durham, David A. Rothenberger, Beth A Virnig,
Tópico(s)Colorectal Cancer Surgical Treatments
ResumoBackground & Aims: Radiation therapy for prostate cancer has been associated with an increased rate of pelvic malignancies, particularly bladder cancer. The association between radiation therapy and colorectal cancer has not been established. Methods: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) registry data from 1973 through 1994. We focused on men with prostate cancer, but with no previous history of colorectal cancer, treated with either surgery or radiation who survived at least 5 years. We evaluated the effect of radiation on development of cancer for 3 sites: definitely irradiated sites (rectum), potentially irradiated sites (rectosigmoid, sigmoid, and cecum), and nonirradiated sites (the rest of the colon). Using a proportional hazards model, we evaluated the effect of radiation on development of colorectal cancer over time. Results: A total of 30,552 men received radiation, and 55,263 underwent surgery only. Colorectal cancers developed in 1437 patients: 267 in irradiated sites, 686 in potentially irradiated sites, and 484 in nonirradiated sites. Radiation was independently associated with development of cancer over time in irradiated sites but not in the remainder of the colon. The adjusted hazards ratio for development of rectal cancer was 1.7 for the radiation group, compared with the surgery-only group (95% CI: 1.4–2.2). Conclusions: We noted a significant increase in development of rectal cancer after radiation for prostate cancer. Radiation had no effect on development of cancer in the remainder of the colon, indicating that the effect is specific to directly irradiated tissue. Background & Aims: Radiation therapy for prostate cancer has been associated with an increased rate of pelvic malignancies, particularly bladder cancer. The association between radiation therapy and colorectal cancer has not been established. Methods: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) registry data from 1973 through 1994. We focused on men with prostate cancer, but with no previous history of colorectal cancer, treated with either surgery or radiation who survived at least 5 years. We evaluated the effect of radiation on development of cancer for 3 sites: definitely irradiated sites (rectum), potentially irradiated sites (rectosigmoid, sigmoid, and cecum), and nonirradiated sites (the rest of the colon). Using a proportional hazards model, we evaluated the effect of radiation on development of colorectal cancer over time. Results: A total of 30,552 men received radiation, and 55,263 underwent surgery only. Colorectal cancers developed in 1437 patients: 267 in irradiated sites, 686 in potentially irradiated sites, and 484 in nonirradiated sites. Radiation was independently associated with development of cancer over time in irradiated sites but not in the remainder of the colon. The adjusted hazards ratio for development of rectal cancer was 1.7 for the radiation group, compared with the surgery-only group (95% CI: 1.4–2.2). Conclusions: We noted a significant increase in development of rectal cancer after radiation for prostate cancer. Radiation had no effect on development of cancer in the remainder of the colon, indicating that the effect is specific to directly irradiated tissue. The lifetime risk of developing prostate cancer for men in the United States is about 17%. 1Cancer Society Website. Cancer Statistics. American Cancer Society, cancer facts and figures, 2004. Available at: http://www.cancer.org/downloads/STT/CAFF_finalPWSecured.pdfAmerican. Accessed July 15, 2004.Google Scholar Over 230,000 men will be diagnosed with prostate cancer in 2004 alone. Most of those cancers will be nonmetastatic and will be treated with either external beam radiation therapy or radical prostatectomy. 2Lai S. Lai H. Lamm S. Obek C. Krongrad A. Roos B. Radiation therapy in non-surgically-treated nonmetastatic prostate cancer geographic and demographic variation.Urology. 2001; 57: 510-517Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Because 10-year survival rates for prostate cancer exceed 80%, 3Brenner H. Long-term survival rates of cancer patients achieved by the end of the 20th century a period analysis.Lancet. 2002; 360: 1131-1135Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar most men will survive their disease and be at risk of experiencing negative consequences of therapy. Treatment of localized prostate cancer is controversial, 4Holmberg L. Bill-Axelson A. Helgesen F. Salo J.O. Folmerz P. Haggman M. Andersson S.O. Spangberg A. Busch C. Nordling S. Palmgren J. Adami H.O. Johansson J.E. Norlen B.J. Scandinavian Prostatic Cancer Group Study Number 4. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer.N Engl J Med. 2002; 347: 781-789Crossref PubMed Scopus (736) Google Scholar, 5Fowler Jr, F.J. McNaughton Collins M. Albertsen P.C. Zietman A. Elliott D.B. Barry M.J. Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer.JAMA. 2000; 283: 3217-3222Crossref PubMed Scopus (365) Google Scholar, 6Alibhai S.M. Naglie G. Nam R. Trachtenberg J. Krahn M.D. Do older men benefit from curative therapy of localized prostate cancer?.J Clin Oncol. 2003; 21: 3318-3327Crossref PubMed Scopus (161) Google Scholar the disease is common, and survivorship is likely, so understanding the long-term sequelae of the treatment options is particularly important. Radiation-induced secondary malignancies are a known but infrequent complication of radiation therapy. 7Hall P.F. Cancer risks after medical radiation.Med Oncol Tumor Pharmacother. 1991; 8: 141-145PubMed Google Scholar, 8Ron E. Ionizing radiation and cancer risk evidence from epidemiology.Radiat Res. 1998; 150: S30-S41Crossref PubMed Scopus (158) Google Scholar The latency period (after radiation exposure until the development of radiation-induced solid organ neoplasm) is 5 to 15 years. 9Thompson D.E. Mabuchi K. Ron E. Soda M. Tokunaga M. Ochikubo S. Sugimoto S. Ikeda T. Terasaki M. Izumi S. et al.Cancer incidence in atomic bomb survivors. Part II: Solid tumors, 1958–1987.Radiat Res. 1994; 137: S17-S67Crossref PubMed Scopus (802) Google Scholar, 10Jao S.W. Beart Jr, R.W. Reiman H.M. Gunderson L.L. Ilstrup D.M. Colon and anorectal cancer after pelvic irradiation.Dis Colon Rectum. 1987; 30: 953-958Crossref PubMed Scopus (42) Google Scholar, 11Boice Jr, J.D. Lubin J.H. Occupational and environmental radiation and cancer.Cancer Causes Control. 1997; 8: 309-322Crossref PubMed Scopus (61) Google Scholar, 12Boice Jr, J.D. Cancer following irradiation in childhood and adolescence.Med Pediatr Oncol Suppl. 1996; 1: 29-34Crossref PubMed Scopus (36) Google Scholar Radiation-associated malignancies would be expected to occur within the irradiated field. Pelvic radiation for cervical cancer has been associated with an increased rate of second malignancies of the bladder, kidney, vagina, vulva, bone, and rectum. 13Kleinerman R.A. Boice Jr, J.D. Storm H.H. Sparen P. Andersen A. Pukkala E. Lynch C.F. Hankey B.F. Flannery J.T. Second primary cancer after treatment for cervical cancer. An international cancer registries study.Cancer. 1995; 76: 442-452Crossref PubMed Scopus (178) Google Scholar, 14Kleinerman R.A. Curtis R.E. Boice Jr, J.D. Flannery J.T. Fraumeni Jr, J.F. Second cancers following radiotherapy for cervical cancer.J Natl Cancer Inst. 1982; 69: 1027-1033PubMed Google Scholar, 15Pettersson F. Fotiou S. Einhorn N. Silfversward C. Cohort study of the long-term effect of irradiation for carcinoma of the uterine cervix. Second primary malignancies in the pelvic organs in women irradiated for cervical carcinoma at Radiumhemmet 1914–1965.Acta Radiol Oncol. 1985; 24: 145-151Crossref PubMed Scopus (38) Google Scholar Prostate radiation for cancer has been associated with a small but significant increase in the rates of bladder cancer 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar, 17Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Crossref PubMed Scopus (180) Google Scholar and sarcoma. 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar, 18Pickles T. Phillips N. The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984–2000.Radiother Oncol. 2002; 65: 145-151Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar As part of the standard external beam radiation fields to the prostate, a portion of the rectum will receive a high radiation dose, and other areas will receive lesser radiation doses. Other areas of the colon may lie in or near the pelvis and thus receive more than a nominal radiation dose, particularly the rectosigmoid colon and cecum, especially when pelvic fields are being irradiated, but the literature regarding the risk of radiation-induced colorectal cancer is inconsistent. Some authors have demonstrated an increased risk of rectal cancer, 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar, 18Pickles T. Phillips N. The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984–2000.Radiother Oncol. 2002; 65: 145-151Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar but others have not. 17Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Crossref PubMed Scopus (180) Google Scholar, 19Movsas B. Hanlon A.L. Pinover W. Hanks G.E. Is there an increased risk of second primaries following prostate irradiation?.Int J Radiat Oncol Biol Phys. 1998; 41: 251-255Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar All previous studies have had short follow-up times and thus included many patients who were not yet at risk of radiation-induced neoplasia. We used data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry to conduct this study. SEER, a population-based cancer registry sponsored by the National Cancer Institute, collects information on cancer incidence and survival from 11 population-based cancer registries and 3 supplemental areas; these 11 registries include approximately 14% of the US population. 20Surveillance, Epidemiology and End Results Program Web site. Public use data. Available at: http://seer.cancer.gov/publicdata/. Accessed July 15, 2004.Google Scholar Of the 11 registries, 2 were added in 1992. Given the limited follow-up time, men from those 2 registries were excluded from our study. The information collected by SEER includes patient characteristics, county of residence, primary tumor site, tumor grade, first course of treatment (through completion of the initial treatment plan, including treatment within the first year after diagnosis or until there is evidence either of disease progression or of treatment failure within the first year), timing of radiation, and follow-up for vital status. 20Surveillance, Epidemiology and End Results Program Web site. Public use data. Available at: http://seer.cancer.gov/publicdata/. Accessed July 15, 2004.Google Scholar Included in our study were men 18 to 80 years old who were diagnosed with prostate cancer from January 1, 1973, through December 31, 1994. We limited our analysis to men with invasive, nonmetastatic, microscopically confirmed disease. Excluded were men with a previous diagnosis of colorectal cancer recorded in the SEER registry. To allow time for development of potential radiation effects, we included only men who were alive at least 5 years after their prostate cancer diagnosis and excluded those who developed a colon or rectal cancer within the first 5 years of follow-up. Excluded were men who did not undergo radiation or surgical treatment or who underwent only orchiectomy. Follow-up time was to December 31, 2000, or death. SEER routinely collects data on the first course of treatment, including surgery and radiation. For our study, men who underwent surgery with no radiation were defined as the surgery-only group; men who underwent external beam radiation, with or without surgery, were defined as the radiation group. SEER also routinely collects data on the site of colorectal cancer. For our study, we divided colorectal cancers that developed at least 5 years after prostate cancer diagnosis into 3 separate sites: those located in a definitely irradiated field (rectal cancers, International Classification of Disease Oncology 2 [ICD O 2] topography code C20.9), those located in a potentially irradiated field (rectosigmoid cancers, ICD O 2 code C19.9; sigmoid cancers ICD O 2 code C18.7; and cecal cancers, ICD O 2 code C18.0), and those located in a nonirradiated field (all other colon cancers, ICD O 2 codes C18.2 through C18.6). We calculated Kaplan-Meier curves representing the time from prostate cancer diagnosis to development of colorectal cancer for the 3 sites, plotting the definitely, potentially, and nonirradiated categories separately. These curves were compared using the Wilcoxon test. To control for potential confounders, a proportional hazards model was constructed for each colorectal site, adjusting for diagnosis year (to control for secular trends and changes in radiation technique over time), age at diagnosis, race, and treatment registry. Age was evaluated in 10-year and 5-year increments. We tested the model for possible interaction effects between age and radiation and between diagnosis year and treatment. Because our study used preexisting data with no personal identifiers, the Human Subjects Committee of the University of Minnesota’s Institutional Review Board determined that it was exempt from review. We identified a total of 85,815 men meeting selection criteria, with an average age of 67.6 years. Men undergoing radiation for prostate cancer were older than men undergoing surgery only (68.8 years vs. 66.9 years, respectively; P < .0001) (Table 1). Men diagnosed after 1980 were more likely to undergo radiation than men diagnosed from 1973 through 1979 (36% vs. 29%, respectively; P < .0001). Men whose race was coded as African American or other were more likely to receive radiation than men whose race was noted as white (38%, African American; 41%, other; and 35%, white; P < .0001). Even though the slight difference was statistically significant, the percentage of men who underwent radiation was essentially the same numerically for patients with local vs. regional disease (36% vs. 35%, respectively; P = .0002). Mean follow-up time for the group was over 9 years. A total of 1437 colorectal cancers developed at least 5 years after prostate cancer diagnosis: 267 rectal cancers; 686 rectosigmoid, sigmoid, or cecal cancers; and 484 other colon cancers.Table 1Patient CharacteristicsSurgery-only groupRadiation groupP value for difference between surgery-only and radiation groupsTotal cases55,26330,552Age at diagnosis, y Mean (median)66.9 (67)68.8 (70)P < .0001 at-test, assume unequal variances. <608024 (14.5%)2678 (9%)P < .0001 bχ2 test, 2 df. 60–6925,943 (47%)12,380 (40%) 70–7921,296 (38.5%)15,494 (51%)Race White48,702 (88.1%)26,439 (87%)P < .0001 bχ2 test, 2 df. African American4714 (8.5%)2848 (9%) Other1847 (3.3%)1265 (4%)Stage Localized41,962 (76%)23,531 (77%)P = .0002 cχ2 test, 1 df. Regional13,301 (24%)7011 (23%)Mean follow-up (median)9.5 y (8.3)9.0 y (7.9)P < .0001 at-test, assume unequal variances.Year of diagnosis 1973–19798091 (14.5%)3361 (11%)P < .0001 bχ2 test, 2 df. 1980–198920,772 (37.5%)11,516 (38%) 1990–199426,400 (48%)15,672 (51%)Colorectal cancer Irradiated (rectum)143124P = .0016 dχ2 test, 3 df. Potentially irradiated (rectosigmoid, sigmoid, and cecum)437249 Nonirradiated (remainder of colon)324160 No colorectal cancer54,35930,019a t-test, assume unequal variances.b χ2 test, 2 df.c χ2 test, 1 df.d χ2 test, 3 df. Open table in a new tab The rate of development of rectal cancer over time was higher in patients who underwent radiation (P < .0001) as demonstrated by the Kaplan-Meier curves plotting time to development of colorectal cancer in Figure 1 (patients were not eligible for our study if their colorectal cancer developed during the first 5 years after prostate cancer treatment). The curves for tumors located in potentially irradiated sites and nonirradiated sites were very similar for those who underwent radiation vs. surgery only; we noted no statistically significant differences between groups (P = .082 for radiation vs. surgery in potentially irradiated sites; and P = .97 for radiation vs. surgery in nonirradiated sites) (Figure 2, Figure 3). Because important potential confounders, such as age, were not adjusted for when calculating the Kaplan-Meier curves, a proportional hazards model was constructed to adjust for potential confounders (Table 2). After controlling for other factors, we found that radiation remained a significant risk factor for development of rectal cancer over time (P < .0001). The observed hazard ratio for radiation therapy was 1.7 (95% CI: 1.4–2.2); this value can be interpreted as a 70% increase in the development of rectal cancer for men who underwent radiation (vs. men who did not). The other factor associated with development of rectal cancer in our study was age at diagnosis: an increased risk was associated with older age at diagnosis. Proportional hazards models for colon cancers developing in potentially irradiated and nonirradiated sites did not demonstrate an effect of prostate radiation (P = .3511 for possibly irradiated sites and P = .5781 for nonirradiated sites). We found no interactions between radiation and year of diagnosis or age at diagnosis for any of the 3 sites (irradiated, potentially irradiated, and nonirradiated).Figure 2Time from prostate cancer diagnosis to development of colorectal cancer in potentially irradiated sites (cecum, rectosigmoid, or sigmoid), by prostate cancer treatment group. Solid line, radiation group; dashed line, surgery-only group.View Large Image Figure ViewerDownload (PPT)Figure 3Time from prostate cancer diagnosis to development of colorectal cancer in nonirradiated sites (remainder of colon), by prostate cancer treatment group. Solid line, radiation group; dashed line, surgery-only group.View Large Image Figure ViewerDownload (PPT)Table 2Proportional Hazards Model Predicting Time to Cancer by SiteDistributionDefinitely irradiated sitesPotentially irradiated sitesNonirradiated sitesHazard ratio (95% CI)P valueHazard ratio (95% CI)P valueHazard ratio (95% CI)P valueYear of diagnosis 1970–19791.01.01.0 1980–1989.97 (.70–1.33).831.05 (.86–1.28).621.09 (.86–1.38).47 1990–1994.96 (.65–1.41).83.89 (.69–1.14).361.05 (.78–1.42).74Group Surgery-only group1.01.01.0 Radiation group1.70 (1.4–2.2)<.00011.08 (.92–1.26).35.95 (.78–1.15).58Age at diagnosis (yr) <601.01.01.0 60–692.12 (1.31–3.44).0022.15 (1.57–2.94)<.00012.23 (1.52–3.27)<.0001 70–792.10 (3.44–1.28).0033.11 (2.27–4.26)<.00013.49 (2.37–5.11)<.0001Race White1.01.0 African American.58 (.32–1.03).061.05 (.80–1.39).711.40 (1.02–1.92).03 Other2.4 (1.22–4.79).011.20 (0.72–2.01).48.64 (.32–1.26).19NOTE. Adjusted for registry and all other factors in model. Open table in a new tab NOTE. Adjusted for registry and all other factors in model. Previous studies, including those using SEER data, have produced conflicting results with respect to the risk of rectal cancer after irradiation for prostate cancer. Two previous studies 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar, 17Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Crossref PubMed Scopus (180) Google Scholar used SEER data to evaluate the risk of second malignancies in prostate cancer patients treated with radiation. Both of those studies compared the standardized incidence ratio (the ratio of the observed rate of rectal cancer in prostate cancer patients to the expected rate of rectal cancer in the population) in patients who underwent radiotherapy for prostate cancer vs. either surgery 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar or no irradiation. 17Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Crossref PubMed Scopus (180) Google Scholar In one study, by Brenner et al, 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar a 105% increase in the incidence of rectal cancer was found in prostate cancer patients after radiation (vs. surgery) after more than 10 years of follow-up; in addition, a 24% (nonsignificant) increase in the incidence of colon cancer was found after radiation. In the other study, by Neugut et al, 17Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Crossref PubMed Scopus (180) Google Scholar no increased incidence of rectal cancer was found in prostate cancer patients after radiation (vs. no radiation), even in those with long-term follow-up. Both of those studies have limitations that may explain their discrepant results. Most important, the mean years of follow-up are limited in both studies. The Brenner et al study 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar included patients diagnosed from 1973 through 1993, but the mean survival time after prostate cancer diagnosis was only 4 years. The mean follow-up time was not presented in the Neugut et al study 17Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Crossref PubMed Scopus (180) Google Scholar; however, it included patients diagnosed from 1973 through 1990 and was published 4 years earlier than the Brenner et al study, so follow-up would be even shorter. Given that, biologically, the latency period between radiation exposure and radiation-induced malignancy is at least 5 years, neither study had sufficient follow-up time to determine the true effect of radiation. Similarly, both studies included cases of rectal cancer discovered at 2 months 16Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Crossref PubMed Scopus (493) Google Scholar and 6 months 17Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Crossref PubMed Scopus (180) Google Scholar after prostate cancer diagnosis, yet such early rectal cancers could not have resulted from radiation exposure. Rather, they may have been found simply because of more intensive rectal evaluations or because of symptoms of radiation. Neither study excluded patients with a prior history of colorectal cancer. Additionally, their use of the standardized incidence ratio may have limited their ability to adjust for potential confounders, such as race and geographic location by registry. In a similar study using the population-based cancer registry of British Columbia, Canada, 18Pickles T. Phillips N. The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984–2000.Radiother Oncol. 2002; 65: 145-151Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar an increased incidence of colorectal cancer was found in men who underwent radiation for prostate cancer (vs. men who did not), with a relative risk of 1.21 for colorectal cancer in the radiation group. However, all second cancers diagnosed more than 2 months after radiation were included in that study; men with a previous diagnosis of colorectal cancer were not excluded; and no adjustment was made for confounders. Two smaller studies 19Movsas B. Hanlon A.L. Pinover W. Hanks G.E. Is there an increased risk of second primaries following prostate irradiation?.Int J Radiat Oncol Biol Phys. 1998; 41: 251-255Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 21Johnstone P.A. Powell C.R. Riffenburgh R. Rohde D.C. Kane C.J. Second primary malignancies in T1-3N0 prostate cancer patients treated with radiation therapy with 10-year followup.J Urol. 1998; 159: 946-949Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar did not demonstrate an increase in rectal cancer after irradiation for prostate cancer. Our study represents a significant improvement over prior analyses of the secondary consequences of radiation for prostate cancer. First, our study is based on a large number of men with prostate cancer, all of whom had their prostate disease confirmed microscopically, underwent treatment for their disease, and had long-term follow-up; the mean follow-up time was 9 years in our radiation group and 9.5 years in our surgery-only group. We included only men who survived at least 5 years, thus, biologically, all radiation patients were at risk for radiation-induced rectal cancer. We excluded men with previous colorectal cancer as well as men who developed a colorectal cancer in the first 5 years after prostate cancer treatment. Allowing for this lag time serves 2 purposes: (1) it excludes men diagnosed with colorectal cancer only because of more intense evaluation associated with complications of their prostate cancer treatment, and (2) it is consistent with the hypothesis that radiation-induced carcinogenesis takes at least 5 years to manifest. We found no increase in the incidence of colon cancer in potentially irradiated sites and nonirradiated sites; by using other parts of the colon as control measures, we reduced the likelihood that any observed radiation effect found in the rectum was merely because of confounding and demonstrated that the carcinogenic effect of radiation is specific to irradiated sites. As Figure 1 illustrates, an increased incidence of rectal cancer was minimally apparent at 6 years after radiation but remained constant in terms of the ratio of risk between the radiation group and surgery-only group. Thus, the combined effects of the baseline risk of rectal cancer apparent in an aging population and the increased risk because of radiation give prostate cancer survivors who undergo radiation approximately a 70% increased risk of developing rectal cancer in any given year. This effect is of approximately the same order of magnitude as having a first-degree relative with colorectal cancer or with a 10-year increase in age. 22Slattery M.L. Kerber R.A. Family history of cancer and colon cancer risk the Utah population database.J Natl Cancer Inst. 1994; 86: 1618-1626Crossref PubMed Scopus (189) Google Scholar, 23Fuchs C.S. Giovannucci E.L. Colditz G.A. Hunter D.J. Speizer F.E. Willett W.C. A prospective study of family history and the risk of colorectal cancer.N Engl J Med. 1994; 331: 1669-1674Crossref PubMed Scopus (685) Google Scholar, 24Cooper G.S. Yuan Z. Landefeld C.S. Johanson J.F. Rimm A.A. A national population-based study of incidence of colorectal cancer and age. Implications for screening in older Americans.Cancer. 1995; 75: 775-781Crossref PubMed Scopus (127) Google Scholar The overall rates of rectal cancer in both our radiation group and our surgery-only group were low. Over 10 years of follow-up in our study (from year 5 to 15 after prostate cancer treatment), 5.1 men per 1000 treated with surgery-only developed rectal cancer as compared with 10 men per 1000 treated with radiation. Thus, our findings do not suggest that prostate cancer treatment should change. However, they do suggest that the type of treatment for prostate cancer might have implications for colorectal cancer screening. The magnitude of effect would point to including prostate radiation in the category of factors that move a patient from a normal risk to moderately elevated risk for rectal cancer. Men undergoing radiation for prostate cancer should undergo endoscopic evaluation beginning 5 years after radiation. Our study has several limitations. First, information regarding the type and method of radiation delivery was limited, with no available data on dosage or fields. Changes in radiation delivery techniques over time may have affected risk. However, even with today’s more sophisticated approaches of conformal radiation or intensity-modulated radiation, some portions of the rectum (specifically the anterior rectal wall) will receive radiation during prostate treatment—a dose not substantially different from that delivered to the prostate; other portions of the rectum will receive an intermediate dose of radiation. The use of these smaller radiation fields would likely decrease the incidence of second rectal cancers because a smaller volume of rectum would be in the radiation field and at higher risk. Because our study relied on observational data, rather than results of a randomized trial, the potential for patient selection bias, although small, remains. Likewise, we had no information about colorectal cancer risk factors, other than age, and we do not know whether there was any change in patient lifestyle resulting from the diagnosis of prostate cancer that may have influenced colorectal cancer risk, although it is unlikely that such risk factors would have resulted in differential treatment selection for prostate cancer. Therefore, it is unlikely that these limitations would have altered our final conclusion: that radiation treatment of prostate cancer results in a moderate elevation in the risk of rectal cancer over time. Inflammation’s Role in Rectal Cancer Following Prostate Radiotherapy, and Emerging Evidence for a Protective Role for BalsalazideGastroenterologyVol. 129Issue 2PreviewWe read with great interest the manuscript by Baxter et al1 on rectal cancer following prostate radiotherapy published in the April 2005 issue of Gastroenterology, along with the accompanying editorial by Grady and Russell.2 However, our approach to addressing the important issues raised is different than that suggested in the editorial. The editorial’s authors appropriately highlight the fact that any such radiotherapy-associated rectal cancer is not likely a direct result of radiation to the prostate. Full-Text PDF
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