ORIGINAL INVESTIGATION. Association Between Colorectal Cancer and Urologic Cancers

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1 ORIGINAL INVESTIGATION Association Between Colorectal and Urologic s Audrey H. Calderwood, MD; Dezheng Huo, hd; David T. Rubin, MD Background: Different types of urologic cancers have been associated with colorectal cancer () in hereditary nonpolyposis, but it is still unknown whether there is an association between urologic cancer and in the general population. We sought to quantify the risk for after urologic cancer and the risk for urologic cancer after in patients without known genetic syndromes. Methods: We performed a retrospective cohort analysis of the Surveillance, Epidemiology, and End Results program database from 1973 to Standard incidence ratios (SIRs) of observed to expected cases of invasive were calculated for each urologic cancer site based on age, sex, ethnicity, and calendar year of diagnosis. Similar analysis was performed to determine the SIRs of urologic cancers in patients with previous. Results: Overall, the risk for was increased among patients with previous ureteral cancer (SIR, 1.80; 95% confidence interval [CI], ) and renal pelvis cancer (SIR, 1.44; 95% CI, ). This risk was greatest among patients who received the diagnosis of renal pelvis or ureteral cancer before the age of 60 years. There was a minimal increased risk for subsequent in patients with bladder or renal parenchymal cancer. Overall, the risk for urologic cancer was increased after a diagnosis of (SIR, 1.24; 95% CI, ), with the highest risk for subsequent renal pelvis and ureteral cancers in patients with a diagnosis before the ages of 50 to 60 years or multiple primary s. Conclusions: revious renal pelvis and ureteral cancers, particularly when diagnosed at an early age, increase the risk for subsequent. Likewise, a history of, especially in cases with multiple primary tumors, is associated with an increased risk of renal pelvis and ureteral cancers. These findings support a possible common pathogenetic mechanism between and urologic cancers and may have implications for screening guidelines. Arch Intern Med. 2008;168(9): Author Affiliations: Department of Medicine, Section of Gastroenterology, The University of Chicago Medical Center (Drs Calderwood and Rubin), and Department of Health Studies, The University of Chicago (Dr Huo), Chicago, Illinois. SCREENING GUIDELINES FOR COlorectal cancer () emphasize the importance of identifying individuals at increased risk compared with the general population. 1,2 Among those at increased risk for are patients with a family history of as well as those who meet established criteria for hereditary syndromes. 3,4 The most common hereditary colon cancer syndrome, hereditary nonpolyposis (HNCC), confers an increased risk of colon cancer as well as extracolonic tumors of the uterus, ovaries, stomach, biliary tract, renal pelvis, and ureter. Also, previous studies have shown that a history of ovarian and endometrial cancer increases the risk for subsequent in the general population. 5 There are numerous case reports describing patients with both urologic cancer and, 6-10 but the pathogenetic or environmental factors related to such associations have been incompletely characterized outside of known HNCC pedigrees The primary aim of our study was to quantify the overall risk for after urologic cancer and the risk for urologic cancer after. A secondary aim was to determine the risk for and urologic cancer in different subgroups defined by type of urologic cancer (or ), age at diagnosis, ethnicity, sex, cancer stage at diagnosis, and duration of follow-up. METHODS We performed a retrospective cohort analysis of the Surveillance Epidemiology and End Results (SEER) public database, a network of 14 population-based cancer registries containing data from 1973 to 2000, with 3 registries containing data from 1992 to The catchment area includes approximately 14% of the US population. 16 Approval for this study was obtained from the institutional review board at The University of Chicago Hospitals, Chicago, Illinois. We used an analytic strategy similar to the approach outlined by Schoenberg and My- (RERINTED) ARCH INTERN MED/ VOL 168 (NO. 9), MAY 12,

2 ers, 17 calculating standardized incidence ratios (SIRs) of a second primary cancer in a defined cohort of patients with a first primary cancer. The analysis was performed in 2 directions: (1) the association of urologic cancer with subsequent, and (2) the association of with subsequent urologic cancer. We identified patients in the SEER database who were diagnosed as having urologic cancer and between 1973 and 2000 and had follow-up information. Follow-up time was defined as time from first primary cancer diagnosis to the date of diagnosis of the second primary cancer, the date of last physician visit, or the date of death, whichever occurred first. Using the unique identifier assigned to these patients, we searched the database for records of subsequent invasive or urologic cancer. If multiple primary tumors of the same site were diagnosed, only the first occurrence was included, because for this study, the per-patient analysis was more clinically relevant than the per-event analysis. The incidence rate was calculated as the total number of urologic cancers divided by the total years of follow-up in the cohort of patients with and as the total number of s divided by the total years of follow-up in the cohort of patients with urologic cancer. The rate of in the cohort of patients with urologic cancer and the rate of urologic cancer in the cohort of patients with were then compared with the standard rates in the general population, also derived from the SEER program over the same period from 1973 to An SIR was calculated as the ratio of observed to expected cases on the basis of age-, sex-, ethnicity-, and calendar year specific standard rates. Therefore, SIRs can be interpreted as the age-, sex-, ethnicity-, and calendar year adjusted relative risks. We further calculated the SIR separately for each cancer site, as well as for subgroups within each site defined by age at first primary cancer diagnosis, sex, cancer stage (in situ, local, regional, distant, and unstaged), ethnicity, duration of followup, and whether there were multiple first primary cancers. oisson regression methods incorporating external standard rates were used to estimate the SIR and the corresponding 95% confidence interval (CI). 18 When the number of observed events was fewer than 30, we calculated exact 95% CIs based on oisson distribution. Synchronous was defined as 2 primary s diagnosed within 6 months of each other, whereas metachronous cases were defined as 2 primary nonmetastic s diagnosed more than 6 months apart. RESULTS RISK OF AFTER UROLOGIC CANCER We identified patients with a urologic cancer and excluded those in whom the urologic cancer diagnosis was made at autopsy or on death certificate (n=2536), those with no follow-up (n=4098), and those whose race was unknown (n=723). After these exclusions, patients remained: patients with renal parenchymal cancer, 6403 patients with renal pelvis cancer, 3744 patients with ureteral cancer, and patients with bladder cancer. Table 1 lists the frequency distribution of select baseline characteristics of patients with urologic cancer and the subcohort with subsequent invasive, as reported to the SEER database ( ). The mean (SD) age at diagnosis was 62.0 (16.3) years for patients with renal parenchymal cancer, 68.4 (12.4) years for patients with renal pelvis cancer, 70.4 (10.6) years for patients with ureteral cancer, and 69.2 (12.4) years for patients with bladder cancer. The majority of patients in our analysis were white men, with an underrepresentation of women and minority races. The characteristics of patients in this cohort reflect the overall population included in the SEER database. The urologic cancer stage of patients at diagnosis was most often stage I, II, or III, with only a very small percentage of patients whose stage was unknown. The median follow-up time was 2.5 years for patients with renal parenchymal cancer, 3.2 years for those with renal pelvis cancer, 3.4 years for those with ureteral cancer, and 4.1 years for those with bladder cancer. Of the 6758 cases involving patients with multiple urologic cancers (4% of total patients with urologic cancers), 2666 (39.5%) were synchronous and 4083 (60.5%) were metachronous. We identified 2789 people with urologic cancer who developed subsequent, giving an overall unadjusted invasive incidence rate of per person-years (95% CI, ). This rate was equivalent to an SIR of 1.13 (95% CI, ). Table 2 lists the SIRs in each cohort, both overall and stratified by age at urologic cancer diagnosis, sex, ethnicity, urologic cancer stage, and duration of follow-up. Overall, patients with cancer of the upper urinary tract (ie, renal pelvis cancer and ureteral cancer) had a significant increase in risk of subsequent as compared with the general population (SIR, 1.44; 95% CI, vs SIR, 1.80; 95% CI, ). atients who received the diagnosis of renal pelvis cancer before the age of 50 years were about 5 times more likely to have subsequent (SIR, 4.94; 95% CI, ). Similarly, a diagnosis of ureteral cancer before the age of 60 years conferred a more than 2-fold increased risk for subsequent. There were no statistically significant differences in rates for patients with a diagnosis of renal pelvis cancer based on race, sex, urologic cancer stage at diagnosis, duration of follow-up, or whether patients had multiple primary urologic cancers (all values.05). Certain subgroups, in particular female sex and black race, contained relatively smaller numbers of cases and, as such, their SIRs were not statistically significant. In the subgroup of patients with a diagnosis of ureteral cancer, the incidence of subsequent was not affected by race, sex, stage, duration of follow-up, or whether there were multiple primary urologic cancers. atients with kidney parenchymal cancer and bladder cancer had a less strong but still statistically significant increased risk of (SIR, 1.14; 95% CI, ; and SIR, 1.10; 95% CI, , respectively) as compared with the general population. Also, the SIR of patients with renal parenchymal cancer was 1.12 (95% CI, ) after those who received a diagnosis within the first 6 months were excluded, and the SIR of patients with bladder cancer was 1.08 (95% CI: ) after those who received a diagnosis within the first 6 months were excluded, demonstrating significance even after possible screening bias was controlled for. Finally, whether or not patients had multiple primary urologic cancers did not influence the incidence of subsequent. (RERINTED) ARCH INTERN MED/ VOL 168 (NO. 9), MAY 12,

3 Table 1. Frequency Distribution of Baseline Characteristics of the atients With Urologic and the Subcohort With Subsequent Invasive Colorectal () a Characteristic Renal arenchymal Renal elvis Ureteral Bladder No (n=51 946) (n=503) No (n=6282) (n=121) No (n=3648) (n=96) No (n= ) (n=2069) Age at diagnosis of urologic cancer, y (17.5) 28 (5.6) 493 (7.8) 11 (9.1) 143 (3.9) 2 (2.1) 8384 (6.9) 60 (2.9) (20.4) 87 (17.3) 876 (13.9) 28 (23.1) 399 (10.9) 11 (11.5) (13.3) 239 (11.6) (27.4) 172 (34.2) 1657 (26.4) 33 (27.3) 1024 (28.1) 35 (36.5) (27.0) 638 (30.8) (24.2) 166 (33.0) 2117 (33.7) 34 (28.1) 1341 (36.8) 37 (38.5) (32.4) 797 (38.5) (10.5) 50 (9.9) 1139 (18.1) 15 (12.4) 741 (20.3) 11 (11.5) (20.4) 335 (16.2) Mean (SD) 69.1 (16.4) 66.8 (10.2) 68.5 (12.3) 65.5 (12.9) 70.4 (10.7) 69.1 (8.3) 69.1 (12.5) 69.9 (9.7) Age at diagnosis of colorectal cancer, y Mean (SD) NA 72.7 (9.5) NA 71.9 (12.6) NA 74.3 (8.5) NA 75.7 (8.9) Range NA NA NA NA Sex Male (61.9) 342 (68.0) 3667 (58.4) 82 (67.8) 2276 (62.4) 64 (66.7) (74.0) 1618 (78.2) Female (38.1) 161 (32.0) 2615 (41.6) 39 (32.2) 1372 (37.6) 32 (33.3) (26.0) 451 (21.8) Race White (85.8) 442 (87.9) 5647 (89.9) 111 (91.7) 3315 (90.9) 86 (89.6) (92.3) 1949 (94.2) Black 4811 (9.3) 34 (6.8) 291 (4.6) 4 (3.3) 102 (2.8) 1 (1.0) 5353 (4.4) 59 (2.9) Other 2557 (4.9) 27 (5.4) 344 (5.5) 6 (5.0) 231 (6.3) 9 (9.4) 4021 (3.3) 61 (2.9) Urologic cancer stage In situ 46 (0.1) 3 (0.6) 807 (12.8) 14 (11.6) 624 (17.1) 17 (17.7) Local (48.5) 323 (64.2) 2196 (35.0) 59 (48.8) 1307 (35.8) 42 (43.8) (72.8) 1739 (84.1) Regional (20.7) 124 (24.7) 2319 (36.9) 40 (33.1) 1249 (34.2) 29 (30.2) (19.1) 228 (11.0) Distant (24.3) 25 (5.0) 630 (10.0) 4 (3.3) 227 (6.2) 5 (5.2) 3886 (3.2) 10 (0.5) Unstaged 3285 (6.3) 28 (5.6) 330 (5.3) 4 (3.3) 241 (6.6) 3 (3.1) 6022 (4.9) 92 (4.4) Duration of follow-up, mo (22.2) 56 (11.1) 1045 (16.6) 10 (8.3) 483 (13.2) 10 (10.4) (11.6) 180 (8.7) (23.8) 81 (16.1) 1471 (23.4) 22 (18.2) 862 (23.6) 21 (21.9) (21.3) 392 (18.9) (21.4) 133 (26.4) 1360 (21.6) 33 (27.3) 934 (25.6) 27 (28.1) (23.8) 581 (28.1) (32.6) 233 (46.3) 2406 (38.3) 56 (46.3) 1369 (37.5) 38 (39.6) (43.3) 916 (44.3) Duration of follow-up, y Median Interquartile range Multiple primary urologic cancers Yes 1221 (2.4) 17 (3.4) 1250 (19.9) 30 (24.8) 762 (20.9) 24 (25.0) 3380 (2.8) 74 (3.6) No (97.6) 486 (96.6) 5032 (80.1) 91 (75.2) 2886 (79.1) 72 (75.0) (97.2) 1995 (96.4) Abbreviation: NA, not applicable. a Values are expressed as number (percentage) unless otherwise indicated. RISK OF UROLOGIC CANCER AFTER We identified patients with and excluded those in whom was diagnosed at autopsy or on death certificate (n=4634), those with no follow-up (n=13 513), and those whose race was unknown (n=1187). After these exclusions, patients remained: patients with colon cancer and patients with rectal cancer. As mentioned above, the final analysis included herein combines the data for colon and rectal cancers (as denoted by ) because the results when analyzed separately were similar (data on file, not shown). Table 3 lists the frequency distribution of select baseline characteristics of patients with and the subcohort with subsequent invasive urologic cancers, as reported to the SEER database ( ). The mean (SD) age at diagnosis was 70.0 (12.5) years for patients with colon cancer and 67.5 (12.6) years for patients with rectal cancer. There was a predominance of white men in our patient sample, with an underrepresentation of women and minorities. Most patients were diagnosed as having local or regional. The median follow-up time was 2.8 years (interquartile range [IQR], years). Of the cases involving patients with multiple primary (5% of the total number of patients with ), 9406 (50.4%) were synchronous and 9250 (49.6%) were metachronous. Our analysis of the differences in characteristics between the full cohort and the subcohort in which urologic cancer developed revealed that the average follow-up time in the subcohort was 1 year longer than in the full cohort. As expected, the proportion of men in the subcohort was higher than in the full cohort, as men have a higher risk of urologic cancer than women. Also, the proportion of whites was higher in the subcohort than in the full cohort. (RERINTED) ARCH INTERN MED/ VOL 168 (NO. 9), MAY 12,

4 Table 2. Colorectal Standardized Incidence Ratios (SIRs) in Each Cohort of atients With Urologic Variable Initial Renal arenchymal Initial Renal elvis Initial Ureteral Initial Bladder Overall 1.14 ( ) 1.44 ( ) 1.80 ( ) 1.10 ( ) Age at diagnosis, y ( ) 4.94 ( ) 3.16 ( ) 1.50 ( ) ( ) 2.74 ( ) 2.20 ( ) 1.12 ( ) ( ) 1.27 ( ) 1.99 ( ) 1.06 ( ) ( ) 1.04 ( ) 1.76 ( ) 1.12 ( ) ( ) 1.19 ( ) 1.19 ( ) 1.05 ( ) Race White 1.12 ( ) 1.43 ( ) 1.71 ( ) 1.09 ( ) Black 1.06 ( ) 1.52 ( ) 1.23 ( ) 1.08 ( ) Other 1.78 ( ) 1.65 ( ) 3.78 ( ) 1.37 ( ) Sex Male 1.15 ( ) 1.50 ( ) 1.71 ( ) 1.09 ( ) Female 1.13 ( ) 1.33 ( ) 2.01 ( ) 1.13 ( ) Urologic cancer stage In situ 5.85 ( ) 1.23 ( ) 1.81 ( ) NA Local 1.11 ( ) 1.41 ( ) 1.54 ( ) 1.11 ( ) Regional 1.22 ( ) 1.52 ( ) 2.10 ( ) 0.99 ( ) Distant 0.93 ( ) 2.41 ( ) 6.98 ( ) 0.93 ( ) Unstaged 1.27 ( ) 1.45 ( ) 1.38 ( ) 1.11 ( ) Duration of follow-up, mo ( ) 1.49 ( ) 2.25 ( ) 1.23 ( ) ( ) 1.44 ( ) 2.00 ( ) 1.11 ( ) ( ) 1.52 ( ) 1.84 ( ) 1.13 ( ) ( ) 1.40 ( ) 1.60 ( ) 1.05 ( ) Mutiple primary urologic cancers Yes 1.00 ( ) 1.42 ( ) 1.68 ( ) 1.20 ( ) No 1.15 ( ) 1.45 ( ) 1.84 ( ) 1.09 ( ) Abbreviations: CI, confidence interval; NA, not applicable. a value for differential effect. We identified 3026 patients with who received a subsequent diagnosis of urologic cancer. The overall unadjusted incidence rate for invasive urologic cancer after was per person-years (95% CI, ). This rate translated into an SIR of 1.24 (95% CI, ). The median lag time from a diagnosis of to a diagnosis of urologic cancer was 3.8 years (IQR, years). This lag time varied among the different subcohorts divided by type of urologic cancer: 2.6 years (IQR, years) for patients with renal parenchymal cancer, 4.1 years (IQR, years) for patients with renal pelvis cancer, 5.9 years (IQR, years) for patients with ureteral cancer, and 2.6 years (IQR, years) for patients with bladder cancer. Table 4 lists the SIRs for each cancer outcome stratified by age at diagnosis, sex, ethnicity, stage at diagnosis, and duration of follow-up. atients with had a 59% increased risk of subsequent renal pelvis cancer (SIR, 1.59; 95% CI, ) and a 100% increased risk of subsequent ureteral cancer (SIR, 2.00; 95% CI, ). The risk for the development of renal parenchymal and bladder cancer was also higher, but these increases may be partly the result of intensive screening. After patients who received a diagnosis within the first 6 months were excluded, the SIR was 1.21 (95% CI, ) for patients with renal parenchymal cancer and 1.10 (95% CI, ) for patients with bladder cancer. Overall, the relative risk of subsequent urologic cancer was influenced by several variables, including age at diagnosis, race, duration of follow-up, and presence of multiple primary s. atients diagnosed as having before the age of 50 years had a 2-fold increase in their risk for any subsequent urologic cancers as compared with their counterparts in the general population (SIR, 2.09; 95% CI, ). Relative risk by age of diagnosis differed among the different types of urologic cancer. atients with who received a diagnosis before the age of 50 years had a 2.29-fold (95% CI, ) increase in subsequent renal parenchymal cancer, a 6.20-fold (95% CI, ) increase in subsequent renal pelvis cancer, a 6.37-fold (95% CI, ) increase in subsequent ureteral cancer, and a 1.66-fold (95% CI, ) increase in subsequent bladder cancer. Also, the relative risk of subsequent ureteral and bladder cancer was stronger in nonwhite patients than in white patients. The elevated risks for renal pelvis and ureteral cancer were more dramatic in patients with multiple primary s than in patients with a single. atients with multiple primary s had a 3-fold increased risk (RERINTED) ARCH INTERN MED/ VOL 168 (NO. 9), MAY 12,

5 Table 3. Frequency Distribution of Baseline Characteristics of the atients With Colorectal and the Subcohort With Subsequent Invasive Urologic s a Characteristic Colorectal (n= ) Urologic (n=3026) Renal arenchymal (n=800) Renal elvis (n=113) Ureteral (n=84) Bladder (n=2004) Urologic, Site-Unspecified (n=25) Age at diagnosis of colorectal cancer, y (7.1) 99 (3.3) 42 (5.3) 7 (6.2) 3 (3.6) 45 (2.2) 2 (8.0) (13.8) 380 (12.6) 134 (16.8) 17 (15.0) 19 (22.6) 209 (10.4) 1 (4.0) (26.1) 1017 (33.6) 281 (35.1) 28 (24.8) 26 (31.0) 667 (33.3) 15 (60.0) (31.6) 1097 (36.3) 262 (32.8) 46 (40.7) 27 (32.1) 757 (37.8) 5 (20.0) (21.5) 433 (14.3) 81 (10.1) 15 (13.3) 9 (10.7) 326 (16.3) 2 (8.0) Mean (SD) 69.2 (12.6) 69.1 (9.9) 67.0 (10.1) 68.5 (11.6) 66.8 (10.2) 70.1 (9.6) 66.6 (9.8) Age at diagnosis of urologic cancer, y Mean (SD) NA 74.5 (9.7) 71.5 (10.2) 73.6 (10.2) 74.1 (8.9) 75.7 (9.3) 72.2 (11.7) Range NA Sex Male (50.3) 2221 (73.4) 545 (68.1) 63 (55.8) 59 (70.2) 1534 (76.5) 20 (80.0) Female (49.7) 805 (26.6) 255 (31.9) 50 (44.2) 25 (29.8) 470 (23.5) 5 (20.0) Race White (85.7) 2757 (91.1) 705 (88.1) 102 (90.3) 72 (85.7) 1855 (92.6) 23 (92.0) Black 2859 (8.0) 138 (4.6) 55 (6.9) 6 (5.3) 6 (7.1) 71 (3.5) 0 Other (6.3) 131 (4.3) 40 (5.0) 5 (4.4) 6 (7.1) 78 (3.9) 2 (8.0) Colorectal cancer stage In situ (5.2) 262 (8.7) 65 (8.1) 6 (5.3) 8 (9.5) 181 (9.0) 2 (8.0) Local (35.1) 1460 (48.3) 384 (48.0) 61 (54.0) 41 (48.8) 965 (48.2) 9 (36.0) Regional (35.9) 1086 (35.9) 302 (37.8) 40 (35.4) 29 (34.5) 704 (35.1) 11 (44.0) Distant (18.1) 103 (3.4) 25 (3.1) 3 (2.7) 2 (2.4) 73 (3.6) 0 Unstaged (5.7) 115 (3.8) 24 (3.0) 3 (2.7) 4 (4.8) 81 (4.0) 3 (12.0) Duration of follow-up, mo (16.8) 444 (14.7) 206 (25.75) 9 (8.0) 8 (9.5) 220 (11.0) 1 (4.0) (24.4) 592 (19.6) 159 (19.9) 24 (21.2) 8 (9.5) 392 (19.6) 9 (36.0) (23.9) 758 (25.1) 166 (20.75) 32 (28.3) 22 (26.2) 532 (26.5) 6 (24.0) (34.9) 1232 (40.7) 269 (33.6) 48 (42.5) 46 (54.8) 860 (42.9) 9 (36.0) Duration of follow-up, y Median, y Interquartile range Mutiple primary colorectal cancers Yes (5.2) 256 (8.5) 49 (6.1) 17 (15.0) 17 (20.2) 171 (8.5) 2 (8.0) No (94.8) 2770 (91.5) 751 (93.9) 96 (85.0) 67 (79.8) 1833 (91.5) 23 (92.0) Abbreviation: NA, not applicable. a Values are expressed as number (percentage) unless otherwise indicated. of subsequent renal pelvis cancer (SIR, 3.20; 95% CI, ) and a 5-fold increased risk of subsequent ureteral cancer (SIR, 5.30; 95% CI, ) compared with the general population. COMMENT In this study of a national database, patients with a diagnosis of urologic cancer were found to be at a higher risk for developing subsequent than the general population, and patients with a previous diagnosis of were at a higher risk for developing subsequent urologic cancer. Specifically, patients with previous cancer of the ureter or renal pelvis were at an 80% and a 44% increased risk, respectively, for subsequent compared with the general population, while patients with bladder or renal parenchymal cancer had a minimally increased risk that is statistically significant but unlikely to be clinically meaningful. Diagnosis of these 2 types of urologic cancers before the age of 60 years significantly increased the risk of subsequent. On the other hand, patients with had a 59% increased risk of developing renal pelvis cancer and a 100% increased risk of developing ureteral cancer. The relative risks for these 2 urologic cancers were particularly pronounced in patients with a diagnosis of before the age of 60 years and in those with multiple primary s. ossible explanations of this 2-directional association include shared environmental risk factors for the different types of cancer, screening bias, a genetic predisposition common to both cancers, or the effect of treatment of one type of cancer on the other. Shared environmental risk factors between urologic cancer and, such as smoking, diet, and exposure to carcinogens, may increase the risk for the development of primary cancers in multiple organs and may account for some of the concordance of urologic cancer and in this study. Screening bias is another possible explanation, as patients diagnosed as having 1 cancer will likely undergo a more thorough examination, increasing the chance of finding a second, otherwise asymptomatic can- (RERINTED) ARCH INTERN MED/ VOL 168 (NO. 9), MAY 12,

6 Table 4. Urologic Standardized Incidence Ratios (SIRs) in Each Cohort of atients With Colorectal Subsequent Kidney arenchyma Subsequent Renal elvis Subsequent Ureteral Subsequent Bladder Variable Overall 1.50 ( ) 1.59 ( ) 2.00 ( ) 1.13 ( ) Colorectal cancer type Colon 1.48 ( ) 1.80 ( ) 1.97 ( ) 1.09 ( ) Rectal 1.53 ( ) 1.10 ( ) 2.07 ( ) 1.23 ( ) Age at diagnosis, y ( ) 6.20 ( ) 6.37 ( ) 1.66 ( ) ( ) 2.32 ( ) 4.81 ( ) 1.16 ( ) ( ) 1.25 ( ) 1.88 ( ) 1.19 ( ) ( ) 1.63 ( ) 1.57 ( ) 1.10 ( ) ( ) 1.26 ( ) 1.36 ( ) 1.02 ( ) Race White 1.48 ( ) 1.56 ( ) 1.86 ( ) 1.11 ( ) Black 1.51 ( ) 2.55 ( ) 6.78 ( ) 1.23 ( ) Other 1.92 ( ) 1.63 ( ) 2.53 ( ) 1.64 ( ) Sex Male 1.52 ( ) 1.47 ( ) 2.11 ( ) 1.11 ( ) Female 1.45 ( ) 1.78 ( ) 1.77 ( ) 1.22 ( ) Colorectal cancer stage In situ 1.53 ( ) 1.15 ( ) 2.57 ( ) 1.32 ( ) Local 1.49 ( ) 1.77 ( ) 2.01 ( ) 1.11 ( ) Regional 1.58 ( ) 1.57 ( ) 1.92 ( ) 1.12 ( ) Distant 1.07 ( ) 1.01 ( ) 1.13 ( ) 1.01 ( ) Unstaged 1.20 ( ) 1.05 ( ) 2.35 ( ) 1.14 ( ) Duration of follow-up, mo ( ) 1.47 ( ) 2.18 ( ) 1.50 ( ) ( ) 1.70 ( ) 0.94 ( ) 1.15 ( ) ( ) 1.69 ( ) 1.93 ( ) 1.14 ( ) ( ) 1.51 ( ) 2.49 ( ) 1.05 ( ) Mutiple primary colorectal cancers Yes 1.27 ( ) 3.20 ( ) 5.30 ( ) 1.27 ( ) No 1.51 ( ) 1.46 ( ) 1.72 ( ) 1.12 ( ) Abbreviation: CI, confidence interval. a value for differential effect. cer. Most secondary primary urologic cancers are discovered by computed tomographic scanning, magnetic resonance imaging, and ultrasonography during preoperative examinations. 9,10 We performed stratified analyses according to duration of follow-up. After incidence cases diagnosed in the first 6 months were excluded, the conclusion that was associated with renal pelvis and ureteral cancer remained valid, suggesting that surveillance bias was not an alternative explanation for this association. A third potential explanation for the 2-directional association is a shared genetic predisposition toward both urologic cancer and, such as a mismatch repair defect. Hereditary nonpolyposis, an autosomal dominant condition, is the most common genetic colon cancer syndrome and acts by disrupting the functionality of various mismatch repair genes. Individuals carrying a mutation in 1 of these genes have an 80% lifetime risk of developing 19 and a well-described increased risk of developing extracolonic tumors, including endometrial, ovarian, ureteral, and renal cancers. 20 Finally, therapy of urologic cancer may lead to cellular changes that predispose these patients to the subsequent development of. We believe that this is the first study to demonstrate an association between urologic cancer and in a cancer database of this size and reflects a true association in the population. The findings in this study, which demonstrate that the diagnosis of colorectal or urologic cancer in a single patient increases the likelihood of a subsequent invasive cancer of one or the other type, are of great interest and have implications for the follow-up of patients with one or the other type of cancer. A previous study has described microsatellite instability testing in patients with multiple tumors in the HNCC tumor field to be a cost-effective and feasible method for identifying candidates for HNCC testing, 21 indicating that microsatellite instability testing may be a reasonable diagnostic tool for patients with colorectal and urologic cancers. The fact that the association was strongest for patients with specific urologic cancers and in general for patients who received a diagnosis at a younger age is not surprising, since the young age is suggestive of a more likely genetic (and less likely environmental) effect. Although the strength of our study is the substantial size of the patient population, there are several limita- (RERINTED) ARCH INTERN MED/ VOL 168 (NO. 9), MAY 12,

7 tions. Although the SEER database is a well-described database of high quality, there is always the possibility of some misclassifications and miscoding of tumor types, stages, or timing of diagnosis, as this information is dependent on accurate reporting by the clinician. We were unable to account for confounding variables, such as smoking history, family history, or treatment history, that might provide insight into the cancers that were identified. As mentioned, it is unclear how much impact a screening bias may have had, although our analysis attempted to address this limitation. In conclusion, our study findings show that some patients with specific urologic cancers are at a higher risk for a subsequent invasive and may benefit from earlier screening and more frequent surveillance colonoscopic examinations. Likewise, patients with a primary diagnosis of, especially those of a younger age, should be considered at increased risk for specific urologic cancers. Further studies need to determine whether screening with urinalysis or renal imaging would be beneficial and cost-effective. In the ongoing efforts to stratify colonoscopic resources and prevention strategies, patients with certain urologic cancers should be considered a group at increased risk for. Accepted for ublication: November 21, Correspondence: David T. Rubin, MD, Department of Medicine, Section of Gastroenterology, The University of Chicago Medical Center, 5841 S Maryland Ave, MC 4076, Chicago, IL (drubin@medicine.bsd.uchicago.edu). Author Contributions: Dr Rubin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Calderwood and Rubin. Acquisition of data: Calderwood, Huo, and Rubin. Analysis and interpretation of data: Calderwood, Huo, and Rubin. Drafting of the manuscript: Calderwood, Huo, and Rubin. 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