Risk of second primary Cancer among bladder Cancer patients: a population-based cohort study in Korea

Risk of second primary Cancer among bladder Cancer patients: a population-based cohort study in... Background: For the expanding population of bladder cancer survivors in Korea, the development of subsequent cancers is a significant concern. Here, we provide the second primary cancer incidence rates and types in Korean patients with bladder cancer. Methods: Using population-based data from the Korea Central Cancer Registry from 1993 to 2013, we studied the standardized incidence ratios among 48,875 individuals with an initial diagnosis of bladder cancer. Standardized incidence ratios for second primary cancers were evaluated according to age at diagnosis, latency, diagnostic year, and treatment. Results: Over the same period, the overall risk of a second primary cancer was reduced by 6% in patients with bladder cancer compared with the development of a new malignancy in the general population (standardized incidence ratio = 0.94; 95% CI, 0.91–0.97, p < 0.05). For specific cancers, the standardized incidence ratios for stomach, colon, liver, and non-Hodgkin lymphoma were significantly lower in patients with bladder cancer. However, the risk of prostate and kidney cancer in patients with bladder cancer were significantly increased. The risk of lung squamous cell carcinoma and lung adenocarcinoma as second primary cancers was significantly elevated in patients with bladder cancer. Conclusion: Korean patients with bladder cancer have a 6% lower risk of developing a second primary cancer. However, they have a higher risk of developing subsequent prostate and kidney cancers, lung squamous cell carcinoma, and lung adenocarcinoma, suggesting the need for continual intensive cancer surveillance among bladder cancer survivors. Keywords: Bladder cancer, Second primary cancer, Prognosis, Incidence, Survival Background There is a long-term survival concern in patients with Bladder cancer (BC) is the 9th most frequent cancer BC, especially those with second primary cancer (SPC). worldwide [1] and the number of BC cases increased For Western patients, compared with the general popu- from 2180 in 1999 to 3549 in 2011, with 37,950 total lation, BC survivors are more likely to develop SPCs, cases during this period in Korea [2]. Moreover, according which frequently occur in the lungs or neck [4, 5]. to the Korea Central Cancer Registry (KCCR) report, 3949 However, to our knowledge, no studies have evaluated new BC cases were diagnosed in 2014, with 7.8 cases per SPC among Asian patients with BC. Although, we have 100,000 person-years [3]. previously detailed the overall risk of SPC development in Korean patients with prostate cancer and kidney cancer [6, 7]. Therefore, we were also interested in * Correspondence: astra67@ncc.re.kr studying SPC in patients with primary BC. Whi-An Kwon and Jae Young Joung contributed equally to this work. Cancer Registration and Statistics Branch, National Cancer Center, Goyang, The purpose of this population-based cohort study Korea was to calculate the incidence of SPC in Korean patients Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kwon et al. BMC Cancer (2018) 18:617 Page 2 of 9 with BC and to estimate the effect of SPC on survival intervals for the SIRs were estimated using Byar’s exact using a nationwide population-based cancer registry. approximation to the accurate Poisson distribution of The primary goal was to produce useful data for man- the observed number. The person-years at risk were aging patients with BC. calculated from two months after the initial BC diagno- sis until death, the date of last known survival, or the Methods study completion date (December 31st, 2013). Study population and data collection Results were classified based on age at the time of ini- A total of 48,875 patients diagnosed with BC were evalu- tial diagnosis with BC (0–39, 40–59, or ≥ 60 years), year ated between 1993 and 2013 as documented in the KCCR. of first BC diagnosis (1993–2000 or 2001–2013), latency The KCCR gathers information on ~ 80–90% of cancer time among first BC diagnosis and subsequent primary cases across 180 hospitals across South Korea. In 1999, cancer (< 12 months, 12–59 months, 60–119 months, the scope of the KCCR was expanded to cover the entire or ≥ 120 months), and treatment type (surgery vs. South Korean population using the Population-Based non-surgery, chemotherapy vs. non-chemotherapy, and Cancer Registry Program [8]. radiotherapy [RT] vs. non-RT). To ensure that SPC remains distinct from primary BC Survival curves using the Kaplan-Meier method were recurrences and metastases, the KCCR uses coding rules calculated for BC patients with or without a subsequent based on the histological or topographical classifications cancer. The log-rank test was employed to verify the of the International Classification of Diseases for difference between groups of survival curves. All of the Oncology 3rd edition [9] and the International Agency statistical tests were determined statistically significant for Research on Cancer (IARC) rules for multiple at P-value < 0.05, and were two-sided. The SIR and 95% primary cancer in 2004 [10]. The IARC classifies cancer CI calculations were performed using SEER*Stat as an SPC when a primary tumor has a different histo- (seer.cancer.gov/seerstat, version 8.3.4). Survival ana- logical type or anatomical site from the indexed cancer. lyses and log-rank tests were performed using STATA KCCR data includes patient information (age at the time (StataCorp LP, version 12.1). of diagnosis and sex), cancer information (diagnosis date, tumor site, histology, and surveillance, epidemi- Results ology, and end results [SEER] summary stage), and We obtained data from 48,875 patients, including 39,351 primary treatment information (surgery, chemotherapy, men (80.5%) and 9524 women (19.5%), with a median or radiotherapy). age at diagnosis of 67 years. The cohort characteristics The first primary BC included patients with a single are shown in Table 1. The overall SPC risk decreased by primary BC and the first BC in patients with multiple 6% in patients with previous BC compared with that in primary cancers. We excluded the following first the general population over the same period (SIR = 0.94; primary BC cases: 1) age at diagnosis, unknown; and 2) 95% CI, 0.91–0.97). Patients examined within one year BC reported at death. In addition, because SPCs diag- of BC diagnosis exhibited an increased risk of all subse- nosed within two months of the first primary cancer quent cancers (SIR = 1.21). Patients who were followed diagnosis are considered synchronous, these cases were up for 1–5 years showed a SIR risk reduction of 0.89. excluded to reduce the misclassification of undetected Finally, after a ≥ 10-year follow-up, the SIR decreased to synchronous cancers and metastases. 0.86. Patients aged < 40 years at BC diagnosis were more Ethical approval for the research protocol was pro- likely to have all SPC types (SIR = 1.50); whereas, those vided by the institutional review board of the National aged 40–59 or ≥ 60 years at diagnosis exhibited a re- Cancer Center (NCC2017–0182). duced SPC incidence (SIR = 1.04 and 0.90, respectively). Two periods were analyzed (1993–2000 and 2001–2013) Statistical analyses to evaluate the potential impact of changes in diagnosis Standardized incidence ratios (SIR) were used to com- and treatment. SPC incidence differed between these pare the relative risk of the SPC incidence rates with two periods (SIR = 0.85 and 0.99, respectively; Table 2). those of the general population at baseline. We esti- Significantly lower SIRs were observed for cancers of the mated cancer incidence for each cancer type according tongue (SIR = 0.37; 95% CI 0.10–0.94), tonsil (SIR = 0.27; to age at diagnosis, latency, and diagnostic year, which 95% CI 0.03–0.99), stomach (SIR = 0.79; 95% CI 0.73–0.86), was multiplied by the cumulative number of years at risk colon (SIR = 0.84; 95% CI 0.74–0.95), and liver (SIR = 0.79; to calculate the number of cancer outbreaks expected 95% CI 0.69–0.90), and for non-Hodgkin lymphoma for each stratum. SIR was estimated by dividing the (SIR = 0.69; 95% CI 0.50–0.91). However, the risks of observed number of SPCs in patients with BC by the prostate cancer and kidney cancer in patients with BC in- number of patients at risk of developing a new malig- creased significantly (SIR = 1.46; 95% CI 1.33–1.59, and nancy in the general population. The 95% confidence SIR = 1.47; 95% CI 1.20–1.79, respectively) (Table 2). Kwon et al. BMC Cancer (2018) 18:617 Page 3 of 9 Table 1 Characteristics of patients with primary BC, 1993–2013 Total Men Women n% n % n % Patients with BC 48,875 100 39,351 100 9524 100 Period of BC diagnosis 1993–1997 6892 14.10 5592 14.21 1300 13.65 1998–2002 10,484 21.45 8377 21.29 2107 22.12 2003–2007 13,585 27.80 10,942 27.81 2643 27.75 2008–2013 17,914 36.65 14,440 36.70 3474 36.48 Average age at diagnosis with BC (years; mean, SD) 65.39 12.46 64.81 12.20 67.80 13.22 Median age at diagnosis with BC (years; median, range) 67 105 (1–106) 66 100 (1–101) 70 105 (1–106) Age at primary BC diagnosis (years) 0–39 1608 3.29 1259 3.20 349 3.66 40–59 12,489 25.55 10,601 26.94 1888 19.82 ≥60 34,778 71.16 27,491 69.86 7287 76.51 Percentage of primary treatment status Surgery 42,448 86.85 34,653 88.06 7795 81.85 Radiation 1298 2.66 1004 2.55 294 3.09 Chemotherapy 6161 12.61 5045 12.82 1116 11.72 Average follow-up after BC diagnosis (years; mean, SD) 5.65 5.09 5.70 5.06 5.46 5.21 Median follow-up after BC diagnosis (years; median, range) 4.13 20.80(0–20.80) 4.21 20.80(0–20.80) 3.67 20.80(0–20.80) Number of patients who developed a SPC 3495 7.15 3116 7.92 379 3.98 Average age at SPC diagnosis (years; mean, SD) 70.57 9.28 70.71 8.94 69.40 11.67 Median age at SPC diagnosis (years; median, range) 71(10–95) 71.5(10–95) 71(12–93) Average interval between primary cancer and SPC 5.23 4.30 5.18 4.29 5.75 4.39 (years; mean, SD) Median interval between primary cancer and SPC 4.17(0.17–0.67) 4.08(0.17–20.67) 4.75(0.17–19.08) (years; median, range) Number of patients by latency between primary cancer and SPC (years) 1 556 15.91 469 12.95 47 16.19 1–4 1409 40.31 1176 39.67 144 40.61 5–9 1000 28.61 813 29.20 106 28.07 ≥10 530 15.16 438 18.18 66 15.12 Number of patients by age at SPC diagnosis (years) 0–39 13 0.37 8 0.26 5 1.32 40–59 396 11.33 327 10.49 69 18.21 ≥60 3086 88.30 2781 89.25 305 80.47 Average follow-up after SPC diagnosis, (years; mean, SD) 2.55 2.91 2.48 2.82 3.10 3.52 Median follow-up after SPC diagnosis (years; median, range) 1.42 20.00(0–20.00) 1.42 20.00(0–20.00) 1.67 19.50(0–19.50) Number of subsequent primary cancers 1 3259 6.67 2896 7.36 363 3.81 2 217 0.44 203 0.52 14 0.15 ≥3 19 0.04 17 0.04 2 0.02 BC: bladder cancer, SD: standard deviation, SPC: second primary cancer Notably, SIR did not increase significantly for total lung cell carcinoma and adenocarcinoma were significantly ele- cancers. However, a subgroup analysis based on lung can- vated (SIR = 1.15; 95% CI 1.02–1.29, and SIR = 1.20; 95% cer histology revealed that the SPC risks of lung squamous CI 1.05–1.37, respectively). By contrast, other lung cancer Kwon et al. BMC Cancer (2018) 18:617 Page 4 of 9 Table 2 Risk of SPC after BC diagnosis by follow-up, age, and period (1993–2013) Total latency (months) Age (years) Period <12 12–59 60–119 ≥120 0–39 40–59 ≥ 60 1993–2000 2001–2013 SIR O/E CI SIR SIR SIR SIR SIR SIR SIR SIR SIR All SPCs 0.94# (3821/4086.59) (0.91–0.97) 1.21# 0.89# 0.92# 0.86# 1.50# 1.04 0.90# 0.85# 0.99 All SPCs excluding BC, KC, 0.96# (3751/3921.87) (0.93–0.99) 1.20# 0.91# 0.95 0.90# 1.36 1.06 0.92# 0.87# 1.01 pelvic and ureteral cancer Buccal cavity, pharynx 0.79 (53/67.09) (0.59–1.03) 0.23# 1.09 0.62 0.76 0 1.03 0.71# 0.68 0.87 Tongue 0.37# (4/10.95) (0.10–0.94) 0 0.43 0.32 0.57 0 0.67 0.26# 0.22 0.47 Salivary gland 0.92 (6/6.51) (0.34–2.01) 0 1.10 1.58 0 0 1.17 0.85 0.76 1.03 Tonsil 0.27# (2/7.32) (0.03–0.99) 0 0.66 0 0 0 0.40 0.21 0 0.44 Hypopharynx 1.19 (19/15.94) (0.72–1.86) 0.49 1.33 0.86 2.01 0 1.69 1.05 1.48 0.98 Digestive system 0.85# (1833/2160.13) (0.81–0.89) 0.81# 0.79# 0.96 0.82# 1.41 0.95 0.81# 0.79# 0.89# Esophagus 0.97 (94/97.04) (0.78–1.19) 0.96 0.96 1.07 0.80 0 1.05 0.95 0.83 1.08 Stomach 0.79# (632/796.08) (0.73–0.86) 0.73# 0.73# 0.87# 0.87 1.47 0.92 0.75# 0.73# 0.84# Small intestine 1.43 (20/14.02) (0.87–2.20) 2.31 1.55 1.22 0.84 0 1.33 1.47 2.13# 0.95 Colon 0.84# (271/321.74) (0.74–0.95) 0.95 0.87 0.86 0.70# 1.72 0.90 0.82# 0.77# 0.88 Rectum, rectosigmoid junction 0.91 (233/255.77) (0.80–1.04) 1.15 0.75# 1.02 0.95 1.59 0.88 0.91 0.82 0.96 Anus, anal canal 0.97 (5/5.15) (0.32–2.27) 1.51 0.46 1.34 1.20 0 2.12 0.72 0.89 1.03 Liver 0.79# (240/304.17) (0.69–0.90) 0.63# 0.74# 0.94 0.79 1.09 0.95 0.71# 0.77# 0.80# Gallbladder 0.77 (43/55.52) (0.56–1.04) 1.18 0.57# 0.86 0.83 0 0.92 0.75 0.71 0.82 Bile ducts, other biliary 0.92 (166/180.66) (0.78–1.07) 0.55# 0.92 1.18 0.73 2.04 0.95 0.91 0.92 0.92 Pancreas 0.98 (122/124.96) (0.81–1.17) 0.67 0.98 1.19 0.82 2.2 1.27 0.90 0.81 1.08 Respiratory system 1.05 (848/807.86) (0.98–1.12) 1.06 1.07 1.01 1.05 0 1.27# 1.01 0.93 1.13# Nose, nasal cavity, ear 1.07 (8/7.51) (0.46–2.10) 2.06 1.57 0.46 0 0 0 1.41 0.62 1.39 Larynx 1.20 (58/48.45) (0.91–1.55) 2.18# 1.09 0.87 1.26 0 1.18 1.21 1.1 1.27 Lung, bronchus 1.05 (782/748.26) (0.97–1.12) 0.98 1.07 1.03 1.06 0 1.30# 1 0.93 1.13# Female breast 1.12 (34/30.38) (0.78–1.56) 1.35 0.72 1.11 1.91 0.90 1.19 1.09 1.70# 0.78 Female genital system 1.10 (33/29.98) (0.76–1.55) 1.71 1.16 0.59 1.33 2.75 0.97 1.07 1.27 0.96 Male genital system 1.45# (513/353.32) (1.33–1.58) 4.04# 1.30# 1.04 0.95 5.18 1.66# 1.41# 1.30# 1.53# Prostate 1.46# (505/346.97) (1.33–1.59) 4.08# 1.31# 1.03 0.95 7.54 1.66# 1.41# 1.32# 1.53# Testis 3.95 (3/0.76) (0.82–11.55) 0 6.05 4.61 0 0 4.17 4.76 0 6.83# Urinary system 0.73# (170/232.70) (0.62–0.85) 2.03# 0.72# 0.42# 0.37# 6.63# 0.89 0.65# 0.61# 0.81# Urinary bladder 0.45# (63/139.70) (0.35–0.58) 1.63# 0.49# 0.12# 0.08# 12.41# 0.46# 0.41# 0.33# 0.54# Kidney parenchyma 1.47# (100/67.98) (1.20–1.79) 3.23# 1.44# 1.04 1.08 4.54# 1.40 1.44# 1.32 1.56# Renal pelvis, other urinary 0.28# (7/25.02) (0.11–0.58) 1.03 0.10# 0.40 0.00# 0 0.90 0.15# 0.43 0.19# Brain, central nervous system 0.76 (16/21.09) (0.43–1.23) 0.38 0.91 0.97 0.28 0 0.56 0.85 0.72 0.79 Thyroid 1.21 (107/88.29) (0.99–1.46) 2.24# 1.29 0.97 0.83 1.08 1.35# 1.09 1.04 1.28# Lymphatic, hematopoietic 0.75# (98/130.52) (0.61–0.92) 1.08 0.64# 0.73 0.83 0.63 0.57# 0.81 0.69# 0.79 Hodgkin lymphoma 0.77 (2/2.58) (0.09–2.80) 3.11 0.92 0 0 0 0 1.15 0.99 0.64 Non-Hodgkin lymphoma 0.69# (47/68.39) (0.50–0.91) 1.21 0.75 0.35# 0.75 1.17 0.43# 0.76 0.64 0.71 Myeloma 0.82 (19/23.27) (0.49–1.28) 1.09 0.64 0.87 0.95 0 0.79 0.83 0.70 0.89 Leukemia 0.82 (32/38.93) (0.56–1.16) 0.84 0.44# 1.31 0.90 0 0.68 0.88 0.78 0.85 SIR: standardized incidence ratio, CI: confidence interval, BC: bladder cancer, SPC: second primary cancer, KC: kidney cancer, O/E: Observed/Expected, # significant at alpha = 0.05 Kwon et al. BMC Cancer (2018) 18:617 Page 5 of 9 histologies (including small cell carcinoma: SIR = 1.06; Discussion 95% CI 0.86–1.28) were not associated with an increased SIRs for cancers that developed after primary BC were SPC risk. Moreover, although not significant, the SIR calculated using KCCR data. Analysis of the data re- increased after one year. SIRs for specific lung cancer vealed that, in the present cohort, BC survivors had a types are shown in Table 3. 6% lower risk of developing a new malignancy compared To estimate the effect of primary BC treatment on with the general population. Cancers of the tongue, ton- SPC risk, we calculated the SIR of the RT, surgery, and sils, digestive system (e.g., stomach, colon, and liver) and chemotherapy groups. For all treatment modalities non-Hodgkin lymphoma were less likely to occur as except RT, the SPC risk was lower than that in comparable SPCs in patients with BC. However, these findings were patients with BC. Effects of treatment on SPC risk are incongruent with those reported previously [4, 5, 11]. summarized in Table 4. While the reasons for reduced SPC risk in the BC At 21 years follow-up, 22,036 of the 48,875 BC patients are unclear, they might be related to smoking patients had died. The 10-year overall survival (OS) rates cessation and lifestyle modification after a BC diagnosis. were 46.2 and 52.6% in the SPC and non-SPC groups, Additionally, these results might, in part, be due to respectively (p = 0.000). The 5- and 15-year OS rates for shared etiologies (genetic background and environment) the SPC group were 72.3 and 28.3%, respectively, and treatment-related factors [12]. whereas those for the non-SPC group were 64.8 and A previous study that evaluated Korean patients with 43.8%, respectively. prostate cancer and kidney cancer using similar methods The survival curves crossed over time. The SPC group revealed SPC SIRs of 0.75 and 1.13, respectively [6, 7]. had higher OS rates compared with the non-SPC group In the present study, the incidences of prostate cancer for the first 8 years, but the OS of the SPC group and kidney cancer were greater. This increased incidence declined thereafter (Fig. 1). After the onset of SPC, might be due to shared etiological, environmental, and women had higher OS rates compared with men (Fig. 2). genetic factors between the first and second malignancies We conducted a subgroup analysis of the patients [13]. Moreover, a surveillance effect might contribute to treated between 2006 and 2013 to analyze any correla- increased risk immediately after diagnosis and might tions between the SPC incidence and OS according to explain the elevated prostate cancer and kidney cancer the SEER stage which were collected since 2006. After risk after primary BC. BC diagnosis, the OS curves of patients with SPC and In a study examining associations between urinary non-SPC group crossed at 2.5 years (Additional file 1: tract cancers, Kinoshita et al. demonstrated that BC Figure S1). Moreover, distant staging in SPC and and prostate cancer share similar traits such as DNA non-SPC groups was estimated at 2.32 and 4.04% of repair and N-acetyl transferase polymorphism [14]. cases, respectively. For patients with a follow-up of Kellen et al. reported that prostate cancer risk in- < 2.5 years, the proportion of distant staging was creases in patients < 70 years old within one year of 5.31% at diagnosis, whereas that in those BC diagnosis [15]. Lococo et al. also reported a sig- followed-up for ≥2.5 years it was 0.8% (p =0.000). nificant increase in the relative risk of kidney cancer Before 2.5 years, the presence of SPC accounted for following BC [16]. 5.38% of distant stage cases in the non-SPC group, In this study, we interestingly found that the risk for and 3.45% of cases in the SPC group (p =0.183). tongue and tonsil cancer significantly decreased in patients Afterwards, the proportions of distant staging were 0.48% with BC, and the result for tongue cancer is significantly in SPC and 0.82% in non-SPC group (p =0.719) lower in those over 60 compared to those aged 40–59. (Additional file 2: Figure S2). Chemical factors like tobacco and alcohol, biological factors Table 3 Risk of SPC by lung cancer histology after BC diagnosis (1993–2013) Latency (months) Total < 12 12–59 60–119 ≥120 SIR (O/E) 95% CI SIR (O/E) SIR (O/E) SIR (O/E) SIR (O/E) Lung, bronchus 1.05 (782/748.26) (0.97–1.12) 0.98 (90/91.90) 1.07 (331/309.19) 1.03 (227/220.22) 1.06 (134/126.96) Squamous cell carcinoma 1.15# (280/243.85) (1.02–1.29) 0.94 (29/30.71) 1.18 (121/102.47) 1.08 (77/71.04) 1.34# (53/39.63) Adenocarcinoma 1.20# (221/183.65) (1.05–1.37) 1.39 (30/21.61) 1.27# (94/74.26) 1.15 (63/54.55) 1.02 (34/33.23) Small cell carcinoma 1.06 (99/93.82) (0.86–1.28) 0.69 (8/11.64) 1.10 (43/39.13) 1.13 (31/27.46) 1.09 (17/15.58) Other and unspecified 0.80# (182/226.95) (0.69–0.93) 0.82 (23/27.95) 0.78# (73/93.32) 0.83 (56/67.16) 0.78 (30/38.51) SPC: second primary cancer, BC: bladder cancer, SIR: standardized incidence ratio, CI: confidence interval, O/E: Observed/Expected # significant at alpha = 0.05 Kwon et al. BMC Cancer (2018) 18:617 Page 6 of 9 Table 4 Risk of SPC according to treatment for primary BC (1993–2013) RT Non-RT Surgery Non-Surgery Chemotherapy Non-chemotherapy SIR SIR SIR SIR SIR SIR All SPCs 1.01 0.93# 0.94# 0.85# 0.94 0.93# All SPCs excluding BC, KC, pelvic and ureteral cancers 1.04 0.96# 0.97# 0.86# 0.94 0.96# Buccal cavity, pharynx 0 0.80 0.83 0.35 0.56 0.82 Tongue 0 0.37# 0.40 0 0.86 0.31# Salivary gland 0 0.94 1.01 0 0 1.03 Tonsil 0 0.28 0.30 0 0 0.31 Hypopharynx 0 1.21 1.30 0 0.59 1.26 Digestive system 0.88 0.85# 0.87# 0.66# 0.78# 0.86# Esophagus 0.60 0.98 0.97 0.95 0.86 0.98 Stomach 0.59 0.80# 0.81# 0.64# 0.71# 0.80# Small intestine 4.18 1.38 1.49 0.79 0.68 1.51 Colon 1.35 0.83# 0.89# 0.39# 1.04 0.82# Rectum, rectosigmoid junction 1.20 0.91 0.91 0.90 0.87 0.92 Anus, anal canal 0 0.99 0.86 1.98 1.86 0.87 Liver 0.98 0.79# 0.80# 0.70 0.73 0.80# Gallbladder 0 0.79 0.78 0.74 0.17# 0.84 Bile ducts, other biliary 0.64 0.92 0.96 0.53 0.91 0.92 Pancreas 1.4 0.97 1.01 0.69 0.62 1.02 Respiratory system 1.16 1.05 1.05 1.01 0.98 1.06 Nose, nasal cavity, ear 7.75 0.95 1.17 0 1.25 1.04 Larynx 0 1.22 1.13 1.90 0.95 1.23 Lung, bronchus 1.18 1.04 1.05 0.97 0.98 1.05 Female breast 0 1.14 1.20 0.34 0.62 1.18 Female genital system 1.50 1.09 1.12 0.93 1.86 1.01 Male genital system 2.23# 1.44# 1.43# 1.74# 1.85# 1.41# Prostate 2.28# 1.44# 1.43# 1.70# 1.83# 1.41# Testis 0 4.02 4.32 0 12.33 2.95 Urinary system 1.03 0.73# 0.69# 1.1 1.28 0.67# Urinary bladder 0 0.46# 0.43# 0.61 1.03 0.38# Kidney parenchyma 2.81 1.45# 1.40# 2.29# 1.98# 1.41# Renal pelvis, other urinary 2.43 0.24# 0.22# 0.90 0.78 0.22# Brain, central nervous system 0 0.77 0.78 0.54 0 0.85 Thyroid 0 1.23# 1.23# 1 1.65 1.16 Lymphatic, hematopoietic 0.46 0.76# 0.76# 0.61 0.52 0.78# Hodgkin lymphoma 0 0.79 0.84 0 3.65 0.43 Non-Hodgkin lymphoma 0 0.70# 0.71# 0.50 0.42 0.72# Myeloma 0 0.83 0.80 1.01 1.66 0.72 Leukemia 1.53 0.81 0.85 0.58 0.00# 0.92 SIR, standardized incidence ratio, RT: radiotherapy, BC: bladder cancer, SPC: second primary cancer, KC: kidney cancer, # significant at alpha = 0.05 like human papillomavirus (HPV), syphilis, oro-dental fac- tongue and tonsil cancer is still unclear. However, we tors, dietary deficiencies, chronic candidiasis and viruses speculated that life style modification (smoking cessa- have been known to be significantly associated with oral tion, diet, and so on) may reduce chance of developing cancer [17]. The mechanism of the declined risk of tongue and tonsil cancer. Kwon et al. BMC Cancer (2018) 18:617 Page 7 of 9 Fig. 1 Kaplan-Meier curve: survival after bladder cancer according to the incidence of second primary cancer (SPC) in all patients Smoking is a well-known risk factor for BC, kidney, that the other cancers were smoking-related and oc- lung, mouth, and pharynx cancers [18] and has been es- curred before the BC diagnosis. timated to cause half of all BC cases in Western coun- The risk of cancer caused by radiation follows the in- tries [19]. In contrast to our hypothesis, the present dividual exposed to radiation and continues to increase study did not show an increase in the number of subse- throughout the individual’s lifetime [20]. Studies evaluat- quent respiratory system malignancies. Therefore, a sub ing the risk of secondary cancers after radiation therapy analysis according to histological lung cancer type was for prostate cancer have shown mixed results [21–23]. performed, showing a significant increase in the inci- Recent meta-analyses have shown that patients who dence of lung squamous cell carcinoma and adenocar- received prostate cancer radiotherapy are more likely to cinoma as SPCs. Possible reasons include potential have a second malignancy of the bladder, colon and etiological or genetic background differences between rectum than patients who have not received radiother- the Western and Asian patients, decreased smoking con- apy [24]. To our knowledge, although no studies have tribution compared with the West, and the possibility reported the risk of secondary cancer after radiation Fig. 2 Kaplan-Meier curve: survival after second cancer according to sex in patients with second cancers Kwon et al. BMC Cancer (2018) 18:617 Page 8 of 9 therapy for bladder cancer, our study showed that which was not relatively long duration. Further studies secondary cancers were more common in the digestive with long follow-up periods will be needed to estimate organs, such as the small intestine, colon, rectum, and the precise risk of developing SPC and to overcome sur- female/male genital systems than patients who do not veillance bias. Fifth, it was impossible to divide into received radiotherapy. We assume that this result is non-muscle invasive cancer and muscle invasive cancer related to the radiation field and is similar to the results in our study. The survival of patients with bladder of the meta-analysis mentioned above [24]. However, the cancer may be affected by degree of muscle invasion. lack of information such as the specific type of radiation treatment and dose of radiation is another limitation of Conclusion this study. The risk is lower among Korean survivors of BC compared To our knowledge, this is the first study to evaluate to the expected risk of developing SPC in the general popu- the histological subtypes of lung cancers as an SPC. lation. However, patients with BC remain at increased risk Cigarette smoking is an established risk factor for lung of some cancers, particularly prostate and kidney, lung cancer, but the severity of its association with other squamous cell carcinoma, and lung adenocarcinoma. histologic types is unclear. Khuder [25, 26] reported that Therefore, longer and closer surveillance could be recom- all histologic lung cancer types were significantly associ- mended for the early detection of SPC. ated with cigarette smoking, and the association was stronger for squamous cell and small cell carcinomas Additional files compared with large cell cancer and adenocarcinoma. In the present study, squamous cell carcinoma and adeno- Additional file 1: Figure S1. Kaplan-Meier curve: survival after bladder cancer (BC) according to the incidence of a second primary cancer (SPC) carcinoma exhibited a significantly elevated risk of in all patients (2006–2013). (TIF 1011 kb) occurring as an SPC. Although not significant, small cell Additional file 2: Figure S2. Stage distributions by bladder cancer lung cancer risk also increased over an extended occurrence and follow-up years. (JPG 184 kb) follow-up period. If smoking is a shared risk factor for BC and secondary lung cancer, the influence of smoking Abbreviations on each histologic type of secondary lung cancer in BC BC: Bladder cancer; CI: Confidence interval; KCCR: Korea Central Cancer Registry; RT: Radiotherapy; SD: Standard deviation; SEER: Surveillance patients might be presumed to be different to that for epidemiology and end results; SIR: Standardized incidence ratio; SPC: Second primary lung cancer. primary cancer Cumulative survival curves of patients with or without Funding SPC were estimated to investigate whether SPC affects the This work was supported by a research grant from the National Cancer survival rate of patients who have BC. In particular, for Center (No. 1610201), Republic of Korea. The National Cancer Center had no the first 8 years, the SPC group had superior survival rates role in the design of the study, or the collection, analysis, and interpretation of data, or the manuscript preparation. compared with the non-SPC group. Overall, this study demonstrated that patients in the non-SPC group had sig- Availability of data and materials nificantly more advanced BC at the time of diagnosis. All data generated or analyzed during this study are included in this published article. Therefore, the survival rate of the non-SPC group was lower than that of the SPC group for the first 2.5 years Authors’ contributions after diagnosis of BC. Conversely, after 2.5 years the Conception and design: YJW, WAK, JYJ. Acquisition of data: YJW, CMO, KWJ. reverse was noted with survival in the SPC group being Analysis of data: JL, YJW. Drafting of the manuscript: WAK, JYJ, JL, YJW. Critical revision and final approval of the manuscript: All authors read and inferior to that in the non-SPC group. These findings sug- approved the final manuscript. gested that the SPC group would require more attentive and systemic surveillance after 2.5 years of follow-up. Ethics approval and consent to participate Ethical approval for the research protocol was provided by the institutional The present study has several limitations. First, infor- review board of the National Cancer Center (NCC2017–-0182). mation concerning several potential confounding vari- Information was de-identified prior to analysis. The authorization for data ables including smoking, alcohol consumption, obesity, processing was obtained from the National Cancer Act. and familial cancer history were not available. Second, Competing interests there was limited data available concerning genetic The authors declare that they have no competing interests. factors and specific cancer stages among the patients, making it impossible to evaluate the correlation between Publisher’sNote disease severity and SPC incidence. Third, the higher in- Springer Nature remains neutral with regard to jurisdictional claims in cidence of SPC might be associated with close surveil- published maps and institutional affiliations. lance or misclassifications because BC, prostate cancer, Author details and kidney cancer often develop synchronously [15, 16]. 1 2 Center for Prostate Cancer, National Cancer Center, Goyang, Korea. Cancer Fourth, the median follow-up period was 4.13 years, Registration and Statistics Branch, National Cancer Center, Goyang, Korea. Kwon et al. BMC Cancer (2018) 18:617 Page 9 of 9 Received: 28 September 2017 Accepted: 18 May 2018 23. 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Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000; 88:398–406. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Risk of second primary Cancer among bladder Cancer patients: a population-based cohort study in Korea

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Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine, general; Medicine/Public Health, general
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Abstract

Background: For the expanding population of bladder cancer survivors in Korea, the development of subsequent cancers is a significant concern. Here, we provide the second primary cancer incidence rates and types in Korean patients with bladder cancer. Methods: Using population-based data from the Korea Central Cancer Registry from 1993 to 2013, we studied the standardized incidence ratios among 48,875 individuals with an initial diagnosis of bladder cancer. Standardized incidence ratios for second primary cancers were evaluated according to age at diagnosis, latency, diagnostic year, and treatment. Results: Over the same period, the overall risk of a second primary cancer was reduced by 6% in patients with bladder cancer compared with the development of a new malignancy in the general population (standardized incidence ratio = 0.94; 95% CI, 0.91–0.97, p < 0.05). For specific cancers, the standardized incidence ratios for stomach, colon, liver, and non-Hodgkin lymphoma were significantly lower in patients with bladder cancer. However, the risk of prostate and kidney cancer in patients with bladder cancer were significantly increased. The risk of lung squamous cell carcinoma and lung adenocarcinoma as second primary cancers was significantly elevated in patients with bladder cancer. Conclusion: Korean patients with bladder cancer have a 6% lower risk of developing a second primary cancer. However, they have a higher risk of developing subsequent prostate and kidney cancers, lung squamous cell carcinoma, and lung adenocarcinoma, suggesting the need for continual intensive cancer surveillance among bladder cancer survivors. Keywords: Bladder cancer, Second primary cancer, Prognosis, Incidence, Survival Background There is a long-term survival concern in patients with Bladder cancer (BC) is the 9th most frequent cancer BC, especially those with second primary cancer (SPC). worldwide [1] and the number of BC cases increased For Western patients, compared with the general popu- from 2180 in 1999 to 3549 in 2011, with 37,950 total lation, BC survivors are more likely to develop SPCs, cases during this period in Korea [2]. Moreover, according which frequently occur in the lungs or neck [4, 5]. to the Korea Central Cancer Registry (KCCR) report, 3949 However, to our knowledge, no studies have evaluated new BC cases were diagnosed in 2014, with 7.8 cases per SPC among Asian patients with BC. Although, we have 100,000 person-years [3]. previously detailed the overall risk of SPC development in Korean patients with prostate cancer and kidney cancer [6, 7]. Therefore, we were also interested in * Correspondence: astra67@ncc.re.kr studying SPC in patients with primary BC. Whi-An Kwon and Jae Young Joung contributed equally to this work. Cancer Registration and Statistics Branch, National Cancer Center, Goyang, The purpose of this population-based cohort study Korea was to calculate the incidence of SPC in Korean patients Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kwon et al. BMC Cancer (2018) 18:617 Page 2 of 9 with BC and to estimate the effect of SPC on survival intervals for the SIRs were estimated using Byar’s exact using a nationwide population-based cancer registry. approximation to the accurate Poisson distribution of The primary goal was to produce useful data for man- the observed number. The person-years at risk were aging patients with BC. calculated from two months after the initial BC diagno- sis until death, the date of last known survival, or the Methods study completion date (December 31st, 2013). Study population and data collection Results were classified based on age at the time of ini- A total of 48,875 patients diagnosed with BC were evalu- tial diagnosis with BC (0–39, 40–59, or ≥ 60 years), year ated between 1993 and 2013 as documented in the KCCR. of first BC diagnosis (1993–2000 or 2001–2013), latency The KCCR gathers information on ~ 80–90% of cancer time among first BC diagnosis and subsequent primary cases across 180 hospitals across South Korea. In 1999, cancer (< 12 months, 12–59 months, 60–119 months, the scope of the KCCR was expanded to cover the entire or ≥ 120 months), and treatment type (surgery vs. South Korean population using the Population-Based non-surgery, chemotherapy vs. non-chemotherapy, and Cancer Registry Program [8]. radiotherapy [RT] vs. non-RT). To ensure that SPC remains distinct from primary BC Survival curves using the Kaplan-Meier method were recurrences and metastases, the KCCR uses coding rules calculated for BC patients with or without a subsequent based on the histological or topographical classifications cancer. The log-rank test was employed to verify the of the International Classification of Diseases for difference between groups of survival curves. All of the Oncology 3rd edition [9] and the International Agency statistical tests were determined statistically significant for Research on Cancer (IARC) rules for multiple at P-value < 0.05, and were two-sided. The SIR and 95% primary cancer in 2004 [10]. The IARC classifies cancer CI calculations were performed using SEER*Stat as an SPC when a primary tumor has a different histo- (seer.cancer.gov/seerstat, version 8.3.4). Survival ana- logical type or anatomical site from the indexed cancer. lyses and log-rank tests were performed using STATA KCCR data includes patient information (age at the time (StataCorp LP, version 12.1). of diagnosis and sex), cancer information (diagnosis date, tumor site, histology, and surveillance, epidemi- Results ology, and end results [SEER] summary stage), and We obtained data from 48,875 patients, including 39,351 primary treatment information (surgery, chemotherapy, men (80.5%) and 9524 women (19.5%), with a median or radiotherapy). age at diagnosis of 67 years. The cohort characteristics The first primary BC included patients with a single are shown in Table 1. The overall SPC risk decreased by primary BC and the first BC in patients with multiple 6% in patients with previous BC compared with that in primary cancers. We excluded the following first the general population over the same period (SIR = 0.94; primary BC cases: 1) age at diagnosis, unknown; and 2) 95% CI, 0.91–0.97). Patients examined within one year BC reported at death. In addition, because SPCs diag- of BC diagnosis exhibited an increased risk of all subse- nosed within two months of the first primary cancer quent cancers (SIR = 1.21). Patients who were followed diagnosis are considered synchronous, these cases were up for 1–5 years showed a SIR risk reduction of 0.89. excluded to reduce the misclassification of undetected Finally, after a ≥ 10-year follow-up, the SIR decreased to synchronous cancers and metastases. 0.86. Patients aged < 40 years at BC diagnosis were more Ethical approval for the research protocol was pro- likely to have all SPC types (SIR = 1.50); whereas, those vided by the institutional review board of the National aged 40–59 or ≥ 60 years at diagnosis exhibited a re- Cancer Center (NCC2017–0182). duced SPC incidence (SIR = 1.04 and 0.90, respectively). Two periods were analyzed (1993–2000 and 2001–2013) Statistical analyses to evaluate the potential impact of changes in diagnosis Standardized incidence ratios (SIR) were used to com- and treatment. SPC incidence differed between these pare the relative risk of the SPC incidence rates with two periods (SIR = 0.85 and 0.99, respectively; Table 2). those of the general population at baseline. We esti- Significantly lower SIRs were observed for cancers of the mated cancer incidence for each cancer type according tongue (SIR = 0.37; 95% CI 0.10–0.94), tonsil (SIR = 0.27; to age at diagnosis, latency, and diagnostic year, which 95% CI 0.03–0.99), stomach (SIR = 0.79; 95% CI 0.73–0.86), was multiplied by the cumulative number of years at risk colon (SIR = 0.84; 95% CI 0.74–0.95), and liver (SIR = 0.79; to calculate the number of cancer outbreaks expected 95% CI 0.69–0.90), and for non-Hodgkin lymphoma for each stratum. SIR was estimated by dividing the (SIR = 0.69; 95% CI 0.50–0.91). However, the risks of observed number of SPCs in patients with BC by the prostate cancer and kidney cancer in patients with BC in- number of patients at risk of developing a new malig- creased significantly (SIR = 1.46; 95% CI 1.33–1.59, and nancy in the general population. The 95% confidence SIR = 1.47; 95% CI 1.20–1.79, respectively) (Table 2). Kwon et al. BMC Cancer (2018) 18:617 Page 3 of 9 Table 1 Characteristics of patients with primary BC, 1993–2013 Total Men Women n% n % n % Patients with BC 48,875 100 39,351 100 9524 100 Period of BC diagnosis 1993–1997 6892 14.10 5592 14.21 1300 13.65 1998–2002 10,484 21.45 8377 21.29 2107 22.12 2003–2007 13,585 27.80 10,942 27.81 2643 27.75 2008–2013 17,914 36.65 14,440 36.70 3474 36.48 Average age at diagnosis with BC (years; mean, SD) 65.39 12.46 64.81 12.20 67.80 13.22 Median age at diagnosis with BC (years; median, range) 67 105 (1–106) 66 100 (1–101) 70 105 (1–106) Age at primary BC diagnosis (years) 0–39 1608 3.29 1259 3.20 349 3.66 40–59 12,489 25.55 10,601 26.94 1888 19.82 ≥60 34,778 71.16 27,491 69.86 7287 76.51 Percentage of primary treatment status Surgery 42,448 86.85 34,653 88.06 7795 81.85 Radiation 1298 2.66 1004 2.55 294 3.09 Chemotherapy 6161 12.61 5045 12.82 1116 11.72 Average follow-up after BC diagnosis (years; mean, SD) 5.65 5.09 5.70 5.06 5.46 5.21 Median follow-up after BC diagnosis (years; median, range) 4.13 20.80(0–20.80) 4.21 20.80(0–20.80) 3.67 20.80(0–20.80) Number of patients who developed a SPC 3495 7.15 3116 7.92 379 3.98 Average age at SPC diagnosis (years; mean, SD) 70.57 9.28 70.71 8.94 69.40 11.67 Median age at SPC diagnosis (years; median, range) 71(10–95) 71.5(10–95) 71(12–93) Average interval between primary cancer and SPC 5.23 4.30 5.18 4.29 5.75 4.39 (years; mean, SD) Median interval between primary cancer and SPC 4.17(0.17–0.67) 4.08(0.17–20.67) 4.75(0.17–19.08) (years; median, range) Number of patients by latency between primary cancer and SPC (years) 1 556 15.91 469 12.95 47 16.19 1–4 1409 40.31 1176 39.67 144 40.61 5–9 1000 28.61 813 29.20 106 28.07 ≥10 530 15.16 438 18.18 66 15.12 Number of patients by age at SPC diagnosis (years) 0–39 13 0.37 8 0.26 5 1.32 40–59 396 11.33 327 10.49 69 18.21 ≥60 3086 88.30 2781 89.25 305 80.47 Average follow-up after SPC diagnosis, (years; mean, SD) 2.55 2.91 2.48 2.82 3.10 3.52 Median follow-up after SPC diagnosis (years; median, range) 1.42 20.00(0–20.00) 1.42 20.00(0–20.00) 1.67 19.50(0–19.50) Number of subsequent primary cancers 1 3259 6.67 2896 7.36 363 3.81 2 217 0.44 203 0.52 14 0.15 ≥3 19 0.04 17 0.04 2 0.02 BC: bladder cancer, SD: standard deviation, SPC: second primary cancer Notably, SIR did not increase significantly for total lung cell carcinoma and adenocarcinoma were significantly ele- cancers. However, a subgroup analysis based on lung can- vated (SIR = 1.15; 95% CI 1.02–1.29, and SIR = 1.20; 95% cer histology revealed that the SPC risks of lung squamous CI 1.05–1.37, respectively). By contrast, other lung cancer Kwon et al. BMC Cancer (2018) 18:617 Page 4 of 9 Table 2 Risk of SPC after BC diagnosis by follow-up, age, and period (1993–2013) Total latency (months) Age (years) Period <12 12–59 60–119 ≥120 0–39 40–59 ≥ 60 1993–2000 2001–2013 SIR O/E CI SIR SIR SIR SIR SIR SIR SIR SIR SIR All SPCs 0.94# (3821/4086.59) (0.91–0.97) 1.21# 0.89# 0.92# 0.86# 1.50# 1.04 0.90# 0.85# 0.99 All SPCs excluding BC, KC, 0.96# (3751/3921.87) (0.93–0.99) 1.20# 0.91# 0.95 0.90# 1.36 1.06 0.92# 0.87# 1.01 pelvic and ureteral cancer Buccal cavity, pharynx 0.79 (53/67.09) (0.59–1.03) 0.23# 1.09 0.62 0.76 0 1.03 0.71# 0.68 0.87 Tongue 0.37# (4/10.95) (0.10–0.94) 0 0.43 0.32 0.57 0 0.67 0.26# 0.22 0.47 Salivary gland 0.92 (6/6.51) (0.34–2.01) 0 1.10 1.58 0 0 1.17 0.85 0.76 1.03 Tonsil 0.27# (2/7.32) (0.03–0.99) 0 0.66 0 0 0 0.40 0.21 0 0.44 Hypopharynx 1.19 (19/15.94) (0.72–1.86) 0.49 1.33 0.86 2.01 0 1.69 1.05 1.48 0.98 Digestive system 0.85# (1833/2160.13) (0.81–0.89) 0.81# 0.79# 0.96 0.82# 1.41 0.95 0.81# 0.79# 0.89# Esophagus 0.97 (94/97.04) (0.78–1.19) 0.96 0.96 1.07 0.80 0 1.05 0.95 0.83 1.08 Stomach 0.79# (632/796.08) (0.73–0.86) 0.73# 0.73# 0.87# 0.87 1.47 0.92 0.75# 0.73# 0.84# Small intestine 1.43 (20/14.02) (0.87–2.20) 2.31 1.55 1.22 0.84 0 1.33 1.47 2.13# 0.95 Colon 0.84# (271/321.74) (0.74–0.95) 0.95 0.87 0.86 0.70# 1.72 0.90 0.82# 0.77# 0.88 Rectum, rectosigmoid junction 0.91 (233/255.77) (0.80–1.04) 1.15 0.75# 1.02 0.95 1.59 0.88 0.91 0.82 0.96 Anus, anal canal 0.97 (5/5.15) (0.32–2.27) 1.51 0.46 1.34 1.20 0 2.12 0.72 0.89 1.03 Liver 0.79# (240/304.17) (0.69–0.90) 0.63# 0.74# 0.94 0.79 1.09 0.95 0.71# 0.77# 0.80# Gallbladder 0.77 (43/55.52) (0.56–1.04) 1.18 0.57# 0.86 0.83 0 0.92 0.75 0.71 0.82 Bile ducts, other biliary 0.92 (166/180.66) (0.78–1.07) 0.55# 0.92 1.18 0.73 2.04 0.95 0.91 0.92 0.92 Pancreas 0.98 (122/124.96) (0.81–1.17) 0.67 0.98 1.19 0.82 2.2 1.27 0.90 0.81 1.08 Respiratory system 1.05 (848/807.86) (0.98–1.12) 1.06 1.07 1.01 1.05 0 1.27# 1.01 0.93 1.13# Nose, nasal cavity, ear 1.07 (8/7.51) (0.46–2.10) 2.06 1.57 0.46 0 0 0 1.41 0.62 1.39 Larynx 1.20 (58/48.45) (0.91–1.55) 2.18# 1.09 0.87 1.26 0 1.18 1.21 1.1 1.27 Lung, bronchus 1.05 (782/748.26) (0.97–1.12) 0.98 1.07 1.03 1.06 0 1.30# 1 0.93 1.13# Female breast 1.12 (34/30.38) (0.78–1.56) 1.35 0.72 1.11 1.91 0.90 1.19 1.09 1.70# 0.78 Female genital system 1.10 (33/29.98) (0.76–1.55) 1.71 1.16 0.59 1.33 2.75 0.97 1.07 1.27 0.96 Male genital system 1.45# (513/353.32) (1.33–1.58) 4.04# 1.30# 1.04 0.95 5.18 1.66# 1.41# 1.30# 1.53# Prostate 1.46# (505/346.97) (1.33–1.59) 4.08# 1.31# 1.03 0.95 7.54 1.66# 1.41# 1.32# 1.53# Testis 3.95 (3/0.76) (0.82–11.55) 0 6.05 4.61 0 0 4.17 4.76 0 6.83# Urinary system 0.73# (170/232.70) (0.62–0.85) 2.03# 0.72# 0.42# 0.37# 6.63# 0.89 0.65# 0.61# 0.81# Urinary bladder 0.45# (63/139.70) (0.35–0.58) 1.63# 0.49# 0.12# 0.08# 12.41# 0.46# 0.41# 0.33# 0.54# Kidney parenchyma 1.47# (100/67.98) (1.20–1.79) 3.23# 1.44# 1.04 1.08 4.54# 1.40 1.44# 1.32 1.56# Renal pelvis, other urinary 0.28# (7/25.02) (0.11–0.58) 1.03 0.10# 0.40 0.00# 0 0.90 0.15# 0.43 0.19# Brain, central nervous system 0.76 (16/21.09) (0.43–1.23) 0.38 0.91 0.97 0.28 0 0.56 0.85 0.72 0.79 Thyroid 1.21 (107/88.29) (0.99–1.46) 2.24# 1.29 0.97 0.83 1.08 1.35# 1.09 1.04 1.28# Lymphatic, hematopoietic 0.75# (98/130.52) (0.61–0.92) 1.08 0.64# 0.73 0.83 0.63 0.57# 0.81 0.69# 0.79 Hodgkin lymphoma 0.77 (2/2.58) (0.09–2.80) 3.11 0.92 0 0 0 0 1.15 0.99 0.64 Non-Hodgkin lymphoma 0.69# (47/68.39) (0.50–0.91) 1.21 0.75 0.35# 0.75 1.17 0.43# 0.76 0.64 0.71 Myeloma 0.82 (19/23.27) (0.49–1.28) 1.09 0.64 0.87 0.95 0 0.79 0.83 0.70 0.89 Leukemia 0.82 (32/38.93) (0.56–1.16) 0.84 0.44# 1.31 0.90 0 0.68 0.88 0.78 0.85 SIR: standardized incidence ratio, CI: confidence interval, BC: bladder cancer, SPC: second primary cancer, KC: kidney cancer, O/E: Observed/Expected, # significant at alpha = 0.05 Kwon et al. BMC Cancer (2018) 18:617 Page 5 of 9 histologies (including small cell carcinoma: SIR = 1.06; Discussion 95% CI 0.86–1.28) were not associated with an increased SIRs for cancers that developed after primary BC were SPC risk. Moreover, although not significant, the SIR calculated using KCCR data. Analysis of the data re- increased after one year. SIRs for specific lung cancer vealed that, in the present cohort, BC survivors had a types are shown in Table 3. 6% lower risk of developing a new malignancy compared To estimate the effect of primary BC treatment on with the general population. Cancers of the tongue, ton- SPC risk, we calculated the SIR of the RT, surgery, and sils, digestive system (e.g., stomach, colon, and liver) and chemotherapy groups. For all treatment modalities non-Hodgkin lymphoma were less likely to occur as except RT, the SPC risk was lower than that in comparable SPCs in patients with BC. However, these findings were patients with BC. Effects of treatment on SPC risk are incongruent with those reported previously [4, 5, 11]. summarized in Table 4. While the reasons for reduced SPC risk in the BC At 21 years follow-up, 22,036 of the 48,875 BC patients are unclear, they might be related to smoking patients had died. The 10-year overall survival (OS) rates cessation and lifestyle modification after a BC diagnosis. were 46.2 and 52.6% in the SPC and non-SPC groups, Additionally, these results might, in part, be due to respectively (p = 0.000). The 5- and 15-year OS rates for shared etiologies (genetic background and environment) the SPC group were 72.3 and 28.3%, respectively, and treatment-related factors [12]. whereas those for the non-SPC group were 64.8 and A previous study that evaluated Korean patients with 43.8%, respectively. prostate cancer and kidney cancer using similar methods The survival curves crossed over time. The SPC group revealed SPC SIRs of 0.75 and 1.13, respectively [6, 7]. had higher OS rates compared with the non-SPC group In the present study, the incidences of prostate cancer for the first 8 years, but the OS of the SPC group and kidney cancer were greater. This increased incidence declined thereafter (Fig. 1). After the onset of SPC, might be due to shared etiological, environmental, and women had higher OS rates compared with men (Fig. 2). genetic factors between the first and second malignancies We conducted a subgroup analysis of the patients [13]. Moreover, a surveillance effect might contribute to treated between 2006 and 2013 to analyze any correla- increased risk immediately after diagnosis and might tions between the SPC incidence and OS according to explain the elevated prostate cancer and kidney cancer the SEER stage which were collected since 2006. After risk after primary BC. BC diagnosis, the OS curves of patients with SPC and In a study examining associations between urinary non-SPC group crossed at 2.5 years (Additional file 1: tract cancers, Kinoshita et al. demonstrated that BC Figure S1). Moreover, distant staging in SPC and and prostate cancer share similar traits such as DNA non-SPC groups was estimated at 2.32 and 4.04% of repair and N-acetyl transferase polymorphism [14]. cases, respectively. For patients with a follow-up of Kellen et al. reported that prostate cancer risk in- < 2.5 years, the proportion of distant staging was creases in patients < 70 years old within one year of 5.31% at diagnosis, whereas that in those BC diagnosis [15]. Lococo et al. also reported a sig- followed-up for ≥2.5 years it was 0.8% (p =0.000). nificant increase in the relative risk of kidney cancer Before 2.5 years, the presence of SPC accounted for following BC [16]. 5.38% of distant stage cases in the non-SPC group, In this study, we interestingly found that the risk for and 3.45% of cases in the SPC group (p =0.183). tongue and tonsil cancer significantly decreased in patients Afterwards, the proportions of distant staging were 0.48% with BC, and the result for tongue cancer is significantly in SPC and 0.82% in non-SPC group (p =0.719) lower in those over 60 compared to those aged 40–59. (Additional file 2: Figure S2). Chemical factors like tobacco and alcohol, biological factors Table 3 Risk of SPC by lung cancer histology after BC diagnosis (1993–2013) Latency (months) Total < 12 12–59 60–119 ≥120 SIR (O/E) 95% CI SIR (O/E) SIR (O/E) SIR (O/E) SIR (O/E) Lung, bronchus 1.05 (782/748.26) (0.97–1.12) 0.98 (90/91.90) 1.07 (331/309.19) 1.03 (227/220.22) 1.06 (134/126.96) Squamous cell carcinoma 1.15# (280/243.85) (1.02–1.29) 0.94 (29/30.71) 1.18 (121/102.47) 1.08 (77/71.04) 1.34# (53/39.63) Adenocarcinoma 1.20# (221/183.65) (1.05–1.37) 1.39 (30/21.61) 1.27# (94/74.26) 1.15 (63/54.55) 1.02 (34/33.23) Small cell carcinoma 1.06 (99/93.82) (0.86–1.28) 0.69 (8/11.64) 1.10 (43/39.13) 1.13 (31/27.46) 1.09 (17/15.58) Other and unspecified 0.80# (182/226.95) (0.69–0.93) 0.82 (23/27.95) 0.78# (73/93.32) 0.83 (56/67.16) 0.78 (30/38.51) SPC: second primary cancer, BC: bladder cancer, SIR: standardized incidence ratio, CI: confidence interval, O/E: Observed/Expected # significant at alpha = 0.05 Kwon et al. BMC Cancer (2018) 18:617 Page 6 of 9 Table 4 Risk of SPC according to treatment for primary BC (1993–2013) RT Non-RT Surgery Non-Surgery Chemotherapy Non-chemotherapy SIR SIR SIR SIR SIR SIR All SPCs 1.01 0.93# 0.94# 0.85# 0.94 0.93# All SPCs excluding BC, KC, pelvic and ureteral cancers 1.04 0.96# 0.97# 0.86# 0.94 0.96# Buccal cavity, pharynx 0 0.80 0.83 0.35 0.56 0.82 Tongue 0 0.37# 0.40 0 0.86 0.31# Salivary gland 0 0.94 1.01 0 0 1.03 Tonsil 0 0.28 0.30 0 0 0.31 Hypopharynx 0 1.21 1.30 0 0.59 1.26 Digestive system 0.88 0.85# 0.87# 0.66# 0.78# 0.86# Esophagus 0.60 0.98 0.97 0.95 0.86 0.98 Stomach 0.59 0.80# 0.81# 0.64# 0.71# 0.80# Small intestine 4.18 1.38 1.49 0.79 0.68 1.51 Colon 1.35 0.83# 0.89# 0.39# 1.04 0.82# Rectum, rectosigmoid junction 1.20 0.91 0.91 0.90 0.87 0.92 Anus, anal canal 0 0.99 0.86 1.98 1.86 0.87 Liver 0.98 0.79# 0.80# 0.70 0.73 0.80# Gallbladder 0 0.79 0.78 0.74 0.17# 0.84 Bile ducts, other biliary 0.64 0.92 0.96 0.53 0.91 0.92 Pancreas 1.4 0.97 1.01 0.69 0.62 1.02 Respiratory system 1.16 1.05 1.05 1.01 0.98 1.06 Nose, nasal cavity, ear 7.75 0.95 1.17 0 1.25 1.04 Larynx 0 1.22 1.13 1.90 0.95 1.23 Lung, bronchus 1.18 1.04 1.05 0.97 0.98 1.05 Female breast 0 1.14 1.20 0.34 0.62 1.18 Female genital system 1.50 1.09 1.12 0.93 1.86 1.01 Male genital system 2.23# 1.44# 1.43# 1.74# 1.85# 1.41# Prostate 2.28# 1.44# 1.43# 1.70# 1.83# 1.41# Testis 0 4.02 4.32 0 12.33 2.95 Urinary system 1.03 0.73# 0.69# 1.1 1.28 0.67# Urinary bladder 0 0.46# 0.43# 0.61 1.03 0.38# Kidney parenchyma 2.81 1.45# 1.40# 2.29# 1.98# 1.41# Renal pelvis, other urinary 2.43 0.24# 0.22# 0.90 0.78 0.22# Brain, central nervous system 0 0.77 0.78 0.54 0 0.85 Thyroid 0 1.23# 1.23# 1 1.65 1.16 Lymphatic, hematopoietic 0.46 0.76# 0.76# 0.61 0.52 0.78# Hodgkin lymphoma 0 0.79 0.84 0 3.65 0.43 Non-Hodgkin lymphoma 0 0.70# 0.71# 0.50 0.42 0.72# Myeloma 0 0.83 0.80 1.01 1.66 0.72 Leukemia 1.53 0.81 0.85 0.58 0.00# 0.92 SIR, standardized incidence ratio, RT: radiotherapy, BC: bladder cancer, SPC: second primary cancer, KC: kidney cancer, # significant at alpha = 0.05 like human papillomavirus (HPV), syphilis, oro-dental fac- tongue and tonsil cancer is still unclear. However, we tors, dietary deficiencies, chronic candidiasis and viruses speculated that life style modification (smoking cessa- have been known to be significantly associated with oral tion, diet, and so on) may reduce chance of developing cancer [17]. The mechanism of the declined risk of tongue and tonsil cancer. Kwon et al. BMC Cancer (2018) 18:617 Page 7 of 9 Fig. 1 Kaplan-Meier curve: survival after bladder cancer according to the incidence of second primary cancer (SPC) in all patients Smoking is a well-known risk factor for BC, kidney, that the other cancers were smoking-related and oc- lung, mouth, and pharynx cancers [18] and has been es- curred before the BC diagnosis. timated to cause half of all BC cases in Western coun- The risk of cancer caused by radiation follows the in- tries [19]. In contrast to our hypothesis, the present dividual exposed to radiation and continues to increase study did not show an increase in the number of subse- throughout the individual’s lifetime [20]. Studies evaluat- quent respiratory system malignancies. Therefore, a sub ing the risk of secondary cancers after radiation therapy analysis according to histological lung cancer type was for prostate cancer have shown mixed results [21–23]. performed, showing a significant increase in the inci- Recent meta-analyses have shown that patients who dence of lung squamous cell carcinoma and adenocar- received prostate cancer radiotherapy are more likely to cinoma as SPCs. Possible reasons include potential have a second malignancy of the bladder, colon and etiological or genetic background differences between rectum than patients who have not received radiother- the Western and Asian patients, decreased smoking con- apy [24]. To our knowledge, although no studies have tribution compared with the West, and the possibility reported the risk of secondary cancer after radiation Fig. 2 Kaplan-Meier curve: survival after second cancer according to sex in patients with second cancers Kwon et al. BMC Cancer (2018) 18:617 Page 8 of 9 therapy for bladder cancer, our study showed that which was not relatively long duration. Further studies secondary cancers were more common in the digestive with long follow-up periods will be needed to estimate organs, such as the small intestine, colon, rectum, and the precise risk of developing SPC and to overcome sur- female/male genital systems than patients who do not veillance bias. Fifth, it was impossible to divide into received radiotherapy. We assume that this result is non-muscle invasive cancer and muscle invasive cancer related to the radiation field and is similar to the results in our study. The survival of patients with bladder of the meta-analysis mentioned above [24]. However, the cancer may be affected by degree of muscle invasion. lack of information such as the specific type of radiation treatment and dose of radiation is another limitation of Conclusion this study. The risk is lower among Korean survivors of BC compared To our knowledge, this is the first study to evaluate to the expected risk of developing SPC in the general popu- the histological subtypes of lung cancers as an SPC. lation. However, patients with BC remain at increased risk Cigarette smoking is an established risk factor for lung of some cancers, particularly prostate and kidney, lung cancer, but the severity of its association with other squamous cell carcinoma, and lung adenocarcinoma. histologic types is unclear. Khuder [25, 26] reported that Therefore, longer and closer surveillance could be recom- all histologic lung cancer types were significantly associ- mended for the early detection of SPC. ated with cigarette smoking, and the association was stronger for squamous cell and small cell carcinomas Additional files compared with large cell cancer and adenocarcinoma. In the present study, squamous cell carcinoma and adeno- Additional file 1: Figure S1. Kaplan-Meier curve: survival after bladder cancer (BC) according to the incidence of a second primary cancer (SPC) carcinoma exhibited a significantly elevated risk of in all patients (2006–2013). (TIF 1011 kb) occurring as an SPC. Although not significant, small cell Additional file 2: Figure S2. Stage distributions by bladder cancer lung cancer risk also increased over an extended occurrence and follow-up years. (JPG 184 kb) follow-up period. If smoking is a shared risk factor for BC and secondary lung cancer, the influence of smoking Abbreviations on each histologic type of secondary lung cancer in BC BC: Bladder cancer; CI: Confidence interval; KCCR: Korea Central Cancer Registry; RT: Radiotherapy; SD: Standard deviation; SEER: Surveillance patients might be presumed to be different to that for epidemiology and end results; SIR: Standardized incidence ratio; SPC: Second primary lung cancer. primary cancer Cumulative survival curves of patients with or without Funding SPC were estimated to investigate whether SPC affects the This work was supported by a research grant from the National Cancer survival rate of patients who have BC. In particular, for Center (No. 1610201), Republic of Korea. The National Cancer Center had no the first 8 years, the SPC group had superior survival rates role in the design of the study, or the collection, analysis, and interpretation of data, or the manuscript preparation. compared with the non-SPC group. Overall, this study demonstrated that patients in the non-SPC group had sig- Availability of data and materials nificantly more advanced BC at the time of diagnosis. All data generated or analyzed during this study are included in this published article. Therefore, the survival rate of the non-SPC group was lower than that of the SPC group for the first 2.5 years Authors’ contributions after diagnosis of BC. Conversely, after 2.5 years the Conception and design: YJW, WAK, JYJ. Acquisition of data: YJW, CMO, KWJ. reverse was noted with survival in the SPC group being Analysis of data: JL, YJW. Drafting of the manuscript: WAK, JYJ, JL, YJW. Critical revision and final approval of the manuscript: All authors read and inferior to that in the non-SPC group. These findings sug- approved the final manuscript. gested that the SPC group would require more attentive and systemic surveillance after 2.5 years of follow-up. Ethics approval and consent to participate Ethical approval for the research protocol was provided by the institutional The present study has several limitations. First, infor- review board of the National Cancer Center (NCC2017–-0182). mation concerning several potential confounding vari- Information was de-identified prior to analysis. The authorization for data ables including smoking, alcohol consumption, obesity, processing was obtained from the National Cancer Act. and familial cancer history were not available. Second, Competing interests there was limited data available concerning genetic The authors declare that they have no competing interests. factors and specific cancer stages among the patients, making it impossible to evaluate the correlation between Publisher’sNote disease severity and SPC incidence. Third, the higher in- Springer Nature remains neutral with regard to jurisdictional claims in cidence of SPC might be associated with close surveil- published maps and institutional affiliations. lance or misclassifications because BC, prostate cancer, Author details and kidney cancer often develop synchronously [15, 16]. 1 2 Center for Prostate Cancer, National Cancer Center, Goyang, Korea. Cancer Fourth, the median follow-up period was 4.13 years, Registration and Statistics Branch, National Cancer Center, Goyang, Korea. Kwon et al. BMC Cancer (2018) 18:617 Page 9 of 9 Received: 28 September 2017 Accepted: 18 May 2018 23. 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Journal

BMC CancerSpringer Journals

Published: May 31, 2018

References

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