Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries

ARTICLE IN PRESS Cancer Letters ■■ (2015) ■■–■■

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Original Articles

Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries Tianhui Chen a,*, Mahdi Fallah a, Lina Jansen b, Felipe A. Castro b, Agne Krilavicuite b, Alexander Katalinic c, Nora Eisemann c, Katharina Emrich d, Bernd Holleczek e, Karla Geiss f, Andrea Eberle g, Jan Sundquist h,i, Hermann Brenner b,j,k, Kari Hemminki a,h for the GEKID Cancer Survival Working Group 1 a

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany Institute of Cancer Epidemiology, University of Lübeck, Lübeck, Germany d Cancer Registry of Rhineland-Palatinate, Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center, Johannes Gutenberg, Germany e Saarland Cancer Registry, Saarbrüken, Germany f Bayern Cancer Registry, Munich, Germany g Cancer Registry of Bremen, Leibniz-Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany h Center for Primary Health Care Research, Lund University, Malmö, Sweden i Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA 94305-5705, USA j Division of Preventive Oncology, German Cancer Research Center, Heidelberg, Germany k German Cancer Consortium (DKTK), Heidelberg, Germany b c

A R T I C L E

I N F O

Article history: Received 10 June 2015 Received in revised form 17 August 2015 Accepted 17 August 2015 Keywords: Second primary cancers Cancer registry Standardized incidence ratios Discordant cancer Age at diagnosis

A B S T R A C T

We aimed at investigating the distribution and risk of all second discordant primary cancers (SDPCs) after a specific first primary cancer in Germany and Sweden to provide etiological understanding of SDPCs and insight into their incidence rates and recording practices. Among 1,537,004 survivors of first primary cancers in Germany and 588,103 in Sweden, overall 80,162 and 32,544 SDPCs were recorded, respectively. Standardized incidence ratios (SIRs) of all SDPCs were elevated at levels between 1.1 and 2.1 after 23 (out of overall 29) cancers in Germany and at levels between 1.1 and 1.6 after 24 cancers in Sweden, and among them, elevated SIRs were found after 19 cancers in both populations. Decreased SIRs at levels ranging from 0.5 to 0.9 were found for some cancers with poor prognosis in Germany only. We found elevated risk after 19 out of 29 cancers in both countries, suggesting common etiology of SDPCs after most of first cancers and registration similarity. Decreased risks after some fatal cancers were found only in Germany, which may be attributed to reporting practices or missed death data in Germany. © 2015 Elsevier Ireland Ltd. All rights reserved.

Introduction Second primary cancers (SPCs) have become a long-term outcome with increasing importance because of their steadily growing numbers as a result of continued improvement in early detection, treatment, and supportive care [1]. For instance, the total number of SPCs accounted approximately for one sixth of all cancers reported to the US Surveillance, Epidemiology, and End Results (SEER)

Abbreviations: SDPCs, second discordant primary cancers; SIRs, standardized incidence ratios; ICD, International Classification of Diseases; FCD, Family-Cancer Database. * Corresponding author. Tel.: +49 6221 421805; fax: +49 6221 421810. E-mail address: [email protected] (T. Chen). 1 Members of the GEKID Cancer Survival Working Group are listed in the Acknowledgement.

program in 2012 [1], while this number reached one fifth of all registered cancers in Sweden in 2012 [2]. SPC can be classified as second concordant primary cancer (the same type of cancer as first cancer, e.g., newly diagnosed left breast cancer after right breast cancer) and second discordant primary cancer (SDPC, e.g., newly diagnosed breast cancer after melanoma). Carcinogenesis of SPCs is a complex process as many risk factors could contribute to the etiology, including intensive medical surveillance after the diagnosis of the first primary cancer, therapy effect of first cancer, shared genetic or lifestyle factors between first cancer and SPC, or interactions among aforementioned factors [3,4]. Numerous studies on SPCs have been published, originating from the Nordic cancer registries (e.g., Sweden), the US SEER Program, and the International Agency for Research on Cancer (IARC) coordinated collaborations [5–7]. Although recent European studies showed steady increases in survival and incidence rates for cancer patients,

http://dx.doi.org/10.1016/j.canlet.2015.08.014 0304-3835/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

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persistent difference between countries has been reported despite general improvement in overall cancer treatment (though detailed treatment information is commonly absent in populationbased cancer registries) [8–12], which may influence SPC rates in different populations. Nevertheless, to our knowledge, investigations on the risk of SPCs after first primary cancers in different populations have not been reported. Additionally, the distribution of all SPCs combined after a specific first primary cancers has also not been reported, though our group has reported the distribution of five most common SPCs after ten common first cancers in the present populations [13]. We aimed at investigating the distribution and risk of all SDPCs combined (except for non-melanoma skin cancer) after a specific first primary cancer in the two populations, using the pooled database from 12 German cancer registries [14] and the nationwide Swedish Family-Cancer Database (FCD) [15]. While investigations on the distribution of all SPCs combined in different populations may provide an overall picture on SPCs, investigations on the risk of all SDPCs combined after a specific first primary cancer in two populations may provide insight into the epidemiology, etiology and registration practices of SDPCs in different populations. The findings may validate the use of data on SPCs in etiological studies, particularly regarding side effects of treatment when therapies are changing.

(except non-melanoma skin cancer) in the Swedish and German general populations, respectively, multiplied by the corresponding person-years in survivors of first primary cancer. Person-years at risk were accumulated for each patient, starting from the date of diagnosis of the first primary cancer (diagnosed from 1997 to 2010), and terminating on the date of SDPCs of any type, date of death, date of emigration, or December 31, 2010 (end of the study), whichever came earliest. All SIRs for Germany and Sweden were adjusted for three identical variables [sex, age (5-year bands), and calendar period (1995–2000, 2001–2005, and 2006–2010)] and a regional category (12 states in Germany and 4 categories in Sweden). The 95% confidence intervals (CIs) for SIRs were calculated assuming that the cases followed a Poisson distribution. Statistical significance for SIRs higher or lower than 1.00 was assessed by whether or not the 95% CIs for those SIRs included 1.00. Further analyses were stratified by characteristics of cancer patients [sex, age at diagnosis of first cancer (<65 years, 65–74, and ≥75 years), and follow-up time after first cancer (<1 year, 1–4, and ≥5 years)]. In order to avoid chance findings, we set up rules for showing results. Only cancer sites with a total number of all SDPCs ≥100 in both countries are presented in tables. Additionally, sensitivity analyses restricted to eight (out of 12 in total) German cancer registries with full follow-up period 1997–2010 were conducted because four German registries started cancer registration later than 1997, i.e., Lower Saxony in 2003, Schleswig–Holstein in 1999, and Bremen and Rhineland-Palatinate in 1998. SAS software (version 9.3, SAS Institute Inc., Cary, NC) was used for the data analyses. Data collection within the German PopulationBased Cancer Registries was carried out according to state cancer registry laws and only completely anonymous data transferred from the cancer registries were analyzed, while although the data in the Swedish Family-Cancer Database were completely anonymous and their use did not entail ethical problems either, ethical approval by the Institutional Review Board, Karolinska Institute was obtained.

Results

Materials and methods German data Details on the pooled German database were described elsewhere [14]. Briefly, data were originally collected from cancer registries covering 13 of 16 German federal states. According to the criteria related to data quality, e.g., cancer patients who had a Death Certificate or autopsy only (DCO) cancer were all excluded [14]. Finally, data from 12 cancer registries, covering a population of 26.7 million people (33% of the total German population), were retained in the pooled German database for further analyses [14]. According to the rules set up by the IARC [16], Germany cancer registries did not systematically register tumors occurring at the same organ or at the contralateral organ for SPCs; non-melanoma skin cancers were not collected. Therefore, second cancers in this study were only limited to second discordant primary cancers of any type except non-melanoma skin cancer (simply called SDPCs). Cancers were recorded according to the International Classification of Diseases, 10th version (ICD-10) [16], and the percentage of microscopically verified cancer diagnosis was larger than 95% in all registries [14]. Patients with a primary malignant tumor diagnosed in 1997–2010 at age ≥15 years and with follow-up information until the end of December 2010 were included in the current analyses. Swedish data Swedish FCD2010 (updated in 2013) was used for the current study and its details were described elsewhere [15]. For comparability and consistency, same criteria for German data were adopted for Swedish data, e.g., the definition of primary cancers was recorded and restricted to the study period 1997–2010; cancer DCO cases were excluded and only SDPC (second concordant cancers and non-melanoma skin cancers were excluded) cases diagnosed in 1997–2010 at age ≥15 years were selected. Briefly, we used all first primary cancer (except non-melanoma skin cancers) patients diagnosed 1997–2010, covering approximately 9 million Swedish population. Information on cancer cases was retrieved from the Swedish Cancer Registry for the years 1997–2010, relying on separate compulsory notifications from clinicians, pathologists and cytologists [17]; cancers during the study period were recorded according to both International Classification of Diseases, 7th version (ICD-7) and ICD-10 codes. The Swedish Cancer Registry only records primary cancers. Metastasized cancers to other sites were only registered at primary sites; for multiple primary cancers occurring in the same organ or same organ system, only clearly separated malignancies were accepted as multiple primaries and were registered [18]. Close to 100% of the registered neoplasms were histologically verified and approximately 98% of second neoplasms were correctly verified according to a reevaluation study of 209 multiple primary tumors [17]. Statistical analyses For both German and Swedish datasets, standardized incidence ratio (SIR), calculated as the ratio of observed to expected numbers of cases, was used to assess the risk of all SDPCs combined after a specific first primary cancer. The expected numbers of all SDPCs combined after a specific first primary cancer were calculated from the strata-specific incidence rate of the combination of first primary cancers

Distribution of all SDPCs after a specific first primary cancer in the two populations The distribution of all SDPCs after a specific first primary cancer is presented in Table 1. We found 80,162 SDPCs in Germany and 32,544 in Sweden. Overall, the frequency ranking order of all SDPCs after a specific first primary cancer was similar in Germany and Sweden, i.e., the ranking order of the four most frequent SDPCs was identical in Germany and Sweden in the sequence of prostate, colorectal, breast and urinary bladder cancers, while the ranking order after other cancers was generally similar, except for nervous system cancer (27th versus 12th) and unknown primary cancer (21st versus 15th). The total number of any first primary cancers (except non-melanoma skin cancer) diagnosed at age ≥15 years during the 1997–2010 period was 1,537,004 in Germany and 588,103 in Sweden (Table A1). Among them, the percentages for unknown primary, nervous system and non-thyroid endocrine cancers were low in Germany with 1.9% (28,418), 1.4% (20,872) and 0.1% (850), respectively, while in Sweden these were 3.5% (20,287), 2.8% (16,371) and 1.4% (8402), respectively. The percentages of other cancers were rather similar between Germany and Sweden (Table A1). The relationship of frequency (percentage and rank) between first primary cancer and all SDPCs combined after a specific first cancer in Germany and Sweden is presented in Table A2. The percentage for first primary cancer was generally similar to the percentage for all SDPCs combined after the same first cancer in both countries, with exceptions for fatal cancers (liver and gallbladder, pancreatic, lung, nervous system and unknown primary cancers), for which the percentages were halved. SIRs of all SDPCs after a specific first primary cancer in the two populations The overall SIRs of all SDPCs after a specific first primary cancer and the stratification by sex are presented in Table 2. We found that SIRs of all SDPCs were elevated at levels between 1.1 and 2.1 after 23 (out of overall 29) cancers in Germany and at levels between 1.1 and 1.6 after 24 cancers in Sweden, and among them, SIRs after 19 cancers were elevated in both Germany and Sweden. It shall be noted that elevated overall SIR reached ≥2.0-fold in Germany after urinary

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

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Table 1 Distribution of all SDPCs after a specific first primary cancer in Germany and Sweden. Sites of first primary cancers

Prostate Colorectum Breast Urinary bladder Kidney Upper aerodigestive tract Lung Melanoma Endometrium Non-Hodgkin lymphoma Stomach Leukemia Ovary Esophagus Cervix uteri Liver and gallbladder Thyroid glands Connective tissue Multiple myeloma Pancreas Unknown primary Other female genital Anus Small intestine Hodgkin lymphoma Other male genital Nervous system Eye Salivary glands Totala

N

Rankb,c

% of total

Germany

Sweden

Germany

Sweden

Germany

Sweden

13,545 11,583 8738 7329 4780 4684 4295 3136 2988 2686 2555 1743 1459 1116 1081 982 910 786 752 683 667 611 365 357 324 232 230 229 221 80,162

7317 4022 3850 3353 1123 950 1063 1673 1348 1244 446 1051 488 151 307 269 240 258 349 127 418 146 111 241 106 110 644 107 110 32,544

16.9 14.4 10.9 9.1 6.0 5.8 5.4 3.9 3.7 3.4 3.2 2.2 1.8 1.4 1.3 1.2 1.1 1.0 0.9 0.9 0.8 0.8 0.5 0.4 0.4 0.3 0.3 0.3 0.3 100

22.5 12.4 11.8 10.3 3.5 2.9 3.3 5.1 4.1 3.8 1.4 3.2 1.5 0.5 0.9 0.8 0.7 0.8 1.1 0.4 1.3 0.4 0.3 0.7 0.3 0.3 2.0 0.3 0.3 100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

1 2 3 4 8 11 9 5 6 7 14 10 13 22 17 18 21 19 16 24 15 23 25 20 28 29 12 27 26

SDPC: second discordant primary cancer. Only cancer sites with a total number of all SDPCs ≥100 in both countries are presented. a Total number included the cancer sites not presented (all SDPCs <100). b Frequency rank. c There was no significant difference in rank between Germany and Sweden assessed by Wilcoxon’s two-sample test.

bladder cancer (2.1) and upper aerodigestive tract cancer (2.0), while it was slightly elevated in Sweden (1.3 and 1.2, respectively). Decreased SIRs at levels ranging from 0.5 to 0.9 were found for five cancers with poor prognosis (pancreatic, lung, nervous system and unknown primary cancers, and multiple myeloma) in Germany only. Additionally, SIRs of all SDPCs after most of first cancers were similar between men and women in both countries, with three exceptions, i.e., higher SIR in men than in women was found after urinary bladder cancer in Germany (2.3 for men versus 1.3 for women) and in Sweden (1.4 for men versus 1.2 for women), while lower SIR in men than in women was found only in Germany after lung cancer (0.9 versus 1.1) and connective tissue cancer (1.2 versus 1.7). We further stratified our analyses by calendar period (1997– 2003 and 2004–2010), which is presented in Table 3. SIRs of all SDPCs after 18 of first cancers (29 in total) were higher in early period (1997–2003) compared to late period (2004–2010) in Germany, while in Sweden SIRs for six cancers (esophageal, stomach, colorectal, pancreatic, lung, and unknown primary cancers) were higher in late period compared to early period. We observed a declining trend of SIRs along with increasing age at diagnosis after most of first cancers in Germany and after a few first cancers in Sweden (Table 4). Decreased SIRs at levels ranging from 0.3 to 0.9 were found only in Germany, i.e., for diagnosis age <65 years after nervous system cancer, for diagnosis age at 65–74 years after four fatal cancers (pancreatic, lung and nervous system cancers, and multiple myeloma), and for diagnosis age ≥75 years after eight fatal cancers (stomach, liver and gallbladder, pancreatic, lung, nervous system and unknown primary cancers, multiple myeloma and leukemia).

The SIRs stratified by follow-up time after first primary cancer (<1 year, 1–4, and ≥5 years) are presented in Table 5. While a tendency of deceasing SIR along with prolonged follow-up time was observed after the majority of first cancers in both Germany and Sweden, we found elevated SIR (≥1.5-fold) for ≥5 years’ follow-up in Germany after upper aerodigestive tract cancer (1.9), Hodgkin lymphoma (1.8) and thyroid cancer (1.5) and in Sweden after esophageal cancer (1.6). Additionally, SIRs for <1 year follow-up were elevated at levels between 1.2 and 4.0 after 21 cancers in Germany and at levels between 1.4 and 2.5 after 15 cancers in Sweden. Nevertheless, decreased SIRs at levels ranging from 0.4 to 0.9 were found in Germany throughout follow-up time after some fatal cancers (for <1 year follow-up after three fatal cancers, for 1–4 year follow-up after six fatal cancers, and for ≥5 years follow-up after one fatal cancer), while decreased SIRs at a level of 0.8 were found in Sweden for <1 year follow-up only after both breast cancer and melanoma (Table 5). Additionally, sensitivity analyses restricted to eight (out of 12 in total) German cancer registries with full follow-up period 1997– 2010 did not essentially change our results (Tables A3–A6), we therefore reported data based on 12 German cancer registries to ensure larger sample size. Discussion At the onset of investigations on the SPC rates in two populations, some basic demographic and epidemiological data should be known. Firstly, overall, life expectancy is a relevant parameter. Life expectancy in 2010 for men generally was 77.5 years in Germany

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

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Sites of first primary cancers

Germany

Sweden

Men

Overall

Men

Women

Overall

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

3927 140 920 1695 196 7203 146 597 389 3311 134 0 0 0 0 13545 232 3402 6483 1823 131 138 301 474 1626 193 470 1206 394

2.0 1.6 1.8 1.1 1.7 1.1 1.8 0.9 0.7 0.9 1.1

(1.9–2.1) (1.3–1.9) (1.7–1.9) (1.1–1.2) (1.4–1.9) (1.0–1.1) (1.5–2.1) (0.8–1.0) (0.6–0.8) (0.9–0.9) (0.9–1.3)

2.0 1.6 2.0 1.2 2.2 1.2 1.8 1.1 0.8 1.1 1.2 1.8 1.5 1.6 1.4

(1.9–2.2) (1.3–2.0) (1.8–2.3) (1.1–1.3) (1.9–2.6) (1.1–1.2) (1.5–2.0) (1.0–1.2) (0.7–0.9) (1.0–1.2) (1.1–1.2) (1.7–1.9) (1.4–1.5) (1.6–1.7) (1.3–1.6)

2.0 1.6 1.9 1.1 1.9 1.1 1.8 1.0 0.7 0.9 1.2 1.8 1.5 1.6 1.4 1.1 1.4 1.5 2.1 1.2 1.4 0.5 1.5 1.3 1.2 1.7 0.9 1.1 0.9

(1.9–2.1) (1.4–1.8) (1.7–2.0) (1.1–1.2) (1.7–2.1) (1.1–1.1) (1.6–2.0) (0.9–1.0) (0.7–0.8) (0.9–1.0) (1.1–1.2) (1.7–1.9) (1.4–1.5) (1.6–1.7) (1.3–1.6) (1.0–1.1) (1.2–1.6) (1.4–1.5) (2.0–2.1) (1.2–1.3) (1.2–1.6) (0.4–0.6) (1.4–1.6) (1.2–1.4) (1.2–1.2) (1.5–1.9) (0.8–0.9) (1.0–1.1) (0.8–1.0)

705 62 114 278 145 2392 43 157 61 640 52 0 0 0 0 7316 104 724 2767 967 53 281 83 166 743 58 208 627 200

(1.1–1.3) (1.1–1.8) (1.2–1.8) (1.0–1.3) (1.2–1.7) (1.1–1.2) (0.8–1.4) (1.3–1.8) (0.7–1.2) (1.2–1.3) (0.8–1.5)

(1.0–1.3) (0.9–1.7) (1.4–2.7) (1.0–1.4) (1.4–2.2) (1.1–1.2) (0.7–1.1) (1.2–1.7) (1.0–1.6) (1.2–1.5) (1.0–1.1) (1.1–1.4) (1.1–1.3) (1.2–1.4) (1.0–1.4)

1.1 1.3 1.4 1.4 1.1 1.1 1.1 1.2 1.3 1.2 1.0 1.3 1.2 1.3

(1.1–1.1) (1.1–1.6) (1.3–1.5) (1.3–1.4) (1.0–1.2) (0.8–1.4) (1.0–1.2) (1.0–1.5) (1.1–1.5) (1.1–1.2) (0.8–1.3) (1.1–1.5) (1.1–1.3) (1.1–1.4)

245 48 37 168 96 1630 68 112 66 423 3797 307 1348 488 146 0 0 399 586 705 54 363 157 92 500 48 141 424 218

1.2 1.2 1.9 1.2 1.8 1.1 0.9 1.4 1.3 1.4 1.1 1.3 1.2 1.3 1.2

(1.0–1.1) (1.2–1.6) (1.5–1.6) (2.2–2.3) (1.1–1.2) (1.1–1.6) (0.4–0.6) (1.2–1.6) (1.1–1.3) (1.1–1.3) (1.4–1.8) (0.8–1.0) (1.1–1.2) (0.8–1.0)

4684 221 1116 2555 357 11,583 365 982 683 4295 8738 1081 2988 1459 611 13,545 232 4780 7329 3136 229 230 910 786 2686 324 752 1743 667

1.2 1.4 1.5 1.2 1.5 1.1 1.1 1.5 0.9 1.2 1.1

1.1 1.4 1.5 2.3 1.2 1.3 0.5 1.4 1.2 1.2 1.6 0.9 1.1 0.9

757 81 196 860 161 4380 219 385 294 984 8604 1081 2988 1459 611 0 0 1378 846 1313 98 92 609 312 1060 131 282 537 273

1.4 1.2 1.1 1.3 1.1 1.3 1.1 1.1 1.1 1.3 1.1 1.4

(1.2–1.5) (1.1–1.3) (1.0–1.1) (1.0–1.7) (1.0–1.2) (1.1–1.5) (0.9–1.4) (1.0–1.2) (0.8–1.4) (1.1–1.5) (1.0–1.2) (1.2–1.5)

950 110 151 446 241 4022 111 269 127 1063 3849 307 1348 488 146 7316 104 1123 3353 1672 107 644 240 258 1243 106 349 1051 418

1.2 1.3 1.6 1.2 1.6 1.1 1.0 1.5 1.1 1.3 1.1 1.3 1.2 1.3 1.2 1.1 1.3 1.4 1.3 1.1 1.2 1.1 1.2 1.2 1.1 1.0 1.3 1.1 1.3

(1.1–1.3) (1.1–1.6) (1.3–1.8) (1.1–1.3) (1.4–1.8) (1.1–1.2) (0.8–1.1) (1.3–1.7) (0.9–1.3) (1.2–1.4) (1.0–1.1) (1.1–1.4) (1.1–1.3) (1.2–1.4) (1.0–1.4) (1.1–1.1) (1.1–1.6) (1.3–1.5) (1.3–1.4) (1.0–1.1) (1.0–1.4) (1.0–1.2) (1.1–1.4) (1.1–1.4) (1.1–1.2) (0.8–1.2) (1.2–1.4) (1.1–1.2) (1.2–1.4)

1.4 1.3 1.3 1.5 0.5 1.5 1.7 1.2 1.9 0.9 1.0 0.9

(1.3–1.4) (1.2–1.4) (1.2–1.3) (1.3–1.9) (0.4–0.7) (1.4–1.6) (1.5–1.8) (1.1–1.3) (1.6–2.2) (0.8–1.0) (0.9–1.1) (0.8–1.0)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

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Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

Women

T. Chen et al./Cancer Letters ■■ (2015) ■■–■■

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Table 2 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer in Germany and Sweden; for overall and by sex.

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Table 3 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer by calendar period (1997–2003 and 2004–2010) in Germany and Sweden. Sites of first primary cancers

Germany

Sweden

1997–2003

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

2004–2010

1997–2003

2004–2010

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

1171 52 287 760 82 2804 91 287 202 1253 1836 308 808 493 154 2631 63 1273 2040 610 71 73 213 220 602 51 193 380 174

2.8 2.1 2.4 1.6 2.9 1.6 2.6 1.3 1.0 1.2 1.5 2.5 2.3 2.7 2.1 1.6 2.5 2.3 3.1 1.7 2.5 0.8 2.1 2.0 1.6 1.6 1.2 1.4 1.1

(2.7–3.0) (1.6–2.7) (2.1–2.7) (1.5–1.7) (2.3–3.6) (1.5–1.6) (2.1–3.2) (1.2–1.5) (0.9–1.2) (1.2–1.3) (1.5–1.6) (2.2–2.8) (2.2–2.5) (2.5–2.9) (1.8–2.5) (1.5–1.6) (1.9–3.2) (2.1–2.4) (2.9–3.2) (1.6–1.9) (1.9–3.1) (0.6–1.0) (1.9–2.5) (1.8–2.3) (1.5–1.8) (1.2–2.1) (1.1–1.4) (1.2–1.5) (0.9–1.2)

2102 107 675 1202 215 5332 192 552 419 2248 3493 415 1264 669 321 6610 102 2043 3859 1428 91 103 331 412 1234 144 350 825 388

2.2 2.0 2.2 1.2 2.3 1.2 2.2 1.1 0.8 1.0 1.2 2.2 1.8 1.9 1.7 1.2 1.3 1.7 2.9 1.3 1.3 0.5 1.5 1.6 1.3 2.1 0.9 1.2 1.1

(2.1–2.3) (1.6–2.4) (2.1–2.4) (1.2–1.3) (2.0–2.7) (1.2–1.2) (1.9–2.5) (1.0–1.2) (0.8–0.9) (1.0–1.1) (1.2–1.3) (2.0–2.4) (1.7–1.9) (1.8–2.1) (1.5–1.9) (1.1–1.2) (1.1–1.6) (1.6–1.8) (2.8–2.9) (1.2–1.4) (1.0–1.6) (0.4–0.6) (1.3–1.6) (1.4–1.7) (1.2–1.3) (1.7–2.4) (0.8–1.0) (1.1–1.3) (1.0–1.2)

280 41 63 169 95 1210 26 135 49 392 994 96 430 182 44 2097 39 376 1082 429 35 181 73 86 374 23 124 334 169

1.0 1.6 1.0 1.0 1.4 1.0 1.0 1.2 0.6 1.0 1.0 1.3 1.3 1.4 1.1 1.0 1.3 1.4 1.3 1.0 1.3 1.0 1.3 1.1 1.1 1.3 1.0 1.1 0.9

(0.9–1.2) (1.1–2.1) (0.8–1.3) (0.8–1.1) (1.2–1.7) (1.0–1.1) (0.7–1.5) (1.0–1.4) (0.5–0.8) (0.9–1.1) (1.0–1.1) (1.1–1.6) (1.2–1.4) (1.2–1.6) (0.8–1.5) (1.0–1.1) (0.9–1.8) (1.3–1.6) (1.3–1.4) (0.9–1.1) (0.9–1.7) (0.8–1.1) (1.0–1.6) (0.9–1.4) (1.0–1.2) (0.8–1.9) (0.9–1.2) (1.0–1.2) (0.8–1.1)

337 32 58 151 86 1442 34 100 54 448 1131 99 428 143 58 2709 28 449 1313 548 36 189 68 85 414 30 124 372 159

1.2 1.3 1.8 1.5 1.7 1.3 1.3 1.6 2.1 1.6 1.1 1.4 1.3 1.3 1.3 1.1 1.2 1.5 1.5 1.1 1.3 1.1 1.3 1.4 1.2 1.2 1.3 1.1 1.8

(1.1–1.4) (0.9–1.9) (1.4–2.4) (1.2–1.7) (1.3–2.1) (1.2–1.4) (0.9–1.8) (1.3–2.0) (1.6–2.7) (1.4–1.7) (1.1–1.2) (1.1–1.7) (1.2–1.4) (1.1–1.6) (1.0–1.7) (1.1–1.2) (0.8–1.7) (1.4–1.6) (1.4–1.6) (1.0–1.2) (0.9–1.8) (1.0–1.3) (1.0–1.7) (1.1–1.7) (1.1–1.3) (0.8–1.7) (1.1–1.6) (1.0–1.3) (1.5–2.1)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

versus 79.2 years in Sweden, while for women it reached 82.8 years in Germany versus 83.5 years in Sweden [19]. Thus, life expectancy was similar in the two populations. Secondly, the incidence rate of first primary cancer may influence the SPC rates in the two populations. Age-standardized incidence rate (European standard) in 2012 for men was higher (483 per 100,000) in Germany than in Sweden (428 per 100,000), while for women it was similar (344 in Germany versus 346 per 100,000 in Sweden) [11]. Smoking-related cancers could largely explain the higher incidence rate for German men compared to Swedish men. Thirdly, the survival rate of first primary cancer may influence the SPC rates in the two populations because the survival rate in the 1995–1999 period for most cancers is commonly lower in Germany compared to Sweden; e.g., for all malignant neoplasms, age-standardized 5-year relative survival in 1995– 1999 reached 52% in Germany and 58% in Sweden, while for multiple myeloma, it reached 30% in Germany and 40% in Sweden [20]. Nevertheless, age-standardized 5-year relative survival rate increased recently, reaching 61% for German men in 2010 versus 70% for Swedish men for the 2009–2012 period, while it was 67% for women in both countries in the related periods [12]. The male difference was largely contributed by the high prevalence of lung cancer in Germany, e.g., the percentage of first primary lung cancer was 10.6% in Germany, while it was 7.4% in Sweden (Table A1). We found elevated overall risks after 23 cancers (out of 29 cancers in total) in Germany and after 24 cancers in Sweden, which is principally consistent with previous reports on the risk of a second primary cancer after a concordant or discordant cancer in a single country [21–23]. Our findings of similar distribution of all SDPCs after any specific first cancer and of elevated risks after 19 cancers in both populations may suggest common etiology of SDPCs after most of first primary cancers and similar registration practices for those cancers in the two populations. Our finding of elevated higher

risk of SDPCs after urinary bladder cancer (2.1 versus 1.3) and upper aerodigestive tract cancer (2.0 versus 1.2) in Germany compared to Sweden is in line with the higher incidence rate of smokingrelated cancers (upper aerodigestive tract and urinary bladder cancers) for German men compared to Swedish men. Although survival estimates might increase during the study period and observed cases will increase, the reference rate (the incidence rate of the combination of first primary cancers in the Swedish and German general population, respectively) might also change during the study period. Thus, SIRs of all SDPCs combined might change in another direction during the study period, which may partially explain our analyses stratified by calendar period (Table 3). We found decreased overall SIRs at levels ranging from 0.5 to 0.9 only in Germany after five fatal cancers (Table 2), which may be largely attributed to reporting practices in Germany as SIRs below 1.0 generally imply underreporting. Nevertheless, SIRs below 1.0 could also be a medical care problem because in the presence of a severe first primary cancer with poor prognosis, especially before 2000 in Germany [20,24], no diagnostics for other SPCs could be made in fatal cancers in Germany. Furthermore, missed deaths data could also contribute to SIR < 1.0. Additionally, we found that the number of all SDPCs was small after nervous system tumors (0.3% of all SDPCs in Germany versus 2.0% in Sweden; Table 1), which may appear to be underreporting of first primary nervous system tumors (Table A1) because those cancers may include benign tumors. The etiology of an individual SPC is already very complex and has not been explicitly known because many risk factors could contribute, e.g., characteristics of cancer patients such as genetic predisposition to both first cancer and an SPC and shared lifestyle risk factors (e.g., smoking), as suggested by other studies [21,22]. Intensive medical surveillance after first primary cancer could be another reason, as suggested by our data for <1-year follow-up

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

6

Sites of first primary cancers

Germany

Sweden

<65 years

<65 years

≥75 years

65–74 years

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

2748 100 581 741 142 3125 164 311 265 1555 3698 659 1086 755 208 2763 78 1757 1739 1293 86 131 517 344 1006 204 245 598 311

2.6 2.3 2.9 1.5 2.4 1.3 2.4 1.5 1.3 1.3 1.3 1.9 1.7 2.2 2.0 1.1 1.5 1.6 2.6 1.3 1.7 0.7 1.5 2.1 1.4 2.1 1.1 1.3 1.8

(2.5–2.7) (1.9–2.8) (2.7–3.2) (1.4–1.6) (2.0–2.8) (1.2–1.3) (2.0–2.7) (1.4–1.7) (1.2–1.5) (1.3–1.4) (1.3–1.3) (1.8–2.1) (1.6–1.8) (2.0–2.3) (1.8–2.3) (1.0–1.1) (1.2–1.9) (1.6–1.7) (2.5–2.7) (1.2–1.4) (1.4–2.1) (0.6–0.9) (1.4–1.7) (1.9–2.3) (1.3–1.5) (1.8–2.4) (1.0–1.2) (1.2–1.4) (1.6–2.0)

1493 71 391 1008 137 4753 110 389 266 1892 2868 250 1184 418 192 6866 106 1990 3322 1130 94 68 271 253 1017 78 305 710 236

1.7 1.5 1.5 1.2 1.8 1.1 1.6 0.9 0.7 0.9 1.2 1.7 1.6 1.4 1.4 1.1 1.6 1.4 2.3 1.2 1.5 0.4 1.4 1.1 1.2 1.3 0.9 1.1 0.9

(1.6–1.8) (1.2–2.0) (1.4–1.7) (1.1–1.2) (1.5–2.1) (1.1–1.1) (1.3–1.9) (0.8–1.0) (0.6–0.8) (0.9–1.0) (1.1–1.2) (1.5–1.9) (1.5–1.6) (1.2–1.5) (1.2–1.6) (1.0–1.1) (1.3–1.9) (1.4–1.5) (2.2–2.4) (1.2–1.3) (1.2–1.8) (0.3–0.5) (1.3–1.6) (1.0–1.2) (1.1–1.3) (1.1–1.7) (0.8–1.0) (1.0–1.2) (0.8–1.0)

443 50 144 806 78 3705 91 282 152 848 2172 172 718 286 211 3916 48 1033 2268 713 49 31 122 189 663 42 202 435 120

1.1 1.0 1.0 0.9 1.4 1.0 1.4 0.7 0.4 0.6 1.0 1.4 1.2 1.2 1.1 1.1 0.9 1.3 1.6 1.1 1.0 0.3 1.3 1.0 1.0 1.3 0.7 0.9 0.4

(1.0–1.2) (0.7–1.3) (0.8–1.2) (0.8–0.9) (1.1–1.8) (0.9–1.0) (1.1–1.7) (0.6–0.8) (0.4–0.5) (0.6–0.7) (1.0–1.0) (1.2–1.6) (1.1–1.3) (1.1–1.3) (1.0–1.3) (1.0–1.1) (0.7–1.2) (1.2–1.4) (1.6–1.7) (1.0–1.2) (0.8–1.4) (0.2–0.5) (1.1–1.5) (0.9–1.1) (0.9–1.0) (0.9–1.7) (0.6–0.8) (0.8–1.0) (0.3–0.5)

400 41 51 100 76 829 49 74 38 301 1732 167 476 257 47 1323 35 312 729 665 38 355 142 92 401 57 87 318 159

1.2 1.4 1.8 1.3 1.5 1.2 0.9 1.6 1.3 1.3 1.1 1.3 1.3 1.5 1.3 1.1 1.5 1.4 1.5 1.1 1.1 1.1 1.3 1.2 1.2 1.1 1.2 1.2 1.8

(1.1–1.4) (1.0–2.0) (1.3–2.3) (1.0–1.6) (1.2–1.9) (1.1–1.2) (0.7–1.3) (1.3–2.1) (0.9–1.8) (1.2–1.5) (1.1–1.2) (1.1–1.5) (1.2–1.4) (1.4–1.7) (1.0–1.8) (1.0–1.1) (1.0–2.0) (1.3–1.6) (1.4–1.6) (1.0–1.2) (0.8–1.5) (1.0–1.3) (1.1–1.6) (1.0–1.5) (1.1–1.3) (0.8–1.4) (1.0–1.5) (1.1–1.3) (1.5–2.1)

275 34 63 159 69 1349 28 85 41 404 1196 65 474 134 33 3014 33 454 1303 513 35 168 54 89 429 32 124 368 121

1.2 1.2 1.7 1.2 1.6 1.1 1.0 1.5 1.0 1.2 1.0 1.1 1.1 1.1 1.1 1.1 1.1 1.4 1.4 1.0 1.1 1.0 1.0 1.4 1.1 0.9 1.4 1.1 1.2

(1.0–1.3) (0.8–1.7) (1.3–2.2) (1.0–1.4) (1.2–2.0) (1.1–1.2) (0.6–1.4) (1.2–1.8) (0.7–1.3) (1.1–1.4) (1.0–1.1) (0.9–1.5) (1.0–1.2) (0.9–1.3) (0.8–1.6) (1.0–1.1) (0.8–1.6) (1.3–1.5) (1.3–1.4) (1.0–1.1) (0.8–1.6) (0.8–1.2) (0.7–1.3) (1.1–1.7) (1.0–1.2) (0.6–1.2) (1.2–1.7) (1.0–1.2) (1.0–1.4)

275 35 37 187 96 1844 34 110 48 358 922 75 398 97 66 2980 36 357 1321 495 34 121 44 77 414 17 138 365 138

1.2 1.3 1.2 1.1 1.6 1.1 0.9 1.4 1.0 1.3 1.1 1.3 1.2 1.1 1.1 1.1 1.4 1.4 1.3 1.1 1.4 1.1 1.3 1.0 1.2 1.2 1.2 1.1 1.1

(1.0–1.3) (0.9–1.8) (0.8–1.6) (1.0–1.3) (1.3–2.0) (1.1–1.2) (0.7–1.3) (1.1–1.7) (0.8–1.4) (1.2–1.4) (1.0–1.1) (1.1–1.7) (1.1–1.3) (0.9–1.3) (0.9–1.4) (1.1–1.1) (1.0–1.9) (1.2–1.5) (1.2–1.3) (1.0–1.2) (0.9–1.9) (0.9–1.3) (0.9–1.7) (0.8–1.3) (1.0–1.3) (0.7–1.9) (1.0–1.5) (1.0–1.3) (0.9–1.3)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

ARTICLE IN PRESS

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

≥75 years

65–74 years

T. Chen et al./Cancer Letters ■■ (2015) ■■–■■

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Table 4 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer by age at diagnosis of first cancer in Germany and Sweden.

Sites of first primary cancers

Germany

Sweden

<1 year

<1 year

≥5 years

1–4 years

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

1157 59 581 1055 186 3184 137 483 404 1866 1489 343 935 727 215 2994 70 1295 3419 558 39 86 148 338 604 74 198 403 357

2.1 1.9 2.4 1.4 3.7 1.3 2.9 1.0 0.8 1.0 1.1 3.0 2.5 3.1 2.1 1.2 1.9 2.0 4.0 1.2 1.2 0.4 1.4 1.9 1.2 2.1 0.8 1.0 1.0

(2.0–2.3) (1.4–2.4) (2.2–2.6) (1.3–1.5) (3.2–4.2) (1.3–1.3) (2.4–3.4) (0.9–1.1) (0.7–0.9) (0.9–1.0) (1.1–1.2) (2.7–3.3) (2.4–2.7) (2.9–3.3) (1.8–2.3) (1.2–1.3) (1.4–2.3) (1.9–2.1) (3.9–4.2) (1.1–1.3) (0.9–1.7) (0.3–0.5) (1.2–1.6) (1.7–2.1) (1.1–1.2) (1.6–2.6) (0.7–1.0) (0.9–1.1) (0.9–1.1)

2382 113 434 1037 130 5575 156 393 228 1837 4326 443 1286 497 286 7141 105 2240 2775 1670 131 93 433 330 1339 139 402 878 229

2.0 1.6 1.5 1.0 1.3 1.0 1.5 0.9 0.6 0.9 1.2 1.6 1.3 1.1 1.3 1.0 1.2 1.4 1.6 1.3 1.5 0.5 1.5 1.1 1.2 1.5 0.9 1.1 0.8

(1.9–2.1) (1.3–1.9) (1.4–1.7) (0.9–1.0) (1.1–1.6) (1.0–1.1) (1.3–1.8) (0.8–1.0) (0.6–0.7) (0.9–0.9) (1.1–1.2) (1.4–1.7) (1.2–1.3) (1.0–1.2) (1.2–1.5) (1.0–1.1) (1.0–1.4) (1.3–1.5) (1.5–1.6) (1.2–1.3) (1.3–1.8) (0.4–0.6) (1.3–1.6) (1.0–1.3) (1.1–1.2) (1.3–1.8) (0.8–1.0) (1.0–1.2) (0.7–0.9)

1145 49 101 463 41 2824 72 106 51 592 2923 295 767 235 110 3410 57 1245 1135 908 59 51 329 118 743 111 152 462 81

1.9 1.4 1.4 1.1 0.9 1.1 1.3 0.9 0.9 1.0 1.2 1.4 1.1 1.1 1.1 1.0 1.3 1.2 1.3 1.1 1.4 0.8 1.5 1.0 1.3 1.8 1.0 1.2 0.8

(1.8–2.0) (1.0–1.8) (1.1–1.7) (1.0–1.2) (0.7–1.3) (1.0–1.1) (1.0–1.7) (0.8–1.1) (0.6–1.1) (1.0–1.1) (1.2–1.2) (1.2–1.5) (1.0–1.2) (1.0–1.3) (0.9–1.3) (1.0–1.0) (1.0–1.7) (1.2–1.3) (1.2–1.3) (1.1–1.2) (1.1–1.8) (0.6–1.1) (1.3–1.6) (0.8–1.2) (1.2–1.4) (1.4–2.1) (0.8–1.2) (1.1–1.4) (0.6–1.0)

178 29 63 171 107 954 20 143 69 432 430 77 349 159 40 1281 25 334 1013 216 14 88 50 43 231 19 88 174 161

1.1 2.0 1.5 1.4 2.5 1.2 1.1 1.7 1.0 1.4 0.8 1.7 1.7 2.0 1.5 1.0 1.6 1.6 1.7 0.8 0.8 0.9 1.6 1.0 1.1 1.4 1.1 0.9 1.1

(1.0–1.3) (1.3–2.8) (1.2–1.9) (1.2–1.6) (2.0–3.0) (1.1–1.3) (0.7–1.7) (1.4–2.0) (0.8–1.3) (1.3–1.5) (0.7–0.9) (1.4–2.1) (1.6–1.9) (1.7–2.3) (1.1–2.0) (0.9–1.0) (1.0–2.4) (1.5–1.8) (1.6–1.8) (0.7–0.9) (0.5–1.4) (0.7–1.1) (1.2–2.1) (0.7–1.4) (0.9–1.2) (0.9–2.2) (0.9–1.4) (0.8–1.0) (0.9–1.3)

489 47 66 167 84 1920 48 92 40 442 1883 127 576 183 65 3878 53 536 1554 862 64 296 102 141 625 38 199 578 189

1.2 1.3 1.6 1.0 1.2 1.1 1.0 1.3 1.1 1.2 1.1 1.1 1.1 1.0 1.0 1.1 1.2 1.4 1.3 1.1 1.5 1.1 1.2 1.4 1.1 0.9 1.4 1.2 1.6

(1.1–1.3) (0.9–1.7) (1.2–2.0) (0.9–1.2) (1.0–1.5) (1.1–1.2) (0.8–1.4) (1.0–1.6) (0.8–1.5) (1.1–1.4) (1.0–1.1) (1.0–1.4) (1.0–1.2) (0.9–1.2) (0.8–1.3) (1.0–1.1) (0.9–1.6) (1.3–1.5) (1.2–1.3) (1.0–1.2) (1.1–1.9) (0.9–1.2) (1.0–1.4) (1.1–1.6) (1.0–1.2) (0.6–1.2) (1.2–1.6) (1.1–1.3) (1.4–1.8)

283 34 22 108 50 1148 43 34 18 189 1537 103 423 146 41 2158 26 253 786 595 29 260 88 74 388 49 62 299 68

1.2 1.1 1.6 1.1 1.2 1.1 0.8 1.3 1.2 1.2 1.1 1.2 1.1 1.3 1.3 1.2 1.2 1.2 1.1 1.2 1.0 1.2 1.2 1.1 1.2 1.1 1.3 1.2 1.2

(1.1–1.4) (0.7–1.5) (1.0–2.4) (0.9–1.4) (0.9–1.6) (1.0–1.2) (0.6–1.1) (0.9–1.9) (0.7–1.9) (1.0–1.3) (1.1–1.2) (1.0–1.4) (1.0–1.2) (1.1–1.5) (0.9–1.8) (1.1–1.2) (0.8–1.8) (1.0–1.3) (1.1–1.2) (1.1–1.3) (0.7–1.4) (1.1–1.4) (0.9–1.4) (0.9–1.4) (1.1–1.4) (0.8–1.4) (1.0–1.7) (1.1–1.4) (0.9–1.5)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

ARTICLE IN PRESS

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

≥5 years

1–4 years

T. Chen et al./Cancer Letters ■■ (2015) ■■–■■

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Table 5 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer by follow-up time after first cancer in Germany and Sweden.

7

ARTICLE IN PRESS T. Chen et al./Cancer Letters ■■ (2015) ■■–■■

8

(Table 5), i.e., elevated risk after 21 cancers in Germany and after 15 cancers in Sweden and decreased risk (SIR = 0.8) after both breast cancer and melanoma in Sweden; consequently, we cautiously did not consider as a major finding. For all SDPCs combined, there could be an even more complex etiology as more risk factors could contribute, i.e., accumulating different risk factors for a specific SPC after a specific first primary cancer. Since the risk of a SPC depends greatly on the specific type of first–second cancer pair regardless of whether an SPC was the same type of first cancer and, there is substantial heterogeneity in the risk of an individual SPC after different type of first primary cancer [21,22], further investigations on the SPC risk of a specific pair of first-second cancer (e.g., a specific SPC after multiple myeloma) in different populations for overall and by characteristics of cancer patients (age at diagnosis of and followup time after first primary cancer) shall be warranted. Our study has a number of strengths and limitations. Its major strength is the design of population-based investigations on risk of all SPCs after first primary cancers in two different populations. Second strength is using very large databases (covering approximately 27 million Germans and 9 million Swedes) with high quality of data. All SIRs in the two populations were adjusted for three identical co-variables (age, sex, and calendar period) and additionally for a regional category (12 states in Germany and 4 categories in Sweden). A few of the first primary cancers reported in the early years of German cancer registry might be actually second primary cancers because the German cancer registries included in this study were generally established in 1997 (except that four German registries even started data collection after 1997); nevertheless, for comparability and consistency, the same criteria were also adopted for Swedish data, i.e., the definition of first and second primary cancers was recorded according to the study period 1997–2010. Additionally, because the sensitivity analyses restricted to eight German cancer registries with full follow-up period 1997–2010 did not essentially change our results (Tables A3–A6), we reported here with data from all 12 German cancer registries; nevertheless, we have taken into account this difference in data collection for personyear calculations in the German dataset. Finally, variables for race and smoking status were not available in German and Swedish datasets, but race is not an issue in these countries.

cancers (out of 29 cancers in total) in Germany and after 24 cancers in Sweden. Among them, risks after 19 cancers were elevated in both populations, which may suggest common etiology of SDPCs after most of first primary cancers and similar registration practices for those cancers in the two populations, but the former is more important as it is the fundamental cause of second primary cancers. We found a substantially higher risk of SDPCs after urinary bladder and upper aerodigestive tract cancers in Germany compared to Sweden, which is likely due to higher incidence of smokingrelated cancer for German men compared to Swedish men. While decreased overall SIRs found only in Germany after five fatal cancers may be attributed to reporting practices or missed death data in Germany. Consequently, our data validate their potential use in etiological studies. Nevertheless, further investigations on the SPC risk based on a specific pair of first-second cancers (e.g., a specific SPC after multiple myeloma) for overall and by characteristics of cancer patients in different populations are warranted, which may reveal the reasons behind different rates of second cancers that has clinical significance. Funding This work was supported by the German Cancer Aid (Deutsche Krebshilfe) [grant number 108257 and 110446]. Acknowledgements Members of the GEKID Cancer Survival Working Group: Karla Geiss, Martin Meyer (Cancer Registry of Bavaria), Andrea Eberle, Sabine Luttmann (Cancer Registry of Bremen), Roland Stabenow (Cancer Registry of Berlin and the New Federal States), Stefan Hentschel, Alice Nennecke (Hamburg Cancer Registry), Joachim Kieschke, Eunice Sirri (Cancer Registry of Lower Saxony), Bernd Holleczek (Saarland Cancer Registry), Katharina Emrich (Cancer Registry of Rhineland-Palatinate), Hiltraud Kajüter, Volkmar Mattauch (Cancer Registry of North Rhine-Westphalia), Alexander Katalinic, Nora Eisemann (Cancer Registry of Schleswig–Holstein), Klaus Kraywinkel (Robert Koch Institute, Berlin), Hermann Brenner, Lina Jansen, and Felipe Castro (German Cancer Research Center).

Conclusion Conflict of interest We found similar distribution of all SDPCs after any specific first cancer in the two populations and elevated overall risks after 23

None of the authors declared any conflict of interest.

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

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Appendices

Table A1 Distribution of first primary cancer (except non-melanoma skin cancer) diagnosed at ≥15 years in Germany and Sweden. Sites of first primary cancers

Breast Colorectum Prostate Lung Stomach Urinary bladder Kidney Upper aerodigestive tract Melanoma Non-Hodgkin lymphoma Endometrium Pancreas Liver and gallbladder Leukemia Unknown primary Ovary Cervix uteri Nervous system Esophagus Multiple myeloma Thyroid glands Testis Connective tissue Other female genital Hodgkin lymphoma Anus Small intestine Any other cancers Eye Salivary gland Other male genital Bone Nose Other uterus Non-thyroid endocrine glands Total a

Germany

Sweden

N

%

Ranka

N

%

Ranka

234,863 219,468 202,961 163,537 59,835 58,779 57,156 54,550 53,605 47,242 41,103 40,514 36,811 35,711 28,418 28,265 21,232 20,872 19,534 18,735 16,314 16,148 14,825 11,095 7233 4801 4449 3536 2916 2837 2623 2516 2447 1223 850 1,537,004

15.28 14.28 13.20 10.64 3.89 3.82 3.72 3.55 3.49 3.07 2.67 2.64 2.39 2.32 1.85 1.84 1.38 1.36 1.27 1.22 1.06 1.05 0.96 0.72 0.47 0.31 0.29 0.23 0.19 0.18 0.17 0.16 0.16 0.08 0.06 100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

87,448 69,774 114,088 43,502 12,666 28,710 12,696 11,966 26,500 19,772 17,406 11,748 11,536 17,096 20,287 10,591 6123 16,371 5121 7560 4215 3827 3737 2727 2303 1614 2752 550 1483 1204 1100 814 842 1572 8402 588,103

14.87 11.86 19.40 7.40 2.15 4.88 2.16 2.03 4.51 3.36 2.96 2.00 1.96 2.91 3.45 1.80 1.04 2.78 0.87 1.29 0.72 0.65 0.64 0.46 0.39 0.27 0.47 0.09 0.25 0.20 0.19 0.14 0.14 0.27 1.43 100

2 3 1 4 13 5 12 14 6 8 9 15 16 10 7 17 20 11 21 19 22 23 24 26 27 28 25 35 30 31 32 34 33 29 18

Frequency rank.

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

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Table A2 Frequency, percentage and rank for a specific first primary cancer and for all SDPCs after a specific first primary cancer in Germany and Sweden. Sites of first primary cancers

Germany

Sweden

First cancer

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary Totala

SDPCs combined b,c

First cancer

N

%

Rank

N

%

Rank

54,550 2837 19,534 59,835 4449 219,468 4801 36,811 40,514 163,537 234,863 21,232 41,103 28,265 11,095 202,961 2623 57,156 58,779 53,605 2916 20,872 16,314 14,825 47,242 7233 18,735 35,711 28,418 1,537,004

3.55 0.18 1.27 3.89 0.29 14.28 0.31 2.39 2.64 10.64 15.28 1.38 2.67 1.84 0.72 13.2 0.17 3.72 3.82 3.49 0.19 1.36 1.06 0.96 3.07 0.47 1.22 2.32 1.85

8 30 19 5 27 2 26 13 12 4 1 17 11 16 24 3 31 7 6 9 29 18 21 23 10 25 20 14 15

4684 221 1116 2555 357 11,583 365 982 683 4295 8738 1081 2988 1459 611 13,545 232 4780 7329 3136 229 230 910 786 2686 324 752 1743 667 80,162

5.84 0.28 1.39 3.19 0.45 14.45 0.46 1.23 0.85 5.36 10.90 1.35 3.73 1.82 0.76 16.90 0.29 5.96 9.14 3.91 0.29 0.29 1.14 0.98 3.35 0.40 0.94 2.17 0.83

6 29 14 11 24 2 23 16 20 7 3 15 9 13 22 1 26 5 4 8 28 27 17 18 10 25 19 12 21

b

SDPCs combined b,c

N

%

Rank

N

%

Rankb

11,966 1204 5121 12,666 2752 69,774 1614 11,536 11,748 43,502 87,448 6123 17,406 10,591 2727 114,088 1100 12,696 28,710 26,500 1483 16,371 4215 3737 19,772 2303 7560 17,096 20,287 588,103

2.03 0.20 0.87 2.15 0.47 11.86 0.27 1.96 2.00 7.40 14.87 1.04 2.96 1.80 0.46 19.4 0.19 2.16 4.88 4.51 0.25 2.78 0.72 0.64 3.36 0.39 1.29 2.91 3.45

14 31 21 13 25 3 28 16 15 4 2 20 9 17 26 1 32 12 5 6 30 11 22 24 8 27 19 10 7

950 110 151 446 241 4022 111 269 127 1063 3850 307 1348 488 146 7317 110 1123 3353 1673 107 644 240 258 1244 106 349 1051 418 32,544

2.92 0.34 0.46 1.37 0.74 12.36 0.34 0.83 0.39 3.27 11.83 0.94 4.14 1.50 0.45 22.48 0.34 3.45 10.30 5.14 0.33 1.98 0.74 0.79 3.82 0.33 1.07 3.23 1.28

11 26 22 14 20 2 25 18 24 9 3 17 6 13 23 1 26 8 4 5 28 12 21 19 7 29 16 10 15

SDPC: second discordant primary cancer. a Total number included the cancer sites not presented (all SDPCs combined <100). b Frequency rank. c Ranking order included cancer sites not presented here but shown in Table A1.

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Sites of first primary cancers

Germany

Sweden

Men

Overall

Men

Women

Overall

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

2949 103 690 1321 157 5299 110 477 309 2532 104 0 0 0 0 9506 178 2766 4922 1280 100 104 232 356 1157 145 334 929 312

2.0 1.6 2.0 1.1 1.9 0.9 2.0 1.0 0.8 1.0 1.1

(2.0–2.1) (1.3–2.0) (1.9–2.2) (1.1–1.2) (1.6–2.2) (0.9–1.0) (1.6–2.4) (0.9–1.1) (0.7–0.9) (0.9–1.0) (0.9–1.4)

2.0 1.7 2.3 1.2 2.5 1.0 1.8 1.2 0.9 1.2 1.2 1.8 1.5 1.8 1.5

(1.8–2.2) (1.3–2.2) (2.0–2.8) (1.1–1.3) (2.0–2.9) (0.9–1.0) (1.5–2.1) (1.1–1.3) (0.8–1.0) (1.1–1.3) (1.2–1.2) (1.7–1.9) (1.5–1.6) (1.7–1.9) (1.4–1.6)

2.0 1.7 2.1 1.2 2.1 0.9 1.9 1.1 0.8 1.0 1.2 1.8 1.5 1.8 1.5 1.1 1.4 1.5 2.1 1.2 1.5 0.5 1.5 1.5 1.2 1.8 0.9 1.2 1.0

(2.0–2.1) (1.4–1.9) (1.9–2.2) (1.1–1.2) (1.9–2.4) (0.9–1.0) (1.6–2.1) (1.0–1.2) (0.8–0.9) (1.0–1.0) (1.2–1.2) (1.7–1.9) (1.5–1.6) (1.7–1.9) (1.4–1.6) (1.1–1.1) (1.2–1.7) (1.5–1.6) (2.0–2.1) (1.2–1.3) (1.3–1.7) (0.4–0.6) (1.4–1.6) (1.4–1.6) (1.2–1.3) (1.5–2.0) (0.8–1.0) (1.1–1.2) (0.9–1.1)

705 62 114 278 145 2392 43 157 61 640 52 0 0 0 0 7316 104 724 2767 967 53 281 83 166 743 58 208 627 200

(1.1–1.3) (1.1–1.8) (1.2–1.8) (1.0–1.3) (1.2–1.7) (1.1–1.2) (0.8–1.4) (1.3–1.8) (0.7–1.2) (1.2–1.3) (0.8–1.5)

(1.0–1.3) (0.9–1.7) (1.4–2.7) (1.0–1.4) (1.4–2.2) (1.1–1.2) (0.7–1.1) (1.2–1.7) (1.0–1.6) (1.2–1.5) (1.0–1.1) (1.1–1.4) (1.1–1.3) (1.2–1.4) (1.0–1.4)

1.1 1.3 1.4 1.4 1.1 1.1 1.1 1.2 1.3 1.2 1.0 1.3 1.2 1.3

(1.1–1.1) (1.1–1.6) (1.3–1.5) (1.3–1.4) (1.0–1.2) (0.8–1.4) (1.0–1.2) (1.0–1.5) (1.1–1.5) (1.1–1.2) (0.8–1.3) (1.1–1.5) (1.1–1.3) (1.1–1.4)

245 48 37 168 96 1630 68 112 66 423 3797 307 1348 488 146 0 0 399 586 705 54 363 157 92 500 48 141 424 218

1.2 1.2 1.9 1.2 1.8 1.1 0.9 1.4 1.3 1.4 1.1 1.3 1.2 1.3 1.2

(1.1–1.1) (1.2–1.7) (1.5–1.6) (2.2–2.3) (1.1–1.3) (1.1–1.7) (0.4–0.6) (1.2–1.6) (1.2–1.5) (1.2–1.3) (1.4–2.0) (0.8–1.0) (1.1–1.3) (0.9–1.1)

3480 167 832 1966 277 8447 269 807 541 3258 6323 849 2306 1119 451 9506 178 3877 5575 2172 180 172 718 600 1916 239 532 1344 520

1.2 1.4 1.5 1.2 1.5 1.1 1.1 1.5 0.9 1.2 1.1

1.1 1.4 1.6 2.3 1.2 1.4 0.5 1.4 1.3 1.3 1.7 0.9 1.2 1.0

531 64 142 645 120 3148 159 330 232 726 6219 849 2306 1119 451 0 0 1111 653 892 80 68 486 244 759 94 198 415 208

1.4 1.2 1.1 1.3 1.1 1.3 1.1 1.1 1.1 1.3 1.1 1.4

(1.2–1.5) (1.1–1.3) (1.0–1.1) (1.0–1.7) (1.0–1.2) (1.1–1.5) (0.9–1.4) (1.0–1.2) (0.8–1.4) (1.1–1.5) (1.0–1.2) (1.2–1.5)

950 110 151 446 241 4022 111 269 127 1063 3849 307 1348 488 146 7316 104 1123 3353 1672 107 644 240 258 1243 106 349 1051 418

1.2 1.3 1.6 1.2 1.6 1.1 1.0 1.5 1.1 1.3 1.1 1.3 1.2 1.3 1.2 1.1 1.3 1.4 1.3 1.1 1.2 1.1 1.2 1.2 1.1 1.0 1.3 1.1 1.3

(1.1–1.3) (1.1–1.6) (1.3–1.8) (1.1–1.3) (1.4–1.8) (1.1–1.2) (0.8–1.1) (1.3–1.7) (0.9–1.3) (1.2–1.4) (1.0–1.1) (1.1–1.4) (1.1–1.3) (1.2–1.4) (1.0–1.4) (1.1–1.1) (1.1–1.6) (1.3–1.5) (1.3–1.4) (1.0–1.1) (1.0–1.4) (1.0–1.2) (1.1–1.4) (1.1–1.4) (1.1–1.2) (0.8–1.2) (1.2–1.4) (1.1–1.2) (1.2–1.4)

1.4 1.3 1.3 1.7 0.6 1.6 1.8 1.2 1.9 0.9 1.1 1.0

(1.3–1.5) (1.2–1.4) (1.2–1.4) (1.4–2.1) (0.4–0.7) (1.4–1.7) (1.6–2.1) (1.1–1.3) (1.5–2.3) (0.8–1.0) (1.0–1.2) (0.8–1.1)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

ARTICLE IN PRESS

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

Women

T. Chen et al./Cancer Letters ■■ (2015) ■■–■■ 11

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Table A3 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer for overall and by sex in Germany (exclude 4 cancer registries started data collection later than 1997 ) and Sweden.

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Table A4 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer for overall and by calendar period in Germany (exclude 4 cancer registries started data collection later than 1997) and Sweden. Sites of first primary cancers

Germany

Sweden

1997–2003

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

2004–2010

1997–2003

2004–2010

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

995 45 242 656 78 2423 78 268 184 1101 1565 275 703 411 132 2251 60 1162 1786 514 67 61 191 193 523 42 167 344 158

2.8 2.2 2.4 1.6 3.2 1.6 2.5 1.4 1.1 1.3 1.5 2.5 2.3 2.6 2.1 1.6 2.6 2.3 3.0 1.7 2.5 0.7 2.1 2.1 1.6 1.6 1.2 1.4 1.1

(2.6–2.9) (1.6–2.9) (2.1–2.7) (1.4–1.7) (2.5–4.0) (1.5–1.6) (2.0–3.2) (1.2–1.5) (0.9–1.2) (1.2–1.3) (1.5–1.6) (2.2–2.8) (2.1–2.5) (2.3–2.9) (1.7–2.5) (1.5–1.6) (2.0–3.4) (2.2–2.4) (2.9–3.2) (1.6–1.9) (2.0–3.2) (0.6–0.9) (1.8–2.5) (1.8–2.4) (1.5–1.8) (1.1–2.1) (1.0–1.4) (1.2–1.5) (0.9–1.3)

1390 69 487 823 154 3365 126 422 307 1538 2111 287 845 452 217 4081 66 1474 2586 835 60 66 202 279 750 94 213 556 288

2.5 2.1 2.9 1.4 2.9 1.3 2.6 1.3 1.0 1.0 1.3 2.5 2.0 2.2 2.0 1.2 1.5 1.8 3.0 1.4 1.4 0.5 1.5 1.9 1.4 2.4 0.9 1.3 1.3

(2.3–2.6) (1.6–2.7) (2.6–3.1) (1.3–1.5) (2.5–3.4) (1.3–1.4) (2.2–3.1) (1.2–1.4) (0.9–1.1) (1.0–1.1) (1.3–1.4) (2.3–2.9) (1.9–2.1) (2.0–2.5) (1.7–2.3) (1.2–1.3) (1.1–1.9) (1.7–1.9) (2.9–3.1) (1.3–1.5) (1.1–1.9) (0.4–0.6) (1.3–1.7) (1.7–2.2) (1.3–1.5) (1.9–2.9) (0.8–1.1) (1.2–1.5) (1.2–1.5)

280 41 63 169 95 1210 26 135 49 392 994 96 430 182 44 2097 39 376 1082 429 35 181 73 86 374 23 124 334 169

1.0 1.6 1.0 1.0 1.4 1.0 1.0 1.2 0.6 1.0 1.0 1.3 1.3 1.4 1.1 1.0 1.3 1.4 1.3 1.0 1.3 1.0 1.3 1.1 1.1 1.3 1.0 1.1 0.9

(0.9–1.2) (1.1–2.1) (0.8–1.3) (0.8–1.1) (1.2–1.7) (1.0–1.1) (0.7–1.5) (1.0–1.4) (0.5–0.8) (0.9–1.1) (1.0–1.1) (1.1–1.6) (1.2–1.4) (1.2–1.6) (0.8–1.5) (1.0–1.1) (0.9–1.8) (1.3–1.6) (1.3–1.4) (0.9–1.1) (0.9–1.7) (0.8–1.1) (1.0–1.6) (0.9–1.4) (1.0–1.2) (0.8–1.9) (0.9–1.2) (1.0–1.2) (0.8–1.1)

337 32 58 151 86 1442 34 100 54 448 1131 99 428 143 58 2709 28 449 1313 548 36 189 68 85 414 30 124 372 159

1.2 1.3 1.8 1.5 1.7 1.3 1.3 1.6 2.1 1.6 1.1 1.4 1.3 1.3 1.3 1.1 1.2 1.5 1.5 1.1 1.3 1.1 1.3 1.4 1.2 1.2 1.3 1.1 1.8

(1.1–1.4) (0.9–1.9) (1.4–2.4) (1.2–1.7) (1.3–2.1) (1.2–1.4) (0.9–1.8) (1.3–2.0) (1.6–2.7) (1.4–1.7) (1.1–1.2) (1.1–1.7) (1.2–1.4) (1.1–1.6) (1.0–1.7) (1.1–1.2) (0.8–1.7) (1.4–1.6) (1.4–1.6) (1.0–1.2) (0.9–1.8) (1.0–1.3) (1.0–1.7) (1.1–1.7) (1.1–1.3) (0.8–1.7) (1.1–1.6) (1.0–1.3) (1.5–2.1)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Sites of first primary cancers

Germany

Sweden

<65 years

<65 years

≥75 years

65–74 years

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

2086 78 449 595 117 2374 116 259 213 1189 2694 518 869 575 160 2002 59 1466 1340 938 72 100 413 274 731 150 184 480 252

2.6 2.3 3.3 1.6 2.8 1.3 2.4 1.7 1.5 1.4 1.3 1.9 1.8 2.3 2.2 1.1 1.5 1.7 2.5 1.3 1.8 0.7 1.6 2.3 1.4 2.0 1.1 1.3 2.1

(2.5–2.7) (1.8–2.9) (3.0–3.6) (1.5–1.7) (2.3–3.3) (1.2–1.3) (2.0–2.9) (1.5–1.9) (1.3–1.7) (1.3–1.5) (1.3–1.4) (1.8–2.1) (1.7–1.9) (2.1–2.5) (1.9–2.6) (1.0–1.1) (1.1–1.9) (1.6–1.8) (2.4–2.7) (1.2–1.4) (1.4–2.3) (0.6–0.9) (1.4–1.7) (2.0–2.6) (1.3–1.5) (1.7–2.4) (1.0–1.3) (1.2–1.5) (1.8–2.3)

1089 52 279 770 100 3516 83 321 211 1437 2074 196 889 323 141 4879 89 1613 2561 742 73 45 220 186 735 56 212 543 179

1.7 1.6 1.6 1.2 1.9 1.1 1.6 1.0 0.8 1.0 1.2 1.7 1.6 1.5 1.4 1.1 1.9 1.5 2.3 1.2 1.5 0.4 1.5 1.2 1.2 1.4 0.9 1.2 1.0

(1.6–1.8) (1.2–2.1) (1.4–1.8) (1.1–1.3) (1.5–2.3) (1.1–1.2) (1.3–2.0) (0.9–1.1) (0.7–0.9) (0.9–1.0) (1.1–1.2) (1.5–2.0) (1.5–1.7) (1.3–1.7) (1.2–1.7) (1.1–1.1) (1.5–2.3) (1.4–1.6) (2.2–2.4) (1.1–1.3) (1.2–1.9) (0.3–0.5) (1.3–1.7) (1.0–1.3) (1.2–1.3) (1.1–1.9) (0.7–1.0) (1.1–1.3) (0.8–1.1)

305 37 104 601 60 2557 70 227 117 632 1555 135 548 221 150 2625 30 798 1674 492 35 27 85 140 450 33 136 321 89

1.1 1.1 1.1 0.9 1.6 1.0 1.5 0.8 0.5 0.7 1.0 1.5 1.3 1.3 1.2 1.1 0.8 1.4 1.7 1.2 1.1 0.4 1.3 1.1 1.0 1.5 0.7 1.0 0.4

(1.0–1.3) (0.8–1.5) (0.9–1.3) (0.9–1.0) (1.3–2.1) (1.0–1.0) (1.2–1.9) (0.7–0.9) (0.4–0.6) (0.6–0.8) (1.0–1.1) (1.2–1.7) (1.1–1.4) (1.2–1.5) (1.0–1.4) (1.1–1.1) (0.6–1.2) (1.3–1.5) (1.6–1.7) (1.1–1.3) (0.7–1.5) (0.3–0.6) (1.0–1.6) (1.0–1.3) (0.9–1.1) (1.0–2.1) (0.6–0.9) (0.9–1.1) (0.3–0.5)

400 41 51 100 76 829 49 74 38 301 1732 167 476 257 47 1323 35 312 729 665 38 355 142 92 401 57 87 318 159

1.2 1.4 1.8 1.3 1.5 1.2 0.9 1.6 1.3 1.3 1.1 1.3 1.3 1.5 1.3 1.1 1.5 1.4 1.5 1.1 1.1 1.1 1.3 1.2 1.2 1.1 1.2 1.2 1.8

(1.1–1.4) (1.0–2.0) (1.3–2.3) (1.0–1.6) (1.2–1.9) (1.1–1.2) (0.7–1.3) (1.3–2.1) (0.9–1.8) (1.2–1.5) (1.1–1.2) (1.1–1.5) (1.2–1.4) (1.4–1.7) (1.0–1.8) (1.0–1.1) (1.0–2.0) (1.3–1.6) (1.4–1.6) (1.0–1.2) (0.8–1.5) (1.0–1.3) (1.1–1.6) (1.0–1.5) (1.1–1.3) (0.8–1.4) (1.0–1.5) (1.1–1.3) (1.5–2.1)

275 34 63 159 69 1349 28 85 41 404 1196 65 474 134 33 3014 33 454 1303 513 35 168 54 89 429 32 124 368 121

1.2 1.2 1.7 1.2 1.6 1.1 1.0 1.5 1.0 1.2 1.0 1.1 1.1 1.1 1.1 1.1 1.1 1.4 1.4 1.0 1.1 1.0 1.0 1.4 1.1 0.9 1.4 1.1 1.2

(1.0–1.3) (0.8–1.7) (1.3–2.2) (1.0–1.4) (1.2–2.0) (1.1–1.2) (0.6–1.4) (1.2–1.8) (0.7–1.3) (1.1–1.4) (1.0–1.1) (0.9–1.5) (1.0–1.2) (0.9–1.3) (0.8–1.6) (1.0–1.1) (0.8–1.6) (1.3–1.5) (1.3–1.4) (1.0–1.1) (0.8–1.6) (0.8–1.2) (0.7–1.3) (1.1–1.7) (1.0–1.2) (0.6–1.2) (1.2–1.7) (1.0–1.2) (1.0–1.4)

275 35 37 187 96 1844 34 110 48 358 922 75 398 97 66 2980 36 357 1321 495 34 121 44 77 414 17 138 365 138

1.2 1.3 1.2 1.1 1.6 1.1 0.9 1.4 1.0 1.3 1.1 1.3 1.2 1.1 1.1 1.1 1.4 1.4 1.3 1.1 1.4 1.1 1.3 1.0 1.2 1.2 1.2 1.1 1.1

(1.0–1.3) (0.9–1.8) (0.8–1.6) (1.0–1.3) (1.3–2.0) (1.1–1.2) (0.7–1.3) (1.1–1.7) (0.8–1.4) (1.2–1.4) (1.0–1.1) (1.1–1.7) (1.1–1.3) (0.9–1.3) (0.9–1.4) (1.1–1.1) (1.0–1.9) (1.2–1.5) (1.2–1.3) (1.0–1.2) (0.9–1.9) (0.9–1.3) (0.9–1.7) (0.8–1.3) (1.0–1.3) (0.7–1.9) (1.0–1.5) (1.0–1.3) (0.9–1.3)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

ARTICLE IN PRESS

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

≥75 years

65–74 years

T. Chen et al./Cancer Letters ■■ (2015) ■■–■■ 13

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Table A5 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer by age at diagnosis of first cancer in Germany (exclude 4 cancer registries started data collection later than 1997) and Sweden.

14

Sites of first primary cancers

Germany

Sweden

<1 year

<1 year

≥5 years

1–4 years

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

N

SIR

95% CI

890 46 471 823 157 2376 110 429 332 1472 1074 276 752 564 164 2204 56 1074 2538 377 34 65 112 271 465 60 156 317 297

2.5 2.1 3.0 1.6 4.7 1.5 3.5 1.2 1.0 1.1 1.3 3.4 3.1 3.6 2.4 1.4 2.2 2.2 4.2 1.3 1.6 0.5 1.5 2.5 1.4 2.5 1.0 1.1 1.2

(2.3–2.6) (1.6–2.9) (2.7–3.2) (1.5–1.7) (4.0–5.5) (1.4–1.5) (2.9–4.2) (1.1–1.4) (0.9–1.1) (1.1–1.2) (1.2–1.3) (3.0–3.8) (2.9–3.3) (3.3–3.9) (2.0–2.8) (1.3–1.5) (1.7–2.9) (2.1–2.4) (4.1–4.4) (1.2–1.4) (1.1–2.2) (0.4–0.6) (1.2–1.8) (2.2–2.8) (1.2–1.5) (1.9–3.3) (0.8–1.2) (1.0–1.3) (1.0–1.3)

1680 78 290 753 85 3855 102 289 167 1316 2933 325 905 357 206 4723 75 1723 2060 1087 99 68 315 221 888 91 259 637 159

2.0 1.6 1.6 1.0 1.3 1.0 1.5 0.9 0.7 0.9 1.2 1.6 1.3 1.2 1.4 1.1 1.2 1.4 1.6 1.3 1.6 0.5 1.5 1.1 1.2 1.5 0.8 1.1 0.8

(1.9–2.1) (1.3–2.0) (1.4–1.8) (0.9–1.1) (1.1–1.6) (1.0–1.1) (1.2–1.8) (0.8–1.0) (0.6–0.8) (0.9–1.0) (1.1–1.2) (1.4–1.8) (1.2–1.4) (1.1–1.3) (1.2–1.6) (1.0–1.1) (1.0–1.5) (1.4–1.5) (1.5–1.7) (1.2–1.4) (1.3–2.0) (0.4–0.6) (1.3–1.7) (1.0–1.3) (1.1–1.3) (1.2–1.8) (0.7–0.9) (1.0–1.2) (0.7–0.9)

910 43 71 390 35 2216 57 89 42 470 2316 248 649 198 81 2579 47 1080 977 708 47 39 291 108 563 88 117 390 64

1.8 1.4 1.2 1.1 1.0 1.0 1.3 1.0 0.9 1.0 1.2 1.4 1.2 1.2 1.0 1.0 1.3 1.2 1.3 1.2 1.2 0.7 1.5 1.1 1.2 1.7 1.0 1.3 0.8

(1.7–1.9) (1.0–2.0) (1.0–1.6) (1.0–1.2) (0.7–1.4) (1.0–1.1) (1.0–1.7) (0.8–1.2) (0.6–1.2) (0.9–1.1) (1.2–1.3) (1.2–1.5) (1.1–1.3) (1.0–1.3) (0.8–1.2) (0.9–1.0) (0.9–1.7) (1.2–1.3) (1.2–1.4) (1.1–1.2) (0.9–1.7) (0.5–1.0) (1.3–1.7) (0.9–1.3) (1.1–1.4) (1.4–2.2) (0.8–1.2) (1.1–1.4) (0.6–1.0)

178 29 63 171 107 954 20 143 69 432 430 77 349 159 40 1281 25 334 1013 216 14 88 50 43 231 19 88 174 161

1.1 2.0 1.5 1.4 2.5 1.2 1.1 1.7 1.0 1.4 0.8 1.7 1.7 2.0 1.5 1.0 1.6 1.6 1.7 0.8 0.8 0.9 1.6 1.0 1.1 1.4 1.1 0.9 1.1

(1.0–1.3) (1.3–2.8) (1.2–1.9) (1.2–1.6) (2.0–3.0) (1.1–1.3) (0.7–1.7) (1.4–2.0) (0.8–1.3) (1.3–1.5) (0.7–0.9) (1.4–2.1) (1.6–1.9) (1.7–2.3) (1.1–2.0) (0.9–1.0) (1.0–2.4) (1.5–1.8) (1.6–1.8) (0.7–0.9) (0.5–1.4) (0.7–1.1) (1.2–2.1) (0.7–1.4) (0.9–1.2) (0.9–2.2) (0.9–1.4) (0.8–1.0) (0.9–1.3)

489 47 66 167 84 1920 48 92 40 442 1883 127 576 183 65 3878 53 536 1554 862 64 296 102 141 625 38 199 578 189

1.2 1.3 1.6 1.0 1.2 1.1 1.0 1.3 1.1 1.2 1.1 1.1 1.1 1.0 1.0 1.1 1.2 1.4 1.3 1.1 1.5 1.1 1.2 1.4 1.1 0.9 1.4 1.2 1.6

(1.1–1.3) (0.9–1.7) (1.2–2.0) (0.9–1.2) (1.0–1.5) (1.1–1.2) (0.8–1.4) (1.0–1.6) (0.8–1.5) (1.1–1.4) (1.0–1.1) (1.0–1.4) (1.0–1.2) (0.9–1.2) (0.8–1.3) (1.0–1.1) (0.9–1.6) (1.3–1.5) (1.2–1.3) (1.0–1.2) (1.1–1.9) (0.9–1.2) (1.0–1.4) (1.1–1.6) (1.0–1.2) (0.6–1.2) (1.2–1.6) (1.1–1.3) (1.4–1.8)

283 34 22 108 50 1148 43 34 18 189 1537 103 423 146 41 2158 26 253 786 595 29 260 88 74 388 49 62 299 68

1.2 1.1 1.6 1.1 1.2 1.1 0.8 1.3 1.2 1.2 1.1 1.2 1.1 1.3 1.3 1.2 1.2 1.2 1.1 1.2 1.0 1.2 1.2 1.1 1.2 1.1 1.3 1.2 1.2

(1.1–1.4) (0.7–1.5) (1.0–2.4) (0.9–1.4) (0.9–1.6) (1.0–1.2) (0.6–1.1) (0.9–1.9) (0.7–1.9) (1.0–1.3) (1.1–1.2) (1.0–1.4) (1.0–1.2) (1.1–1.5) (0.9–1.8) (1.1–1.2) (0.8–1.8) (1.0–1.3) (1.1–1.2) (1.1–1.3) (0.7–1.4) (1.1–1.4) (0.9–1.4) (0.9–1.4) (1.1–1.4) (0.8–1.4) (1.0–1.7) (1.1–1.4) (0.9–1.5)

SDPC: second discordant primary cancer; CI: confidence interval. Only cancer sites shown in Table 1 are presented; bold type (elevated risk) and underscored type (decreased risk): 95% CIs did not include 1.00.

ARTICLE IN PRESS

Upper aerodigestive tract Salivary gland Esophagus Stomach Small intestine Colorectum Anus Liver and gallbladder Pancreas Lung Breast Cervix uteri Endometrium Ovary Other female genital Prostate Other male genital Kidney Urinary bladder Melanoma Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin lymphoma Hodgkin lymphoma Multiple myeloma Leukemia Unknown primary

≥5 years

1–4 years

T. Chen et al./Cancer Letters ■■ (2015) ■■–■■

Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014

Table A6 Standardized incidence ratios (SIRs) of all SDPCs after a specific first primary cancer by follow-up time after first cancer in Germany and Sweden.

ARTICLE IN PRESS T. Chen et al./Cancer Letters ■■ (2015) ■■–■■

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Please cite this article in press as: Tianhui Chen, et al. for the GEKID Cancer Survival Working Group, Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.08.014