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Second cancers after testicular cancer diagnosed after 1980 in Sweden
original article
Annals of Oncology 21: 1546–1551, 2010 doi:10.1093/annonc/mdp562 Published online 17 December 2009
Second cancers after testicular cancer diagnosed after 1980 in Sweden K. Hemminki1,2,3*, H. Liu1 & J. Sundquist2,4 1
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany; 2Center for Primary Health Care Research, Lund University, Malmo¨; 3Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden and 4Stanford Prevention Research Center, Stanford University School of Medicine, CA, USA
Received 27 October 2009; accepted 5 November 2009
original article
Background: Testicular cancer treatment has become standardized in the 1980s involving radiotherapy preferentially for seminoma and chemotherapy for nonseminoma. The late effects of these therapeutic practices have not been properly evaluated because of the relatively short time since their application. Patients and methods: We conducted a study among 5533 survivors of testicular cancer on the basis of Swedish Family-Cancer Database for which the cancer data were retrieved from the nationwide Cancer Registry. Standardized incidence ratios (SIRs) of second cancer were calculated by comparing with the rates of the first cancers. The followup was started in 1980 and carried on through 2006. Results: A total of 370 second cancers (6.7% of all patients) were recorded, more in seminoma than in nonseminoma patients. Second testicular cancer showed an SIR of 29 after seminoma and an SIR of 13 after nonseminoma. A total of 10 discordant sites were increased after seminoma compared with seven sites after nonseminoma. Gastrointestinal tract cancers occurred mainly after seminoma and bladder cancers (SIR 8.6 when diagnosis before age 30) occurred after nonseminoma. Conclusions: Of the selective affected second tumors, it will be important to confirm the association of bladder cancer with nonseminoma treatment. Key words: chemotherapy, multiple cancers, radiotherapy, seminoma, teratoma
introduction The incidence of testicular cancer has increased in many countries, including Sweden, for unknown reasons and it is the most frequently occurring cancer in young white men [1, 2]. The known risk factors for testicular cancer include undescended testis (cryptorchidism), in utero hormonal exposures, testicular dysfunction, perinatal factors, prior history of cancer in one testis (the opposite testis is at increased risk) and family history of testicular cancer [2, 3]. The firstgeneration immigrants to Sweden and Denmark show generally a decreased risk of testicular cancer compared with the natives, but this difference tends to disappear in the next generation born in the new host country, indicating a role for environmental factors [4–8]. Testicular cancers are predominantly germ-cell tumors of two main types, seminomas and nonseminomas; the later include teratomas, with somatic differentiation, and undifferentiated embryonal tumors [3]. However, about one half of the germ-cell tumors of the testis contain multiple histological types and the remainder contains *Correspondence to: Dr K. Hemminki, Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Tel: +49-6221-42-1800; Fax: +49-6221-42-1810; E-mail: [email protected]
a single histological type [3]. Similar incidence trends in seminoma and nonseminoma have been indicated to imply sharing of etiological factors between the histological types [9]. Survival in testicular cancer is high with a 10-year relative survival of >95% for both seminoma and nonseminoma in Sweden since the current treatment and diagnostic modalities were consolidated [10]. The treatment depends on whether the disease is localized or metastatic, including orchiectomy and primarily radiation for seminoma and BEP (bleomycin, etoposide and cisplatin) for nonseminoma and mixed tumors [11–13]. For metastatic seminoma, the radiation therapy is intensified and targeted into wider fields, and BEP may be administered; for nonseminoma and mixed tumors, more cycles of BEP are administered. As these therapeutic principles with some variation were taken to use in the 1980s, the maximal follow-up times of the surviving patients are barely exceeding two decades. Previous large studies on survivors of testicular cancer reported an increased risk of several second malignancies but, as the follow-up times ended at or before the year 2000, the number of patients treated with the current protocols was small and no second testicular cancer were included [14–16]. For example, the multicenter study of 13 cancer registries with 29 500 testicular cancer patients included only 491 second cancers (27%) in testicular cancer patients
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
diagnosed since 1980 [16]. In that study, Swedish patients diagnosed from 1961 to 1998 constituted 16.3% of the study population. Considering that the effects of radiotherapy and chemotherapy may extend to at least four decades, it is important that testicular cancers are followed for the effects of the treatments adopted in the 1980s [14–20]. We conducted a study among 5533 survivors of testicular cancer on the basis of Swedish Family-Cancer Database for which the cancer data were retrieved from the nationwide Cancer Registry. The follow-up was started in 1980 and carried on through 2006 covering the time of relatively standard treatment protocols for the two main types of testicular cancers. All cancers including second testicular cancers were included in the follow-up.
Cancer Registry found 98% to be correctly classified [23]. In the present analyses, 5533 patients with first primary testicular cancer were followed from diagnosis after 1 January 1980 until death, detection of a second primary cancer, emigration or 31 December 2006, whichever came first. Second cancers were classified as such by the Cancer Registry, including synchronous tumors. The incidences of second malignancies among testicular cancer patients were compared with the rates in the general Swedish population by standardized incidence ratios (SIRs) and 95% confidence intervals (CIs), adjusting for covariates age (5 year bands), sex, socioeconomic index (six groups), region (four groups) and calendar year (1961–1965, 1965–1969, . , 2000–2004). Separate analyses were carried out according to age at testicular cancer diagnosis (20–39, 40–49, 50–59, 60–69 and 70+ years), time since testicular cancer diagnosis (0–10, 11–20, 21–30 and 31+ years) and period of testicular cancer diagnosis (1961–2004 and 1975–2004). SIR applies indirect standardization, which is particularly suitable for cells with small numbers of subjects [24–26]. In this method, the observed numbers of cases are divided by the expected numbers of cases, calculated from the whole background population of 11.8 million. CIs (95%) were calculated assuming a Poisson distribution. SAS software version 9.1 was used for data analysis.
patients and methods The Swedish Family-Cancer Database was first assembled from the national databases in 1996 and since then it has been periodically updated most recently in 2008 [21, 22]. The database contains those born in Sweden since 1932 with their biological parents, totaling >11.8 million persons and >1.2 million tumor notifications. Cancer cases were retrieved from the Swedish Cancer Registry, which relies on separate compulsory notifications from clinicians who diagnosed the neoplasms and pathologists/cytologists. All registered testicular cancers cases are histologically verified. An ad hoc study on the diagnostic accuracy of second neoplasms in the Swedish
results The Family-Cancer Database included 3001 seminomas and 2532 nonseminomas diagnosed since the year 1980. Table 1 shows SIRs for a total of 370 (6.7% of all patients) second
Table 1. SIRs for second cancer in patients diagnosed with testicular cancer according to histological type Second cancer site All excluding testis Upper aerodigestive tract Esophagus Stomach Colorectum Pancreas Lung Prostate Testis Other male genital organs Kidney Urinary bladder Melanoma Skin Skin, squamous cell Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin’s lymphoma Leukemia AML CML ALL CLL Others
Seminoma O SIR
95% CI
193 4 6 8 21 6 14 41 63 1 11 12 8 6 6 3 5 3 3 14 12 4 2 1 3 2
1.67–2.23 0.33–3.13 1.82–10.78 1.23–5.63 1.21–2.99 1.00–5.94 0.94–2.88 1.02–1.93 22.52–37.49 0.06–13.56 1.82–6.53 0.97–3.28 0.62–2.85 0.54–3.23 0.65–3.85 1.84–26.07 0.40–2.86 1.08–15.31 0.74–10.43 1.86–5.71 1.98–6.68 1.80–16.89 0.68–20.16 0.16–34.16 0.55–7.82 0.33–9.94
1.93 1.22 4.95 2.86 1.95 2.73 1.72 1.43 29.30 2.43 3.65 1.88 1.45 1.48 1.77 8.92 1.22 5.24 3.57 3.40 3.83 6.60 5.58 6.13 2.68 2.75
Nonseminoma O SIR
95% CI
81 2
2.14 1.47
1.70–2.66 0.18–5.30
8
2.09
0.90–4.12
5 18 33 2 5 7 3 5 3
1.85 2.17 12.97 10.92 4.19 3.23 0.95 3.77 3.04
0.60–4.31 1.29–3.44 8.93–18.22 1.32–39.46 1.36–9.79 1.30–6.65 0.20–2.78 1.22–8.80 0.63–8.88
4 1 2 7 6 1 2 1
1.56 2.74 4.29 3.69 4.08 3.42 8.24 6.87
0.42–3.99 0.07–15.25 0.52–15.51 1.48–7.60 1.50–8.89 0.09–19.03 1.00–29.76 0.17–38.26
2
6.32
0.77–22.82
Total O
SIR
95% CI
274 6 6 8 29 6 19 59 96 3 16 19 11 11 9 3 9 4 5 21 18 5 4 2 3 4
1.99 1.29 3.66 2.12 1.99 2.03 1.75 1.59 20.45 5.05 3.81 2.22 1.27 2.05 2.06 5.96 1.35 4.26 3.83 3.49 3.91 5.56 6.65 6.48 1.99 3.83
1.76–2.24 0.47–2.82 1.34–7.97 0.92–4.18 1.33–2.86 0.74–4.42 1.05–2.73 1.21–2.06 16.57–24.98 1.04–14.76 2.18–6.18 1.34–3.47 0.63–2.26 1.02–3.66 0.94–3.90 1.23–17.43 0.62–2.57 1.16–10.92 1.24–8.93 2.16–5.34 2.32–6.18 1.81–12.98 1.81–17.04 0.78–23.40 0.41–5.80 1.04–9.82
Bold type: 95% CI does not include 1.00. SIR, standardized incidence ratio; O, observed; CI, confidence interval; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia.
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Second cancer site
All excluding testis Upper aerodigestive tract Esophagus Stomach Colorectum Pancreas Lung Prostate Testis Other male genital organs Kidney Urinary bladder Melanoma Skin Skin, squamous cell Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin’s lymphoma Leukemia AML CML ALL CLL Others
Seminoma <30 O SIR
95% CI
8 1
2.71 9.13
1.17–5.34 0.23–50.89
1 1 1
16.73 3.78 27.43
0.42–93.20 0.10–21.08 0.69–152.82
24
35.87
22.98–53.37
1
11.97
0.30–66.69
2
4.68
0.57–16.91
‡30 O
SIR
95% CI
185 3 6 7 20 5 14 41 39 1 10 12 8 6 6 3 3 3 3 14 12 4 2 1 3 2
1.91 0.95 5.03 2.56 1.91 2.31 1.74 1.43 26.34 2.55 3.41 1.91 1.58 1.51 1.78 9.42 0.82 5.87 3.92 3.59 4.05 7.01 6.45 7.25 2.72 2.89
1.64–2.21 0.20–2.77 1.85–10.95 1.03–5.27 1.17–2.95 0.75–5.40 0.95–2.91 1.03–1.94 18.73–36.00 0.06–14.20 1.64–6.28 0.99–3.34 0.68–3.11 0.56–3.30 0.66–3.90 1.94–27.53 0.17–2.40 1.21–17.14 0.80–11.44 1.96–6.03 2.09–7.07 1.91–17.94 0.78–23.29 0.18–40.40 0.56–7.96 0.35–13.35
Nonseminoma <30 O SIR 95% CI
‡30 O SIR
95% CI
Total <30 O SIR
25 1
3.78 4.64
2.45–5.58 0.12–25.88
56 1
1.79 0.87
1.35–2.32 0.02–4.85
33 2
3.45 6.16
2.37–4.84 0.75–22.24
2
3.59
0.43–12.96
6
1.83
0.67–3.99
1
5.48
0.14–30.51 8.45–20.00 0.68–150.11 6.44–60.48 1.04–31.03 0.02–5.10 0.14–29.84
0.43–4.06 1.32–3.51 5.86–22.49 0.17–38.16 0.02–5.45 0.84–6.02 0.12–3.50 0.96–8.99 0.68–9.65
0.15–31.98 0.75–10.67 0.23–51.47 0.09–19.55
13.33 26.94 23.62 8.59 0.91 5.36
1.59 2.22 12.23 6.85 0.98 2.58 0.97 3.51 3.30
5.74 3.65 9.24 3.51
23 1 4 2 1 1
4 18 10 1 1 5 2 4 3
1 3 1 1 47 1 5 2 1 1
19.62 17.94 19.77 5.81 0.64 3.69
14.42–26.10 0.45–99.97 6.42–46.14 0.70–20.99 0.02–3.56 0.10–20.56
3 1 2 1 3 1
2.91 6.71 11.59 2.02 7.07 11.12
0.60–8.50 0.17–37.40 1.40–41.87 0.02–11.26 1.46–20.66 0.28–61.93
1
0.65
0.02–3.63
6 3
4.27 2.87
1.57–9.30 0.59–8.39
5 1 2 1 3 1
3.43 4.76 8.10 1.41 5.03 7.97
1.11–8.00 0.12–26.53 0.98–29.28 0.04–7.85 1.04–14.70 0.20–44.42
2
14.87
1.80–53.72
1
11.56
0.29–64.40
1
8.95
0.23–49.88
1
13.35
0.34–74.40
1
9.20
0.23–51.26
1
4.14
0.10–23.06
95% CI
‡30 O
SIR
95% CI
241 4 6 7 26 5 18 59 49 2 11 17 10 10 9 3 4 3 3 20 15 4 4 1 3 3
1.88 0.93 3.78 1.95 1.89 1.76 1.70 1.61 21.32 3.71 2.78 2.07 1.40 1.96 2.11 6.70 0.77 4.12 2.83 3.77 3.74 5.17 8.99 5.08 2.06 3.21
1.65–2.13 0.25–2.38 1.39–8.23 0.78–4.01 1.24–2.77 0.57–4.10 1.01–2.69 1.22–2.07 15.77–28.18 0.45–13.42 1.39–4.98 1.21–3.31 0.67–2.58 0.94–3.61 0.97–4.01 1.40–19.86 0.21–1.97 0.85–12.05 0.58–8.28 2.30–5.83 2.09–6.17 1.41–13.24 2.45–23.03 0.13–28.28 0.43–6.03 0.66–9.38
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Table 2. SIRs for second cancer in patients diagnosed with testicular cancer according to histological type and age at diagnosis
Bold type: 95% CI does not include 1.00. SIR, standardized incidence ratio; O, observed; CI, confidence interval; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia.
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original article
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cancers recorded in seminoma and nonseminoma patients any time until the year 2006. Shown are only sites with at least five cases in total or with significant results. After seminoma, 193 (6.4%) second cancers were diagnosed; 63 (2.1%) testicular cancers were excluded from this figure. The respective figures after nonseminoma were 81 (3.2%) and 33 (1.3%). Second testicular cancer showed an SIR of 29 after seminoma and an SIR of 13 after nonseminoma. All other sites combined showed an SIR of 1.93 after seminoma and an SIR of 2.14 after nonseminoma. A total of 10 discordant sites were increased after seminoma, with the highest SIRs for eye (8.92), thyroid (5.24) and esophageal cancers (4.95). Among leukemia subtypes, only acute myeloid leukemia was significantly increased (6.60). The number of cases was fewer after nonseminoma and cancers only at seven discordant sites were increased. Notably, no increases were noted for gastrointestinal tract cancers. Sites increased only after nonseminoma were male genital (10.92), bladder (3.23) and squamous cell skin (3.77) cancers; the five skin cancers were located in various parts of the body. Chronic myeloid leukemia (8.24) was the only significant leukemia subtype.
Table 2 shows separate analyses for second cancers following testicular cancers diagnosed before age 30 or later. Second testicular cancer was increased in young (<30 years) seminoma patients more (SIR 35) than in older ones (26); for nonseminoma, the difference was small (13 versus 12). After both seminoma and nonseminoma, the SIRs of all discordant subsequent cancers were higher when testicular cancer was diagnosed before age 30, i.e. 2.71 versus 1.91 after seminoma and 3.78 versus 1.79 after nonseminoma. All significant increases after seminoma diagnosed after age 29 years were in line with Table 1. For subsequent cancers after nonseminoma diagnosed before age 30, high SIRs were recorded for kidney (23.26), bladder (8.59) and connective tissue (11.59) cancers. Unfortunately, the body parts of the connective tissue tumors were not specified. In Table 3, the effect of follow-up was analyzed. The risk for second testicular cancer is very high within the year of the initial diagnosis but it remained elevated even 10–19 years later (14.10 after seminoma and 12.02 after nonseminoma). Discordant cancers diagnosed within the year of testicular cancer diagnosis showed the highest SIRs but these constituted
Table 3. SIRs for second cancer in patients diagnosed with seminoma and nonseminoma testicular cancer according to time after diagnosis Second cancer site
Seminoma All excluding testis Esophagus Stomach Colorectum Pancreas Lung Prostate Testis Kidney Urinary bladder Skin Skin, squamous cell Connective tissue Non-Hodgkin’s lymphoma Leukemia Nonseminoma All excluding testis Colorectum Lung Prostate Testis Kidney Urinary bladder Skin Skin, squamous cell Connective tissue Non-Hodgkin’s lymphoma Leukemia
Years after first primary cancer diagnosis <1 1–9 O SIR 95% CI O SIR 95% CI 20 2 1
4 33 6 2
2
11 1 2 14 2 1 1 1 1 1
4.04
2.47–6.23
5.96
2.98–10.67
10–19 O SIR
95% CI
20+ O SIR
95% CI
1+ O
SIR
95% CI
71 1.49 1.16–1.88 81 2.11 1.67–2.62 21 2.40 1.48–3.66 173 1.82 1.56–2.12 3 5.24 1.08–15.32 3 6.24 1.29–18.25 6 5.18 1.90–11.28 11.23 1.36–40.57 1 0.68 0.02–3.79 5 5.18 1.68–12.10 6 2.29 0.84–4.98 1.88 0.05–10.47 2 0.39 0.05–1.40 11 2.66 1.33–4.75 7 7.78 3.13–16.04 20 1.96 1.20–3.02 2 1.82 0.22–6.58 2 2.45 0.30–8.86 2 12.05 1.46–43.53 6 2.89 1.06–6.28 6 1.49 0.55–3.24 6 1.94 0.71–4.23 2 3.20 0.39–11.57 14 1.81 0.99–3.03 3.72 1.01–9.53 13 1.09 0.58–1.87 21 1.71 1.06–2.61 3 0.85 0.18–2.50 37 1.34 0.94–1.84 130.50 89.83–183.27 23 15.95 10.11–23.93 6 14.10 5.17–30.69 1 34.21 0.87–190.63 30 15.81 10.67–22.58 35.64 13.08–77.58 3 1.94 0.40–5.66 2 1.84 0.22–6.65 5 1.76 0.57–4.10 6.19 0.75–22.36 5 1.62 0.53–3.79 4 1.63 0.44–4.17 1 1.88 0.05–10.46 10 1.65 0.79–3.03 6 3.22 1.18–7.00 6 1.55 0.57–3.38 6 3.98 1.46–8.67 6 1.85 0.68–4.02 1 2.18 0.05–12.16 1 3.60 0.10–20.06 1 19.91 0.50–110.90 3 3.82 0.79–11.15 8.92 1.08–32.23 6 2.84 1.04–6.18 4 2.68 0.73–6.85 2 7.08 0.86–25.56 12 3.09 1.59–5.39 7 4.45 1.79–9.17 4 3.46 0.94–8.86 1 4.33 0.11–24.13 12 4.06 2.10–7.08 27
1.71
7.20 0.18–40.11 1 6.60 0.80–23.85 5 63.16 34.53–105.97 11 36.43 4.41-131.62 3 10.02 0.25–55.84 4 15.41 0.39–85.84 22.72 0.58–126.57 2 10.53 0.27–58.68 2 11.54 0.29–64.29 5
0.89 1.89 6.88 5.97 4.48
8.62 2.34 7.51
1.13–2.48
39 2.38 7 4.16 0.02–4.95 3 2.56 0.61–4.42 11 2.73 3.43–12.31 8 12.02 1.23–17.43 1.22–11.48 2 2.09 3 5.25 1 2.22 1.01–31.15 0.28–8.44 3 3.79 2.44–17.53
1.69–3.26 1.67–8.58 0.53–7.48 1.36–4.88 5.19–23.68
4 1
1.03 0.28–2.64 2.64 0.07–14.71
0.25–7.55 1.08–15.34 0.06–12.36
1 1
7.82 0.20–43.59 9.12 0.23–50.80
0.78–11.08
1
6.40 0.16–35.68
70 8 4 16 19 3 6 4 2 2 6 5
1.94 2.19 1.56 2.01 8.18 2.64 2.90 3.17 2.12 4.59 3.33 3.62
1.51–2.45 0.95–4.32 0.42–3.99 1.15–3.26 4.93–12.78 0.54–7.71 1.06–6.31 0.86–8.12 0.26–7.66 0.57–16.59 1.22–7.24 1.17–8.44
Bold type: 95% CI does not include 1.00. SIR, standardized incidence ratio; O, observed; CI, confidence interval.
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original article <15% of all subsequent cancers. For any subsequent cancer showing increased SIRs after seminoma increase were noted at least in one period after the first year of testicular cancer diagnosis, for example, squamous cell skin (3.22, 1–9 years), colorectal (7.78, 20+ years) and pancreatic (12.05, 20+ years) cancers. Similarly, for subsequent cancers after nonseminoma, significant increases were observed for any increased site even after the first year of testicular cancer diagnosis. High SIRs were noted for connective tissue (8.62), leukemia (7.51), kidney (5.97) and bladder (4.48) cancers 1–9 years after testicular cancer diagnosis. In Table 3, as in other tables, high risks for second testicular cancer were observed. Of the 96 second testicular cancers, 53 were in the contralateral testis, 8 were in the same testis (all diagnosed with the first year of the initial diagnosis) and for the remaining 35, no side information was available.
discussion In studies of subsequent cancers, it is often debated whether synchronous discordant cancers should be included because they may be affected by lead time bias, i.e. they are diagnosed earlier than in cases without diagnosis of the first cancer. In the Swedish Cancer Registry, 99% of the diagnoses are histologically or cytologically verified [27]. Thus, excluding synchronous cancers would cause a deficit in subsequent observation periods. In the present study, we included all cancers diagnosed after testicular cancer. The risks for many cancers were high in the first year after testicular cancer diagnosis but the case numbers corresponded to £15% of all discordant cases. The risk of second testicular cancer is well known but many recent large studies have not included concordant tumors because many cancer registries do not record them. A small clinical study adhering to the current treatment protocol found 2.5% (5.2% after pure seminoma and 1.2% after nonseminoma) of the testicular cancer patients to be diagnosed with a contralateral tumor [28]. The present figures for second testicular cancer were 2.1% after seminoma and 1.3% after nonseminoma; however, a proportion of cases lacked data on laterality. The SIRs for second testicular cancer diagnosed within 1 year of the initial diagnosis were 130 after seminoma and 63 after nonseminoma. After seminoma, the SIRs remained at 15 up to 20 years of follow-up; after nonseminoma, they varied between 7 and 12. The initial very high risks were obviously contributed by lead time bias but even the subsequent risks were high enough to warrant alertness in the patient follow-up. Therapy is likely to contribute to the high risks but even other factors such as shared risk factors and individual susceptibility found for many types of multiple cancers may be present [29, 30]. Also nontesticular second tumors were more common (6.4%) after seminoma than after nonseminoma (3.2%). In our earlier Swedish study, on cases diagnosed from 1958 to 1996, the percentages were 8.4 and 3.4, respectively [31]. In the present study, the SIRs for all nontesticular tumors were 1.93 after seminoma and 2.14 after nonseminoma. Risks for second cancer were high if nonseminoma was diagnosed before age 30 (3.78 compared with 2.71 after seminoma) and they
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decreased for patients treated at an older age (1.79 after nonseminoma and 1.91 after seminoma). The case numbers were limited to make definite statements about the spectrum of individual cancer sites after seminoma and nonseminoma. However, gastrointestinal tract cancers occurred mainly after seminoma and bladder cancers occurred after nonseminoma. The risk of bladder cancer was 8.59 and that of connective tissue cancer was 11.59 in patients treated for nonseminoma before age 30. Other tumors that preferentially occurred in nonseminoma patients where squamous cell skin cancer and chronic myeloid leukemia. Acute and chronic myeloid leukemias have previously been associated with chemotherapyrelated late effects of testicular cancer treatment while gastrointestinal tract tumors have been associated with supradiaphragmatic radiotherapy [14, 16, 32, 33]. Bladder, skin and connective tissue cancers can all be induced by radiation therapy and it is also possible that they are induced by chemotherapy [20]. Active ingredients of the BEP regimen are likely to be excreted in bladder with a possibility to transform bladder epithelial cells. The possible association of bladder cancer with therapy for nonseminoma needs to be considered in future studies.
funding Deutsche Krebshilfe; Swedish Cancer Society; Swedish Council for Working Life and Social Research.
acknowledgement The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.
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12. Huddart R, Kataja V. Testicular seminoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008; 19 (Suppl 2): ii49–ii51. 13. Huddart R, Kataja V. Mixed or non-seminomatous germ-cell tumors: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008; 19 (Suppl 2): ii52–ii54. 14. Travis LB, Fossa SD, Schonfeld SJ et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005; 97: 1354–1365. 15. Howard RA, Gilbert ES, Chen BE et al. Leukemia following breast cancer: an international population-based study of 376,825 women. Breast Cancer Res Treat 2007; 105: 359–368. 16. Richiardi L, Scelo G, Boffetta P et al. Second malignancies among survivors of germ-cell testicular cancer: a pooled analysis between 13 cancer registries. Int J Cancer 2006; 120(3): 623–631. 17. Metayer C, Lynch C, Clarke E et al. Second cancers among long-term survivors of Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol 2000; 18: 2435–2443. 18. Swerdlow A, Barber J, Hudson G et al. Risk of second malignancy after Hodgkin’s disease in a collaborative British cohort: the relation to age at treatment. J Clin Oncol 2000; 18: 498–509. 19. Maule M, Scelo G, Pastore G et al. Risk of second malignant neoplasms after childhood leukemia and lymphoma: an international study. J Natl Cancer Inst 2007; 99: 790–800. 20. Hemminki K, Lenner P, Sundquist J, Bermejo JL. Risk of subsequent solid tumors after non-Hodgkin’s lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 2008; 26: 1850–1857. 21. Hemminki K, Li X, Plna K et al. The nation-wide Swedish Family-Cancer Database: updated structure and familial rates. Acta Oncol 2001; 40: 772–777.
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original article 22. Hemminki K, Ji J, Brandt A et al. The Swedish Family-Cancer Database 2009: prospects for histology-specific and immigrant studies. Int J Cancer 2009; doi: 10.1002/ijc.24795. 23. Fro¨din J-E, Ericsson J, Barlow L. Multiple primary malignant tumors in a national cancer registry. Reliability of reporting. Acta Oncol 1997; 36: 465–469. 24. Breslow NE, Day NE. Statistical methods in cancer research. Volume II—the design and analysis of cohort studies. IARC Sci Publ 1987; (82): 1–406. 25. IARC. Quantitative Estimation and Prediction of Human Cancer Risks. Lyon, France: IARC Press 1999. 26. dos Santos Silva I. Cancer Epidemiology: Principles and Methods. Lyon, France: IARC 1999. 27. Centre for Epidemiology. Cancer Incidence in Sweden 2005. Stockholm, Sweden: The National Board of Health and Welfare 2007. 28. van der Poel H, Sedelaar J, Debruyne F, Witjes J. Recurrence of germ cell tumor after orchiectomy. Urology 2000; 56: 467–473. 29. Dong C, Hemminki K. Second primary neoplasms in 633,964 cancer patients in Sweden, 1958–1996. Int J Cancer 2001; 93: 155–161. 30. Travis LB. The epidemiology of second primary cancers. Cancer Epidemiol Biomarkers Prev 2006; 15: 2020–2026. 31. Dong C, Lonnstedt I, Hemminki K. Familial testicular cancer and second primary cancers in testicular cancer patients by histological type. Eur J Cancer 2001; 37: 1878–1885. 32. Wierecky J, Kollmannsberger C, Boehlke I et al. Secondary leukemia after firstline high-dose chemotherapy for patients with advanced germ cell cancer. J Cancer Res Clin Oncol 2005; 131: 255–260. 33. Howard R, Gilbert E, Lynch CF et al. Risk of leukemia among survivors of testicular cancer: a population-based study of 42,722 patients. Ann Epidemiol 2008; 18: 416–421.
doi:10.1093/annonc/mdp562 | 1551
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Annals of Oncology 21: 1546–1551, 2010 doi:10.1093/annonc/mdp562 Published online 17 December 2009
Second cancers after testicular cancer diagnosed after 1980 in Sweden K. Hemminki1,2,3*, H. Liu1 & J. Sundquist2,4 1
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany; 2Center for Primary Health Care Research, Lund University, Malmo¨; 3Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden and 4Stanford Prevention Research Center, Stanford University School of Medicine, CA, USA
Received 27 October 2009; accepted 5 November 2009
original article
Background: Testicular cancer treatment has become standardized in the 1980s involving radiotherapy preferentially for seminoma and chemotherapy for nonseminoma. The late effects of these therapeutic practices have not been properly evaluated because of the relatively short time since their application. Patients and methods: We conducted a study among 5533 survivors of testicular cancer on the basis of Swedish Family-Cancer Database for which the cancer data were retrieved from the nationwide Cancer Registry. Standardized incidence ratios (SIRs) of second cancer were calculated by comparing with the rates of the first cancers. The followup was started in 1980 and carried on through 2006. Results: A total of 370 second cancers (6.7% of all patients) were recorded, more in seminoma than in nonseminoma patients. Second testicular cancer showed an SIR of 29 after seminoma and an SIR of 13 after nonseminoma. A total of 10 discordant sites were increased after seminoma compared with seven sites after nonseminoma. Gastrointestinal tract cancers occurred mainly after seminoma and bladder cancers (SIR 8.6 when diagnosis before age 30) occurred after nonseminoma. Conclusions: Of the selective affected second tumors, it will be important to confirm the association of bladder cancer with nonseminoma treatment. Key words: chemotherapy, multiple cancers, radiotherapy, seminoma, teratoma
introduction The incidence of testicular cancer has increased in many countries, including Sweden, for unknown reasons and it is the most frequently occurring cancer in young white men [1, 2]. The known risk factors for testicular cancer include undescended testis (cryptorchidism), in utero hormonal exposures, testicular dysfunction, perinatal factors, prior history of cancer in one testis (the opposite testis is at increased risk) and family history of testicular cancer [2, 3]. The firstgeneration immigrants to Sweden and Denmark show generally a decreased risk of testicular cancer compared with the natives, but this difference tends to disappear in the next generation born in the new host country, indicating a role for environmental factors [4–8]. Testicular cancers are predominantly germ-cell tumors of two main types, seminomas and nonseminomas; the later include teratomas, with somatic differentiation, and undifferentiated embryonal tumors [3]. However, about one half of the germ-cell tumors of the testis contain multiple histological types and the remainder contains *Correspondence to: Dr K. Hemminki, Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Tel: +49-6221-42-1800; Fax: +49-6221-42-1810; E-mail: [email protected]
a single histological type [3]. Similar incidence trends in seminoma and nonseminoma have been indicated to imply sharing of etiological factors between the histological types [9]. Survival in testicular cancer is high with a 10-year relative survival of >95% for both seminoma and nonseminoma in Sweden since the current treatment and diagnostic modalities were consolidated [10]. The treatment depends on whether the disease is localized or metastatic, including orchiectomy and primarily radiation for seminoma and BEP (bleomycin, etoposide and cisplatin) for nonseminoma and mixed tumors [11–13]. For metastatic seminoma, the radiation therapy is intensified and targeted into wider fields, and BEP may be administered; for nonseminoma and mixed tumors, more cycles of BEP are administered. As these therapeutic principles with some variation were taken to use in the 1980s, the maximal follow-up times of the surviving patients are barely exceeding two decades. Previous large studies on survivors of testicular cancer reported an increased risk of several second malignancies but, as the follow-up times ended at or before the year 2000, the number of patients treated with the current protocols was small and no second testicular cancer were included [14–16]. For example, the multicenter study of 13 cancer registries with 29 500 testicular cancer patients included only 491 second cancers (27%) in testicular cancer patients
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
diagnosed since 1980 [16]. In that study, Swedish patients diagnosed from 1961 to 1998 constituted 16.3% of the study population. Considering that the effects of radiotherapy and chemotherapy may extend to at least four decades, it is important that testicular cancers are followed for the effects of the treatments adopted in the 1980s [14–20]. We conducted a study among 5533 survivors of testicular cancer on the basis of Swedish Family-Cancer Database for which the cancer data were retrieved from the nationwide Cancer Registry. The follow-up was started in 1980 and carried on through 2006 covering the time of relatively standard treatment protocols for the two main types of testicular cancers. All cancers including second testicular cancers were included in the follow-up.
Cancer Registry found 98% to be correctly classified [23]. In the present analyses, 5533 patients with first primary testicular cancer were followed from diagnosis after 1 January 1980 until death, detection of a second primary cancer, emigration or 31 December 2006, whichever came first. Second cancers were classified as such by the Cancer Registry, including synchronous tumors. The incidences of second malignancies among testicular cancer patients were compared with the rates in the general Swedish population by standardized incidence ratios (SIRs) and 95% confidence intervals (CIs), adjusting for covariates age (5 year bands), sex, socioeconomic index (six groups), region (four groups) and calendar year (1961–1965, 1965–1969, . , 2000–2004). Separate analyses were carried out according to age at testicular cancer diagnosis (20–39, 40–49, 50–59, 60–69 and 70+ years), time since testicular cancer diagnosis (0–10, 11–20, 21–30 and 31+ years) and period of testicular cancer diagnosis (1961–2004 and 1975–2004). SIR applies indirect standardization, which is particularly suitable for cells with small numbers of subjects [24–26]. In this method, the observed numbers of cases are divided by the expected numbers of cases, calculated from the whole background population of 11.8 million. CIs (95%) were calculated assuming a Poisson distribution. SAS software version 9.1 was used for data analysis.
patients and methods The Swedish Family-Cancer Database was first assembled from the national databases in 1996 and since then it has been periodically updated most recently in 2008 [21, 22]. The database contains those born in Sweden since 1932 with their biological parents, totaling >11.8 million persons and >1.2 million tumor notifications. Cancer cases were retrieved from the Swedish Cancer Registry, which relies on separate compulsory notifications from clinicians who diagnosed the neoplasms and pathologists/cytologists. All registered testicular cancers cases are histologically verified. An ad hoc study on the diagnostic accuracy of second neoplasms in the Swedish
results The Family-Cancer Database included 3001 seminomas and 2532 nonseminomas diagnosed since the year 1980. Table 1 shows SIRs for a total of 370 (6.7% of all patients) second
Table 1. SIRs for second cancer in patients diagnosed with testicular cancer according to histological type Second cancer site All excluding testis Upper aerodigestive tract Esophagus Stomach Colorectum Pancreas Lung Prostate Testis Other male genital organs Kidney Urinary bladder Melanoma Skin Skin, squamous cell Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin’s lymphoma Leukemia AML CML ALL CLL Others
Seminoma O SIR
95% CI
193 4 6 8 21 6 14 41 63 1 11 12 8 6 6 3 5 3 3 14 12 4 2 1 3 2
1.67–2.23 0.33–3.13 1.82–10.78 1.23–5.63 1.21–2.99 1.00–5.94 0.94–2.88 1.02–1.93 22.52–37.49 0.06–13.56 1.82–6.53 0.97–3.28 0.62–2.85 0.54–3.23 0.65–3.85 1.84–26.07 0.40–2.86 1.08–15.31 0.74–10.43 1.86–5.71 1.98–6.68 1.80–16.89 0.68–20.16 0.16–34.16 0.55–7.82 0.33–9.94
1.93 1.22 4.95 2.86 1.95 2.73 1.72 1.43 29.30 2.43 3.65 1.88 1.45 1.48 1.77 8.92 1.22 5.24 3.57 3.40 3.83 6.60 5.58 6.13 2.68 2.75
Nonseminoma O SIR
95% CI
81 2
2.14 1.47
1.70–2.66 0.18–5.30
8
2.09
0.90–4.12
5 18 33 2 5 7 3 5 3
1.85 2.17 12.97 10.92 4.19 3.23 0.95 3.77 3.04
0.60–4.31 1.29–3.44 8.93–18.22 1.32–39.46 1.36–9.79 1.30–6.65 0.20–2.78 1.22–8.80 0.63–8.88
4 1 2 7 6 1 2 1
1.56 2.74 4.29 3.69 4.08 3.42 8.24 6.87
0.42–3.99 0.07–15.25 0.52–15.51 1.48–7.60 1.50–8.89 0.09–19.03 1.00–29.76 0.17–38.26
2
6.32
0.77–22.82
Total O
SIR
95% CI
274 6 6 8 29 6 19 59 96 3 16 19 11 11 9 3 9 4 5 21 18 5 4 2 3 4
1.99 1.29 3.66 2.12 1.99 2.03 1.75 1.59 20.45 5.05 3.81 2.22 1.27 2.05 2.06 5.96 1.35 4.26 3.83 3.49 3.91 5.56 6.65 6.48 1.99 3.83
1.76–2.24 0.47–2.82 1.34–7.97 0.92–4.18 1.33–2.86 0.74–4.42 1.05–2.73 1.21–2.06 16.57–24.98 1.04–14.76 2.18–6.18 1.34–3.47 0.63–2.26 1.02–3.66 0.94–3.90 1.23–17.43 0.62–2.57 1.16–10.92 1.24–8.93 2.16–5.34 2.32–6.18 1.81–12.98 1.81–17.04 0.78–23.40 0.41–5.80 1.04–9.82
Bold type: 95% CI does not include 1.00. SIR, standardized incidence ratio; O, observed; CI, confidence interval; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia.
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Second cancer site
All excluding testis Upper aerodigestive tract Esophagus Stomach Colorectum Pancreas Lung Prostate Testis Other male genital organs Kidney Urinary bladder Melanoma Skin Skin, squamous cell Eye Nervous system Thyroid gland Connective tissue Non-Hodgkin’s lymphoma Leukemia AML CML ALL CLL Others
Seminoma <30 O SIR
95% CI
8 1
2.71 9.13
1.17–5.34 0.23–50.89
1 1 1
16.73 3.78 27.43
0.42–93.20 0.10–21.08 0.69–152.82
24
35.87
22.98–53.37
1
11.97
0.30–66.69
2
4.68
0.57–16.91
‡30 O
SIR
95% CI
185 3 6 7 20 5 14 41 39 1 10 12 8 6 6 3 3 3 3 14 12 4 2 1 3 2
1.91 0.95 5.03 2.56 1.91 2.31 1.74 1.43 26.34 2.55 3.41 1.91 1.58 1.51 1.78 9.42 0.82 5.87 3.92 3.59 4.05 7.01 6.45 7.25 2.72 2.89
1.64–2.21 0.20–2.77 1.85–10.95 1.03–5.27 1.17–2.95 0.75–5.40 0.95–2.91 1.03–1.94 18.73–36.00 0.06–14.20 1.64–6.28 0.99–3.34 0.68–3.11 0.56–3.30 0.66–3.90 1.94–27.53 0.17–2.40 1.21–17.14 0.80–11.44 1.96–6.03 2.09–7.07 1.91–17.94 0.78–23.29 0.18–40.40 0.56–7.96 0.35–13.35
Nonseminoma <30 O SIR 95% CI
‡30 O SIR
95% CI
Total <30 O SIR
25 1
3.78 4.64
2.45–5.58 0.12–25.88
56 1
1.79 0.87
1.35–2.32 0.02–4.85
33 2
3.45 6.16
2.37–4.84 0.75–22.24
2
3.59
0.43–12.96
6
1.83
0.67–3.99
1
5.48
0.14–30.51 8.45–20.00 0.68–150.11 6.44–60.48 1.04–31.03 0.02–5.10 0.14–29.84
0.43–4.06 1.32–3.51 5.86–22.49 0.17–38.16 0.02–5.45 0.84–6.02 0.12–3.50 0.96–8.99 0.68–9.65
0.15–31.98 0.75–10.67 0.23–51.47 0.09–19.55
13.33 26.94 23.62 8.59 0.91 5.36
1.59 2.22 12.23 6.85 0.98 2.58 0.97 3.51 3.30
5.74 3.65 9.24 3.51
23 1 4 2 1 1
4 18 10 1 1 5 2 4 3
1 3 1 1 47 1 5 2 1 1
19.62 17.94 19.77 5.81 0.64 3.69
14.42–26.10 0.45–99.97 6.42–46.14 0.70–20.99 0.02–3.56 0.10–20.56
3 1 2 1 3 1
2.91 6.71 11.59 2.02 7.07 11.12
0.60–8.50 0.17–37.40 1.40–41.87 0.02–11.26 1.46–20.66 0.28–61.93
1
0.65
0.02–3.63
6 3
4.27 2.87
1.57–9.30 0.59–8.39
5 1 2 1 3 1
3.43 4.76 8.10 1.41 5.03 7.97
1.11–8.00 0.12–26.53 0.98–29.28 0.04–7.85 1.04–14.70 0.20–44.42
2
14.87
1.80–53.72
1
11.56
0.29–64.40
1
8.95
0.23–49.88
1
13.35
0.34–74.40
1
9.20
0.23–51.26
1
4.14
0.10–23.06
95% CI
‡30 O
SIR
95% CI
241 4 6 7 26 5 18 59 49 2 11 17 10 10 9 3 4 3 3 20 15 4 4 1 3 3
1.88 0.93 3.78 1.95 1.89 1.76 1.70 1.61 21.32 3.71 2.78 2.07 1.40 1.96 2.11 6.70 0.77 4.12 2.83 3.77 3.74 5.17 8.99 5.08 2.06 3.21
1.65–2.13 0.25–2.38 1.39–8.23 0.78–4.01 1.24–2.77 0.57–4.10 1.01–2.69 1.22–2.07 15.77–28.18 0.45–13.42 1.39–4.98 1.21–3.31 0.67–2.58 0.94–3.61 0.97–4.01 1.40–19.86 0.21–1.97 0.85–12.05 0.58–8.28 2.30–5.83 2.09–6.17 1.41–13.24 2.45–23.03 0.13–28.28 0.43–6.03 0.66–9.38
original article
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Table 2. SIRs for second cancer in patients diagnosed with testicular cancer according to histological type and age at diagnosis
Bold type: 95% CI does not include 1.00. SIR, standardized incidence ratio; O, observed; CI, confidence interval; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia.
Annals of Oncology
Volume 21 | No. 7 | July 2010
original article
Annals of Oncology
cancers recorded in seminoma and nonseminoma patients any time until the year 2006. Shown are only sites with at least five cases in total or with significant results. After seminoma, 193 (6.4%) second cancers were diagnosed; 63 (2.1%) testicular cancers were excluded from this figure. The respective figures after nonseminoma were 81 (3.2%) and 33 (1.3%). Second testicular cancer showed an SIR of 29 after seminoma and an SIR of 13 after nonseminoma. All other sites combined showed an SIR of 1.93 after seminoma and an SIR of 2.14 after nonseminoma. A total of 10 discordant sites were increased after seminoma, with the highest SIRs for eye (8.92), thyroid (5.24) and esophageal cancers (4.95). Among leukemia subtypes, only acute myeloid leukemia was significantly increased (6.60). The number of cases was fewer after nonseminoma and cancers only at seven discordant sites were increased. Notably, no increases were noted for gastrointestinal tract cancers. Sites increased only after nonseminoma were male genital (10.92), bladder (3.23) and squamous cell skin (3.77) cancers; the five skin cancers were located in various parts of the body. Chronic myeloid leukemia (8.24) was the only significant leukemia subtype.
Table 2 shows separate analyses for second cancers following testicular cancers diagnosed before age 30 or later. Second testicular cancer was increased in young (<30 years) seminoma patients more (SIR 35) than in older ones (26); for nonseminoma, the difference was small (13 versus 12). After both seminoma and nonseminoma, the SIRs of all discordant subsequent cancers were higher when testicular cancer was diagnosed before age 30, i.e. 2.71 versus 1.91 after seminoma and 3.78 versus 1.79 after nonseminoma. All significant increases after seminoma diagnosed after age 29 years were in line with Table 1. For subsequent cancers after nonseminoma diagnosed before age 30, high SIRs were recorded for kidney (23.26), bladder (8.59) and connective tissue (11.59) cancers. Unfortunately, the body parts of the connective tissue tumors were not specified. In Table 3, the effect of follow-up was analyzed. The risk for second testicular cancer is very high within the year of the initial diagnosis but it remained elevated even 10–19 years later (14.10 after seminoma and 12.02 after nonseminoma). Discordant cancers diagnosed within the year of testicular cancer diagnosis showed the highest SIRs but these constituted
Table 3. SIRs for second cancer in patients diagnosed with seminoma and nonseminoma testicular cancer according to time after diagnosis Second cancer site
Seminoma All excluding testis Esophagus Stomach Colorectum Pancreas Lung Prostate Testis Kidney Urinary bladder Skin Skin, squamous cell Connective tissue Non-Hodgkin’s lymphoma Leukemia Nonseminoma All excluding testis Colorectum Lung Prostate Testis Kidney Urinary bladder Skin Skin, squamous cell Connective tissue Non-Hodgkin’s lymphoma Leukemia
Years after first primary cancer diagnosis <1 1–9 O SIR 95% CI O SIR 95% CI 20 2 1
4 33 6 2
2
11 1 2 14 2 1 1 1 1 1
4.04
2.47–6.23
5.96
2.98–10.67
10–19 O SIR
95% CI
20+ O SIR
95% CI
1+ O
SIR
95% CI
71 1.49 1.16–1.88 81 2.11 1.67–2.62 21 2.40 1.48–3.66 173 1.82 1.56–2.12 3 5.24 1.08–15.32 3 6.24 1.29–18.25 6 5.18 1.90–11.28 11.23 1.36–40.57 1 0.68 0.02–3.79 5 5.18 1.68–12.10 6 2.29 0.84–4.98 1.88 0.05–10.47 2 0.39 0.05–1.40 11 2.66 1.33–4.75 7 7.78 3.13–16.04 20 1.96 1.20–3.02 2 1.82 0.22–6.58 2 2.45 0.30–8.86 2 12.05 1.46–43.53 6 2.89 1.06–6.28 6 1.49 0.55–3.24 6 1.94 0.71–4.23 2 3.20 0.39–11.57 14 1.81 0.99–3.03 3.72 1.01–9.53 13 1.09 0.58–1.87 21 1.71 1.06–2.61 3 0.85 0.18–2.50 37 1.34 0.94–1.84 130.50 89.83–183.27 23 15.95 10.11–23.93 6 14.10 5.17–30.69 1 34.21 0.87–190.63 30 15.81 10.67–22.58 35.64 13.08–77.58 3 1.94 0.40–5.66 2 1.84 0.22–6.65 5 1.76 0.57–4.10 6.19 0.75–22.36 5 1.62 0.53–3.79 4 1.63 0.44–4.17 1 1.88 0.05–10.46 10 1.65 0.79–3.03 6 3.22 1.18–7.00 6 1.55 0.57–3.38 6 3.98 1.46–8.67 6 1.85 0.68–4.02 1 2.18 0.05–12.16 1 3.60 0.10–20.06 1 19.91 0.50–110.90 3 3.82 0.79–11.15 8.92 1.08–32.23 6 2.84 1.04–6.18 4 2.68 0.73–6.85 2 7.08 0.86–25.56 12 3.09 1.59–5.39 7 4.45 1.79–9.17 4 3.46 0.94–8.86 1 4.33 0.11–24.13 12 4.06 2.10–7.08 27
1.71
7.20 0.18–40.11 1 6.60 0.80–23.85 5 63.16 34.53–105.97 11 36.43 4.41-131.62 3 10.02 0.25–55.84 4 15.41 0.39–85.84 22.72 0.58–126.57 2 10.53 0.27–58.68 2 11.54 0.29–64.29 5
0.89 1.89 6.88 5.97 4.48
8.62 2.34 7.51
1.13–2.48
39 2.38 7 4.16 0.02–4.95 3 2.56 0.61–4.42 11 2.73 3.43–12.31 8 12.02 1.23–17.43 1.22–11.48 2 2.09 3 5.25 1 2.22 1.01–31.15 0.28–8.44 3 3.79 2.44–17.53
1.69–3.26 1.67–8.58 0.53–7.48 1.36–4.88 5.19–23.68
4 1
1.03 0.28–2.64 2.64 0.07–14.71
0.25–7.55 1.08–15.34 0.06–12.36
1 1
7.82 0.20–43.59 9.12 0.23–50.80
0.78–11.08
1
6.40 0.16–35.68
70 8 4 16 19 3 6 4 2 2 6 5
1.94 2.19 1.56 2.01 8.18 2.64 2.90 3.17 2.12 4.59 3.33 3.62
1.51–2.45 0.95–4.32 0.42–3.99 1.15–3.26 4.93–12.78 0.54–7.71 1.06–6.31 0.86–8.12 0.26–7.66 0.57–16.59 1.22–7.24 1.17–8.44
Bold type: 95% CI does not include 1.00. SIR, standardized incidence ratio; O, observed; CI, confidence interval.
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original article <15% of all subsequent cancers. For any subsequent cancer showing increased SIRs after seminoma increase were noted at least in one period after the first year of testicular cancer diagnosis, for example, squamous cell skin (3.22, 1–9 years), colorectal (7.78, 20+ years) and pancreatic (12.05, 20+ years) cancers. Similarly, for subsequent cancers after nonseminoma, significant increases were observed for any increased site even after the first year of testicular cancer diagnosis. High SIRs were noted for connective tissue (8.62), leukemia (7.51), kidney (5.97) and bladder (4.48) cancers 1–9 years after testicular cancer diagnosis. In Table 3, as in other tables, high risks for second testicular cancer were observed. Of the 96 second testicular cancers, 53 were in the contralateral testis, 8 were in the same testis (all diagnosed with the first year of the initial diagnosis) and for the remaining 35, no side information was available.
discussion In studies of subsequent cancers, it is often debated whether synchronous discordant cancers should be included because they may be affected by lead time bias, i.e. they are diagnosed earlier than in cases without diagnosis of the first cancer. In the Swedish Cancer Registry, 99% of the diagnoses are histologically or cytologically verified [27]. Thus, excluding synchronous cancers would cause a deficit in subsequent observation periods. In the present study, we included all cancers diagnosed after testicular cancer. The risks for many cancers were high in the first year after testicular cancer diagnosis but the case numbers corresponded to £15% of all discordant cases. The risk of second testicular cancer is well known but many recent large studies have not included concordant tumors because many cancer registries do not record them. A small clinical study adhering to the current treatment protocol found 2.5% (5.2% after pure seminoma and 1.2% after nonseminoma) of the testicular cancer patients to be diagnosed with a contralateral tumor [28]. The present figures for second testicular cancer were 2.1% after seminoma and 1.3% after nonseminoma; however, a proportion of cases lacked data on laterality. The SIRs for second testicular cancer diagnosed within 1 year of the initial diagnosis were 130 after seminoma and 63 after nonseminoma. After seminoma, the SIRs remained at 15 up to 20 years of follow-up; after nonseminoma, they varied between 7 and 12. The initial very high risks were obviously contributed by lead time bias but even the subsequent risks were high enough to warrant alertness in the patient follow-up. Therapy is likely to contribute to the high risks but even other factors such as shared risk factors and individual susceptibility found for many types of multiple cancers may be present [29, 30]. Also nontesticular second tumors were more common (6.4%) after seminoma than after nonseminoma (3.2%). In our earlier Swedish study, on cases diagnosed from 1958 to 1996, the percentages were 8.4 and 3.4, respectively [31]. In the present study, the SIRs for all nontesticular tumors were 1.93 after seminoma and 2.14 after nonseminoma. Risks for second cancer were high if nonseminoma was diagnosed before age 30 (3.78 compared with 2.71 after seminoma) and they
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decreased for patients treated at an older age (1.79 after nonseminoma and 1.91 after seminoma). The case numbers were limited to make definite statements about the spectrum of individual cancer sites after seminoma and nonseminoma. However, gastrointestinal tract cancers occurred mainly after seminoma and bladder cancers occurred after nonseminoma. The risk of bladder cancer was 8.59 and that of connective tissue cancer was 11.59 in patients treated for nonseminoma before age 30. Other tumors that preferentially occurred in nonseminoma patients where squamous cell skin cancer and chronic myeloid leukemia. Acute and chronic myeloid leukemias have previously been associated with chemotherapyrelated late effects of testicular cancer treatment while gastrointestinal tract tumors have been associated with supradiaphragmatic radiotherapy [14, 16, 32, 33]. Bladder, skin and connective tissue cancers can all be induced by radiation therapy and it is also possible that they are induced by chemotherapy [20]. Active ingredients of the BEP regimen are likely to be excreted in bladder with a possibility to transform bladder epithelial cells. The possible association of bladder cancer with therapy for nonseminoma needs to be considered in future studies.
funding Deutsche Krebshilfe; Swedish Cancer Society; Swedish Council for Working Life and Social Research.
acknowledgement The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.
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