the Departments of Epidemiology, Radiotherapy, and Medical Oncology, the Netherlands Cancer Institute
    Department of Radiotherapy, Academic Medical Center Amsterdam, Amsterdam
    Department of Medical Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam
    the Department of Medical Oncology, University Medical Center Groningen, Groningen
    the Department of Radiotherapy, Dr Bernard Verbeeten Institute, Tilburg, the Netherlands

    ABSTRACT

    PURPOSE: To evaluate the long-term risk of cardiovascular disease (CVD) in survivors of testicular cancer (TC).

    PATIENTS AND METHODS: We compared CVD incidence in 2,512 5-year survivors of TC, who were treated between 1965 and 1995, with general population rates. Treatment effects on CVD risk were quantified in multivariate Cox regression analysis.

    RESULTS: After a median follow-up of 18.4 years, 694 cardiovascular events occurred, including 141 acute myocardial infarctions (MIs). The standardized incidence ratio (SIR) for coronary heart disease was 1.17 (95% CI, 1.04 to 1.31), with 14 excess cases per 10,000 person-years. The SIR for MI was significantly increased in nonseminoma survivors with attained ages of less than 45 (SIR = 2.06) and 45 to 54 years (SIR = 1.86) but significantly decreased for survivors with attained ages of 55 years or older (SIR = 0.53). In Cox analysis, mediastinal irradiation was associated with a 3.7-fold (95% CI, 2.2- to 6.2-fold) increased MI risk compared with surgery alone, whereas infradiaphragmatic irradiation was not associated with an increased MI risk. Cisplatin, vinblastine, and bleomycin (PVB) chemotherapy (CT) was associated with a 1.9-fold (95% CI, 1.7- to 2.0-fold) increased MI risk, and bleomycin, etoposide, and cisplatin (BEP) CT was associated with a 1.5-fold (95% CI, 1.0- to 2.2-fold) increased CVD risk and was not associated with increased MI risk (hazard ratio = 1.2; 95% CI, 0.7 to 2.1). Recent smoking was associated with a 2.6-fold (95% CI, 1.8- to 3.9-fold) increased MI risk.

    CONCLUSION: Nonseminomatous TC survivors experience a moderately increased MI risk at young ages. Physicians should be aware of excess CVD risk associated with mediastinal radiotherapy, PVB CT, and recent smoking. Intervention in modifiable cardiovascular risk factors is especially important in TC survivors. Whether BEP treatment increases CVD risk should be evaluated after more prolonged follow-up.

    INTRODUCTION

    Testicular cancer (TC) is the most common malignancy in men aged 20 to 40 years. Cure rates have improved dramatically since the introduction of cisplatin-containing chemotherapy (CT) in the mid-1970s.1-3 Considering the growing number of young TC survivors with a long life expectancy, evaluation of long-term treatment-related sequelae is increasingly important. Recently, TC survivors were found to experience a moderately but significantly increased risk of cardiovascular disease (CVD) after treatment with CT, radiotherapy (RT), or both compared with both TC survivors who underwent orchidectomy only4 and the general male population.5-7 However, published studies had several limitations; the numbers of cardiac events were small,5 validation of cardiac events was limited,4 and/or data on primary treatment of individual patients were lacking.6 Furthermore, although cardiac morbidity has a serious impact on quality of life and also affects life expectancy with longer follow-up, only cardiovascular mortality was investigated in the two largest studies.6,7 Finally, previous studies had insufficient numbers of patients observed for 15 years or more, whereas a treatment-related risk increase may become apparent only after extended follow-up, as demonstrated among long-term survivors of breast cancer8-11 and Hodgkin's lymphoma.12-15

    The purpose of this study was to examine long-term cardiovascular morbidity in a large Netherlands cohort of 5-year survivors of seminomatous or nonseminomatous TC who were treated between 1965 and 1995. A unique feature of our study is the long-term and near-complete follow-up regarding CVD. We compare CVD risks in these patients not only between treatment groups but also with the general population risks.

    PATIENTS AND METHODS

    Data Collection Procedures

    Our Late Adverse Treatment Effects in Netherlands Testicular (LATENT) cancer survivors cohort consists of 2,707 5-year survivors of seminomatous or nonseminomatous TC as first malignancy (Fig 1). The selection of patients and methods of data collection have been described in detail in an earlier report on the incidence of second malignancies.16

    In brief, 5-year survivors of TC treated from 1971 through 1985 were identified through the former nationwide registry of the Netherlands Committee of Testicular Tumors, which covers approximately 65% of all testicular tumors in the Netherlands during this period.16,17 This registry was supplemented with all 5-year survivors of TC treated at several treatment centers in the Netherlands from 1965 through 1970 and from 1982 through 1995 (Fig 1).

    Data were collected on date of birth, date of TC diagnosis, histology, clinical stage,18 cytostatic agents and radiation fields in primary treatment, date and treatment of relapse (including cytostatic agents), dates of diagnoses of cardiovascular events, cardiovascular risk factors at TC diagnosis and at end of follow-up, date of most recent medical information or death, vital status, and cause of death. Data were collected from the medical records and through general practitioners (GPs) and attending physicians. In the Netherlands, nearly all residents have a GP, and GPs receive all medical correspondence from attending physicians regarding their patients. Questionnaires on specific cardiovascular diagnoses and risk factors were sent to the patients' GPs and/or the last known attending physicians; 3,035 questionnaires were sent out for 2,293 patients. In total, 95% of the GPs responded, and 85% provided complete data. For 45% of the 5-year survivors, cardiovascular data were obtained from GPs only; for 39% of survivors, data were obtained from both medical records and the GP, and for 16% of survivors, data were obtained from the medical records alone. Uncertain cardiovascular diagnoses were verified through the patient's cardiologist (n = 52). For patients who died from acute CVD without prior evidence of preceding CVDs, the date of death was recorded as date of CVD diagnosis, and the cause of death was recorded as the CVD diagnosis.

    One hundred seventy-three patients (7.4%) were excluded from the original cohort because medical records could not be obtained and no information on CVD was received from the GP (Fig 1). The analytic cohort comprised 2,339 5-year survivors. For 189 patients (8.1%), CVD information was not complete until at least January 1, 2000, the date of death, or the date of emigration.

    Treatment

    During the study period, treatment for TC after orchidectomy underwent significant changes.

    Seminoma

    Therapy for stage I and II seminoma included RT to the para-aortic and ipsilateral iliac lymph nodes in 86% of patients treated with RT. Prophylactic RT to the mediastinum and/or left supraclavicular fossa was mainly applied in the period from 1972 to 1978 but has been gradually abandoned thereafter.19 Since the mid-1980s, irradiation has been further reduced to the para-aortic lymph nodes only,19 and the RT dose has decreased from 30 to 26 Gy.17 Patients with disseminated seminoma were treated with cisplatin-based CT after 1979.

    Nonseminoma

    Initially, therapy for stage I and II nonseminoma included retroperitoneal lymph node dissection and/or irradiation (infradiaphragmatic with or without supradiaphragmatic) with 40 to 50 Gy. Surveillance after orchidectomy became common beginning in 1985. Patients with disseminated nonseminoma have been treated with CT from the early 1970s, initially with single-agent dactinomycin20 or combinations of vinblastine and bleomycin.21 Beginning approximately in 1976, treatment consisted of four cycles of cisplatin, vinblastine, and bleomycin (PVB) followed by vinblastine maintenance therapy for 2 years.1 Maintenance therapy was omitted after 1984.22 In the mid-1980s, four cycles of bleomycin, etoposide, and cisplatin (BEP) became the standard treatment.23

    Statistical Analysis

    A comparison was made between the incidence of CVDs in the study population and in the Netherlands male population using age-, sex-, and calendar period–specific incidence rates for the period from 1972 through 2000 from the Continuous Morbidity Registration Nijmegen (CMRN) from several Netherlands GP practices. Comparison of recent incidence rates of coronary heart disease (CHD), acute myocardial infarction (MI), and angina pectoris (AP) from the CMRN with the incidence rates of several new registries in the Netherlands, which comprised only short-term incidence rates, showed that incidence rates of the CMRN were similar to the mean of all registries combined, indicating that the CMRN is representative of the Netherlands.24 Data on the incidence of MI, AP, heart failure (HF), and cerebrovascular accidents (CVAs) were registered by CMRN, allowing for multiple separate diagnoses per person, but only the first of a given diagnosis was recorded.25,26 Because our cohort only includes 5-year survivors, time at risk started 5 years from TC diagnosis and ended at the date of diagnosis of a specific cardiovascular event, emigration, death, or most recent information on CVD occurrence, whichever came first. The standardized incidence ratios (SIRs) of the observed and expected numbers of MI, AP, HF, CVA, and combined diagnostic groups in the study population were determined. The confidence intervals of the SIRs were calculated using exact Poisson probabilities of observed numbers. P values for tests for heterogeneity and for tests for trend were calculated according to standard methods.27 Absolute excess risk (AER) was calculated as the observed number of CVDs in our cohort minus the number expected, divided by the number of person-years at risk, and multiplied by 10,000.

    When analyzing one specific cardiovascular diagnosis, observed numbers were based on all first events of this given diagnosis. Two different approaches were used to determine SIRs for combined diagnostic groups. First, an analysis was performed in which all CVD diagnoses within the diagnostic entity of interest were counted, allowing multiple diagnoses per patient, corresponding with the reference rates, because the expected numbers were also based on events rather than individuals. In addition, we also performed analyses in which a patient contributed only one event to the observed numbers, with person-time at risk ending at the first event, which yielded conservative risk estimates because different cardiovascular diagnoses may be more strongly correlated among our patients than in the general population. Attained age was defined as the age of patients during follow-up and was calculated to assess at what ages patients experienced increased risk compared with their peers in the general population.

    Overall and cardiovascular diagnosis-specific actuarial risks were estimated using the Kaplan-Meier method.28 Multivariate Cox regression analysis was performed to quantify the effects of different treatments on CVD risk within the patient group, adjusting for confounders. Cox models were fitted using SPSS statistical software (SPSS Inc, Chicago, IL).

    RESULTS

    Seminomas and nonseminomas were almost equally common in the patient group (48% and 52% of patients, respectively). Median follow-up time was 18.4 years (range, 5.0 to 38.4 years; a total of 42,722 person-years), and 1,500 patients (64%) had more than 15 years of follow-up. Table 1 lists the relevant patient characteristics according to histology. The median ages at diagnosis were 38.3 years and 28.1 years for seminoma and nonseminoma patients, respectively.

    CVD Risk

    We observed 694 CVDs at least 5 years from TC diagnosis in 434 5-year survivors; 168 patients experienced multiple cardiovascular diagnoses (Table 2). Acute MI and AP were most common, with 141 and 150 events, respectively.

    Table 3 lists the overall SIRs of specific CVDs. The overall SIR for MI and AP combined, including all diagnostic events (n = 291), was 1.17 (95% CI, 1.04 to 1.31), yielding an AER of 14 excess cases per 10,000 person-years. The risks for HF and CVA were not increased.

    Table 4 lists the SIRs of MI by histology, according to various patient and treatment characteristics. The median ages at diagnosis of MI were 59.8 years and 50.4 years for seminoma and nonseminoma patients, respectively. For nonseminoma and seminoma patients combined, the SIRs of MI were greater with younger age at diagnosis and especially with younger attained age (P for trend = .0026). In nonseminoma survivors with attained ages of less than 45 and 45 to 54 years, the SIRs for MI were significantly increased (2.06 and 1.86, respectively), whereas the SIR decreased to 0.53 for attained ages of 55 years or older (P for trend < .001). Among seminoma and nonseminoma patients combined, the SIR for MI was significantly increased after both CT and RT (SIR = 2.06), nonsignificantly increased after CT alone (SIR = 1.46), and not increased after surgery only or RT only. Both in seminoma and nonseminoma patients, MI risk increased slightly, although not significantly, with more recent treatment periods. The SIR for MI decreased with follow-up duration. For nonseminoma patients, this trend was significant (P for trend = .015), with the SIR decreasing from 1.91 for a follow-up time of 5 to 9 years to 0.64 after 20 or more years of follow-up. Risk of CVD overall (MI or AP or HF) yielded similar patterns (data not shown).

    Table 5 lists the risks of MI and combined diagnostic groups in relation to specific treatments. Patients irradiated to the mediastinum had 2.5-fold significantly increased risks of both MI and CHD, and patients who also received CT had almost three-fold increased risks. The SIRs for MI and CHD after treatment with both infradiaphragmatic irradiation and CT (SIRs = 1.72 and 1.83, respectively) were higher than the SIRs after CT only (SIRs = 1.46 and 1.35, respectively), whereas risks were not increased after infradiaphragmatic irradiation only. Subgroup analysis showed that the difference between the CT only group and the infradiaphragmatic RT + CT group was a result of salvage RT (data not shown).

    Comparisons Within the Study Cohort

    Twenty-year actuarial risks were 18.1% for any CVD, 10.3% for CHD, 7.2% for MI, 2.6% for HF, and 2.4% for CVA. In multivariate Cox regression analyses, risk estimates for treatment variables were adjusted for age at diagnosis and recent smoking, which were strong risk factors in our data (Table 6). Recent smoking was associated with a 2.6-fold increased risk of MI. TC histology was not an independent risk factor for CVD risk. Mediastinal irradiation was associated with a particularly high risk of CVD overall and especially of MI and HF (hazard ratios = 3.0, 3.7, and 3.1, respectively) compared with surgery only. For other radiation fields (mainly infradiaphragmatic irradiation), no significantly increased risks of any CVD were found. PVB treatment was associated with a 1.9-fold significantly increased MI risk and a 2.2-fold increased risk of peripheral vascular disease compared with surgery only. For patients treated with other CT (mainly BEP), a borderline significantly increased risk of CVD overall, but no increased MI risk, was found. When excluding patients treated with mediastinal RT and/or CT other than BEP, the MI risk after infradiaphragmatic RT only was equal to the MI risk after surgery only (95% CI, 0.6 to 1.7). Cox models for risk of AP and risk of CHD showed quite similar risk estimates compared with the estimates found for MI (data not shown). Figure 2 illustrates the risk of MI by treatment.

    Finally, we estimated outcome after MI among 108 patients with complete cardiovascular histories. Thirty-nine patients died after a mean time of 4.0 years; 16 of these patients died acutely of MI, of whom nine died without any preceding cardiovascular diagnosis and two died from recurrent MI. The 5-year actuarial risk of cardiovascular death after MI was 35.8%.

    DISCUSSION

    In our large and long-term follow-up study, we found a moderately increased risk of CHD in 5-year TC survivors compared with the general population. Remarkably, nonseminoma patients were at particularly high risk of developing an MI at a young age, as illustrated by an approximately two-fold increased risk in patients with attained ages of younger than 45 years. Mediastinal RT, PVB treatment, and recent smoking appeared to be important risk factors for development of CVD.

    MI and AP comprised 42% of all CVDs. Moreover, the SIR for CHD was significantly elevated, resulting in 14 excess cases per 10,000 person-years. The estimated 25-year actuarial risk for MI, AP, and HF combined was 16.5%, indicating that the risk of developing CVD is similar to the risk of developing secondary malignancies (15.7%).29 The importance of assessing cardiovascular morbidity rather than mortality is illustrated by the fact that MI was nonfatal in 64% of patients, and thus, patients are still amenable to secondary preventive measures.

    MI risk decreased with increasing attained age, resulting in a significantly decreased MI risk in nonseminoma patients with attained ages of 55 years or older. The decrease of SIRs with increasing age may be a result of the strongly increasing background risk with advancing age in the general population, but the simultaneous reduction in AER indicates that the burden of MI is indeed declining when patients grow older. The high MI risk at an early age may indicate that CT and/or RT accelerate the development of atherosclerosis and CVD, specifically among patients who are already predisposed to become affected.30

    Consistent with previous studies, we found slightly but not significantly elevated risks for MI and CHD in CT-treated seminoma and nonseminoma patients compared with the general population5 and a 1.9-fold significantly increased CVD risk after PVB CT compared with surgery only.4 Various mechanisms have been proposed to explain this increased risk. A high prevalence of classical cardiovascular risk factors has been demonstrated in TC survivors after CT.31-33 Furthermore, microalbuminuria, decreased fibrinolysis, and inflammation, which are all signs of endothelial dysfunction and early atherosclerosis, have been reported to occur after a median period of 7 years after CT.34 It is largely unknown whether atherosclerotic changes represent direct CT effects on the vasculature or are the result of other CT-related factors. Direct stimulation of the endothelium may result from small amounts of long-term circulating platinum in plasma.35,36 CT-induced hypogonadism may also influence cardiac risk.37 Low testosterone levels have been associated with increasing body mass index and may, through this association, be involved in the development of the metabolic syndrome and CVD.38 The cumulative cisplatin dose in four PVB courses and the neurotoxic agent vinblastine used in maintenance therapy may account for the high risk after PVB. PVB was previously shown to correlate with more gonadal toxicity, peripheral neuropathy, and Raynaud's phenomenon in TC patients.32,39 Vinblastine may not only damage peripheral nerves, but may also affect the autonomic cardiac nervous system.40 Importantly, PVB and maintenance therapy have been replaced by the BEP regimen since the mid-1980s. In our data, BEP was associated with a borderline increased CVD risk and with a nonsignificantly increased MI risk. However, the median follow-up time for patients treated between 1986 and 1995 is still relatively short (12.2 years), whereas the median time until MI was 14.3 years. The effects of BEP treatment on CVD, including MI, need to be evaluated after more prolonged follow-up.

    In accordance with Huddart et al,4 we found even stronger risk elevations for MI and CHD after both CT and RT, especially mediastinal irradiation. This may be a result of the combination of two treatments that are both toxic to the vasculature. Synergistic effects of CT and RT have also been reported. Of note, part of the effect of CT combined with infradiaphragmatic irradiation may be explained by the fact that radiation fields were not registered in salvage treatments. Possibly, some patients in the salvage group also had mediastinal irradiation. When patients treated with salvage RT were excluded from the analysis, the SIR of MI after CT and infradiaphragmatic RT combined was equal to the SIR of MI after CT only.

    Overall, MI risk was not increased after RT only compared with the general population. However, when RT was subdivided according to radiation fields, significantly increased risks of MI and CHD were found after irradiation to the mediastinum. Furthermore, in Cox analysis, mediastinal irradiation was associated with a 3.7-fold increased MI risk compared with surgery only. Previous studies reported an increased cardiovascular risk after mediastinal irradiation in TC patients41,42 and in survivors of breast cancer and Hodgkin's lymphoma who received high RT doses to the heart.9,10,43,44 Since approximately 1985, mediastinal irradiation has no longer been administered to TC patients. However, it was recently shown that infradiaphragmatic RT alone may also increase cardiovascular risk.4,7 Huddart et al4 found a 2.4-fold increased CVD risk after infradiaphragmatic RT compared with surveillance only. Zagars et al7 found a 1.6-fold significantly increased risk of cardiac death in seminoma patients receiving infradiaphragmatic RT only when follow-up was longer than 15 years. In neither study was a satisfactory explanation given for the findings. Infradiaphragmatic RT only did not increase MI risk in the present study, which comprised considerably more patients and a longer period of follow-up compared with the other studies and, consequently, more statistical power to address this issue. Moreover, we adjusted for other risk factors.

    CVD risk in TC patients undergoing surgery only has not been investigated previously. Theoretically, an increased CVD risk in these patients might reflect a relationship with TC itself or an effect of the surgical treatment on hormonal status. Although, we did not observe increased CVD risk in patients treated with surgery only, the number of these survivors was relatively small, and their median follow-up was relatively short (16.9 years).

    Our study has important strengths. First, CVD was assessed after a median period of 18.4 years, which is considerably longer than in other reports. Second, we have near-complete follow-up on both cardiac morbidity and mortality, whereas most late-effect studies assessed cardiac mortality only, thus underestimating the importance of cardiac disease as a long-term complication of TC treatment. The distribution with regard to histology and age in our patient population is similar to that in other reports45 and, thus, seems to be representative of the Netherlands TC population. MI diagnosis was our focus because it is generally confirmed by electrocardiography and increased levels of cardiac-specific serum markers and, thus, likely to give the most reliable estimate of CVD risk. The diagnosis of angina carries a higher risk of misclassification because it is often established without proper evaluation of coronary ischemia by exercise testing.

    In conclusion, we found a moderately increased MI risk in survivors of nonseminomatous TC at young ages. The effects of BEP treatment on CVD, including MI, need to be evaluated after more prolonged follow-up. Mediastinal RT, PVB treatment, and recent smoking are important risk factors for CVD in TC survivors. Particularly in young TC survivors with these risk factors, physicians should consider appropriate risk-reducing strategies such as treatment of hypertension and hypercholesterolemia and lifestyle advice to refrain from smoking, to maintain a healthy body weight, and to exercise regularly.46-48

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Alexandra W. Van den Belt-Dusebout, Berthe M.P. Aleman, Flora E. van Leeuwen

    Provision of study materials or patients: Ronald de Wit, Jourik A. Gietema, Wim W. ten Bokkel Huinink, Patrick T.R. Rodrigus, Erik C. Schimmel

    Collection and assembly of data: Alexandra W. Van den Belt-Dusebout, Janine Nuver, Jourik A. Gietema

    Data analysis and interpretation: Alexandra W. Van den Belt-Dusebout, Janine Nuver, Jourik A. Gietema, Berthe M.P. Aleman, Flora E. van Leeuwen

    Manuscript writing: Alexandra W. Van den Belt-Dusebout, Janine Nuver, Berthe M.P. Aleman, Flora E. van Leeuwen

    Final approval of manuscript: Alexandra W. Van den Belt-Dusebout, Janine Nuver, Ronald de Wit, Jourik A. Gietema, Wim W. ten Bokkel Huinink, Patrick T.R. Rodrigus, Erik C. Schimmel, Berthe M.P. Aleman, Flora E. van Leeuwen

    Acknowledgment

    We thank E.H. v.d. Lisdonk (CMR, Nijmegen); A.A.M. Hart, C.L.M. Noordhout-Modder, G. Besseling, and G.M. Ouwens (Netherlands Cancer Institute, Amsterdam); P. van Hoogdalem (Erasmus Medical Center, Rotterdam); S.B. Oei and J.C.M. Vulto (Dr Bernard Verbeeten Institute, Tilburg); M.C.C.M. Hulshof (Academic Medical Center, Amsterdam), and more than 2,500 general practitioners.

    NOTES

    Supported by the Lance Armstrong Foundation and the Dutch Cancer Society.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

    REFERENCES

    Einhorn LH: Testicular cancer as a model for a curable neoplasm: The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 41:3275-3280, 1981

    Nichols CR: Testicular cancer. Curr Probl Cancer 22:187-274, 1998

    de Wit R, Roberts JT, Wilkinson PM, et al: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: A randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19:1629-1640, 2001

    Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003

    Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000

    Fossa SD, Aass N, Harvei S, et al: Increased mortality rates in young and middle-aged patients with malignant germ cell tumours. Br J Cancer 90:607-612, 2004

    Zagars GK, Ballo MT, Lee AK, et al: Mortality after cure of testicular seminoma. J Clin Oncol 22:640-647, 2004

    Jones JM, Ribeiro GG: Mortality patterns over 34 years of breast cancer patients in a clinical trial of post-operative radiotherapy. Clin Radiol 40:204-208, 1989

    Cuzick J, Stewart H, Rutqvist L, et al: Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy. J Clin Oncol 12:447-453, 1994

    Rutqvist LE, Lax I, Fornander T, et al: Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 22:887-896, 1992

    Early Breast Cancer Trialists' Collaborative Group: Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 355:1757-1770, 2000

    Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270:1949-1955, 1993

    Lee CK, Aeppli D, Nierengarten ME: The need for long-term surveillance for patients treated with curative radiotherapy for Hodgkin's disease: University of Minnesota experience. Int J Radiat Oncol Biol Phys 48:169-179, 2000

    Eriksson F, Gagliardi G, Liedberg A, et al: Long-term cardiac mortality following radiation therapy for Hodgkin's disease: Analysis with the relative seriality model. Radiother Oncol 55:153-162, 2000

    Reinders JG, Heijmen BJ, Olofsen-van Acht MJ, et al: Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up. Radiother Oncol 51:35-42, 1999

    Van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW, et al: Second cancer risk following testicular cancer: A follow-up study of 1,909 patients. J Clin Oncol 11:415-424, 1993

    Zwaveling A, Soebhag R: Testicular tumors in the Netherlands. Cancer 55:1612-1617, 1985

    Peckham MJ, McElwain TJ, Barrett A, et al: Combined management of malignant teratoma of the testis. Lancet 2:267-270, 1979

    Zagars GK, Babaian RJ: Stage I testicular seminoma: Rationale for postorchiectomy radiation therapy. Int J Radiat Oncol Biol Phys 13:155-162, 1987

    Li MC, Whitmore WF Jr, Golbey R, et al: Effects of combined drug therapy on metastatic cancer of the testis. JAMA 174:1291-1299, 1960

    Samuels ML, Lanzotti VJ, Holoye PY, et al: Combination chemotherapy in germinal cell tumors. Cancer Treat Rev 3:185-204, 1976

    Einhorn LH, Williams SD, Troner M, et al: The role of maintenance therapy in disseminated testicular cancer. N Engl J Med 305:727-731, 1981

    Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435-1440, 1987

    Gijsen R, Poos MJJM: Achtergronden en details bij cijfers uit huisartsenregistraties: Gezondheid en ziekte\ziekte en aandoeningen\hartvaatstelsel\coronaire hartziekten—Volksgezondheid Toekomst Verkenning, Nationaal Kompas Volksgezondheid. Bilthoven, RIVM, 2003. http://www.rivm.nl/vtv/object_document/o3171n17964.html

    van der Pal-de Bruin KM, Verkleij H, Jansen J, et al: The incidence of suspected myocardial infarction in Dutch general practice in the period 1978-1994. Eur Heart J 19:429-434, 1998

    Lisdonk van de EH, Bosch van den WJHM, Huygen FJA, et al: Ziekten in de Huisartspraktijk (ed 3). Maarssen, the Netherlands, Elsevier/Bunge, 1999

    Breslow NE, Day NE: Statistical methods in cancer research: Volume II. The design and analysis of cohort studies. Lyon, France, International Agency for Research on Cancer Scientific Publication No. 1-406, 1987

    Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

    Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 89:1429-1439, 1997

    Pherwani AD, Reid JA, Keane PF, et al: Synergism between radiotherapy and vascular risk factors in the accelerated development of atherosclerosis: A report of three cases. Ann Vasc Surg 16:671-675, 2002

    Raghavan D, Cox K, Childs A, et al: Hypercholesterolemia after chemotherapy for testis cancer. J Clin Oncol 10:1386-1389, 1992

    Bokemeyer C, Berger CC, Kuczyk MA, et al: Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 14:2923-2932, 1996

    Nord C, Fossa SD, Egeland T: Excessive annual BMI increase after chemotherapy among young survivors of testicular cancer. Br J Cancer 88:36-41, 2003

    Nuver J, Smit AJ, Sleijfer DT, et al: Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. Eur J Cancer 40:701-706, 2004

    Gietema JA, Meinardi MT, Messerschmidt J, et al: Circulating plasma platinum more than 10 years after cisplatin treatment for testicular cancer. Lancet 355:1075-1076, 2000

    Gerl A: Vascular toxicity associated with chemotherapy for testicular cancer. Anticancer Drugs 5:607-614, 1994

    Nord C, Bjoro T, Ellingsen D, et al: Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol 44:322-328, 2003

    Nuver J, Smit AJ, Wolffenbuttel BH, et al: The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 23:3718-3725, 2005

    Berger CC, Bokemeyer C, Schuppert F, et al: Endocrinological late effects after chemotherapy for testicular cancer. Br J Cancer 73:1108-1114, 1996

    Pai VB, Nahata MC: Cardiotoxicity of chemotherapeutic agents: Incidence, treatment and prevention. Drug Saf 22:263-302, 2000

    Lederman GS, Sheldon TA, Chaffey JT, et al: Cardiac disease after mediastinal irradiation for seminoma. Cancer 60:772-776, 1987

    Peckham MJ, McElwain TJ: Radiotherapy of testicular tumours. Proc R Soc Med 67:300-303, 1974

    Boivin JF, Hutchison GB, Lubin JH, et al: Coronary artery disease mortality in patients treated for Hodgkin's disease. Cancer 69:1241-1247, 1992

    Glanzmann C, Kaufmann P, Jenni R, et al: Cardiac risk after mediastinal irradiation for Hodgkin's disease. Radiother Oncol 46:51-62, 1998

    Muir C, Waterhouse J, Mack T, et al: Cancer Incidence in Five Continents (volume V). Lyon, France, International Agency for Research on Cancer, 1987

    Raghavan D: Hidden by HIPAA: The costs of cure. J Clin Oncol 23:3663-3665, 2005

    National Cholesterol Education Program Panel: Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Final report. Circulation 106:3143-3421, 2002

    Chobanian AV, Bakris GL, Black HR, et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 289:2560-2572, 2003

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