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Treatment-Specific Risks of Second Malignancies and Cardiovascular Disease in 5-Year Survivors of Testicular Cancer

Alexandra W. van den Belt-Dusebout, Ronald de Wit, Jourik A. Gietema, Simon Horenblas, Marieke W.J. Louwman, Jacques G. Ribot, Harald J. Hoekstra, Gabey M. Ouwens, Berthe M.P. Aleman, Flora E. van Leeuwen

From the Departments of Epidemiology, Radiotherapy, and Urology, the Netherlands Cancer Institute, Amsterdam; the Department of Medical Oncology, Erasmus Medical Center-Daniel den Hoed Cancer Center, Rotterdam; the Departments of Medical Oncology and Surgical Oncology, University Medical Center Groningen, Groningen; Eindhoven Cancer Registry, Comprehensive Cancer Center South; and the Department of Radiotherapy, Catharina Hospital, Eindhoven, the Netherlands

Address reprint requests to Flora E. van Leeuwen, PhD, Department of Epidemiology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: f.v.leeuwen{at}nki.nl

	ABSTRACT

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Purpose: To compare radiotherapy and chemotherapy effects on long-term risks of second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs) in testicular cancer (TC) survivors.

Patients and Methods: In our nationwide cohort comprising 2,707 5-year TC survivors, incidences of SMNs and CVDs were compared with general-population rates by calculating standardized incidence ratios (SIRs) and absolute excess risks (AERs). Treatment effects on risks of SMN and CVD were quantified in multivariable Cox regression and competing risks analyses.

Results: After a median follow-up time of 17.6 years, 270 TC survivors developed SMNs. The SIR of SMN overall was 1.7 (95% CI, 1.5 to 1.9), with an AER of 32.3 excess occurrences per 10,000 person-years. SMN risk was 2.6-fold (95% CI, 1.7- to 4.0-fold) increased after subdiaphragmatic radiotherapy and 2.1-fold (95% CI, 1.4- to 3.1-fold) increased after chemotherapy, compared with surgery only. Subdiaphragmatic radiotherapy increased the risk of a major late complication (SMN or CVD) 1.8-fold (95% CI, 1.3- to 2.4-fold), chemotherapy increased the risk of a major late complication 1.9-fold (95% CI, 1.4- to 2.5-fold), and smoking increased the risk of a major late complication 1.7-fold (95% CI, 1.4- to 2.1-fold), compared with surgery only. The median survival time was 1.4 years after SMN and 4.7 years after CVD.

Conclusion: Radiotherapy and chemotherapy increased the risk of developing SMN or CVD to a similar extent as smoking. Subdiaphragmatic radiotherapy strongly increases the risk of SMNs but not of CVD, whereas chemotherapy increases the risks of both SMNs and CVDs. Prolonged follow-up after chemotherapy is needed to reliably compare the late complications of radiotherapy and chemotherapy after 20 years.

	INTRODUCTION

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With the introduction of cisplatin-containing chemotherapy (CT) in the mid-1970s, testicular cancer (TC) has become a highly curable disease.^1-4 Given the long life expectancy of this young patient population, evaluation of long-term complications of effective TC treatments has become increasingly important. Life-threatening diseases, such as second malignant neoplasms (SMNs) and cardiovascular diseases (CVDs), occur more frequently in TC patients than in the general population.^5-19 Radiotherapy (RT) has been associated with increased incidence of solid SMNs in TC survivors,^5-21 particularly when combined with CT.^11,14 Long-term data regarding potentially carcinogenic effects of cisplatin-containing CT regimens are sparse.^22-24 Risk of SMNs after cisplatin-containing CT alone was not increased in earlier studies,^{10,11,14,20,25} but the longest mean follow-up duration was only 12.5 years,^14,25 small numbers of patients were included,^14,25 or no data on CT regimens and treatment for recurrences were available.²¹ CT recently has been reported to increase the incidence of CVD.^16,19,26,27 So far, direct comparison of the risk of long-term complications after various TC treatments was difficult because studies focused on either SMNs or CVDs. Therefore, in this study, we evaluated the development of treatment-specific risks of CVD and SMN, combined and separately, with an emphasis on the effects of recent treatments (subdiaphragmatic RT, cisplatin-containing CT, or surgery). Taking into account the two most important long-term complications of TC treatment will enable clinicians to weigh more accurately the adverse outcomes of various treatments. Other features of this study are the risk assessment in a large cohort of TC survivors with detailed treatment data and near-complete long-term follow-up.

	PATIENTS AND METHODS

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Data Collection Procedures
Our Late Adverse Treatment Effects in Netherlands Testicular Cancer Survivors cohort consists of 2,707 5-year survivors of seminomatous or nonseminomatous TC as first malignancy. The selection of patients and methods of data collection have been described in detail in earlier reports.^11,19 In brief, 5-year TC survivors treated in the period 1965 to 1995 were identified through the former registry of the Netherlands Committee of Testicular Tumors^11,28 and through several Dutch cancer registries.

Data were collected on dates of birth and TC diagnosis, histology, primary treatment (RT fields and CT regimens), date and treatment of relapse (including CT regimens), dates of diagnoses of SMNs and CVDs, smoking and CVD 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 cancer registries, medical records, through general practitioners (GPs) and attending physicians. In the Netherlands, nearly all residents have a GP, who receives all medical correspondence from attending physicians. Medical follow-up information regarding TC treatment and development of SMNs was complete until at least January 1, 2000, date of death, or date of emigration for 90% of all patients. Information regarding CVD was collected for 2,339 patients, because data collection on CVD was not feasible in one center.¹⁹ Pathology reports and/or medical correspondence containing clinical information and conclusions from pathology reports were reviewed for 97% of SMNs.

Treatment
Changes over time in TC treatment after orchidectomy have been described in detail previously.^11,19 In brief, therapy included RT to the infradiaphragmatic lymph nodes for stage I to II seminoma (30 to 35 Gy) and nonseminoma (40 to 50 Gy). Supradiaphragmatic lymph nodes were irradiated prophylactically mainly until 1978. Since the mid-1980s, RT doses have been reduced to 26 Gy^28,29 for seminoma and surveillance became common for stage I nonseminoma. Disseminated nonseminoma has been treated with CT (from the early 1970s with dactinomycin³⁰ or vinblastine and bleomycin).³¹ Disseminated seminoma and nonseminoma have been treated primarily with cisplatin, vinblastine, and bleomycin (PVB) since 1977,² and with bleomycin, etoposide, and cisplatin (BEP) from the mid-1980s.^32-34

Statistical Analysis
The incidence of SMNs and CVDs in the cohort was compared with age-specific, sex-specific, and calendar year–specific incidence rates in the male general population, accounting for person-years of observation. Population-based cancer incidence data from the Eindhoven Cancer Registry³⁵ for the period 1975 to 1988 and from the Netherlands Cancer Registry³⁶ for the period 1989 to 2002, and incidence rates of acute myocardial infarction (MI), angina pectoris (AP), and congestive heart failure (CHF) for the period 1972 to 2000 from the Continuous Morbidity Registration Nijmegen³⁷ from several Netherlands GP practices were used as reference rates. Detailed information on statistical methods regarding the CVD analyses has been published previously.¹⁹ In this study, we focused on the most serious diagnoses (MI, AP, CHF, and peripheral vascular diseases), for which the increased risks were related to treatment in our previous study. Cerebrovascular accidents were excluded because the risk was not increased.¹⁹

We calculated standardized incidence ratios as the ratios of the observed and expected numbers of SMNs or CVDs in the cohort, and the absolute excess risk (AER) as the observed numbers minus the expected numbers, divided by number of person-years at risk, times 10,000. The CIs of the standardized incidence ratios were calculated using exact Poisson probabilities of observed numbers.³⁸ P values for tests for heterogeneity or trend were calculated according to standard methods.³⁹ Because our cohort included only 5-year survivors, time at risk started 5 years from TC diagnosis and ended at the date of diagnosis of an SMN or CVD (depending on outcome of interest), date of emigration, date of death, or most recent medical information, whichever came first. Analyses were performed based on the first SMN or on the second SMN when the first SMN was diagnosed within 5 years from TC diagnosis and was not treated with RT or CT. Deaths as a result of cancer or CVD were considered as an event in the absence of any data on incidence, with the date of death as date of CVD diagnosis. Contralateral TC was not considered as an SMN and its treatment was included in total treatment.

Effects of different treatments on SMN risk were quantified in the full cohort (n = 2,707), whereas risk factors for CVD and for developing CVD or SMN were determined in the subcohort comprising 2,339 survivors for whom data on both SMN and CVD were available, using multivariable Cox regression analyses according to the method of Lunn and McNeil.⁴⁰ Cox models were fitted using SPSS statistical software (SPSS Inc, Chicago, IL). Cumulative incidences of SMN and CVD (combined and separately) were calculated in the subcohort (n = 2,339), with death as a result of other causes as competing risk, stratified by age.⁴¹ Population-expected risks of SMN and CVD were calculated according to Hakulinen's method using S-Plus (version 3.3; Statistical Sciences, Seattle, WA) statistical software (Insightful Corp, Seattle, WA), including user-written functions.⁴²

	RESULTS

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Seminomas and nonseminomas were equally common in the cohort. Table 1 lists the patient characteristics by histology (n = 2,707). The majority of seminoma patients (83%) received RT, whereas most nonseminoma patients received CT (45%) or surgery alone (28%). Median ages at diagnosis were 10 years older in seminoma patients (38.3 years) than in nonseminoma patients (28.2 years). Median follow-up time was 17.6 years. Thirty-nine percent of patients had more than 20 years of follow-up. Characteristics of the subcohort (n = 2,339) were similar (data not shown).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Cumulative risk of second malignant neoplasm (SMN) or cardiovascular disease (CVD) by treatment among nonseminoma survivors. Adjusted for age at diagnosis (continuous) and smoking (yes v no or unknown). RT, radiotherapy; CT, chemotherapy; subdia, subdiaphragmatic; med, mediastinal.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Cumulative risks of second malignant neoplasm (SMN) or cardiovascular disease (CVD) by histology. (A) Cumulative risk of SMN by histology; (B) cumulative risk of acute myocardial infarction (MI) by histology; (C) cumulative risks of SMN and CVD among patients age 30 to 49 years at diagnosis, treated with radiotherapy and/or chemotherapy, by histology. Only SMNs and CVDs (acute myocardial infarction, angina pectoris, and congestive heart failure) diagnosed at least 5 years after testicular cancer diagnosis are included. Adjusted for age at diagnosis (continuous) and smoking (yes v no or unknown).

	DISCUSSION

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Complete data on treatment and follow-up and valid ascertainment of SMNs and CVDs are critical aspects in studies assessing late treatment complications. We evaluated the risks of SMNs and CVDs according to total treatment received for TC, including recurrences or contralateral TC, whereas in population-based studies on SMN risk information on individual treatment is usually missing or limited to primary treatment. Moreover, completeness of follow-up often is not reported, although losses to follow-up can seriously bias the estimated risks of SMNs and CVDs, especially in a cohort of young men with an excellent prognosis.²¹ The follow-up for SMNs and CVDs was complete until at least 2000 for more than 90% of our cohort. The small proportion of patients with incomplete follow-up according to our strict criteria had a similar distribution of vital status and age at diagnosis as the patients with complete follow-up. Furthermore, 97% of all SMN diagnoses were confirmed by pathology reports and/or medical correspondence, unlike in most studies that identify SMNs through linkage with population-based cancer registries.^6,7,43 Regarding risk of CVD, we focused on incidence rather than on mortality, which was the outcome of interest in most other studies on CVD risk.¹⁹

The overall SIR of 1.7 for any SMN is comparable with excess SMN risks found in other studies,^8,9,14,44 and is higher than the overall SIR of 1.1 for CVD. As expected, patients treated with mediastinal RT or RT combined with CT had the highest risks of developing either CVD or SMNs. However, given that these treatments have not been administered commonly after the mid-1980s and only a minor part of the cohort was treated with mediastinal RT or RT combined with CT, we evaluated risks further among patients who received recent treatments, including RT with lower doses, limited to subdiaphragmatic fields, and cisplatin-containing combination CT. Patients treated with surgery only had neither increased risk of CVD nor increased risk of SMNs. Patients treated with subdiaphragmatic RT (mainly seminoma patients treated with 26 to 35 Gy) had no increased risk of CVD, but from approximately 10 to more than 25 years after treatment, they experienced increased risk of SMNs in organs situated in the RT fields, consistent with the recent study by Travis et al.²¹ This pattern is strongly suggestive of a radiation effect, given that RT-related excess risks of cancer typically emerge 10 or more years after RT and increase over time.^9,14,21,44 Furthermore, our results suggest that increased SMN risk might also be related to CT. The increased risk of CVD was related to cisplatin-containing CT, particularly PVB.

SMNs may result from influences other than treatment for TC, such as genetic predisposition, immunodeficiency, common carcinogenic influences, diagnostic surveillance, risk factors unrelated to TC, or the interaction of these factors.⁴³ The risk of CVD is influenced by genetic predisposition, lifestyle, and the presence of cardiovascular risk factors, such as hypercholesterolemia, hypertension, overweight, and metabolic syndrome. In Cox analyses, smoking and treatment increased the risks of SMNs and CVD to a similar extent. Unfortunately, it was not possible to investigate risks of CVDs and/or SMNs among smokers and nonsmokers separately, because recent smoking status was only available for 67% of survivors. Previous studies, however, completely lacked information on smoking. With 6.8 excess occurrences per 10,000 person-years, bladder cancer was one of the most important SMNs. The risk of bladder cancer was approximately 4.5-fold increased after RT, CT, and treatment with both modalities, but not after surgery. Notably, 82% of the irradiated patients with bladder cancer had received RT including the iliac lymph nodes. The increased risk of bladder cancer will probably decrease in more recent years, because from the mid-1980s RT has been applied to the para-aortic lymph nodes only. To date, no study noted increased risk of bladder cancer after CT alone.⁴⁴ Because etoposide combined with cisplatin and bleomycin is carcinogenic to humans,⁴⁵ and platinum is excreted in urine up to 20 years after treatment with PVB CT or BEP CT,^46,47 prolonged platinum exposure may play a role in bladder cancer development. However, too few patients with bladder cancer had been exposed to cisplatin-containing CT to yield conclusive results. The risk of melanoma was increased after all treatments and therefore probably was not related to treatment. Furthermore, 71% of the melanomas occurred after nonseminomas, suggesting shared genetic origins.⁴⁸

Unfortunately, after TC diagnosis, survivors remain at increased risk of developing SMNs and CVDs for more than 25 years. The AERs of SMNs (32 excess occurrences per 10,000 person-years) and CVD (AER = 15) among TC survivors diagnosed between age 20 and 40 years are lower than the AERs among Hodgkin's lymphoma survivors of the same age (AER = 55 for SMN and AER =102 for CVD),⁴⁹ likely because a much lower proportion of TC patients received high-dose RT to the mediastinum. Future follow-up studies are necessary to monitor the long-term risks of SMN and CVD among patients treated with lower RT doses (20 to 26 Gy) or BEP CT, because treatment-related SMNs and CVDs can become apparent more than 25 years after TC diagnosis, and follow-up, particularly after BEP CT, is relatively short (median, 13 years).

A limitation of our study is that we only considered CVD and SMN. Several other complications of platinum-based CT (such as nephrotoxicity, ototoxicity, and peripheral neuropathy) can cause considerable morbidity and therefore negatively influence the quality of life of TC survivors.⁵⁰

In conclusion, CT increases the risk of developing a major late complication, such as a cardiovascular event or an SMN, to a similar extent as subdiaphragmatic RT. The effects of treatment are comparable to the effect of smoking. RT increases the risk of SMNs, particularly in patients treated at a young age, whereas CT (especially PVB) moderately increases the risks of CVDs and SMNs. In view of the observed risks, surveillance is preferable for the majority of future stage I seminomas and nonseminomas. More than 50% of the patients with nonseminomas and up to 80% of the patients with seminomas will never experience relapse after orchidectomy only and are even overtreated when treated with adjuvant low-dose RT or one course of carboplatin.^51,52 Moreover, none of these adjuvant treatment options are definitive; the majority of relapses occur within 2 years and most of these patients can be cured with CT (and resection of residual disease) at relapse.^51,53 However, surveillance is only possible in treatment centers with a broad experience in treating TC patients and when patients fully comply with regular and prolonged surveillance to maintain an excellent prognosis when metastases develop.^51,52 Alternative treatment options should be discussed with the patients.

After being treated successfully, most TC patients are currently observed for 5 to 10 years by an oncologist.^54,55 However, none of the recent treatment and follow-up guidelines for TC patients include details on how to monitor and handle the occurrence of SMNs and CVDs or cardiovascular risk factors. In accordance with other groups of cancer survivors, we recommend the development of guidelines on follow-up management that include monitoring for late effects of TC treatment in collaboration with primary-care professionals.^56,57

Meanwhile, given that most 5-year survivors of TC are no longer under medical surveillance, there is an important role for their GPs. For decades after RT, GPs should be alert to possible symptoms of tumors in the digestive and urinary tract to allow early diagnosis and treatment. Among CT-treated survivors, physicians should be alert to the development of cardiac risk factors; should treat hypertension and hypercholesterolemia; and should advise patients to maintain a healthy body weight, to exercise regularly and, most importantly, to refrain from smoking to reduce their CVD risk.¹⁹

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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

Financial support: Berthe M.P. Aleman, Flora E. van Leeuwen

Administrative support: Gabey M. Ouwens

Provision of study materials or patients: Ronald de Wit, Jourik A. Gietema, Simon Horenblas, Marieke W.J. Louwman, Jacques G. Ribot, Harald J. Hoekstra

Collection and assembly of data: Alexandra W. Van den Belt-Dusebout, Gabey M. Ouwens

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

Manuscript writing: Alexandra W. Van den Belt-Dusebout, Ronald de Wit, Jourik A. Gietema, Berthe M.P. Aleman, Flora E. van Leeuwen

Final approval of manuscript: Alexandra W. Van den Belt-Dusebout, Ronald de Wit, Jourik A. Gietema, Simon Horenblas, Marieke W.J. Louwman, Jacques G. Ribot, Harald J. Hoekstra, Berthe M.P. Aleman, Flora E. van Leeuwen

	Appendix

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	ACKNOWLEDGMENTS

 
We thank O. Visser, J.W.W. Coebergh, A.A.M. Hart, M. Hauptmann, E.H. v.d. Lisdonk, G. Besseling, J. Nuver, J. Peterse (deceased), C.L.M. Noordhout-Modder, P. van Hoogdalem, E.C. Schimmel, J.C.M. Vulto, P.T.R. Rodrigus, M.C.C.M. Hulshof, and more than 2,500 GPs.

	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.

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Submitted December 22, 2006; accepted June 11, 2007.

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