Annals of Oncology Advance Access originally published online on October 23, 2006
Annals of Oncology 2007 18(2):241-248; doi:10.1093/annonc/mdl372
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© 2006 European Society for Medical Oncology
urogenital tumors |
Components of the metabolic syndrome in long-term survivors of testicular cancer
1 Department of Oncology, Institute of Clinical Medicine, University of Tromsø, Tromsø
2 Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Oslo
3 Medical Faculty, University of Oslo, Oslo
4 Section of Oncology, Institute of Medicine, University of Bergen, Bergen
5 Department of Oncology, Haukeland University Hospital, Bergen
6 Department of Oncology, St Olav University Hospital, Trondheim
7 Department of Oncology, Ullevål University Hospital, Oslo
8 Department of Endocrinology, University Hospital of North Norway, Tromsø
9 Institute of Community Medicine, University of Tromsø, Tromsø
10 Department of Oncology, University Hospital of North Norway, Tromsø, Norway
* Correspondence to: Dr H. S. Haugnes, Department of Oncology, Institute of Clinical Medicine, University of Tromsø, N-9037 Tromsø, Norway. Tel: +47-77-64-54-27; Fax: +47-77-64-53-00; E-mail: hegesa{at}fagmed.uit.no
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Abstract |
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Background: A possible explanation of the excess cardiovascular risk in testicular cancer (TC) survivors is development of metabolic syndrome. The association between metabolic syndrome and TC treatment is examined in long-term survivors.
Patients and methods: In a national follow-up study (1998–2002), 1463 TC survivors (diagnosed 1980–1994) participated. Patients >60 years were excluded in the present study, leaving 1135 patients eligible. The patients were divided in four treatment groups: surgery (n = 225); radiotherapy (n = 446) and two chemotherapy groups: cumulative cisplatin dose (Cis) 
850 mg (n = 376) and Cis >850 mg (n = 88). A control group consisted of 1150 men from the Tromsø Population Study. Metabolic syndrome was defined according to a modified National Cholesterol Education Program definition.
Results: Both chemotherapy groups had increased odds for metabolic syndrome compared with the surgery group, highest for the Cis >850 group [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.6–4.7]. Also, the Cis >850 group had increased odds (OR 2.1, 95% CI 1.3–3.4) for metabolic syndrome compared with the control group. The association between metabolic syndrome and the Cis >850 group was strengthened after adjusting for testosterone, smoking, physical activity, education and family status.
Conclusion: TC survivors treated with cisplatin-based chemotherapy have an increased risk of developing metabolic syndrome compared with patients treated with other modalities or with controls.
Key words: cisplatin, metabolic syndrome, radiotherapy, testicular cancer
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Testicular cancer (TC) is the most common malignancy among young Norwegian men [1]. Due to better diagnostic tools, the multimodal approach and the introduction of cisplatin-based chemotherapy [2], TC patients are assumed to have a life expectancy almost comparable to healthy age-matched men once they achieve a durable remission. Thus, it is essential to detect and treat any therapy-related long-term morbidity.
Cardiovascular morbidity and mortality has been described as late complications among TC survivors [3–6]. An association between cisplatin treatment and an unfavorable cardiovascular risk profile has been demonstrated by several authors [6–10]. Radiotherapy (RT) may also increase the risk for cardiovascular disease [3]. The suggested mechanisms responsible for the development of cardiovascular morbidity in these long-term survivors, however, need to be further evaluated.
The metabolic syndrome comprises insulin resistance, hypertension, dyslipidemia and abdominal obesity. The World Health Organization (WHO) [11], the National Cholesterol Education Program (NCEP) expert panel [12] and recently the International Diabetes Federation [13] have published definitions of the metabolic syndrome. The syndrome is important because it is associated with cardiovascular morbidity and mortality [14–16].
The increased risk for cardiovascular disease in TC survivors may be mediated via the metabolic syndrome. So far, only one paper has described the prevalence of metabolic syndrome in TC survivors [17]. In this study, Nuver et al. [17] reported a higher prevalence of metabolic syndrome in cisplatin-treated patients as well as in patients with stage I disease when compared with healthy controls.
The aim of our study was to assess the prevalence of metabolic syndrome using a modified NCEP definition in long-term survivors of TC treated with different modalities (surgery, RT or chemotherapy) through the following research questions: (i) Does the prevalence of metabolic syndrome among TC survivors differ according to previously administered treatment? (ii) And does it differ from controls?
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients and controls
All Norwegian long-term survivors (
5 years) of unilateral TC aged 18–75 years were invited to participate in a national multicenter follow-up survey. The patients were treated in the period 1980–1994, and the follow-up was conducted during 1998–2002 at five university hospitals. The follow-up survey consisted of (i) a 219-item questionnaire including questions regarding medical history and demographic data and (ii) an outpatient clinical examination including laboratory tests. Of 1814 eligible patients, 1463 (81%) signed the informed consent form and participated in the study [7]. Since the metabolic syndrome is highly prevalent among the elderly [18], patients aged above 60 years were excluded from the present report, leaving 1135 patients eligible (study population, Figure 1). The Ethical Review Board of Region South approved the study.
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A control group was recruited from the Tromsø Study [19], a population-based epidemiological study in Tromsø, Northern Norway. The controls have been described in a previous publication [7]. We selected men from the last survey (Tromsø 5, 2001) as controls, since it was conducted during the same time period as our follow-up survey. Control patients aged above 60 years and those treated with testosterone substitution were excluded. Our control group consisted of 1150 males with a median age of 48 years (range 30–60).
treatment groups
Principles for treatment of TC in Norway in the period 1980–1994 are previously described [20]. For this study, the TC survivors were categorized into four treatment groups according to initial and eventual relapse treatment: (i) surgery only; (ii) RT only; (iii) chemotherapy with a cumulative dose of cisplatin 850 mg (Cis 850); (iv) chemotherapy with a cumulative dose of cisplatin >850 mg (Cis >850).
Patients in the surgery group (n = 225) did not receive treatment with RT or chemotherapy. Of these, 124 had undergone retroperitoneal surgery, while the remaining patients had been included in a surveillance program without subsequent relapse. Patients in the RT group (n = 446) had received either a modified dog-leg (n = 417) or paraaortic (n = 29) field. Two patients had received additional mediastinal irradiation. From early 1980s to mid-1990s the standard applied RT dose was gradually reduced from 40 to 27 Gy.
The cut-off point for the two chemotherapy groups was set at 850 mg Cis to separate patients who received standard four courses or less from those who received more than four courses or ‘higher dose’ chemotherapy regimens due to very advanced disease, poor response, progression or relapse. Overall, 464 patients were treated with chemotherapy, of whom 88 were in the Cis >850 group. Most patients (n = 442, 95%) received cisplatin-based chemotherapy, primarily in combination with etoposide and bleomycin or vinblastine and bleomycin. Twenty-two patients (5%) who received carboplatin instead of cisplatin were also included in the Cis 850 group, as their risk for the metabolic syndrome did not differ from those who received standard cisplatin-based chemotherapy (data not shown).
Overall 304 (66%) of the patients treated with chemotherapy underwent retroperitoneal surgery, and 47 (10%) received additional RT, primarily infradiaphragmatic.
assessments
Resting blood pressure was measured manually or with an automatic device. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters (kg/m2). Blood samples were drawn nonfasting by venipuncture at each hospital laboratory between 0800 and 1200 h to assess the levels of serum cholesterol, serum magnesium (Mg) and serum testosterone. Levels of serum total testosterone were determined using a commercial immunoassay, with similar reference ranges at each hospital.
Information regarding the use of antihypertensive, antidiabetic and/or lipid-lowering medication, the prevalence of diabetes and demographic data was obtained from the questionnaire. Respondents with missing questionnaire data on antihypertensive treatment or diabetes were categorized as being without such treatment or nondiabetic, respectively.
Data for family status and educational level were dichotomized according to married/cohabitant versus living alone, and college/university versus lower education. Physical activity was assessed by two questionnaire items, one assessing a low physical activity level (such as walking) and the other a high level (leading to sweating and breathlessness). Based on responses to these items, physical activity was divided into three categories (no, moderate and high activity) as described previously [21]. Cigarette smoking was assessed by pack-years, calculated as number of cigarette packs smoked per day multiplied by the number of years smoked. Accordingly, the patients were categorized into four groups: never smokers, 0.1–9.9 pack-years, 10–19.9 pack-years and 20 pack-years.
definition of metabolic syndrome
We applied a modified NCEP definition of the metabolic syndrome (Table 1) [12]. Hypertension was defined as blood pressure 140/90 mmHg and/or antihypertensive medication according to the WHO Hypertension Guidelines [22]. As a measure of obesity, we used BMI 30 [23].
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In lack of serum triglycerides and high-density lipoprotein (HDL) cholesterol assessments, we used serum total cholesterol. Hypercholesterolemia was defined as total cholesterol
5.2 mmol/l [12] and/or the use of lipid-lowering drugs. Since blood glucose was measured nonfasting and only in a subgroup of patients, we instead applied patient-reported prevalence of diabetes and/or use of antidiabetic medication. According to our definition, metabolic syndrome was present if two or more of the following four components were present: hypertension, obesity, hypercholesterolemia or diabetes (Table 1). Additionally, we carried out analyses using a more restrictive definition of metabolic syndrome, defined as three or more components present.
statistical analysis
The matching of cases and controls were carried out at a group level, not at an individual level, due to an inadequate number of young controls. Mean chemotherapy values in the two chemotherapy groups were compared using Student's t-test. Multiple logistic regression with metabolic syndrome as the dependent variable was used to evaluate possible differences between treatment groups, between cases and controls and to evaluate the influence of possible predictors for metabolic syndrome. Metabolic syndrome was also analyzed using ordinal logit regression, with the variable divided into quintiles (0, 1, 2, 3 or all 4 components). The model calculated the probability for having a larger number of metabolic syndrome components. A test of parallel lines confirmed that the proportional odds assumption was met.
Differences between treatment groups with respect to continuous variables, such as age, total cholesterol, total testosterone and Mg, were analyzed using multiple linear regression. The surgery group was used as reference when comparing the impact of different treatment modalities. Persons with missing values were excluded from the analyses where the missing variable was the dependent or explanatory variable. All regression analyses were adjusted for age. All P values are two-tailed, with statistical significance set at P < 0.05. The data were analyzed using the SPSS 11.0 statistical package (SPSS Inc., Chicago, IL).
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patient characteristics
Median age at follow-up was 43 years for both responders and nonresponders (P = 0.62). Stage, histology and treatment were similar in both groups (data not shown).
Characteristics of study patients and controls are listed in Table 2. The median observation time was 11.1 years. Compared with the surgery group, the RT group was older at diagnosis and at follow-up (P < 0.001, both), while the Cis >850 group was younger at diagnosis (P = 0.016) and at follow-up (P < 0.001), and had a shorter observation time (P = 0.001). Patients in the Cis >850 group were less educated [odds ratio (OR) 0.58, 95% confidence interval (CI) 0.34–0.99] and had a lower smoking prevalence (OR 0.58, 95% CI 0.35–0.97) than the surgery group. Otherwise, there were no differences across the treatment groups with regard to demographic variables.
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Prevalences of the metabolic syndrome, its components, serum testosterone and serum Mg are presented in Table 3.
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The mean serum total cholesterol was 5.7 (1.1) mmol/l for the total patient population, without any differences across the treatment groups. The Cis >850 group had increased odds for having hypertension, obesity and hypercholesterolemia compared with the surgery group (Figure 2).
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Surgery, 
Radiotherapy, 
Cisplatin 
Cisplatin > 850 mg.Among 30 patients reporting a diagnosis of diabetes, 22 patients were diagnosed after the TC diagnosis (median interval 7.2 years, range 1.8–16 years). The mean prevalence of diabetes in all treatment groups was 2.6%. There were no differences between the treatment groups with regard to odds for diabetes (Figure 2).
Univariate analyses revealed both age and serum total testosterone as important predictors for the metabolic syndrome (P < 0.001, both). The overall mean serum total testosterone was 15.6 (5.4) nmol/l. The Cis >850 group had the lowest mean testosterone value, significantly different from the surgery group (P = 0.01), while the other treatment groups did not differ from the surgery group. The overall mean serum Mg was 0.82 (0.07) mmol/l, and the Cis >850 group did not differ from the surgery group. There was no correlation between serum Mg and metabolic syndrome (P = 0.48).
metabolic syndrome
2 components included.
Metabolic syndrome was seen in 40% of the total patient population. Both the chemotherapy groups had significantly increased odds for metabolic syndrome compared with the surgery group, highest for the Cis >850 group with an OR of 2.8 (95% CI 1.6–4.7, Figure 2). When compared with controls, the odds for metabolic syndrome of the total patient group did not differ (OR 1.0, 95% CI 0.8–1.2). Subgroup analysis showed that only the Cis >850 group differed from the controls, with an OR of 2.1 (95% CI 1.3–3.4). Adjusting for total testosterone did not significantly change any of these results.
3 components included.
On the basis of our more restrictive definition, metabolic syndrome was observed in 8% of all patients. Compared with the surgery group, only the Cis >850 group had increased odds for metabolic syndrome, with an OR of 2.6 (95% CI 1.1–6.0, Figure 3). Compared with the controls, the total patient group had lower odds for metabolic syndrome (OR = 0.7, 95% CI 0.5–1.0). The subgroup analysis showed higher odds for metabolic syndrome in the Cis >850 group when compared with controls, although not significant (OR = 1.6, 95% CI 0.8–3.2). The other treatment groups had lower odds than the controls.
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ordinal logit regression.
Both chemotherapy groups had increased odds for metabolic syndrome compared with the surgery group, with highest odds for the Cis >850 group (OR = 3.1, 95% CI 2.0–5.0; Table 4). When compared with controls, the surgery and RT groups had lower odds, while the Cis >850 group had higher odds (Table 4).
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factors associated with the metabolic syndrome
Variables known to be associated with the metabolic syndrome such as total serum testosterone, smoking (pack-years), physical activity, educational level, family status and treatment group were first tested through age-adjusted analyses. All variables were then included in multiple regression models (Table 5). When analyzing testicular survivors only, treatment group (Cis >850 mg), total serum testosterone and smoking history (
20 pack-years) were independent predictive factors. Table 5 also presents the results of these analyses in patients and controls, using the controls as reference. Here, treatment group (Cis >850 mg) and total serum testosterone appeared as independent predictors.
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impact of chemotherapy
Median chemotherapy doses for the agents cisplatin, bleomycin, etoposide and vinblastine are listed in Table 2. Patients in the Cis >850 group received more cisplatin (P <0.001) and etoposide (P <0.001) than patients in Cis
850 group. Mean vinblastine (P = 0.74) and bleomycin dose (P = 0.06) did not differ significantly between the two groups. Metabolic syndrome was positively associated with cumulative cisplatin (P = 0.001), bleomycin (P = 0.001) and etoposide doses (P = 0.002) in age-adjusted analyses. Cumulative vinblastine dose was not associated with metabolic syndrome (P = 0.27). Logistic regression using a backward stepwise model with all four chemotherapy agents and age included, left only age and cumulative cisplatin dose as significant variables.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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In this study, previously cisplatin-treated TC survivors show an increased age-adjusted risk of developing metabolic syndrome in comparison to those treated with surgery, while patients treated with RT did not differ from the surgery group. The risk was most pronounced after cumulative cisplatin doses above 850 mg. This heavily treated group also had an increased risk compared with the control group. Treatment with surgery or RT alone did not increase the risk for metabolic syndrome in comparison to the control group.
The major strengths of this study are the large patient population permitting subgroup analyses between the different treatment groups and the case–control design allowing comparisons between TC survivors and healthy controls. Another strength is the concurrent assessments of metabolic syndrome-related factors in patients and controls.
A limitation of the study is the age difference between TC survivors and controls (median 43 versus 48 years). Age-adjusted analyses may not completely equalize the impact of age on the metabolic syndrome, but any age bias will underestimate rather than overestimate the association between cisplatin treatment and metabolic syndrome. Another limitation is the inability to evaluate the TC survivors' complete metabolic syndrome status at diagnosis. However, in our recently published longitudinal study in this group [7], there were no differences in BMI and blood pressure between treatment groups at diagnosis.
As the present study was planned and partially conducted before the publication of the WHO and NCEP definitions, we lack necessary data for the correct definition of metabolic syndrome. Surrogate markers were used for fasting blood glucose, triglycerides and HDL cholesterol. The prevalence of diabetes may be underestimated, since those not clearly reporting a diagnosis of diabetes were classified as being nondiabetic. Using a modified definition of metabolic syndrome may complicate comparisons of our results with others. Nevertheless, the major aim of this study was to compare and report possible differences between treatment groups and between these groups and controls, with the same definition applied.
Hypertension, obesity and hypercholesterolemia all seem to be involved in the increased risk for metabolic syndrome in our heavily cisplatin-treated patients. Hypertension and obesity have been discussed in more detail in our previous publication [7]. Our hypercholesterolemia rates of 67% and 73% after standard and high cumulative cisplatin doses, respectively, are in line with previous studies reporting rates at 67% to 84% [6, 8–10].
The first study examining the association between metabolic syndrome and treatment of TC in 86 cisplatin-treated patients, 44 stage I patients treated with orchiectomy and 47 healthy controls was recently published [17]. These investigators reported higher prevalence of metabolic syndrome in both cisplatin-treated (26%) and stage I patients (36%) compared with healthy controls (9%). Surprisingly, they found the highest prevalence of metabolic syndrome in stage I patients. These results are inconsistent with our data since the Cis >850 group alone had a significantly higher prevalence of metabolic syndrome when compared with controls. A possible explanation for the discrepancy between our results and those presented by Nuver et al. [17] may in part be the different criteria applied in the definition of metabolic syndrome. Besides the larger number of cases and controls in our study, our control group may be more representative for the general population. The median follow-up time of 11 years in our study, compared with 7 years in the Dutch study, may also influence the results.
It has been demonstrated that a low serum total testosterone level is an independent predictor for the development of metabolic syndrome [24]. Gonadal dysfunction is a possible long-term complication after treatment of TC, particularly after high cumulative doses of cisplatin [25]. In line with this, both our study and the Nuver study [17] found a strong negative association between total testosterone and the prevalence of metabolic syndrome. Thus, a more liberal policy regarding testosterone substitution in TC survivors to prevent metabolic syndrome may be justified. Yet, our analyses show an unaltered OR for metabolic syndrome in the Cis >850 group after adjusting for total testosterone. This indicates the importance of other causative mechanisms beyond gonadal dysfunction.
Several demographic factors are known to influence the development of the metabolic syndrome. Physical activity may reduce the risk of the metabolic syndrome [26], while smoking is associated with an increased risk [27]. The metabolic syndrome is less prevalent in persons with a university education [28], and marriage seems to protect against cardiovascular death [29]. Although patients in the Cis >850 group had a lower smoking prevalence compared with the surgery group, the association between the metabolic syndrome and the Cis >850 group was actually strengthened after adjusting for demographic factors.
The increased risk for metabolic syndrome reported in this article may be related to other agents than cisplatin. However, since cumulative cisplatin dose alone was associated with the metabolic syndrome in our backward stepwise model, this agent appears to be an important causative factor.
Nephrotoxicity is a well-known side-effect after high cumulative cisplatin doses or when cisplatin and RT are combined [30]. Persistent hypomagnesemia, a potential consequence of cisplatin-induced damage of proximal renal tubules, has been associated with insulin resistance [31], and may be a possible link between cisplatin treatment and the metabolic syndrome. Mean serum Mg levels in our study were similar in the Cis >850 and the surgery group, and serum Mg was not associated with metabolic syndrome. Possibly, the intracellular level of Mg might be more important with regard to insulin resistance than the serum level [31].
There is increasing evidence for an association between metabolic syndrome and endothelial dysfunction [32]. Microalbuminuria, an important indicator of generalized endothelial dysfunction [33], appears to be prevalent in TC survivors treated with cisplatin-based chemotherapy [6, 34]. In vitro studies have yielded evidence for cisplatin-induced endothelial damage [35]. Recently, it was demonstrated that the level of von Willebrand factor increased during chemotherapy, indicating endothelial activation [36]. Thus, the increased risk of metabolic syndrome following cisplatin-based treatment may be due to endothelial dysfunction, although further studies are needed to evaluate a possible causal mechanism.
Patients treated with surgery or irradiation alone actually had lower ORs for the metabolic syndrome than the controls. A possible explanation could be that these survivors may change their lifestyle after having experienced a TC diagnosis, thereby reducing their risk for metabolic syndrome. Alternatively, TC itself may be associated with a reduced risk for metabolic syndrome.
In summary, TC survivors previously treated with high cumulative cisplatin doses have an increased risk of developing metabolic syndrome years after treatment, when compared with patients without previous chemotherapy or to controls. Therefore, cisplatin-treated TC survivors should be followed regularly with respect to the development of metabolic syndrome.
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Acknowledgements |
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Supported in part by grants from Erna and Olav Aakres Legacy, the Odd Fellow Medical-Scientific Research Fund and the Norwegian Foundation for Health and Rehabilitation (grant no. 1998/27). Thanks to project secretary Vigdis Opperud for assistance with the database. The study is a national clinical study as part of the Norwegian Urological Cancer Group III project.
Received for publication May 16, 2006. Revision received August 3, 2006. Accepted for publication August 30, 2006.
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References |
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1. Cancer in Norway. (2004) http://www.kreftregisteret.no (20 April 2006, date last accessed).
2. Schmoll HJ, Souchon R, Krege S, et al. (2004) European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 15:1377–1399.
3. Zagars GK, Ballo MT, Lee AK, et al. (2004) Mortality after cure of testicular seminoma. J Clin Oncol 22:640–647.
4. van den Belt-Dusebout A, Nuver J, de Wit R, et al. (2006) Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24:467–475.
5. Huddart RA, Norman A, Shahidi M, et al. (2003) Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513–1523.
6. Meinardi MT, Gietema JA, van der Graaf WT, et al. (2000) Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725–1732.
7. Sagstuen H, Aass N, Fosså SD, et al. (2005) Blood pressure and body mass index in long-term survivors of testicular cancer. J Clin Oncol 23:4980–4990.
8. Strumberg D, Brugge S, Korn MW, et al. (2002) Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 13:229–236.
9. Gietema JA, Sleijfer DT, Willemse PH, et al. (1992) Long-term follow-up of cardiovascular risk factors in patients given chemotherapy for disseminated nonseminomatous testicular cancer. Ann Intern Med 116:709–715.
10. Boyer M, Raghavan D, Harris PJ, et al. (1990) Lack of late toxicity in patients treated with cisplatin-containing combination chemotherapy for metastatic testicular cancer. J Clin Oncol 8:21–26.
11. Alberti KG and Zimmet PZ. (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553.[CrossRef][Web of Science][Medline]
12. Third Report of the National Cholesterol Education Program (NCEP). (2002) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421.
13. Alberti KGM, Zimmet P, Shaw J. (2005) The metabolic syndrome—a new worldwide definition. Lancet 366:1059–1062.[CrossRef][Web of Science][Medline]
14. Grundy SM. (2004) Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 89:2595–2600.
15. Lakka HM, Laaksonen DE, Lakka TA, et al. (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716.
16. Isomaa B, Almgren P, Tuomi T, et al. (2001) Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24:683–689.
17. Nuver J, Smit AJ, Wolffenbuttel BH, et al. (2005) The metabolic syndrome and disturbances in hormone levels in long-term survivors of disseminated testicular cancer. J Clin Oncol 23:3718–3725.
18. Ford ES, Giles WH, Dietz WH. (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356–359.
19. Hartz I, Eggen AE, Grimsgaard S, et al. (2004) Whom are we treating with lipid-lowering drugs? Are we following the guidelines? Evidence from a population-based study: the Tromso study 2001. Eur J Clin Pharmacol 60:643–649.[CrossRef][Web of Science][Medline]
20. Brydoy M, Fossa SD, Klepp O, et al. (2005) Paternity following treatment for testicular cancer. J Natl Cancer Inst 97:1580–1588.
21. Thorsen L, Nystad W, Dahl O, et al. (2003) The level of physical activity in long-term survivors of testicular cancer. Eur J Cancer 39:1216–1221.[CrossRef][Web of Science][Medline]
22. 1999 World Health Organization—International Society of Hypertension Guidelines for the Management of Hypertension. (1999) Guidelines Subcommittee. J Hypertens 17:151–183.[Web of Science][Medline]
23. World Health Organization. (1998) Obesity: Preventing and Managing the Global Epidemic: Report of a WHO Consultation on Obesity, Geneva, 3–5 June 1997(WHO, Geneva, Switzerland).
24. Laaksonen DE, Niskanen L, Punnonen K, et al. (2004) Testosterone and sex hormone–binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 27:1036–1041.
25. Nord C, Bjoro T, Ellingsen D, et al. (2003) Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. Eur Urol 44:322–328.[CrossRef][Web of Science][Medline]
26. Rennie KL, McCarthy N, Yazdgerdi S, et al. (2003) Association of the metabolic syndrome with both vigorous and moderate physical activity. Int J Epidemiol 32:600–606.
27. Zhu S, St Onge MP, Heshka S, et al. (2004) Lifestyle behaviors associated with lower risk of having the metabolic syndrome. Metabolism 53:1503–1511.[CrossRef][Web of Science][Medline]
28. Silventoinen K, Pankow J, Jousilahti P, et al. (2005) Educational inequalities in the metabolic syndrome and coronary heart disease among middle-aged men and women. Int J Epidemiol 34:327–334.
29. Johnson NJ, Backlund E, Sorlie PD, et al. (2000) Marital status and mortality: the national longitudinal mortality study. Ann Epidemiol 10:224–238.[CrossRef][Web of Science][Medline]
30. Fossa SD, Aass N, Winderen M, et al. (2002) Long-term renal function after treatment for malignant germ-cell tumours. Ann Oncol 13:222–228.
31. Barbagallo M, Dominguez LJ, Galioto A, et al. (2003) Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Aspects Med 24:39–52.[CrossRef][Medline]
32. Hsueh WA, Lyon CJ, Quinones MJ. (2004) Insulin resistance and the endothelium. Am J Med 117:109–117.[CrossRef][Web of Science][Medline]
33. Stehouwer CD, Henry RM, Dekker JM, et al. (2004) Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: further evidence for a link between microalbuminuria and endothelial dysfunction—the Hoorn Study. Kidney Int Suppl 66:S42–S44.[CrossRef]
34. Nuver J, Smit AJ, Sleijfer DT, et al. (2004) Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. Eur J Cancer 40:701–706.[CrossRef][Web of Science][Medline]
35. Nuver J, Smit AJ, Postma A, et al. (2002) The metabolic syndrome in long-term cancer survivors, an important target for secondary preventive measures. Cancer Treat Rev 28:195–214.[CrossRef][Web of Science][Medline]
36. Nuver J, Smit AJ, van der Meer J, et al. (2005) Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. J Clin Oncol 23:9130–9137.
37. Peckham MJ, McElwain TJ, Barrett A, et al. (1979) Combined management of malignant teratoma of the testis. Lancet 2:267–270.[Web of Science][Medline]
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 H. S. Haugnes, N. Aass, S. D. Fossa, O. Dahl, M. Brydoy, U. Aasebo, T. Wilsgaard, and R. M. Bremnes Pulmonary Function in Long-Term Survivors of Testicular Cancer J. Clin. Oncol., June 10, 2009; 27(17): 2779 - 2786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tandstad, O. Dahl, G. Cohn-Cedermark, E. Cavallin-Stahl, U. Stierner, A. Solberg, C. Langberg, R. M. Bremnes, A. Laurell, H. Wijkstrom, et al. Risk-Adapted Treatment in Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer: The SWENOTECA Management Program J. Clin. Oncol., May 1, 2009; 27(13): 2122 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Horwich Stage I seminoma and carboplatin risks Ann. Onc., March 1, 2008; 19(3): 407 - 408. [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Feldman, G. J. Bosl, J. Sheinfeld, and R. J. Motzer Medical Treatment of Advanced Testicular Cancer JAMA, February 13, 2008; 299(6): 672 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. Bajorin The Graying of Testis Cancer Patients: What Have We Learned? J. Clin. Oncol., October 1, 2007; 25(28): 4341 - 4343. [Full Text] [PDF]
|
|
|
|
|
|
S. D. Fossa, E. Gilbert, G. M. Dores, J. Chen, K. A. McGlynn, S. Schonfeld, H. Storm, P. Hall, E. Holowaty, A. Andersen, et al. Noncancer Causes of Death in Survivors of Testicular Cancer J Natl Cancer Inst, April 4, 2007; 99(7): 533 - 544. [Abstract] [Full Text] [PDF]
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