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© 2000 American Society for Clinical Oncology Cardiovascular Morbidity in Long-Term Survivors of Metastatic Testicular CancerByFrom the Division of Medical Oncology and Departments of Internal MedicineCardiology, Endocrinology, and Surgical Oncology, University Hospital Groningen, Groningen, the Netherlands. Address reprint requests to J.A. Gietema, MD, PhD, Division of Medical Oncology, Department of Internal Medicine, University Hospital, PO Box 30.001, 9700 RB Groningen, the Netherlands; email j.a.gietema{at}int.azg.nl
PURPOSE: To determine whether long-term survivors of metastatic testicular cancer have an increased risk of cardiovascular morbidity more than 10 years after chemotherapy.
PATIENTS AND METHODS: Eighty-seven patients treated with cisplatin-containing chemotherapy before 1987 who were in remission for at least 10 years and whose ages were RESULTS: Major cardiac events were found in five (6%) of the 87 patients (age at time of event, 30 to 42 years; time after chemotherapy, 9 to 16 years): two with myocardial infarction and three with angina pectoris with proven myocardial ischemia. An increased observed-to-expected ratio of 7.1 (95% confidence interval, 1.9 to 18.3) for coronary artery disease, as compared with the general male Dutch population, was found. In addition, one patient experienced a cerebrovascular accident. Exercise ECG did not reveal cases of subclinical coronary artery disease. Echocardiography showed normal systolic left ventricular function in most patients, but diastolic left ventricular function was disturbed in 33% of the patients. Of 62 chemotherapy patients, 79% had hypercholesterolemia, 39% had hypertension, 25% still experienced Raynaud’s phenomenon, and 22% had microalbuminuria. Compared with patients with stage I disease, the chemotherapy patients had higher blood pressure and higher total cholesterol and triglyceride levels and were more insulin-resistant. CONCLUSION: In long-term survivors of metastatic testicular cancer, we observed a significantly increased risk for occurrence of cardiac events accompanied by a persisting unfavorable cardiovascular risk profile. Accurate follow-up, focused on cardiovascular complications and aimed at intervention in these young cancer survivors, seems to be important.
TWENTY YEARS AFTER the introduction of cisplatin-containing chemotherapy for metastatic testicular cancer, this treatment remains one of the few with a high curative potential in disseminated cancer. The success of this therapy has resulted in an increasing number of patients who have been cured of testicular cancer. Because life expectancy of this group of young men is presumed to be normal once they have achieved a durable complete remission, the impact of long-term effects of the cytostatic treatment is becoming increasingly relevant. Attention has, therefore, been drawn to late sequelae of the chemotherapy such as nephrotoxicity and neurotoxicity.1-3 The described cardiovascular complications associated with cisplatin chemotherapy is a cause of increased concern about the ultimate long-term prognosis of these patients.4,5 We previously reported on the unfavorable cardiovascular risk profile that testicular cancer survivors develop several years after chemotherapy.6 This unfavorable profile, which includes hypertension, overweight, and an elevated serum level of total cholesterol in combination with a decreased high-density lipoprotein (HDL) cholesterol level, has also been described by others.7-9 The impact of cardiovascular risk factors in these young patients may be aggravated by the chemotherapy-associated vascular abnormalities such as Raynaud’s phenomenon.10-12 However, because of a relatively limited follow-up, the clinical impact of these cardiovascular risk factors on health status remains unclear. The aim of the present study is to evaluate the incidence of cardiovascular events, the presence of subclinical cardiovascular damage, and the presence of other related late side effects of cisplatin-combination chemotherapy administered to patients with disseminated testicular cancer 10 or more years ago.
In October 1997, the charts of all 208 patients treated before October 1987 with cisplatin-containing chemotherapy for disseminated testicular cancer at the University Hospital Groningen, Groningen, the Netherlands, were reviewed for the occurrence of cardiovascular events. Patients who entered onto this analysis had to meet the following additional criteria: age 50 years or younger in October 1997; no evidence of testicular cancer for at least 3 years after initial treatment; a documented follow-up of at least 10 years; and no treatment with radiotherapy. A total of 87 patients met these criteria. The median age of these patients in October 1997 was 41 years (range, 30 to 50 years); the median follow-up duration was 14 years (range, 10 to 20 years). A cardiac event was defined as a fatal or nonfatal myocardial infarction or angina pectoris with proven myocardial ischemia. By the person-years approach, the ratio was calculated of the observed (O) number and the expected (E) number of cases with angina pectoris with proven myocardial ischemia plus cases with nonfatal myocardial infarction, using age- and sex-specific incidence rates data from two Dutch registration projects.13 Data from these two registration projects originated from a total of 46 general practitioner practices and included data of 92,633 men who were between 15 and 50 years of age. Confidence limits for the ratio of the O and E numbers of patients were determined with the assumption of a Poisson distribution for O numbers. The person-years at risk were counted from the end of chemotherapy treatment through the last follow-up date. Person-years at risk were counted in patients who experienced either a cardiovascular event or a late tumor relapse before or on the date of diagnosis of the cardiovascular event or the date of tumor relapse.
Follow-Up Investigation
Measurements A detailed medical history was obtained on the day of the follow-up investigation with the help of a standardized questionnaire. This questionnaire included questions related to actual and previous cardiac function and to the presence of complaints known to be related to chemotherapy, especially Raynaud’s phenomenon. Concerning Raynaud’s phenomenon, patients were asked the following questions: Compared with before treatment, do/did you experience white, painful fingers or toes as a result of emotion, touching cold objects, or cold weather, followed by a burning feeling and redness of the acra? How did these symptoms develop over time? How would you best describe the severity? Do/did they affect your daily life? Patients who regularly did experience or had experienced these symptoms were considered to have Raynaud’s phenomenon. Furthermore, the family history (first-degree kinship) for cardiovascular disease, as well as the use of medication and tobacco, was documented. A full physical examination was performed. Blood pressure was measured at both arms with the patient in a sitting position after a rest period of 10 minutes with a standard mercury sphygmomanometer. Hypertension was defined as systolic pressure of more than 150 mmHg or diastolic pressure of more than 95 mmHg or by the prescribed use of antihypertensive medication. The body mass index (BMI), defined as body weight (kg) divided by height squared (m2), was used as a measure of corpulence. A patient with a BMI of more than 27.8 kg/m2 was considered overweight.17 Chemotherapy-treated patients underwent an exercise ECG by a bicycle ergometer according to a standard protocol18 to evaluate the existence of silent myocardial ischemia. Patients with abnormal test results underwent further evaluation by standard stress and rest myocardial perfusion scintigraphy using 99mTc-sestamibi.19 Echocardiograms were also performed using a Vingmed CFM 800 (Sonotron, Horten, Norway) equipped with a 3.25 MHz transducer. Two-dimensional images were obtained in the parasternal long-axis and short-axis views and the apical four-chamber and two-chamber views. Transmitral Doppler flow velocity patterns were recorded from the apical four-chamber view.20 The wall motion score index (WMSI) was used as an overall measure of systolic left ventricular function.21 A WMSI of more than 1.5 was considered to indicate significant systolic dysfunction. The early peak flow velocity/atrial peak flow velocity (E/A) ratio was used to assess diastolic left ventricular function to test for early left ventricular dysfunction. An E/A ratio of less than 1.0 was considered to indicate diastolic dysfunction.18 The left ventricle mass (LVM) was calculated by the formula of Devereux and was indexed for body surface area.20 An LVM index of more than 125 g/m2 body surface area was considered to indicate left ventricular hypertrophy (LVH).22 Blood samples collected after an overnight fast were analyzed for serum levels of total cholesterol, triglycerides, magnesium (Mg), and creatinine by the Vitros 750c analyzer (Ortho Clinical Diagnostics, Beerse, Belgium). The HDL cholesterol and low-density lipoprotein (LDL) cholesterol levels were determined as previously described.23,24 Cutoff points for lipid levels were used as recommended by the American National Education Program.25 Hypercholesterolemia was defined as an elevated fasting total serum cholesterol level (> 5.2 mmol/L) or by the use of cholesterol-lowering medication. Because Raynaud’s phenomenon frequently occurs in these chemotherapy-treated patients, they were evaluated for endothelium dysfunction, as tested by urinary albumin excretion in 24-hour urine collections using radioimmunoassay (RIA) (EURO/Diagnostics Products Corporation, Lanberis, United Kingdom). Microalbuminuria was defined by an albumin excretion of more than 20 µg/min.26,27 Creatinine excretion in 24-hour urine collection was determined to estimate renal function. Because the sex-hormonal balance is often disturbed,6,28 levels of serum testosterone, estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were determined using RIAs. Thyroid-stimulating hormone and thyroxin (T4) levels were measured with RIAs to exclude hypothyroidism as the cause of hypercholesterolemia. Fasting insulin and glucose levels were studied to investigate whether these patients who were inclined to being overweight developed insulin resistance.6 Insulin was measured by RIA, and glucose was measured by the glucose oxidase method using the ECA 180 analyzer (Medingen, Dresden, Germany). As a measure for insulin resistance, the insulin-to-glucose ratio (IGR) was calculated by dividing fasting serum insulin (pmol) by fasting serum glucose (mmol). An IGR of more than 22 was considered to indicate insulin resistance.29
Statistical Analysis
Cardiovascular Events Cardiac events occurred during follow-up after completion of chemotherapy in five (6%) of the 87 evaluated patients. These events occurred in two patients who had experienced myocardial infarction (being fatal in one) and in three patients who developed angina pectoris with proven ischemia. None of these five patients had any cardiac problems before the start of chemotherapy. Details of the patients with cardiac events are listed in Table 1. A comparison with the general Dutch male population revealed an O/E ratio of 7.1 (95% CI, 1.9 to 18.3) for cases of nonfatal myocardial infarction plus cases of angina pectoris with proven ischemia. The age range of the patients at the time of the event was from 30 to 42 years. All events occurred between 9 and 16 years after chemotherapy. All of the affected patients had developed hypertension in the course of time after chemotherapy, and three of these patients had additional cardiovascular risk factors. The patients with angina pectoris underwent a revascularization procedure or are currently being treated with antianginal medication. In addition, one patient experienced a cerebrovascular accident at the age of 41 years, 11 years after chemotherapy (cisplatin, vinblastine, bleomycin). He had hypertension and hypertriglyceridemia.
Follow-Up Investigation Cardiovascular risk factors. Sixty (97%) of the 62 chemotherapy patients each had one or more cardiovascular risk factors (hypertension, hypercholesterolemia, a smoking history, or a positive family history for cardiovascular events). Twenty-four (39%) of the 62 chemotherapy patients had hypertension. The blood pressure before the start of chemotherapy was normal in all of these patients. Of the 24 patients with elevated blood pressure, 11 used antihypertensive medication. The median time between chemotherapy treatment and the diagnosis of hypertension was 7.5 years (range, 2 to 17 years), at a median age of 35 years (range, 28 to 42 years). Chemotherapy patients with hypertension had higher left ventricular posterior wall thickness compared with normotensive patients, 9.5 ± 1.4 mm versus 8.7 ± 1.4 mm (P = .02). Compared with the group of patients with stage I disease, hypertension was found more frequently in the chemotherapy group (13% v 39%; P = .003). Both the mean systolic and diastolic blood pressures in the chemotherapy group were significantly higher compared with those of the group with stage I disease (Table 3). Forty-nine (79%) of the 62 chemotherapy patients had hypercholesterolemia, including seven patients who used cholesterol-lowering medication. The comparisons of lipid levels of the chemotherapy group with those of the group with stage I disease are summarized in Table 3. The mean total cholesterol, the mean total cholesterol/HDL cholesterol ratio, and mean triglycerides were significantly higher in the patients who received chemotherapy compared with those of the patients who were treated with orchidectomy only. The differences in lipid levels and blood pressure between both groups could not be attributed to difference in age because the mean age was the same in the two groups.
Twenty-two (36%) of the 62 chemotherapy patients experienced symptoms of Raynaud’s phenomenon during follow-up, but in seven patients (11%), Raynaud’s phenomenon had subsided. Serum Mg level in patients with Raynaud’s phenomenon was not significantly lower compared with that of patients without Raynaud’s phenomenon (0.82 ± 0.08 mmol/L v 0.88 ± 0.11 mmol/L; P = .06). Eleven (22%) of 51 evaluated chemotherapy patients had microalbuminuria with a median albumin excretion of 80 µg/min (range, 22.2 to 718.1). Microalbuminuria is considered to be a sign of endothelial damage. Chemotherapy-treated patients with microalbuminuria had higher mean systolic and diastolic blood pressures when compared with patients without increased albumin excretion (systolic blood pressure, 157 ± 32 mmHg v 136 ± 17 mmHg, P = .05; diastolic blood pressure, 100 ± 11 mmHg v 88 ± 11 mmHg, P = .004, respectively). The mean creatinine clearance of all 62 chemotherapy patients was 111 ± 24 mL/min. The creatinine clearance was decreased (< 100 mL/min) in 19 patients (31%). The mean serum Mg level was 0.85 ± 0.08 mmol/L and was below normal (< 0.74 mmol/L) in five patients. The serum Mg level correlated inversely with the cumulative cisplatin dose (r = -.318; P = .02). Thirteen of the chemotherapy patients (21%) were overweight compared with 11 of the patients with stage I disease (28%). The mean BMIs of the chemotherapy group and the group with stage I disease did not differ significantly (25.8 ± 3.6 kg/m2 v 25.7 ± 3.5 kg/m2; P = .86). The comparison of fasting hormone levels of both the 62 chemotherapy-treated patients and the 40 patients with stage I disease at follow-up investigation is summarized in Table 4. Fasting glucose levels for all but one patient were normal (< 7.8 mmol/L) and did not differ between the two groups. Both the median insulin level and the median IGR as measures for insulin resistance, however, were significantly higher in the chemotherapy group when compared with the group with stage I disease (Table 4). The median testosterone level in the chemotherapy group was significantly lower when compared with that of the group with stage I disease (Table 4). After adjusting for BMI, the IGR correlated inversely with testosterone level in the chemotherapy group (r = -.32; P = .015) but not in the group with stage I disease (r = .18; P = .27). In the chemotherapy group, a decreased testosterone level (< 11 nmol/L) was found in six of the patients (10%), whereas the FSH level was elevated in 42 (68%) and the LH level was above normal in 12 (19%). However, the median FSH and LH levels did not differ significantly between the chemotherapy group and the group with stage I disease. This indicates that subclinical Leydig-cell dysfunction still exists in both patient groups 10 to 20 years after treatment, though it is more pronounced in the chemotherapy group. All patients had normal thyroid-stimulating hormone and T4 levels, though the median T4 level was significantly lower in the chemotherapy patients when compared with that of the patients with stage I disease.
With the increasing number of long-term survivors of metastatic testicular cancer treated with cisplatin-containing chemotherapy, the impact of an increased incidence of cardiovascular risk factors has become a matter of great concern. The results of our current study, which involved a follow-up of 10 to 20 years after chemotherapy, feed this concern. In the studied cohort of 87 patients, all of whom were 30 to 50 years of age at the time of follow-up, five (6%) experienced major cardiac events 9 to 16 years after treatment. The high O/E ratio (7.1; 95% CI, 1.9 to 18.3) for nonfatal myocardial infarction plus angina pectoris with proven myocardial ischemia in this cohort strongly suggests that, in long-term survivors of metastatic testicular cancer cured with cisplatin-containing chemotherapy, the cardiac event rate might be elevated compared with that of the general population. Previous follow-up studies of survivors of metastatic testicular cancer have reported somewhat lower prevalences of major cardiac events, ranging from 0% to 3%.2,4,6,9,31-42 The higher prevalence of cardiac events (6%) that we found may be explained by the fact that the median follow-up duration after chemotherapy in our study was 14 years, compared with 1 to 7 years in previous studies. All cardiac events in our study occurred long after chemotherapy (9 to 16 years), which illustrates the importance of a long follow-up duration to reveal the full impact of the chemotherapy on the cardiovascular status of these cancer survivors. In none of the earlier reports were comparisons made with incidence rates of cardiac events of the local normal population. Therefore, a comparison with our finding is difficult. Whether this observation of a greater-than-expected number of cardiac events is the result of the administered chemotherapy or the natural history of testicular cancer is not clear. Because the total number of patients and events in this study is small and the interval between treatment and occurrence of cardiac events is long, possible confounding factors such as genetic predisposition for cardiovascular disease and environmental factors may have influenced the current observation. Because of the increased cardiac event rate that we found in the chemotherapy-treated patients, additional analysis of subclinical cardiac disease was performed. Exercise-ECG testing and, when indicated, 99mTc-sestamibi scintigraphy did not reveal additional cases of subclinical coronary artery disease. Echocardiographic evaluation, however, showed evidence of a previous silent myocardial infarction in one additional patient. Furthermore, although the systolic left ventricular function was normal in most patients, 33% of the chemotherapy patients had abnormal diastolic function of the left ventricle, which suggested early-stage cardiac dysfunction. Left ventricular diastolic dysfunction has been observed in several conditions, including hypertension, coronary artery disease, and diabetic mellitus.43-45 The left ventricular diastolic dysfunction in the patients studied correlated with age and systolic blood pressure, although approximately one half of the patients with disturbed left ventricular diastolic function had normal blood pressure. The chemotherapy administered, especially the cumulative dosage of cisplatin, was not determined to be an important causal factor, possibly because it was only given in small variations in administered dosages. If the observed diastolic dysfunction reflects the presence of small vessel abnormalities in the myocardium, then this might affect the development of future cardiac events. The same can be stated for LVH, which is known to increase the risk of cardiac events.46,47 In our patients, LVH is probably the result of long-standing hypertension. It remains unresolved whether the high number of cardiac events and the observed echocardiographic signs of cardiac damage represent a direct toxic effect of the administered chemotherapy or a result of the increased incidence of cardiovascular risk factors or other secondary changes that occurred in this patient group. Although the cause-effect relationship between this type of chemotherapy and Raynaud’s phenomenon is well established,48 the role of small-vessel abnormalities in the pathogenesis of major cardiovascular events in these patients is not clear. Raynaud’s phenomenon still persists up to 20 years after chemotherapy in 25% of our patients. Furthermore, we found that 22% of the patients who received chemotherapy had microalbuminuria, which suggests endothelial damage. Because microalbuminuria has been identified as an independent risk factor for cardiovascular disease in large trials, this expression of small-vessel disease might contribute to the high cardiac event rate.49,50 Clustering of risk factors was found in our chemotherapy patients with microalbuminuria. Patients with microalbuminuria particularly showed elevated blood pressure, which suggests that endothelial damage might be a pathogenic factor in the development of hypertension.26 In 1992, we reported on the increased occurrence of cardiovascular risk factors in patients cured with chemotherapy from disseminated testicular cancer.6 These findings have been confirmed by other groups.7-9 The current study demonstrates that this increase in risk factors persists up to 20 years after chemotherapy and may have a substantial influence on the development of cardiovascular events found in the present study. The reason these patients develop this unfavorable cardiovascular risk profile is still unknown. Comparing the cardiovascular risk profile of the chemotherapy-treated patients with that of the patients with stage I disease who did not receive chemotherapy revealed significantly higher blood pressure, higher total cholesterol level, higher total cholesterol/HDL cholesterol ratio, and higher triglyceride level in the chemotherapy group. Because both groups were comparable in terms of age and follow-up duration, these differences may be caused by the administered chemotherapy. Besides the direct toxicity of chemotherapy, secondary metabolic and hormonal changes in patients treated with chemotherapy may play a role in the development of cardiovascular morbidity. Elevated LH and FSH levels were found in a large portion of patients in both the chemotherapy group and the group with stage I disease. This indicates persistent Leydig-cell dysfunction.6,28,51,52 However, in addition, we found that testosterone levels were significantly lower in the chemotherapy-treated patients, which suggests a more pronounced damage of gonadal function in these patients. Because the negative correlation between the marker of insulin resistance (IGR) and testosterone was demonstrated only in the chemotherapy-treated patients, this might be interpreted as a metabolic consequence of long-term gonadal toxicity of the chemotherapy. The combination of overweight, microalbuminuria, hypertension, insulin resistance, and dyslipidemia suggests the presence of a metabolic syndrome-X-like state53 in the patients who were cured with chemotherapy. This combination of factors might influence the high incidence of cardiovascular risk factors and increased cardiac event rate observed in patients treated with cisplatin-containing chemotherapy Our results should be interpreted within the framework of a small cohort study. To determine with certainty why patients cured from disseminated testicular cancer can develop cardiovascular disease, case-control studies with healthy controls and with patients with testicular cancer who have not received chemotherapy are needed. This study illustrates the importance of accurate long-term follow-up of patients who have been cured of disseminated testicular cancer with cisplatin-containing chemotherapy. The risk of tumor relapse decreases with increasing follow-up. The risk of a second malignancy, however, increases gradually.54 We found that the risk of developing a major cardiac event is higher than expected in these young patients. The development of cardiovascular disease might be a greater threat to these patients than developing a second malignancy. Although several pathogenic mechanisms such as endothelial damage, sex-hormonal imbalance, and insulin resistance may contribute to the development of cardiovascular problems in these patients, the exact mechanism is still unclear and needs to be unraveled so that rational intervention measures can be designed. Further guidelines need to be developed in the short term to prevent or treat cardiovascular risk factors in these patients, with the ultimate goal of improving life expectancy.
We thank M. Schaapveld and R. Gijssen for assistance in analyzing a part of the data.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 years at the time of analysis were evaluated for the occurrence of cardiovascular events. Sixty-two of 87 patients were additionally evaluated for cardiac damage and cardiovascular risk factors. Their cardiovascular risk profile was compared with that of 40 patients with comparable age and follow-up duration treated with orchidectomy only for stage I disease. 
2 test. Pearson’s correlation coefficient and the Spearman rank-sum tests were applied when indicated. Multiple-linear regression analysis was performed to evaluate the effect of different cumulative cytostatic dosages or cytostatics administration on the cardiovascular parameters with adjustment for potential confounding factors. Unless otherwise stated, data are expressed as mean ± SD. All tests were two-sided; P values less than .05 were considered to indicate significance. 
