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© 2003 American Society for Clinical Oncology Cardiovascular Disease as a Long-Term Complication of Treatment for Testicular Cancer
From the Academic Unit of Radiotherapy and Oncology and Department of Computing and Information, Institute of Cancer Research and Royal Marsden National Health Service Trust, Sutton, Surrey, United Kingdom. Address reprint requests to R.A. Huddart, MA, PhD, Academic Unit of Radiotherapy and Oncology, Royal Marsden NHS Trust and Institute of Cancer Research, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; email: roberth{at}icr.ac.uk.
Purpose: To assess the risk of cardiovascular morbidity and cardiac risk factors in long-term survivors of testicular cancer according to treatment received. Patients and Methods: All resident male patients registered in the United Kingdom between 1982 and 1992 attending for follow-up were eligible for recruitment. Patients completed a current health questionnaire and underwent clinical review, along with hematologic, biochemical, and hormonal profiles. For patients not under routine review, follow-up information was sought from their general practitioner and mortality data were sought from the Office of National Statistics. Descriptive analysis was performed on all variables and comparisons were made among patients treated by orchidectomy and follow-up only, chemotherapy alone (C), radiotherapy alone (RT), and radiotherapy and chemotherapy (C/RT). Results: Data on cardiovascular events were available on 992 patients. After a median follow-up of 10.2 years, 68 events had been reported, including 18 deaths. After adjusting for age, increased risk for cardiac events was seen after C (relative risk [RR] = 2.59; 95% confidence interval [CI], 1.15 to 5.84; P = .022), RT (RR = 2.40; 95% CI, 1.04 to 5.45; P = .036), and C/RT (RR = 2.78; 95% CI, 1.09 to 7.07; P = .032). There were no significant differences in cardiac risk factors. On multivariate analysis, age, treatment group, free thyroxine, protein, and magnesium levels were associated with cardiovascular disease. Conclusion: In long-term survivors of testicular cancer, we observed a two-fold or greater risk of developing cardiovascular disease. This was not due to increases in cardiac risk factors, which suggests a direct or indirect treatment effect. These data support the continued research into the minimization of treatment in good-prognosis testicular cancer.
TESTICULAR CANCER mainly affects young men in their second and third decades of life. Since the advent of effective multiagent cisplatin-based chemotherapy, the majority of patients are curable by surgery alone or in combination with chemotherapy and/or radiotherapy.1 Cured testicular cancer patients have a long potential life expectancy; thus the risk of long-term toxicity (including mortality) is important. In good-prognosis groups, if there is significant treatment-related mortality, this may represent a larger threat to longevity than the original malignancy. In good-prognosis groups, there has been emphasis on strategies to minimize toxicity.2 The degree of long-term health risk these patients face remains uncertain. Some early data have indicated there is an increase in cardiovascular risk factors (including hypertension and increased cholesterol), which suggests that testicular cancer patients may experience long-term cardiovascular morbidity.3–7 We investigated the risk of cardiovascular morbidity by undertaking a cross-sectional study of patients treated for testicular cancer between 1982 and 1992 at our institution to determine the prevalence of cardiovascular risk factors and cardiac morbidity.
All United Kingdom resident male patients registered between 1982 and 1992 at the Royal Marsden National Health Service Trust with a diagnosis of germ cell tumor were eligible for entry onto this study. A total of 1,603 patients were registered during this time period. Of these, 200 were considered ineligible (largely because of overseas residence). Two hundred three had died (Fig 1  ); of these, 62 died of causes other than testicular cancer and were included in our analysis of morbidity. A total of 1,200 patients were eligible for recruitment, of whom 798 were asked to participate during the time frame of the study (October 1997 to February 1999). Fifty-nine patients declined consent, resulting in a cohort of 739 patients who entered the study.
The remaining 402 patients were either lost to follow-up or were not seen in clinic during the time frame of the study. For these patients, updated follow-up information was sought from their local doctor and the Office of National Statistics (ONS; Fig 1  ). Information was sought on the current status of patients, with particular focus on cardiovascular events, second malignancy, and known toxicity of chemotherapy. Information was received for an additional 191 patients. For the remaining 211 patients, no information was received. For patients attending the clinic, all were contacted at least 2 weeks before clinic visit by mail. The nature of the study was explained by letter, and patients were asked to provide written consent and complete a general health questionnaire and quality-of-life form (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30), along with the testicular cancer module. On arrival at clinic, consent was confirmed and questionnaires were collected. A systemic review was undertaken, with particular reference to cardiovascular and abdominal symptoms, evidence of Raynaud’s phenomenon, and peripheral neuropathy. A diagnosis of Raynaud’s phenomenon was accepted on the basis of clear cold-related peripheral discomfort and skin color changes, including skin blanching. Patients underwent full physical examination, including peripheral nerve function testing for light touch sensation, deep tendon reflexes, and vibration sensation. The last of these was tested using a 128-MHz tuning fork. Blood pressure was taken using a standard 12-cm blood pressure cuff with the patient lying supine. Blood was drawn for complete blood cell count, urea and electrolytes, creatinine, liver function tests (including bilirubin, AST, ALT, and alkaline phosphatase), calcium, albumin, magnesium, luteinizing hormone, follicle-stimulating hormone, testosterone, thyroid function tests, and tumor markers (alpha-fetoprotein/beta human chorionic gonadotropin). Patient height and weight were measured to estimate body mass index and creatinine clearance by the method of Cockcroft and Gault.8 All biochemical results and blood pressure were reported to the patients’ local doctor. The study was undertaken according to a protocol approved by the local research ethics committee. Patients who agreed to take part in the study provided written informed consent. This report focuses on the major end point of the study, the risk of cardiovascular events and cardiac risk factors. Data on other aspects will be the subject of future analyses.
Statistical Methods Information collected at the clinic visit, including blood tests, hearing tests, and lung function tests, as well as the questionnaire information, was prospectively entered onto the Bob Champion Unit research database. Once data collection was complete, eligible patients who had not been enrolled at the clinic were then identified and their general practitioners (GPs) contacted with a long-term health questionnaire. The remaining patients for whom there was no response from the GP were then flagged at the ONS to identify any deaths.
For all patients with data collected in clinic, descriptive analysis was performed on all variables and comparisons were made among the four treatment groups. Categorical data were examined using the Cardiac events and second malignancies were derived from a combination of prospectively collected information of the Bob Champion Unit research system, clinical data in the questionnaire collected at the follow-up clinic visit, GP questionnaire data, and mortality data from the ONS. Cardiac events were defined as follows: (1) patient died from a myocardial infarction (MI) or similar cardiac related episode; (2) angina or MI reported on GP forms (only for patients lost to follow-up); (3) cardiac abnormality on the assessment form at the long-term follow-up clinic visit; (4) angina or chest pains reported at the long-term follow-up clinic visit; (5) cardiac surgery for coronary artery disease. An inverted life table of time to a cardiac event from treatment was calculated using the methods of Kaplan and Meier,9 and the log-rank10 test was used to detect differences among groups. Date of event was the date stated by patient or GP or, if not stated, the date on which the event was entered in the database. Patients with no cardiac events were censored on the date of last follow-up in the database. Univariate after the inclusion of age as a covariate and multivariate analyses were performed using logistic regression analysis to calculate risk ratios for cardiovascular disease (CVD) of the three treatment groups relative to the surveillance group.
Patient Characteristics Characteristics of the patient cohort are listed in Tables 1 and 2. Patients were classified into four groups according to treatment received. The surveillance group received no treatment except for orchidectomy and consisted of 341 patients diagnosed between 1982 and 1992, for whom cardiac morbidity data are available for 242 patients (71%). This group acted as a reference for derivation of treatment-related effects. The other groups consisted of 331 patients (230 [69%] with cardiac data) treated with radiotherapy alone and 660 patients (390 with cardiac data; 65% of patients surviving their testicular cancer) who had treatment with chemotherapy alone. Two hundred seventy-one patients (130 with cardiac data; 66% of patients surviving their testicular cancer) had received both chemotherapy and radiotherapy at some stage of their treatment and have been included as a separate group for analysis purposes.
The majority of patients in the radiotherapy group received dog-leg radiotherapy to a dose of 30 Gy for stage I seminoma. Thirty patients (8%) in this cohort also received mediastinal radiotherapy. The majority of patients treated with chemotherapy received cisplatin-based chemotherapy, most commonly with the bleomycin, etoposide, cisplatin regimen (37%), but one third of patients received a carboplatin-based regimen (carboplatin alone or carboplatin, etoposide, bleomycin). Patients in the combined group most commonly (67%) received radiotherapy after chemotherapy for advanced disease, although approximately 10% of these patients had received single-agent carboplatin and radiotherapy for stage IIA/B seminoma.
Prevalence of Cardiovascular Events
Relationship of Cardiac Events and Treatment
On unadjusted analysis, a statistically nonsignificant trend was also seen for patients treated with chemotherapy alone, with an RR of 1.85 (95% CI, 0.85 to 4.02; P = .12), and for patients receiving any chemotherapy (with or without radiotherapy), with an RR of 1.98 (95% CI, 0.94 to 4.18; P = .07). However, patients receiving chemotherapy had a median age 3 years younger than that of the surveillance group, and when adjustment is made in a logistic regression model, this represents an age-adjusted RR of 2.59 (95% CI, 1.15 to 5.84; P = .022).
Actuarial analysis was limited because date of event was not available for all patients. When not stated, the date the event was reported was entered. Thus this analysis may overestimate the time to onset of cardiac events. This analysis suggests the risk of a cardiac event starts to increase after 5 to 8 years. After 10 years of follow-up, the actuarial risks are as follows: surveillance, 1.4% (95% CI, 0.46 to 4.4); radiotherapy, 7.2% (95% CI, 4.2 to 12.2); chemotherapy, 3.43% (95% CI, 1.9 to 6.1); and chemotherapy and radiotherapy, 4.1% (95% CI, 1.69 to 9.66; Fig 2
We investigated the influence that the extent and type of chemotherapy has on the risk of developing a cardiac event, but the small number of events within subgroups means the power of this analysis is limited. There was no evidence of heterogeneity between patients treated with cisplatin and those treated with carboplatin. Cardiac events were reported in 7.25% of 345 patients treated with cisplatin-based chemotherapy alone, compared with 9.75% of 175 patients treated with carboplatin-based chemotherapy (P = .87). There was also no significant difference in the incidence of cardiac events between patients who did or did not receive bleomycin-containing chemotherapy (five [6%] of 81 patients not receiving bleomycin compared with 32 [7.2%] of 439 patient receiving bleomycin; P = not significant) and between those who received one to four cycles of chemotherapy versus five or more cycles (23 [6.8%] of 339 patients receiving one to four cycles compared with 14 [8.3%] of 167 receiving five or more cycles; P = not significant).
Risk Factors for Cardiac Disease
Random cholesterol levels were studied in 675 patients (Table 4 ). The median level was 5.40 mmol/L; 1.6% of patients had a cholesterol level above the normal range. There was no significant increase in cholesterol levels in groups receiving treatment. Patients who had received radiotherapy had a median cholesterol of 5.50 mmol/L compared with 5.4 mmol/L for the surveillance group, but this difference was not significant (P = .14). More patients in the radiotherapy group had an increased cholesterol level or were being treated with lipid-lowering medication than in the surveillance group (2% for surveillance patients compared with 6.2% for radiotherapy-treated patients; P = .09). Whether this observation is related to increased secondary prevention in patients who had experienced a cardiac event is uncertain.
More patients received treatment for hypertension in the group receiving chemotherapy and radiotherapy (21.2% v 8.9%; P < .01), with nonsignificant trends to increased diagnosis of hypertension in the other treatment groups (Table 4
Patients receiving radiotherapy and/or chemotherapy had some evidence of impairment in renal function, with elevated median urea and creatinine levels as well as an increased proportion of patients with creatinine and urea elevated above the normal range (Table 5
Overall, 31% of patients treated with chemotherapy had one or more levels of urea, creatinine, magnesium, or cholesterol outside the normal range, compared with 19% of surveillance patients (P = .003). Likewise, 31% of radiotherapy patients had one or more of these parameters outside the normal range (P = .007).
Univariate and Multivariate Analysis
Results of the univariate analysis are given in Table 6
On logistic multivariate analysis of the full set of cardiac events, age and treatment groups were related to cardiovascular disease. When the subgroup of patients with full results is considered with the reduced base of events and subsequent lack of power, age (P < .001) remained a significant predictive factor for CVD, but treatment group became statistically nonsignificant (Table 7 ). In this analysis, other predictors of CVD were magnesium (RR = 0.003; P = .021), free thyroxine (RR = 1.152; P = .03), and total protein levels (RR = 0.91; P = .03).
Cardiac Irradiation in Para-Aortic Irradiation Computed tomography scans from six patients were studied to calculate the radiation dose to the heart during para-aortic radiotherapy. Cardiac volumes were outlined on each scan slice. Parallel fields as used in para-aortic radiotherapy were inputted using the target 2 planning system. In each instance, cardiac volumes and dose-volume histograms were produced. The results of this analysis are listed in Table 8 . For the usual dose of 30 Gy in 15 fractions, the mean cardiac dose to the heart was 0.76 Gy (range, 0.54 to 1.35), with a mean maximum cardiac dose of 3.36 Gy (range, 0.82 to 14.1 Gy). An average of 14% (range, 8% to 45%) of cardiac volume received a dose of 0.9 Gy or more (Table 8).
In this study, we investigated whether there is an increased risk of CVD in long-term survivors of testicular cancer. To minimize the risk of bias and to establish a firm denominator, we studied a cohort of patients treated between 1982 and 1992. During this time period, 1,603 patients were treated at this institution. Four hundred patients were not studied because they had died of disease (141 patients), refused consent (59 patients), or did not meet other entry criteria (200 patients). Of the remainder, we obtained information on 992 patients. The remaining 211 patients for whom we have no information are a potential source of bias. Flagging at the ONS means we are confident that these patients are currently alive but can only speculate on their current health status. Because these patients are equally distributed between the subgroups studied, we do not believe that absence of data on these patients has introduced any systematic bias In the patients studied, we demonstrated a statistically significant, greater than two-fold, age-adjusted increased risk for a cardiac event for patients treated with radiotherapy and/or chemotherapy. After a median follow-up of approximately 10 years, 6.7% of patients treated with chemotherapy and 9.6% of patients treated with radiotherapy had experienced a cardiac event, compared with 3.7% of patients treated by orchidectomy alone.
The findings in chemotherapy patients are similar to the findings of Meinardi et al.11 They investigated 87 patients treated with cisplatin-based chemotherapy. After a median follow-up of 14 years, five patients (6%) suffered a major cardiac event. Compared with the normal population, this equated to a seven-fold increased risk. In our study, 6.7% of patients had experienced a cardiac event, compared with 3.7% of patients treated with orchidectomy only (surveillance group). After adjusting for the younger age of patients receiving chemotherapy, this equates to an increased risk of 2.59. Other smaller series have reported cardiac events in 1% to 5% of patients, though these studies are largely based on small numbers of patients and/or case note review (which are likely to underestimate the incidence of cardiac events; Table 9
The data presented here raise a number of issues related to the management of testicular germ cell tumors. There is no doubt that effective treatment of the malignancy is important and should not be compromised. At the time of this study, overall 1.8% of patients had died of a cardiac event and 6.9% had evidence of CVD, with the risk of having a cardiac event being twice as large for patients receiving radiotherapy and/or chemotherapy. Because the incidence of cardiac mortality is likely to increase with time, even without making allowance for the risk of treatment-induced second malignancy,19,20 it is likely that more patients in good prognostic categories will eventually die of their treatment than will die of their cancer. What are the possible causes of the increased risk of CVD? Anthracyclines are the chemotherapy agent most closely associated with cardiac toxicity but were used only in a small number of patients (< 1%). The drugs used in testicular cancer treatment are not normally associated with CVD. However, many patients exhibit long-term damage to the peripheral vasculature, an effect demonstrated by the long-term persistence of Raynaud’s phenomena,21 which is usually attributed to bleomycin (with or without vinblastine). This raises the question of whether coronary arteries could be affected in a similar way. We could not demonstrate any difference between patients who received bleomycin and those who did not, but as the numbers of patients not treated with bleomycin are small, the power of this analysis is low. Meinardi et al7,11 have reported that endothelial damage is evidenced by the presence of urinary microalbuminuria in up to 22% of patients after treatment for testicular cancer. This parameter was not examined in this study. Abnormalities in levels of magnesium, albumin, and protein were associated with chemotherapy treatment and are associated with CVD on multivariate analysis. These changes would be consistent with this hypothesis. Recent data have suggested that platination of DNA can be detected at low levels in long-term survivors of treatment, and this could be responsible for long-term effects of cisplatin treatment.7 Essentially all chemotherapy-treated patients in this series received a platinum-based compound. In approximately one third of patients, this was carboplatin, with the remainder receiving cisplatin. There was no evidence for heterogeneity in the risk of CVD between these two groups, suggesting that if long-term platination is the mechanism of the increased risk of CVD, this risk applies equally for carboplatin and cisplatin. Alternatively, the increased risk could be a secondary effect of other systemic changes. Gietema et al6 reported a high incidence of increased cholesterol and low-density lipoprotein levels along with increases in body mass index in patients after chemotherapy treatment for germ cell tumors. In a recent update,11 total fasting cholesterol, total cholesterol/high-density lipoprotein cholesterol ratios, and trigylcerides were all elevated in chemotherapy-treated patients compared with surveillance controls. Likewise, Boyer et al17 found increased cholesterol levels in 67% of patients after cisplatin-based chemotherapy for germ cell tumors, with Bokemeyer et al4 reporting increased cholesterol levels in one third of patients. Our data, although limited by an assessment that was based on random cholesterol, demonstrated no such effect of treatment; median cholesterol levels and the number of patients taking cholesterol-lowering drugs or above-normal cholesterol were similar between groups. It has also been suggested4,6,11,21,22 that patients receiving chemotherapy may have a higher rate of hypertension and body mass index. Evidence from our biochemical evaluation did demonstrate evidence of subclinical renal impairment after chemotherapy treatment, even though there was little difference in calculated creatinine clearance except in the chemotherapy and radiotherapy group. As noted above, some of these biochemical changes are associated with CVD on univariate and multivariate analysis. The significance of these observations is uncertain. However, in our series for the patients receiving chemotherapy alone, there was no evidence of higher systolic or diastolic blood pressure levels. More patients reported using antihypertensive medication, but the difference compared with surveillance was not statistically significant unless patients had received radiotherapy as well. Patients who had received radiotherapy either alone or in combination with chemotherapy had an approximately doubled risk of a cardiovascular event, which persisted even when allowance was made for the slightly older age of patients in the radiotherapy-treated group. An increased risk of CVD had been previously suggested after radiotherapy in patients with seminoma when the radiation fields included the mediastinum,23 and recently we noted similar findings in a series of patients with stage IIA/B seminoma treated at our institution.24 It is known that direct cardiac irradiation can damage cardiac microvasculature and indirectly damage the coronary vasculature.25 Increased risk of cardiac morbidity after direct cardiac irradiation has been reported for a number of tumors. For instance, after mediastinal irradiation of patients with Hodgkin’s disease with age similar to that of patients with testicular cancer, relative risks in the order of three to seven times the expected rate have been reported.26,27 Increased risks of CVD of approximately 1.3 to 3.0 have also been reported after chest wall radiotherapy of breast cancer which in some patients includes partial cardiac irradiation.28–31 In both instances, the risk of CVD is thought to be associated with direct cardiac irradiation. Indeed, in one study of breast cancer patients, a direct relationship with volume irradiated and risk was made.28 In this study, only 30 patients received mediastinal irradiation. Two (6.7%) of these patients had a cardiac event, and the risk of CVD remained after these patients were excluded. The majority of the remaining patients would have received infradiaphragmatic radiotherapy. Our routine treatment during the period in which these patients were treated would be dog-leg radiotherapy extending superiorly to the bottom T10. We have modeled the extent of cardiac irradiation with this technique. The amount of cardiac irradiation is modest largely because of scattered irradiation; the mean dose to the heart is approximately 2.5% of the applied dose. The results of this limited study indicate that direct cardiac irradiation is uncommon, and on average only 14% of the cardiac volume receives 0.9 Gy or more. These doses are less than those seen in either the treatment of lymphomas or in irradiation of the left side of the breast. Whether such low doses could be responsible for the increased risk of cardiac morbidity is questionable. The aim of extending the radiation field to the bottom of T10 has been to treat the retrocrural nodes. This practice could be considered questionable because retrocrural nodal relapses are rarely seen in surveillance studies32,33 and essentially never seen as a sole site of relapse. The value of irradiating them adjuvently may therefore be limited. If this had no impact on morbidity, perhaps such considerations are trivial, but given these data on risk of CVD, any precaution to minimize cardiac irradiation—even if to reduce scattered dose—may be worthwhile. It was on this important consideration of reducing morbidity that widespread use of the para-aortic strip in preference to dog-leg irradiation in stage I seminoma has gained acceptance.34 If direct cardiac irradiation is not the cause of the increased risk of CVD, then could this represent a secondary effect of radiotherapy? Evidence from animal models and clinical studies suggests that fractionated doses greater than 20 Gy can induce radiation nephropathy, which can result in hypertension.35 For example, Kim et al36 reported radiation nephropathy in nine of 18 patients who had half or more of one kidney treated with radiotherapy to a dose of 22.5 to 45 Gy, of whom five subsequently developed hypertension. Likewise, Dewit et al37 reported evidence of nephropathy in 12 patients receiving radiation for lymphomas and increased diastolic blood pressure in a subgroup of these patients. It is generally believed that this is due to a renovascular effect involving the rennin-angiotensin system.35,37,38 Data on patients receiving radiotherapy for seminoma are sparse. In the study of Dewit et al,37 among seven patients treated for seminoma with radiation doses between 25 and 35 Gy, only minor inconsistent changes in early renal function could be detected, although two patients had transient changes in technetium-99m diethylenetriamine penta-acetic acid renograms during treatment, indicating that the radiation received can affect the kidney. None of these patients developed hypertension in the period studied. In a follow-up study, they did demonstrate that the one seminoma patient studied had a decline in glomerular filtration rate, despite being normotensive. It is possible that follow-up of these patients is too short; some reports have suggested that prolonged follow-up is required and effects may take 8 years or more to develop.35 The standard dog-leg technique we use routinely includes some renal tissue, especially at the upper poles and on the side ipsilateral to the tumor. That this can affect renal function in the long-term is illustrated here by small but detectable differences in urea and creatinine and other biochemical parameters. In turn, some of the parameters that are abnormal in radiotherapy-treated patients are independently associated with CVD in our multivariate analysis. Therefore, there is the potential that this renal damage could increase the risk of hypertension, which in turn could increase the risk of CVD. We are unaware of any studies that have systematically investigated this aspect, and our own data on this issue are equivocal. There was the indication that groups receiving radiotherapy as part of their treatment more frequently received antihypertensive treatment than surveillance patients, but measured blood pressures were not significantly different between groups. This issue therefore remains unresolved. Whatever the cause of the increased incidence of CVD, these data would support vigorous examination of minimal treatment strategies, particularly in good-prognosis groups. On the other hand, we would not advocate uncritical adoption of new treatment strategies. A careful assessment of each strategy should be performed and cancer cure and overall treatment burden should be examined. It is possible that surveillance strategies might not result in the least amount of treatment if treatment of relapse results in a larger total treatment burden for the population studied. In conclusion, we have identified a potential long-term risk of CVD in long-term survivors of testicular cancer. After a median of 10 years’ follow-up, the risk of experiencing a cardiac event is approximately 10% for patients after radiotherapy treatment and 6.7% after chemotherapy. When adjusted for differences in age, this represents a statistically significant 2.4 to 2.8 increased risk for patients receiving treatment compared with patients undergoing surveillance. In some groups, this effect may be a greater risk to long-term survival than testicular cancer itself and argues that in good-prognosis groups, attempts to minimize treatment should continue.
Supported by the Institute of Cancer Research, the Bob Champion Cancer Trust, and Cancer Research UK. This work was undertaken in the Royal Marsden National Health Service (NHS) Trust, which received a proportion of its funding from the NHS Executive. The views expressed in this article are those of the authors and not necessarily those of the NHS Executive.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. The one-sample Kolmogorov-Smirnov test was used to test for normal distribution. This was highly significant in most cases (P < .01), so continuous variables were compared using the Mann-Whitney U nonparametric test. 
