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Originally published as JCO Early Release 10.1200/JCO.2005.01.4092 on November 21 2005 © 2005 American Society of Clinical Oncology. Acute Chemotherapy-Induced Cardiovascular Changes in Patients With Testicular CancerFrom the Departments of Medical Oncology, Vascular Medicine, Hematology, Cardiology, and Surgical Oncology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands Address reprint requests to J.A. Gietema, MD, PhD, Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, the Netherlands; e-mail: j.a.gietema{at}int.umcg.nl
PURPOSE: After cisplatin- and bleomycin-containing chemotherapy for testicular cancer, part of the patient population will develop acute or long-term cardiovascular toxicity. It is largely unknown whether standard tests can be used to assess chemotherapy-induced cardiovascular changes. PATIENTS AND METHODS: In 65 testicular cancer patients (median age, 27 years; range, 18 to 48 years), we measured the following cardiovascular parameters before and within 10 weeks after completion of cisplatin-based chemotherapy: platelet numbers, plasma levels of hemostatic and fibrinolytic factors, 24-hour ambulatory blood pressure, baroreflex sensitivity, intima-media thickness of the common carotid artery, and flow-mediated vasodilation of the brachial artery. RESULTS: Compared with prechemotherapy values, the intima-media thickness of the carotid artery and plasma von Willebrand factor levels increased significantly after treatment. Platelet numbers and plasma levels of other hemostatic and fibrinolytic factors did not appear to change significantly. Blood pressure decreased significantly, but flow-mediated vasodilation and baroreflex sensitivity did not change. CONCLUSION: In testicular cancer patients treated with cisplatin-based chemotherapy, we found an increase in plasma von Willebrand factor levels and in the intima-media thickness of the carotid artery. These changes may indicate chemotherapy-induced vascular damage and be of prognostic significance for the development of cardiovascular complications in the long term.
Testicular germ cell cancer is the most common malignancy in men between 20 and 40 years of age. Approximately half of these germ cell tumors are nonseminomas. Nonseminomas are disseminated in approximately 50% of the patients at presentation. After an orchidectomy, standard treatment of disseminated nonseminoma consists of chemotherapy with a combination of bleomycin, etoposide, and cisplatin. Approximately 80% of patients with a disseminated nonseminoma then become long-term survivors.1 Because of the high cure rate and the increasing incidence of testicular cancer,2 the number of long-term survivors is increasing. Cisplatin- and bleomycin-containing chemotherapy for testicular cancer has been associated with both acute and long-term vascular toxicity. Endothelial injury has been described after the administration of cisplatin and bleomycin in vitro.3,4 Raynaud’s phenomenon, believed to be a vascular toxic effect of bleomycin, has been reported in up to 37% of patients.5,6 Several patients have also been reported in whom myocardial infarction occurred during or shortly after the administration of cisplatin.7 Furthermore, long-term survivors of disseminated testicular cancer have an increased risk for cardiovascular disease.8-10 This risk seems to become particularly overt after more than 10 years of follow-up, although the development of cardiovascular risk factors and signs of atherosclerosis may take place at an earlier stage.11-13 Together, these data suggest toxic effects of chemotherapy directed toward the vasculature. Chemotherapy-induced vascular toxicity may not only result in acute cardiovascular complications during treatment, but may also be involved in the initiation and progression of atherosclerosis and the increased risk of vascular events after long-term follow-up. So far, few studies have investigated acute chemotherapy-induced cardiovascular changes in testicular cancer patients.14,15 It is largely unknown whether standard vascular tests can also be used to detect chemotherapy-induced cardiovascular alterations. Cardiovascular alterations during treatment may have prognostic significance for the development of cardiovascular complications in the long term. In a prospective cohort study, we investigated chemotherapy-induced cardiovascular changes in patients with disseminated testicular cancer. Standard tests were used to evaluate cardiovascular structure and function before and after completion of bleomycin, etoposide, and cisplatin (BEP) combination chemotherapy.
Patients All consecutive patients with a disseminated nonseminomatous germ cell tumor who were scheduled to receive BEP chemotherapy as first-line therapy at the University Hospital Groningen, the Netherlands, between August 1998 and May 2004, were approached to participate. Exclusion criteria for participation were an extragonadal tumor, extrapulmonary visceral metastases, previous radiotherapy, a pretreatment history of cardiac disease, use of erythropoietin, and age older than 55 years at the start of chemotherapy. The study was approved by the local ethics committee and informed consent was obtained from each participant.
Measurements
Markers in Blood Before and after completion of chemotherapy, blood samples were drawn after an overnight fast and analyzed for von Willebrand factor (vWF), fibrinogen, tissue-type plasminogen activator antigen (t-PA), plasminogen activator inhibitor type 1 antigen (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI) activity, and platelets (reference values, 150 to 350 x 109/L). vWF was measured using an enzyme-linked immunosorbent assay (reference values 50% to 150%; Dako A/S, Glostrup, Denmark). Fibrinogen was measured using the Clauss functional assay (reference values, 1.7 to 3.5 g/L). PAI-1 (reference values, 4 to 43 ng/mL) and t-PA (reference values, 1 to 10 ng/mL) were measured using an enzyme-linked immunosorbent assay (Asserachrom; Diagnostica Stago, Asnieres-sur-Seine, France). TAFI activity (reference values, 79% to 126%) was determined using a chromogenic assay (Kordia/Pentapharm, Basel, Switzerland). From March 2001, cardiac-specific troponin I in plasma was measured by a microparticle enzyme immunoassay (AxSYM; Abbott, Wiesbaden, Germany) at least once during the first 8 days of each chemotherapy course. Troponin I levels less than 0.2 ng/mL are considered normal. Troponin levels more than 0.8 ng/mL are suggestive for myocardial damage. For troponin I levels between 0.2 and 0.8 ng/mL, myocardial damage cannot be excluded.
Vascular Structure
Vascular Function
Ambulatory Blood Pressure
Cardiovascular Autonomic Function
Statistical Analysis
Patients Between August 1998 and May 2004, BEP chemotherapy was started as first-line therapy for a nonseminomatous germ cell tumor in 131 patients younger than age 55 years. Fifty-one patients were not eligible because they fulfilled exclusion criteria or had comorbidity interfering with the study investigations. Reasons for not being eligible were an extragonadal primary tumor (eight patients), extrapulmonary visceral metastases (10 patients), congenitally heart defects (three patients), comorbidity interfering with study investigations (17 patients [postorchidectomy infection, n = 3; dyspnea/cough interfering with prolonged supine position, n = 3; the need to start chemotherapy without delay, n = 6; mental retardation, n = 4; history of alcohol and/or hard drugs abuse, n = 1]), and concomitant administration of erythropoietin (13 patients). Of the remaining 80 patients, 69 (86%) agreed to participate, of whom four dropped out during treatment because of toxicity or patient refusal. Therefore, 65 patients were fully assessable. Table 1 shows the disease characteristics of the 65 included patients. After orchidectomy, all patients received four courses of a combination BEP: bleomycin 30 mg on days 2, 8, and 15 of the first three courses; etoposide 100 mg/m2 on days 1 to 5 of each course; and cisplatin 20 mg/m2 on days 1 to 5 of each course. One patient received two additional courses of etoposide, ifosfamide, and cisplatin. Patients were admitted to the hospital for intensive hydration during the first week of each course only. All patients received dexamethasone and ondansetron as standard antiemetic therapy.
Measurements The first measurement was performed a median of 1 day (range, 0 to 7 days) before the start of chemotherapy. The median time between the completion of chemotherapy and the postchemotherapy evaluation was 36 days (range, 11 to 100 days). Thirty-eight patients were evaluated between the second and third course of chemotherapy as well (median, 9 days; range, 2 to 16 days after the last cisplatin administration of the second course).
Events
Five patients experienced a venous thromboembolic event (Table 2). One patient presented with a deep vein thrombosis of a leg at diagnosis, two patients had pulmonary emboli established by lung scintigraphy, and two patients had thrombosis of a subclavian vein presumably related to their venous access port. Anticoagulant treatment was started in these five patients.
Markers in Blood and Urine
Cardiac troponin I was measured in 37 patients during treatment (mean, 5.5 measurements per patient). Troponin I elevations (any value > 0.0 ng/mL) were found in 10 (27%) patients, including two patients with a myocardial infarction and one patient with pulmonary emboli. The myocardial infarctions occurred when the patients were at home; troponin I values measured in hospital during the preceding course were 0.0 and 0.4 ng/mL, respectively. The remaining seven patients with troponin I elevations (range, 0.1 to 1.6 ng/mL: four patients < 0.2 ng/mL, two patients 0.2 to 0.8 ng/mL, and one patient > 0.8 ng/mL) did not develop a vascular event.
Vascular Structure
Vascular Function FMD did not change significantly during treatment (Table 4). NTG-mediated vasodilation, measured in a subgroup of patients (n = 25), was also not affected (median before, 7.2% [interquartile range, 3.7% to 10.4%] v median after, 8.4% [interquartile range, 3.0% to 11.9%]; P = .38).
Ambulatory Blood Pressure
Cardiovascular Autonomic Function BRS measured between the second and third course of chemotherapy was significantly lower than BRS measured before chemotherapy (median before, 2.42 [interquartile range, 2.06 to 2.79] v median after, 2.23 [interquartile range, 1.85 to 2.56]; P = .01). Median BRS after completion of the chemotherapy was also lower than mean BRS prechemotherapy, but this difference was not statistically significant (Table 5). Furthermore, the change in BRS after postural change from the supine to the standing position was not significantly different between the measurements before and after chemotherapy.
We investigated changes in cardiovascular parameters in patients with disseminated testicular cancer after treatment with cisplatin- and bleomycin-containing chemotherapy. We found an increase in vWF plasma levels and an increase in common carotid IMT. vWF is considered a marker of endothelial function. Compared with baseline, the median vWF level and the number of patients with a vWF level greater than 150% increased significantly after treatment, which may indicate stimulation of and/or damage to endothelial cells by chemotherapy. The regulation of the balance between coagulation and fibrinolysis by the endothelium did not seem affected, given that fibrinogen levels and fibrinolytic capacity, as assessed by PAI-1 and t-PA levels and TAFI activity, did not change significantly. Increased vWF levels have been associated with an increased cardiovascular risk in patients with angina and after myocardial infarction 18 and in study participants from the general population,19 and may also correlate with the risk of vascular complications in cancer patients during chemotherapy. Persistent endothelial activation, as reflected by continuously increased vWF levels, may prove to be associated with the development of vascular complications after a longer period of follow-up.
From the start of chemotherapy, thromboembolic complications, including two arterial events, developed in six (9%) of the 65 patients, which is in agreement with a previous study in which thromboembolic complications were found in 15 (8%) of 179 testicular cancer patients during chemotherapy.7 The development of thrombotic complications during cancer treatment may result from tumor-associated hypercoagulability, compression of blood vessels by tumor, direct damage from venous access ports, and possibly chemotherapy-induced endothelial damage. Although patient numbers are small, the results of our study suggest a different pathophysiological mechanism for arterial and venous thromboembolism during cancer treatment. Patients who developed a venous thromboembolic complication had normal vWF and t-PA levels at baseline, whereas patients with an arterial event had elevated levels of vWF and t-PA. In these latter patients, platelet numbers and fibrinogen levels were also above the upper limit of normal at baseline, whereas platelet numbers and vWF plasma levels increased even further during chemotherapy. Licciardello et al20 previously found an association between vWF and arterial thrombosis in cisplatin-treated patients. They described highly elevated levels of vWF ( An increased IMT of the carotid artery is associated with a higher prevalence of vascular risk factors and with an increased risk of myocardial infarction and stroke.21-23 We found an increase in common carotid IMT in young testicular cancer patients after chemotherapy. A median of 3.5 months after the start of chemotherapy, IMT increased 0.020 mm on average (median difference score, 0.025 mm; interquartile range, –0.011 to 0.071 mm), whereas the mean annual increase in common carotid IMT in men from the general population has been estimated to be 0.010 mm.24 These data suggest a more rapid increase in IMT in patients with disseminated testicular cancer after BEP chemotherapy than would be expected from an increase in age alone. Effects of other cytostatic agents on IMT are unknown. A rapid increase in IMT during chemotherapy may indicate susceptibility to vascular toxicity and be of prognostic significance for cardiovascular complications in the long term. It is not clear whether the rapid progression of wall thickness in our study actually reflects an increase in atherosclerotic lesions in the common carotid artery (intimal layer) or rather is a resultant of changes in shear stress and transmural pressures (hypertrophy of medial layer). This latter mechanism has been described to be especially important for IMT values below 1.00 mm.25,26 A change in IMT was positively correlated with a change in systolic blood pressure in our study. Therefore, the rapid increase in IMT may also be compatible with an adaptive response to changes in pressure, besides an increase in atherosclerotic lesions. Nevertheless, increases in IMT in the range below 1.00 mm have also been associated with increases in cardiovascular risk.21,22,25 Therefore, increases in blood pressure and IMT during chemotherapy may be of prognostic significance for long-term vascular complications in cancer survivors. Only a few relatively small studies previously investigated treatment-induced changes in IMT in cancer patients. Compared with healthy controls, an increased IMT was reported in 42 survivors of Hodgkin’s lymphoma and in 51 survivors of nasopharyngeal carcinoma after radiation therapy to the neck.27,28 Reduced growth hormone secretion as a result of cranial irradiation was correlated with an increased IMT in survivors of childhood cancer.29,30 Only one prospective study has been reported, in which IMT was measured in 36 patients before and 12 and 24 months after radiation therapy for squamous cell carcinoma of the head and neck.31 This study found rapid progression of the carotid IMT after both 12 and 24 months of follow-up. However, this study contained a small group of older patients who, in some cases, already had evidence of plaque before irradiation. Effects of cytostatic agents (which act systemically rather than locally) on vascular structure are largely unknown. We found previously that IMT values in survivors of testicular cancer a median of 7 years after cisplatin-based chemotherapy were not different from IMT values in healthy controls in a cross-sectional study.13 We now report an increase in IMT in testicular cancer patients during chemotherapy, which indicates that cytostatic agents may affect IMT at least temporarily. In this study, we did not find significant chemotherapy-induced changes in the function of large arteries. Flow-mediated vasodilation of the brachial artery, a response dependent on the release of nitric oxide by endothelial cells, did not change significantly. Furthermore, the relatively long time interval between the last cisplatin administration and the postchemotherapy evaluation probably did not affect our results, given that additional measurements in a subgroup of patients between the second and third course of chemotherapy, a median of 9 days (range, 2 to 16 days) after the last cisplatin administration, in general produced comparable results. Therefore, BEP chemotherapy administered to testicular cancer patients seems to induce structural changes, as shown by an increase in IMT, but no functional alterations in large arteries, although changes in smaller arteries cannot be excluded. Cardiac troponins are sensitive plasma markers that are released in the circulation when myocardial cells are damaged. Minor elevations of concentrations of cardiac-specific troponin I were measured in patients with hematologic malignancies and breast cancer after anthracycline treatment.32,33 Troponin elevations have also been reported to correlate with decreases in left ventricular function in these patients.32 During chemotherapy, troponin I was measurable in 27% of patients at least once. Two of the troponin I–positive patients developed a myocardial infarction. However, troponin I determinations did not contribute to a timely detection of these events, given that the events took place when the patients were at home. Therefore, standardized measurements of cardiac troponin I during each course of chemotherapy are probably of limited value in the early detection of cardiac damage. However, as in breast cancer patients receiving anthracycline treatment, troponin I elevations during cisplatin-based chemotherapy, although minor, might predict cardiac dysfunction after longer follow-up. Cisplatin-based BEP chemotherapy may induce toxic effects on cardiac autonomic function. Sensory neuropathy is a well-known adverse effect of cisplatin, whereas autonomic cardiovascular dysfunction has been described in small groups of patients after cisplatin-based chemotherapy.34,35 A decrease in BRS, a test of cardiac autonomic function, is associated with cardiovascular morbidity and mortality in diabetic and postmyocardial infarction patients, and may also increase cardiovascular risk in patients during cisplatin-based chemotherapy.36,37 Compared with baseline, BRS and blood pressure decreased and heart rate increased after treatment. Theoretically, a toxic effect of cisplatin on baroreceptors or autonomic nerves would have resulted in a decrease in BRS, but also in increases in blood pressure and heart rate. The decrease in blood pressure in our study makes this relationship less likely. Nevertheless, the decrease in BRS during chemotherapy may be accompanied by an increase in cardiovascular risk. In conclusion, in patients with disseminated testicular cancer treated with BEP chemotherapy, we found an increase in plasma vWF levels and an increase in common carotid IMT as signs of chemotherapy-induced vascular toxicity. Changes in these parameters during treatment may be of prognostic significance for cardiovascular complications in the long term.
The authors indicated no potential conflicts of interest.
Supported by Grant No. RUG2000-2177 from the Dutch Cancer Society. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Bokemeyer C, Berger CC, Kuczyk MA, et al: Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 14:2923-2932, 1996[Abstract] 7. Weijl NI, Rutten MF, Zwinderman AH, et al: Thromboembolic events during chemotherapy for germ cell cancer: A cohort study and review of the literature. J Clin Oncol 18:2169-2178, 2000 8. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000 9. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003 10. Fossa SD, Aass N, Harvei S, et al: Increased mortality rates in young and middle-aged patients with malignant germ cell tumours. Br J Cancer 90:607-612, 2004[CrossRef][Medline] 11. Raghavan D, Cox K, Childs A, et al: Hypercholesterolemia after chemotherapy for testis cancer. J Clin Oncol 10:1386-1389, 1992 12. 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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
400%) before cisplatin-based chemotherapy in three of 13 patients with a squamous carcinoma of the head and neck, esophagus, or lung. Levels of vWF increased further in these three patients during treatment, and each developed an arterial thrombotic complication. If we speculate on the observed changes in patients with venous thromboembolism, the consistent increase of vWF and t-PA levels might be explained by endothelial damage, although it was less pronounced than in patients with an arterial event, whereas decreasing platelet numbers and fibrinogen levels possibly represent the response of the tumor to chemotherapy. It is unlikely that this combination of changes is due to either the thrombotic event or anticoagulant treatment. 
