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Originally published as JCO Early Release 10.1200/JCO.2005.04.1731 on November 21 2005 © 2005 American Society of Clinical Oncology.
Mechanisms of Late Cardiovascular Toxicity From Cancer ChemotherapyMemorial Sloan-Kettering Cancer Center, New York, NY Germ cell tumors (GCTs), which most commonly arise in the testes, represent one of the most curable of the solid neoplasms. This status is the consequence of treatment advances developed during the last 30 years, including surgery, radiotherapy, and chemotherapy. The 5-year survival exceeds 90%, so additional improvement in the treatment of these cancer patients must include a focus on quality of life, and on minimizing or eliminating the long-term complications of the disease and its therapy. The work by Nuver et al1 presented in this issue of the Journal of Clinical Oncology is novel and potentially important in this regard. Combination chemotherapy with etoposide, cisplatin, and bleomycin is the key contributor to the high cure rate in patients with GCTs. However, since the initial reported series in 1981 of Raynaud's phenomenon as a complication of GCT treatment,2 evidence has been accumulating that suggests that acute and long-term vascular toxicity is the most important late consequence of cisplatin-based chemotherapy in the treatment of men with metastatic GCTs. More recent reports highlight this problem. Meinardi et al3 reported that five (6%) of 87 men between the ages of 30 and 42 who were in remission for longer than 10 years after cisplatin-based chemotherapy developed myocardial ischemia (observed-to-expected ratio = 7.1; 95% CI, 1.9 to 18.3). Huddart et al4 studied all male GCT patients registered in the United Kingdom between 1982 and 1992. After a median follow-up of 10.2 years, and adjusting for age, increased risk for cardiac events was seen after chemotherapy alone (relative risk [RR] = 2.59), radiation therapy (RR = 2.40), and combined therapy (RR = 2.78). On the basis of these and other observations, Huddart et al concluded that long-term survivors of testicular cancer have a two-fold or greater risk of developing cardiovascular disease that was not due to increases in cardiac risk factors, suggesting a direct or indirect treatment-related cardiovascular toxicity. In addition to myocardial ischemia, hypertension developed during or after therapy in 15% to 54% of GCT patients who received cisplatin-based chemotherapy.3,5-8 In the study by Meinardi et al,3 hypertension was three times more frequent in treated men than in a group of 40 men treated with orchiectomy alone for stage I disease (39% v 13%). Cholesterol may also increase after treatment.3 Not all observational studies support cisplatin chemotherapy as etiologically related to a statistical increase in late cardiovascular morbidity and mortality. In a Norwegian study,9 mortality rates were established for three periods of GCT treatment, including an interval during which cisplatin-based chemotherapy was not administered. The standard mortality rates for cardiovascular diseases were increased by 1.2 times in treated patients, regardless of whether the treatment regimen included cisplatin-based chemotherapy. These authors concluded that the introduction of cisplatin-based chemotherapy into the treatment had not yet resulted in increased death rates due to cardiovascular diseases, although they stated in the discussion that, "...survivors have a significantly increased risk of dying from diseases of the circulatory system..."9 Therefore, studies to elucidate potential pathophysiologic mechanisms of chemotherapy-related cardiovascular toxicity occurring during treatment would add to the evidence supporting downstream cardiac morbidity and mortality. Such studies could suggest means of prevention. In this issue of the Journal of Clinical Oncology, Nuver et al1 take the novel approach of prospectively examining potential immediate mechanisms that might lead to later cardiovascular toxicity in a group of 65 men with nonseminomatous GCTs who were undergoing chemotherapy with bleomycin, etoposide, and cisplatin. Selection criteria, clearly defined by the authors, reduced the study group from 131 to 65 treated patients. Six different measurements of the propensity for thrombosis and arterial injury were measured before and after treatment in these 65 patients. Intima-media thickness (IMT), vascular reactivity, ambulatory blood pressure, and baroreflex sensitivity were also measured. Troponin I was assessed in a subset. All measurements were taken a median of 1 day before and 36 days after chemotherapy. Each patient served as his own control. The principal findings of the study were significant increases in von Willebrand factor (vWF) levels and a small but statistically significant increase in carotid IMT. The persistent elevation of vWF suggests that persistent endothelial stimulation and/or damage exists well after the last dose of chemotherapy. Mechanistically, one can conceive of damage to an organ, such as the kidney, that destroys key structural or functional components, leading to a process that establishes and perpetuates hypertension. It is more difficult to explain how a transient insult from chemotherapy would permanently damage the endothelium, leading to persistent endothelial stimulation and/or damage. However, nearly 20 years ago, hyperreninemia, hypomagnesemia, and hyperaldosteronemia were observed in a group of normotensive men after cisplatin-based chemotherapy for GCTs, and the researchers warned of the development of late cardiovascular consequence.10 The results of troponin measurements are difficult to interpret because of the small number of patients studied and indeterminate values in some patients. Future studies will be required to determine whether and why vWF levels remain elevated, and the relationship of vWF levels to the development of long-term cardiovascular toxicity. The increase in IMT in this study was greater than expected for age alone. The increase in IMT was related to increased blood pressure during chemotherapy in some patients, and may indicate susceptibility to vascular toxicity. Increased IMT has proven useful as a marker for more generalized atherosclerosis and prevalent atherosclerotic cardiovascular disease. Decreases in IMT have been suggested as a surrogate end point for determining the success of interventions that lower the levels of known cardiac risk factors. A few studies show an association between increased IMT and new myocardial infarction or stroke.11 Therefore, serial measurements of IMT in a matched control group of GCT patients who do not receive cisplatin-based chemotherapy would be of interest. Patients with testicular cancer are living longer, but appear to be more susceptible, at a younger age, to serious late cardiovascular consequences. Evidence is accumulating that hypertension and hypercholesterolemia are increased in frequency, are likely to be superimposed in some patients on a background of other common risk factors (such as tobacco use and family history), and that direct endothelial toxicity may be involved in the pathogenesis. The study by Nuver1 supports direct endothelial toxicity and suggests that future clinical trials may be able to direct preventative interventions. GCT patients cured by cisplatin/etoposide chemotherapy (with or without bleomycin) are increasingly prevalent because of the high cure rate of the disease, and all physicians (including family physicians, general practitioners, and internists) should be aware of these consequences and be prepared to monitor regularly and intervene as early as possible. Current guidelines call for screening for hypertension every 2 years in individuals older than age 20,12 and checking a lipid profile every 5 years.13 Despite the generally young age of patients with GCTs, their risk for hypertension and atherosclerotic heart disease is significantly greater than that of the general population. Therefore, these patients should be examined for cardiac risk factors at least as often as suggested above. Furthermore, a heightened index of suspicion is needed to detect clinical signs or symptoms suggestive of premature ischemic heart disease, so that appropriate diagnostic and therapeutic interventions can be undertaken in a timely manner. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Nuver J, Smit AJ, van der Meer J, et al: Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. J Clin Oncol 23:9130-9137, 2005 2. Vogelzang NJ, Bosl GJ, Johnson K, et al: Raynaud's phenomenon: A common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med 95:288-292, 1981 3. 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 4. 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 5. Sagstuen H, Aass N, Fossa SD, et al: Blood pressure and body mass index in long-term survivors of testicular cancer. J Clin Oncol 23:4980-4990, 2005 6. Strumberg D, Brugge S, Korn MW, et al: Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 13:229-236, 2002 7. Bokemeyer C, Berger CC, Kuczyk MA: Evaluation of long-term toxicity after chemotherapy for testicular cancer. J Clin Oncol 14:2923-2932, 1996[Abstract] 8. Bissett D, Kunkeler L, Zwanenburg L, et al: Long-term sequelae of treatment for testicular germ cell tumours. Br J Cancer 62:655-659, 1990[Medline] 9. 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] 10. Bosl GJ, Leitner SP, Atlas SA, et al: Increased plasma renin and aldosterone in patients treated with cisplatin-based chemotherapy for metastatic germ-cell tumors. J Clin Oncol 4:1684-1689, 1986 11. O'Leary DH, Polak JF, Kronmal RA, et al: Carotid-artery intima and medial thickness as a risk factor for myocardial infarction and stroke in older patients. N Engl J Med 340:14-22, 1999 12. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 157:2413-2446, 1997 13. National Institutes of Health: National Cholesterol Education Program, National Heart, Lung, and Blood Institute. Bethesda, MD, National Institutes of Health. NIH publication 01-3670, May 2001
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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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