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Mechanisms of late cardiovascular toxicity from cancer chemotherapy.

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 al 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, 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 al 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 al 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. In the study by Meinardi et al, 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. Not all observational studies support cisplatin chemotherapy as etiologically related to a statistical increase in late cardiovascular morbidity and mortality. In a Norwegian study, 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. . .” 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 al 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. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 36 DECEMBER 2