The late cardiac and pulmonary effects of therapy on cancer survivors have recently been reviewed 14
. The estimated aggregate incidence of radiation-induced cardiac disease is 10% - 30%, occurring 5 to 10 years from treatment. Radiation pneumonitis is reported in 5% - 15% of lung cancer patients, with a smaller percent developing progressive pulmonary fibrosis. However, in patients with severe underlying chronic obstructive pulmonary disease before radiation therapy or chemoradiation therapy the outcomes are substantially worse.
Valdivieso et al. reported an increase in pulmonary and infection morbidity during induction chemoradiation therapy, including mitomycin C, etoposide and cisplatin, in 43 patients with stage IIIB non-small cell lung cancer compared to a group of 41 stage IV non-small cell lung cancer patients receiving the same chemotherapy but without chest irradiation. The frequency of these complications was greater according to the pre-treatment severity of underlying small airway disease measured by forced expiratory flow (FEF25-75
). In the group who received chemoradiation therapy, there were 14/24, 4/8 and 0/11 episodes of pneumonia in patients with severe, moderate or normal FEF25-75
, respectively (p 0.005) 15
. Brooks et al. also reported on the increase in pulmonary toxicity of 80 small cell lung cancer patients receiving combined chemoradiation versus chemotherapy alone for limited disease (p 0.017). Bilateral pulmonary infiltrates beyond the radiation therapy port were found in 28% of patients compared to 5% in those receiving chemotherapy alone. Eight of 13 patients died from pulmonary complications with no clinical evidence of tumor in five. Pretreatment pulmonary function tests (PFT) revealed a significantly lower forced vital capacity (FVC) (p 0.03) and forced expiratory volume in 1 second (FEV-1) (p 0.04) in patients with subsequent pulmonary complications 16
Theuws reported results of pulmonary function evaluations of 69 breast cancer patients and 41 lymphoma patients before and after radiation therapy alone or combined with chemotherapy, including combinations of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, cyclophosphamide, epidoxorubicin, fluorouracil, thiotepa, carboplatin and methotrexate. After an initial reduction in PFTs at 3 months, significant recovery took place at 18 months for all patients. Thereafter, no further improvement could be documented 17
. Thus, pretreatment pulmonary abnormalities have a significant impact on the pulmonary complications from radiation therapy as they could be mild and transient or more severe and long lasting.
Because of the increased risk associated with cancer treatment administered at a young age, adult survivors of pediatric cancer who received mediastinal radiation (most commonly patients with Hodgkin's disease) have a reported increase in the incidence of coronary artery disease, fatal myocardial infarction and other cardiac complications. Hodgkin's disease patients receiving mediastinal radiation have up to a 7.2 higher risk for fatal cardiovascular events than age and sex matched general population controls 18-20
Doxorubicin-induced cardiomyopathy is the most frequent and most studied chemotherapy-induced cardiotoxicity. The risk of developing cardiotoxicity is mainly related to the cumulative dose of doxorubicin (1% to 5% up to 550 mg/M2
, 30% at 600 mg/M2
, and 50% at 1 g/M2
with individual variation) 21
. Other anthracyclines are also cardiotoxic. Cardiac abnormalities are likely to be observed in survivors from childhood cancer and in adults undergoing long-term follow-up. A higher risk population is described as those in the extremes of age, higher cumulative dose, mediastinal radiation and female sex. An overall 9% incidence of doxorubicin-related cardiac abnormalities in asymptomatic survivors that required treatment and close follow-up has been reported 22
. An abnormality of systolic function (abnormal wall stress, hypertrophy, contractility) was reported in 65 (43%) of 151 patients.
The cardiotoxicity of breast cancer therapy among survivors has recently been reviewed 23
. Patients with doxorubicin-induced congestive heart failure (CHF) had an 87% improvement with cardiac medications; combined treatment with β-blockers and ACE inhibitors seemed superior to ACE inhibitors alone 24
. These results contrast with retrospective reviews that reported mortality rates of 43% to 59% in similar patients 25
Epirubicin appears less cardiotoxic than doxorubicin at equimolar doses, due to a lower level of secondary alcohol metabolites produced from epirubicin 26
. Cumulative epirubicin doses of >950 mg/m2
are associated with an exponential increase in CHF risk 27
. Little cardiotoxicity was observed with a cumulative epirubicin dose of 300 mg/m2 28
Dexrazone is the sole cardioprotective agent proved to decrease anthracycline-induced cardiomyopathy. However, some suggest that it may interfere with anthracycline chemotherapy because anthracyclines enhance DNA cleavage by topoisomerase II, but the closed ring form of dexrazone stabilizes DNA-topoisomerase II complexes 29
Taxanes, particularly paclitaxel, have shown evidence of cardiotoxicity. In contrast to previous reports, a large database has shown that only 0.1% of patients have serious bradycardia and could not confirm that taxanes increased the frequency of ventricular tachycardia or myocardial infarction 30
. Taxanes interfere with the metabolism and excretion of anthracyclines and potentiate anthracycline-induced cardiotoxicity, especially at high cumulative anthracycline doses. When combined with paclitaxel, the cumulative doxorubicin dose should not exceed 360 mg/m2
, and doxorubicin should be given before paclitaxel 31
. Combination treatments with epirubicin and taxanes may be less cardiotoxic. A cumulative epirubicin dose limit of 990 mg/m2
in combination treatments with paclitaxel has been proposed 32
Recently, interest regarding the potential cardiac toxicity of trastuzumab has developed. Trastuzumab is a humanized monoclonal antibody that binds to the extracellular portion of the receptor HER2, a product of the HER2/neu gene. Although the exact mechanism of cardiotoxicity of trastuzumab is unknown, HER2 is required for cardiac development. Single agent trastuzumab is toxic to rat myocytes in-vitro
because it induces activation of the mitochondrial apoptosis pathway and the caspase cascade. Neuroregulin, a cardiac stress peptide, may have a role in this problem 33
. The cardiotoxicity of trastuzumab has been recognized when given in combination with doxorubicin (A) and cyclophosphamide (C). The combination produces a 16% incidence of NYHA (New York Heart Association) classes III and IV relative to 3% with AC alone. Trastuzumab-related cardiac dysfunction differs from anthracycline-induced myocardial damage in that it rarely causes death, is not dose related, and, in most instances, is reversible with improvement in cardiac function when the drug is discontinued and/or the patient is treated with cardiac medications.