Cardiac Complications of Radiation Therapy

Radiation therapy treatment volumes that include portions of the heart are part of standard therapy for many malignancies, most commonly lymphomas, breast, esophageal, and lung cancers. Risks of serious acute and late clinical effects on the heart may follow either curative or palliative radiation therapy. Increased cardiac mortality among irradiated patients may offset any potential reduced risk of recurrence or of death from cancer. Alternatively, substandard radiation doses to avoid cardiac toxicity could increase relapse risk. Concurrent or sequential cardiotoxic chemotherapy agents may substantially increase the incidence of radiation-associated cardiotoxicity. Nevertheless, clinically significant radiation cardiotoxicity is rare even with older radiation therapy techniques.

Cardiac complications after radiation to ports that include the heart can affect pericardium, myocardium, valves, coronary arteries and the conduction system as well as damage pacemakers. Clinical manifestations can be acute or delayed by decades and correlate with cardiac radiation dose volume. Initially, pericarditis and pericardial effusions were the most common cardiac complications, but with newer equipment and techniques, coronary artery disease is becoming the most common long-term risk of cardiac radiation. Risk is associated with the volume of the heart irradiated, dose, and dose fractionation. Computerized blocking can be used to decrease the exposure of the heart when increasing levels of radiation are required. Cardiac toxicity due to radiation therapy is uncommon and should become increasingly rare with modern equipment.

In a study conducted in the University Hospital in Lund, Sweden, of 90 patients younger than 50 years of age at the time of adjuvant radiotherapy after mastectomy examined at least 10 years later, the cardiovascular derangements identified included 14 patients with abnormal ECG, 5 with positive exercise test results, 6 with positive myocardial scintigraphic findings, 14 with thickened valve cusps, 20 with mild valvular regurgitation, and 6 with diastolic dysfunction (abnormal relaxation in 4 patients, and 2 with restrictive filling abnormalities). All patients had normal systolic function.

Prevention of Cardiac Radiation Toxicity

Left-sided radiation fields for the treatment of breast, lung, or esophageal cancer or lymphoma often include the heart within the treatment volume. Radiation therapy techniques to preserve radiation dosage to the target and reduce late morbidity and decrease irradiated cardiac volume and thus possibly reduce associated cardiovascular toxicity and mortality include sophisticated three-dimensional planning,  optimal patient positioning, and deep inspiratory maneuvers designed to minimize cardiac volume in the radiation field. Extended blocking of cardiac volume decreases cardiac risk  but may compromise treatment efficacy.

PERICARDIAL COMPLICATIONS OF CARDIAC IRRADIATION.

The spectrum of pericardial complications includes pericarditis during and up to several years after radiation and late constrictive pericarditis. Given its high incidence in patients treated for Hodgkin disease with mantle radiotherapy, radiation-associated hypothyroidism must be considered in the differential diagnosis of constrictive pericarditis.

Low radiation doses to even a substantial volume of pericardium in the field carry a small risk of 2 to 5 percent. Pathologically, the pericardium becomes thickened and effusion develops. Small blood vessels proliferate, and collagen replaces pericardial tissue.

Acute pericarditis during radiation, associated with pain and fever, does not correlate with late pericardial damage. Pericarditis can be delayed for several years after mediastinal radiation. Symptoms can start with pain and fever, and there can be ST segment changes and a decrease in QRS voltage on the ECG. The chest radiograph may show a pericardial effusion with an enlarged cardiac silhouette sometimes resulting in tamponade, which requires pericardiocentesis.

Steroids may be helpful in treating radiation-associated pericardial disease, but symptoms can reemerge during tapering of the steroid drug. The rate of mortality due to pericardiectomy has been reported to be high, in the range of 20 to 35 percent, because of fibrosis and underlying radiation-associated cardiomyopathy.

MYOCARDIAL RADIATION TOXICITY.

During and after radiation, left ventricular dysfunction can be documented with decreased filling and a decreased LVEF. Interactions with anthracyclines can occur, but when cumulative doses of anthracyclines are kept to standard levels, the risk remains low despite later radiotherapy. Restrictive cardiomyopathy can be difficult to distinguish from constrictive pericarditis. Pathological examination reveals interstitial fibrosis proportional to the radiation dose. Valvular disease includes abnormalities and new murmurs, but associated symptoms are few. Mitral and aortic valves are most commonly affected, with fibrous thickening of the valvular endocardium developing decades after radiation.

Investigators from Southern Hospital, Stockholm, Sweden evaluated the incidence of myocardial infarction in 960 women after mastectomy randomized to preoperative radiation therapy, postoperative radiation therapy, or surgery alone. At a median follow-up of 20 years (range, 17–23 years), 58 patients had had an acute myocardial infarction, with no significant difference between the three treatment groups. However, patients with the highest cardiac radiation dose-volumes had a relative risk of myocardial infarction of 1.3 (95 percent CI, 0.7–2.6) compared with surgical controls; the relative risk for those receiving intermediate and low dose-volumes was less than 1.0. The risk of death for patients in the high dose-volume group compared with surgical controls was 2.5 for ischemic heart disease (95 percent CI, 1.1–5.7; p = 0.03) and 2.0 for any cardiovascular disease (95 percent CI, 1.0–3.9; p = 0.04). Difference emerged after 4 to 5 years and continued to increase through 10 to 12 years. Increased risk of death from ischemic heart disease but no excess risk of myocardial infarction implies a mechanism such as radiation-associated microvascular damage.

In contrast, the incidence of myocardial infarction for a Canadian cohort of 2128 breast cancer patients with a median follow-up of 10 years was similar to that in an age-matched general population of Ontario women. At least one definite or possible myocardial infarction occurred in 26 patients with left-sided and 23 patients with right-sided breast cancer. Fatal myocardial infarctions occurred in 8 patients with left-sided and 6 with right-sided cancers. No other cardiac abnormalities were found in excess among patients with left-sided cancers as compared with right-sided lesions. Thus, the investigators found no excess morbidity or mortality from coronary artery disease among women treated with radiation therapy to the left breast.

CONDUCTION SYSTEM AND PACEMAKERS.

Electrical abnormalities include complete bundle branch block developing a decade after radiation doses due to fibrosis of the conduction system. Implanted pacemakers have been damaged by radiation as well, and pacemaker function requires careful monitoring.

CORONARY ARTERY DISEASE.

Coronary artery disease has emerged as a late risk of cardiac radiation. Coronary spasm can also occur in patients with angiographically normal-appearing coronary arteries. Deaths have occurred in up to 1 percent of patients irradiated with curative intent for Hodgkin disease and after patients have been irradiated for breast cancer.

Risks of Radiation and Drug-Associated Cardiotoxicity

Cardiac function must be monitored when patients receive combinations of radiation and drugs known to cause dysfunction. In a Duke University study of 20 patients with left-sided breast cancer who underwent cardiac perfusion imaging using single-photon emission computed tomography before doxorubicin chemotherapy (10 patients), before radiation, and 6 months after radiation, 60 percent of the patients had new perfusion defects 6 months after radiation. The defects were dose dependent, with minimal changes at 0 to 10 Gy but a 20 percent decrease in regional perfusion at 41 to 50 Gy. Two patients developed transient pericarditis, although none had myocardial infarction or clinical congestive heart failure. Follow-up was insufficient to determine whether these perfusion changes were transient, permanent, or associated with later clinical dysfunction.

In a Dana-Farber Cancer Institute study, 299 women with breast cancer were randomized to 5 versus 10 cycles of adjuvant cyclophosphamide (500 mg/m² ) and doxorubicin (45 mg/m² ) intravenously every 21 days; 122 patients also received radiation. At a median follow-up of 6.0 years (range, 0.5 to 19.4 years), the rate of cardiac events per 100 patient-years was significantly higher for the patients who received 10 cycles than for those who received 5 cycles (1.7 [CI, 1.0–2.8] vs. 0.5 [CI, 0.1 to 1.2]; p = 0.02]. Cardiac risk in patients receiving 5 months of chemotherapy did not differ significantly from that of women in the Framingham Heart Study, irrespective of cardiac radiation dose-volume. In women receiving 10 chemotherapy cycles, however, cardiac events were significantly increased (relative risk, 3.6; p < 0.00003) compared with the Framingham population, particularly for women who also received moderate and high dose-volume cardiac radiation.

In a retrospective analysis of 825 women entered in randomized adjuvant chemotherapy trials with or without doxorubicin (Adriamycin) at the Istituto Nazionale Tumori (Milan, Italy), 360 women (44 percent) also received breast irradiation. Congestive heart failure occurred in 4 women after doxorubicin-containing chemotherapy (2.6 percent of those who received both doxorubicin and radiation to the left breast) and was fatal in 2. Cardiac events were documented in 6.8 percent, more frequently in women who received left breast radiation and in those older than 55 years of age.