Long-term consequences of radiation therapy

Coronary artery disease

Coronary atherosclerosis in RIHD typically matches radiation dose exposure in location and severity. With RT for HL, ostial disease of both the right and left coronary arteries are the most classic lesions, whereas after RT for left-sided breast cancer the mid (and distal) left anterior descending coronary artery (LAD) is most commonly involved. ^, The clinical presentation of radiation-induced coronary atherosclerosis is similar to that of conventional coronary artery disease (CAD), presenting with stable angina or acute coronary syndrome. For diagnosis, single photon emission computerized tomography myocardial perfusion imaging (SPECT MPI) has indicated perfusion defects in as many as 70% of patients 5 years after RT for breast cancer. However, limited data exist regarding the sensitivity or specificity of SPECT MPI in this specific population and cited data are reflective of other radiation techniques. Positron emission tomography (PET) MPI may be a reasonable alternative to SPECT, given the ability to quantify myocardial blood flow. In comparison with nuclear MPI, stress echocardiography has lower sensitivity but higher specificity the diagnosis of radiation-induced CAD ( Table 26.1 ).

Coronary artery calcium scoring, and coronary computed tomography angiography (CCTA) are gaining increasing interest and may play a larger role for the diagnosis of CAD after RT in the future. In a small cohort study, coronary artery calcium score following mediastinal RT for HL was higher in those with than in those without obstructive CAD (median score of 439 vs. 68), and a score of 0 had a negative predictive value for symptomatic CAD of 100%. Using CTA, another study found a 24% prevalence of CAD in 119 patients who had undergone mediastinal RT as children. Both calcified and noncalcified plaques were seen, primarily in the proximal coronary arteries (57% included the proximal LAD) and mostly non-obstructive. Coronary CTA has thus been attributed a higher sensitivity and negative predictive value for CAD than stress testing. As in general practice, however, catheter-based coronary angiography remains the gold standard for the detection of CAD.

Management of CAD in cases of radiation therapy is not specifically addressed in United States guidelines on management of acute coronary syndrome and stable ischemic heart disease, however, the same principles apply. Revascularization using either percutaneous coronary intervention or coronary artery bypass graft surgery may be necessary when critical stenoses are present; the need for concomitant valve or pericardial surgery may influence the decision. A noteworthy concern is limited usability of the internal mammary arteries after chest radiation; however, a study of 125 patients who had undergone mediastinal irradiation did not identify vessel fibrosis or significant histologic damage. ^, Still, there might be merit in evaluating the internal mammary arteries by conventional or CT angiography before cardiac surgery.

Valvular heart disease

Cardiac valvular abnormalities are common following mediastinal RT ( Fig. 26.2 and 28.3 ), with significant valve disease (defined as mild or greater aortic regurgitation; or moderate or greater mitral or tricuspid regurgitation; or aortic stenosis) in 29% of asymptomatic patients starting 2 years after RT, compared with 4% of age- and gender-matched controls. This rate increases significantly over time to 42% at 14 years and over 60% after 20 years postirradiation in high exposure cohorts, such as patients with lymphoma. Moderate or greater valvular disease is most commonly observed of the aortic and mitral valves, and regurgitation occurs more often than stenosis of these valves. The risk of radiation-induced valvular disease is greatest when the radiation dose exceeds 25 Gy. ^,

When valve disease is symptomatic or other indications for replacement are present, surgical management is indicated, according to standard valve guidelines (see Chapter 28 ). ^, Patients with RIHD undergoing valve surgery have a relatively high rate of morbidity and mortality after valve surgery (30-day mortality of 12%). ^, Because mediastinal RT can result in comorbidities that can result in prohibitively high surgical risk (e.g., frozen mediastinum or porcelain aorta), percutaneous valve therapies may be preferable in many cases. Of note, the Society of Thoracic Surgeons (STS) risk score as a standard tool for surgical risk assessment in patients with aortic stenosis underestimates the risk of surgical aortic valve replacement (SAVR) in this population. Transcatheter aortic valve replacements have been used successfully in patients with severe aortic stenosis whose radiation-induced mediastinal and pulmonary fibrosis precluded surgery. In several nonrandomized analyses, patients who underwent transcatheter aortic valve replacement had a higher survival rate after valve replacement compared with patients who underwent surgical aortic valve replacement. More recently, percutaneous edge-to-edge mitral valve repair, with technologies such as MitraClip (Abbott Medical, Abbott Park, IL), has been used for radiation-induced mitral regurgitatio. One potential concern after MitraClip for RT-induced mitral regurgitation is that if there is ongoing reactive damage to the mitral apparatus, delayed mitral stenosis may occur; however, at 6 months postprocedure there was nearly a 90% rate of improved New York Heart Association (NYHA) functional class.

Cardiomyopathy

Direct damage to the myocardium from radiotherapy may result in cardiomyopathy even in the absence of significant epicardial CAD or VHD. Prior thoracic radiation exposure increases the risk of HF substantially (hazard ratio [HR], 2.7 to 7.4 for HL and HR, 1.5 to 2.4 for breast cancer). Radiation-induced cardiomyopathy (RICM) more commonly presents as HF with preserved ejection fraction. For patients with breast cancer receiving radiotherapy, the odds ratio of developing HF per log of mean cardiac radiation dose is 16.9 (3.9 to 73.7) for HF with preserved ejection fraction (EF), and 3.17 (0.8 to 13.0) for HF with reduced EF. Studies measuring diastolic function in long-term survivors of HL who received RT have, however, shown inconsistent results and many have found none or only mild changes in diastolic parameters.

Patients who develop RICM present similar to those with HF from any other causes. The effects of radiation are synergistic with anthracycline chemotherapy, resulting in doubling of the risk of heart failure compared with RT alone. Myocardial fibrosis, which is a hallmark of RICM, can be seen in a patchy or diffuse distribution on cardiac magnetic resonance (see Table 26.1 ). Echocardiography, including strain imaging using speckle tracking, can be helpful in identifying radiation-induced myocardial dysfunction. Global longitudinal strain may become abnormal before the ejection fraction declines, which is typically reduced compared with controls, but still in the normal range. Fibrosis within the myocardium and endocardium may additionally result in diastolic dysfunction. When HF with reduced ejection fraction is present, therapy for cardiomyopathy does not differ from that of nonradiation-induced cardiomyopathies. In patients with advanced RICM, orthotopic heart transplantation is a last resort; however, it should be noted that mediastinal fibrosis may increase the operative risk significantly. Last but not least, all patients presenting with HF after chest RT should be evaluated for all possible radiation toxicities, including CAD, VHD, and pericardial disease, which can present as or at least contribute to HF in these patients.