Radiation therapy (RT) related toxicity
After therapy for Hodgkin lymphoma (HL), 5% of patients have symptomatic heart disease 10 years after mediastinal radiotherapy. The risk is directly related to mediastinal RT. The risk of significant cardiac disease is increased 3- 5 fold as compared with the general population1.
See etiology for factors which predict the severity of this problem
Late effects can include:
- valvular myopathy
- coronary artery disease
- conduction system problems15
Radiation associated heart disease has a characteristic morphology and patho-physiology consisting of:
- Fibrosis in the interstitium with normal appearing myocytes and narrowing of capillary and arterial lumens15
- Dense collagen and fibrin replace the normal adipose tissue of the outer layer of the heart.
- Fibrosis occurs on the mesothelial surfaces of the pericardium15
Injury to the myocardium results from interstitial fibrosis within the area15.
Pericardium is the most commonly affected structure of the heart after RT (treated in mantle field for HL).
Pericarditis can be:
Acute (during RT)
- Associated with mediastinal tumors affecting the heart possibly due to necrosis of the tumor and does not have long term consequences15
- Present with sudden onset of:
- pleuritic chest pain
- friction rub may be present
- typical signs of ST and T wave changes and decreased QRS voltage15
Delayed (between four months to several years after RT)
- Similar presentation as regular acute pericarditis
- Half of these patients will develop some degree of tamponade, presenting with shortness of breath, pulsus paradoxus or Kussmaul’s sign15
- Usually asymptomatic15
- Discovered on routine chest radiography indicating enlarged cardiac silhouette
- With older techniques tended to “weight” the treatment technique anteriorly and this led to a high (20% to 40%) risk of pericarditis
- Pericardial injury classified as:
- pericardial effusion (may resolve spontaneously in 1 month to 2 years)
- acute fibrinous pericarditis
- chronic constrictive pericarditis (fibrosis and scarring of the pericardium)
- Pericardial injury classified as:
- May develop several years after completion of RT.
- Diagnosis is made by characteristic ST-T changes and decreased QRS voltage on electrocardiogram and the presence of effusion or pericardial thickening on echocardiography.
- Rarely, constrictive pericarditis can develop which requires pericardiectomy.
Coronary artery Injury
After RT there is an increased risk of coronary artery disease and stenosis.23
Morphology similar to spontaneous atherosclerosis.
Usually affects the coronary ostia and the left anterior descending artery23.
Mechanisms of RT injury:
- Endothelial injury (generation of reactive oxygen species secondary to RT with an inflammatory response to endothelial injury leading to decreased availability of nitric oxide may also contribute to the development of atherosclerosis)
- Increased permeability of capillary walls, microvascular hyperplasia, fibrointimal thickening, deposition of lipid and scarring in the adventitia25.
Other coexistent risk factors such as dyslipidemia, hypertension, smoking, and obesity contribute to increased risk of damage23 and need to be treated.
Increased risk usually only becomes apparent 5 to 10 years after the end of therapy, thus screening should be begin after 5 years23.
Valvular disease is common and increases with increasing time after mediastinal RT15.
As of yet, no clear pathophysiological mechanism has been found to link RT and valvular disease15.
One study found that 15 years after RT, there was a 30% incidence of subclinical valvular disease for which endocarditis prophylaxis should be considered.
The proportion of survivors with valvular dysfunction increased with longer latency from RT.
Patients who had RT >20 years earlier had significantly more aortic regurgitation, tricuspid regurgitation, and aortic stenosis than those who had RT within 10 years.
Aortic stenosis and regurgitation commonly seen.
Clinical heart failure is rare in survivors treated with RT alone.
Myocardium is relatively resistant to direct effects of RT due to lack of myocyte cell division25
RT can cause fibrosis of the myocardium and decreased myocardial compliance due to:
- microvascular insufficiency
- ischemia results in interstitial fibrosis
- no inflammatory reaction25
- Usually seen at RT doses above 30 Gy and is often asymptomatic
- Restrictive cardiomyopathy associate with high dose RT25
- Diastolic dysfunction is the predominant abnormality in survivors treated with RT alone.(systolic dysfunction is common in survivors treated with anthracyclines)
- Echocardiogram usually shows regional wall motion abnormalities, mild global left ventricular hypokinesis and impaired myocardial relaxation25
- Subclinical changes are common and may be progressive
- One study of survivors of adolescent or young adulthood HL showed that at a median 14.2 years after diagnosis, treated with an average dose of 4000 cGy, 37.2% had an abnormally low measure of left-ventricular mass and/or end diastolic dimension suggestive of restrictive cardiomyopathy. These survivors also had a high frequency of abnormally low maximum oxygen consumption on an exercise stress test.
- Cardiac dysfunction has been reported in survivors after spinal RT with
- decreased maximal cardiac index on an exercise test
- higher estimated posterior wall stress on echocardiography
- abnormal Q waves on electrocardiography
Treatment of reduced LV function should follow guidelines for management of LV dysfunction with ACE inhibitors and selected B-blockers if LVEF is less than 40%25.
Aldosterone antagonists should be considered for those with decreased EF and severe symptoms25.
Conducting system Abnormalities
Mediastinal RT can cause conducting system abnormalities with various degrees of AV and bundle branch block25.
- ECG findings such as repolarisation abnormalities and premature ventricular complexes found in up to 50% of patients after mediastinal RT25.
- Short term (following first year of treatment) effects show non specific ECG abnormalities which are usually asymptomatic and transient
- Serious arrhythmias and infranodal conduction blocks can occur as late complication after 10 years of treatment.
- Right bundle branch blocks are more common than left due to possibly the increased radiation exposure of the right venture due to its anterior location
- Complete heart blocks and sudden death are rare though ventricular ectopy is more common
- Mediastinal RT can cause:
- Implanted pacemaker dysfunction
- Sick sinus syndrome
- QTc interval prolongation
- Ventricular tachycardia
- Dysfunction of autonomic nervous system leading to persistent tachycardia and loss of circadian heart rhythms
The cause may be tissue fibrosis adjacent to the conduction system (pathology finding)25
Carotid arteries can be damaged by RT
High-dose RT to the neck causes early atherosclerosis and therefore an increased risk of stroke (cerebrovascular event) in survivors treated with RT to this region.
- Long-term survivors of HL have a fivefold increased risk of stroke compared with sibling control subjects.
- Adult patients with head and neck cancer treated with RT have a 10-fold increased risk of carotid artery occlusive disease