Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies

INTRODUCTION — The use of radiation therapy (RT) has contributed to significant improvements in disease-specific survival for patients with Hodgkin lymphoma (HL) and other malignancies involving the thoracic region. However, cancer survivors who were treated with RT, either alone or in combination with other modalities, are at risk for late complications from treatment. Late effects of RT include second cancers and cardiovascular effects.

Treatment of HL frequently includes supradiaphragmatic RT portals that include portions of the heart. HL survivors are at an increased risk for both early and late cardiovascular complications. Clinical manifestations of cardiotoxicity include acute or delayed pericardial disease, myocardial ischemia or infarction, cardiomyopathy, heart failure, valvular abnormalities, and conduction defects. (See "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Cardiovascular disease'.)

Treatment of HL has evolved with the goal of decreasing the intensity of therapy without sacrificing long-term disease control. These efforts include modifications in RT techniques to reduce the volume and dose of incidental cardiac irradiation and the impact of RT when given with chemotherapy (ie, combined modality therapy). Contemporary techniques appear to have substantially decreased the incidence of delayed complications of RT, although the residual risk remains uncertain.

The incidence of cardiotoxicity and its clinical manifestations secondary to RT in patients with HL or pediatric malignancies are discussed in this topic.

Pathophysiology of RT-induced cardiac injury and the role of RT-induced cardiotoxicity in other malignancies are discussed separately. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies", section on 'Pathophysiology'.)

INCIDENCE OF CARDIOVASCULAR DISEASE — A significant increase in the incidence of cardiovascular disease has been observed in multiple studies of long-term survivors of HL [1-4].

The cardiotoxic effects of RT in HL survivors were illustrated by a comprehensive analysis of 1474 patients who were treated between 1965 and 1995 according to European Organisation for Research and Treatment of Cancer (EORTC) protocols [1]. The median age at the start of treatment was 26 years, and the median follow-up was 19 years. The initial treatment consisted of RT only in 28 percent of the patients, chemotherapy alone in 5 percent, and combined RT and chemotherapy in 67 percent. Overall, 84 percent of patients received RT to the mediastinum. The standardized incidence ratios for various complications were calculated compared with age- and sex-matched incidences in the general population.

Key findings included the following:

●The most common cardiovascular diagnoses observed in HL survivors were valvular disorders, angina pectoris, and myocardial infarction. The median time to diagnosis of these cardiac complications was approximately 19 years after treatment. The incidence of each of these complications was significantly elevated, with standardized incidence ratios between 3 and 5.

●Mediastinal irradiation significantly increased the risks of coronary heart disease, heart failure, and valvular disorders, in multivariate analysis. Use of anthracyclines further increased the risks of heart failure and valvular disorders associated with mediastinal irradiation.

●The increased risk of cardiovascular disease persisted for at least 25 years after the index HL treatment.

There is a linear dose-response relationship for coronary heart disease, based on data from a nested case-control study of 2617 five-year survivors treated with mediastinal radiation between 1965 and 1995 in the Netherlands support [5]. The risk was related to both the volume of the heart irradiated and the dose received by the heart. Three hundred and twenty-five patients developed coronary heart disease manifested by myocardial infarction or angina requiring intervention. These patients were compared with 1204 matched controls. For patients receiving a mean heart dose of 20 Gy, there was a 2.5-fold increase in the risk of coronary heart disease compared with patients not treated with mediastinal RT. The excess relative risk seemed to decrease with increasing age, increased for patients with risk factors (diabetes mellitus, hypertension, or hypercholesterolemia), and decreased with high levels of physical activity.

A study of 615 Canadian HL survivors treated between 1988 and 2000 has demonstrated that modern treatment methods continue to be associated with cardiac morbidity, even within 10 to 15 years after therapy. This study also suggested that the risk from combined modality therapy (mediastinal RT of 30 to 35 Gy and doxorubicin of 300 mg/m²) was greater than mediastinal RT alone, although the difference in risk between the two groups was not statistically significant due to small sample size [6]. The relative risk for cardiac disease is increased within the first few years after RT, and this risk appears to increase over time [7].

A large, survey-based study of patients treated for HL on nine collaborative EORTC-Lymphoma Study Association (LYSA) trials (mean follow-up nine years after diagnosis) reported that the hazard ratio for cardiovascular events increased with the estimated mean cardiac doses in an approximately linear fashion, but the confidence intervals were large [8].

The risk of cardiovascular complications following RT appears to be even greater when HL patients are treated during childhood. (See 'Clinical manifestations in pediatric patients' below.)

RISK FACTORS — The factors that influence the risk of cardiac damage in HL patients include the total dose and volume of RT, the dose per fraction, the specific RT technique, and the extent to which the coronary arteries are included in the RT field.

The use of combined modality treatment that includes cardiotoxic chemotherapy, such as an anthracycline, appears to increase the risk of cardiovascular disease, as illustrated by a study of 1474 HL survivors younger than 41 years at treatment and followed for a median of 19 years. Multivariate analysis showed that the combination of mediastinal RT plus anthracycline-based chemotherapy significantly increased the risk of both heart failure and valvular disorders (hazard ratio 2.8 and 2.1, respectively, compared with mediastinal RT alone) [1]. The cumulative incidence of heart failure 25 years after combined RT and anthracycline treatment for HL was 7.9 percent.

In addition to treatment-related issues, patient-specific factors that are likely to influence the risk of developing coronary artery disease can be important. These include the patient age at the time of treatment and the presence of other known cardiac risk factors, such as smoking, high serum cholesterol, and hypertension.

A limited number of exercise intervention studies in lymphoma survivors (HL and non-HL), both on and off active treatment, suggest that aerobic exercise is safe and can improve cardiac function and energy levels, at least in the short term. These included two randomized trials [9,10] and one nonrandomized trial [11] demonstrating increased maximum oxygen consumption and self-reported energy level in HL survivors with chronic fatigue. However, the sample size was too small to correlate these changes, and none of the three studies was limited to just patients who had or were receiving RT. (See 'Clinical manifestations in adults' below.)

CLINICAL MANIFESTATIONS IN ADULTS

Coronary artery disease — Multiple studies have demonstrated that the risk of a fatal myocardial infarction in HL survivors is 2.2 to 7.6-fold greater than in the general population [2,7,12-16]. The increased risk of death from myocardial infarction was illustrated by an analysis of 7033 HL survivors treated between 1967 and 2000 [12].

Key observations from this study included:

●The risk of death from myocardial infarction in this cohort was significantly increased compared with the general population (standardized mortality ratio 2.5, 95% CI 2.1-2.9).

●The increased risk of death from myocardial infarction was limited to those who had received supradiaphragmatic RT or anthracycline-containing chemotherapy. Those whose treatment consisted solely of infradiaphragmatic RT did not have an increase in mortality.

●The increased risk of death persisted beyond 20 years. This persistence of risk for an extended period has been observed in other studies and appears to be greatest in those treated during childhood [14,17].

Heart failure — Patients with a history of cardiac irradiation can present with heart failure due to radiation-induced restrictive-, constrictive-, ischemic-, or valvular-cardiomyopathies. The physiologic correlate of this observation is that mediastinal RT appears to have a greater impact on diastolic, rather than systolic cardiac function [18,19]. This is in contrast to the effects of anthracyclines, which predominantly cause systolic dysfunction. The prevalence of dysfunction varies depending upon RT technique and dose, concomitant use of anthracyclines, length of follow-up, and method of screening.

Preserved ejection fraction — Diastolic dysfunction may be detected by echo Doppler studies in asymptomatic patients who have received radiation therapy for HL. Survivors with diastolic dysfunction have a significantly worse cardiac event-free survival and worse quality of life.

●In one study, diastolic dysfunction was detected in 40 (14 percent) of 282 patients who had received a minimum of 35 Gy to the mediastinum for HL [18]. The average time from radiation treatment to assessment was 18 years. Exercise-induced ischemia was more common in patients with diastolic dysfunction (23 versus 11 percent in those with normal function). Patients with diastolic dysfunction had worse event-free survival than patients with normal function (HR 1.66, 95% CI 1.06-2.4).

●In another series, 20 of 37 (54 percent) patients who had received prior mediastinal RT had echocardiographic evidence of left ventricular dysfunction [19]. The average maximum oxygen consumption measured during exercise stress testing was also decreased compared with normal.

Reduced ejection fraction — Both cardiac irradiation and anthracycline-containing chemotherapy increase the incidence of symptomatic heart failure (HF) in survivors of HL. The rate of HF increases in association with anthracycline dose and increased mean left ventricular dose (MLVD) of radiation. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

A case-control study compared 91 patients with moderate or severe HF as their first cardiovascular event with 278 matched controls who were diagnosed with HL before 51 years of age [20]. Mean heart doses (MHD) and MLVD were estimated from radiation treatment charts or from simulation computerized tomography (CT) images. Findings included:

●HF occurred after a median interval of more than 20 years, most patients had grade 2 or 3 HF, and the median interval from diagnosis of HF to death was 3.6 years.

●HF incidence increased in a non-linear dose-response relationship with radiation dose; there was little evidence of an increased rate of HF for MHDs in the range of 1 to 25 Gy, but a steep increase with MHDs ≥25 Gy.

●HF rate increased nearly threefold in the setting of anthracycline-based chemotherapy irrespective of cardiac radiation exposure, and rates were not affected by anthracycline dose (ie, <280 mg/m² compared with ≥280 mg/m²). There was not a multiplicative (synergistic) effect between RT and anthracycline treatment, but the ability to study the interaction between the two modalities was limited.

Valvular heart disease — Mediastinal RT has been associated with an increased risk of clinically significant valvular abnormalities particularly involving the aortic, mitral and tricuspid valves in 6 to 40 percent of HL survivors [19,21-24]. Many of the common abnormalities that are found in HL patients would lead to consideration for antibiotic prophylaxis for endocarditis [21,25].

The risk of valvular heart disease and its relationship to dose of radiation is well illustrated by a case-control study nested within a cohort of 1852 five-year survivors of HL treated between 1965 and 1995 at three centers in the Netherlands [24]. It should be noted that the radiation techniques utilized during the earlier years of this study would not be used today.

●The cumulative risk for valvular heart disease in the entire series was 8 percent at 30 years. The median interval between the diagnosis of HL and the diagnosis of valvular heart disease was 23 years. However, for patients treated with the doses of 20 to 30 Gy that are currently used, the 30-year risk is increased by only approximately 1.4 percent.

●This study compared the 89 cases (4.8 percent of the total cohort) with valvular heart disease (66 percent severe or life-threatening) with 200 controls in the cohort without valvular disease, matched by age, sex, and year of diagnosis. The median follow-up was 19 years.

●Doses of radiation to the heart valves were calculated for each case. The risk of valvular heart disease increased more than linearly; for affected heart valves receiving ≤30, 31 to 35, 35 to 40, and ≥40 Gy, the relative risks were 1.4, 3.1, 5.4, and 11.8, respectively.

●Following the diagnosis of valvular heart disease, its severity increased by 56 percent over a median follow-up of 7.6 years. This gradual progression is consistent with other reports [22,23,26,27].

A study of 82 HL survivors further demonstrates that RT is associated with valvular disease detected by echocardiography [28]. During a median follow-up of 13.4 years (range 2 to 39), mild or more severe valvular disease was present in 61.2 percent of the 50 HL survivors who had received mediastinal RT (median dose 40 Gy [range 28 to 44]), compared with 31 percent of the 32 HL survivors without mediastinal RT (odds ratio 3.51, 95% CI 1.32-9.30, p = 0.01). Severe disease was present in 24.5 and 3.4 percent of survivors in each group, respectively (p = 0.016). Aortic regurgitation was most prevalent, and irradiated patients had significantly more mild or more severe regurgitation compared with the unirradiated patients (38.2 versus 6.8 percent, p = 0.007).

Arrhythmias — Radiation can cause fibrosis of the conduction pathways in the heart, potentially leading to life-threatening arrhythmias and/or conduction defects years after therapy for HL. Abnormalities observed after mediastinal RT include bradycardia, complete and lesser degrees of heart block, and sinus node dysfunction (ie, sick sinus syndrome) [19,29,30].

●In an electrocardiographic study with a mean follow-up of 15 years, abnormalities were identified in 35 of the 47 survivors who had an electrocardiogram (74 percent) [19]. The most common findings were conduction delays in the right anterior bundle, which suggests that the anterior structures of the intracardiac conduction system are at greatest risk for fibrosis from mediastinal RT. In addition, 24-hour Holter monitoring suggested a high rate of autonomic dysfunction; 24 of 42 patients (57 percent) had a monotonous heart rate and/or loss of circadian variability, while 13 (31 percent) had sustained tachycardia over 24 hours (>90 beats per minute). In this study, only four patients had received anthracyclines, and the average mediastinal radiation dose was 40 Gy.

●In another study of 134 childhood cancer survivors evaluated at a mean of five years after treatment, the incidence of ventricular tachycardia was significantly greater in those treated with mediastinal RT, irrespective of anthracycline treatment, compared with healthy controls [30]. In addition, the frequency of prolonged QT interval was 13 percent in those treated with chest RT alone, 11 percent in those treated with anthracycline chemotherapy alone, and 19 percent in those who had been treated with both RT and anthracyclines.

●In a study of 263 HL survivors, exercise treadmill test results were used to compare patients who had received RT as part of HL management with controls matched based upon age, sex, and clinical risk index [31]. Patients were evaluated at a median of 19 years after their RT. RT was associated with a significantly elevated resting heart rate and an abnormal heart rate recovery compared with controls (odds ratios 4 and 5.3, respectively).

Pericarditis — Although pericarditis historically was one of the most common cardiac complications of mediastinal irradiation, it rarely occurs with the lower doses and modern RT techniques currently used. Moreover, this complication was more likely in patients treated primarily with radiation for HL close to the heart. As an example, the incidence of pericarditis decreased from 20 to 2.5 percent at one center with the changes in methods of RT administration introduced in the 1970s [32].

CLINICAL MANIFESTATIONS IN PEDIATRIC PATIENTS — Cardiac and cardiovascular mortality are increased in survivors of pediatric cancer who received anthracycline therapy and/or radiation to the heart (even relatively low doses). However, reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer.

The Childhood Cancer Survivors Study (CCSS) included more than 23,000 five-year survivors of childhood cancer (age <21 years at diagnosis of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas) [33-35]. Cardiac irradiation was associated with increased risk for heart failure, myocardial infarction, pericarditis, and valvular abnormalities. However, over successive decades, there were significant decreases in the 20-year cumulative incidence of heart failure (0.69 percent for those treated in the 1970s to 0.54 percent for treatment in the 1990s) and coronary artery disease (0.38 to 0.19 percent); rates of valvular disease, pericardial disease, and arrhythmias did not change. Compared with survivors who were not treated with RT to the heart, those who received 5 to 20 gray (Gy) to more than half of the heart had a 1.6-fold (95% CI 1.1 to 2.3) relative risk (RR) for serious cardiac events; the RR was 2.4 (95% CI 1.4-4.2) for those who received high doses (>20 Gy) to smaller volumes of the heart.

In a multicenter study of 4122 survivors <15 years at diagnosis of a solid tumor (leukemia was excluded), cardiac deaths were related to radiation to cardiac irradiation and treatment with an anthracycline [36]. In multivariate analysis, the RR for cardiac death was 7.4-fold for treatment that included RT and 7.9-fold for treatment that included chemotherapy; anthracyclines were associated with significantly increased risk and there was a trend toward increased mortality in those treated with a vinca alkaloid or alkylating agent. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

PREVENTION — We advocate a strategy of minimizing risk of harm, based on modifying both treatment- and patient-related risk factors whenever possible. For patients with favorable, early stage, mediastinal Hodgkin lymphoma, omitting radiation therapy is sometimes an option to minimize the risk of delayed cardiotoxicity.

Other approaches to minimizing cardiotoxicity are discussed separately. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies", section on 'Prevention of cardiotoxicity'.)

Complications after cardiac interventions — The risk of post-procedure complications in patients who were previously radiated for a childhood cancer varies with the patient population, type of procedure, and treatment methods. Transcatheter aortic valve replacement (TAVR) appears to be better tolerated than surgical aortic valve replacement (SAVR) and coronary artery interventions may be needed at the time of valve replacement [37].

Among 59 survivors of thoracic irradiation (most with breast cancer, 10 treated for HL), there were more post-operative complications than would have otherwise been predicted from a prognostic tool for cardiac surgery events (Euroscore II); actual in-hospital post-operative mortality rate was 10.2 percent, compared with 3.6 percent predicted by Euroscore II [38]. However, a retrospective, population-based study of over 220,000 patients undergoing TAVR in the Nationwide Readmissions Database (NRD) between 2013 and 2018 did not note worse outcomes in patients who had received prior thoracic irradiation, compared with those who had not [39].

In a single center study, patients with a history of mediastinal irradiation who underwent SAVR had inferior outcomes, compared with the general population [40]. In another study, for the first two years post-procedure, patients who underwent TAVR had outcomes that were similar to the general population who had TAVR [41]. Similar findings were reported in a study that compared outcomes in thoracic-irradiated patients who underwent TAVR and SAVR at another center [37].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)

SUMMARY

●Description – Patients who received radiation therapy (RT) as a component of treatment for Hodgkin lymphoma (HL) and other thoracic malignancies are at an increased risk for cardiovascular (CV) diseases. While treatment has evolved to decrease the intensity of therapy without sacrificing long-term disease control, patients continue to experience acute and late adverse effects of RT.

●Incidence – The most common CV diagnoses in these cancer survivors are valvular disorders, angina pectoris, and myocardial infarction. The relative risk for CV complications is increased three- to fivefold compared with the general population. The median time to diagnosis is nearly two decades after treatment, and elevated risk persists for at least 25 years. (See 'Incidence of cardiovascular disease' above.)

●Risk factors – Risk for coronary artery disease and valvular disorders is related to aspects of treatment and patient-specific factors (eg, smoking, high serum cholesterol, hypertension). Treatment-related factors include RT technique, treatment volume, total dose and dose per fraction, and inclusion of coronary arteries in the treatment field; chemotherapy (eg, anthracycline dose); and combined modality therapy (chemotherapy plus RT). (See 'Risk factors' above.)

●CV conditions after treatment

•Coronary artery disease – The prevalence varies with RT technique and dose, concomitant use of anthracyclines, length of follow-up, and method of screening survivors. (See 'Coronary artery disease' above.)

•Heart failure (HF) – HF may be due to radiation-induced restrictive-, constrictive-, ischemic-, or valvular-cardiomyopathy and by treatment with chemotherapy. (See 'Heart failure' above.)

-Preserved ejection fraction (EF) – Mediastinal RT has been associated with diastolic dysfunction. (See 'Preserved ejection fraction' above.)

-Reduced EF – The rate of HF with reduced EF increases in association with anthracycline dose and with increased mean left ventricular dose of radiation. (See 'Reduced ejection fraction' above.)

-Valvular heart disease – Mediastinal RT has been associated with an increased risk of clinically significant valvular abnormalities particularly involving the aortic, mitral, and tricuspid valves. (See 'Valvular heart disease' above.)

•Arrhythmias – RT can cause fibrosis of conduction pathways in the heart, including bradycardia, heart block, and sinus node dysfunction (ie, sick sinus syndrome). (See 'Arrhythmias' above.)

•Pericarditis – The incidence of pericarditis has declined with lower RT doses and contemporary techniques. (See 'Pericarditis' above.)

●Pediatric cancers – Cardiac deaths in patients treated as children are related to cardiac RT and anthracycline treatment. (See 'Clinical manifestations in pediatric patients' above.)

●Prevention – Treatment-related and patient-related risk factors should be minimized whenever possible. (See 'Prevention' above.)