ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Cancer survivorship: Cardiovascular and respiratory issues

Cancer survivorship: Cardiovascular and respiratory issues
Authors:
Bonnie Ky, MD, MSCE
Lavanya Kondapalli, MD
Daniel J Lenihan, MD
Section Editor:
Patricia A Ganz, MD
Deputy Editor:
Sonali Shah, MD
Literature review current through: Jun 2022. | This topic last updated: Jan 31, 2022.

INTRODUCTION — With the success of modern cancer therapy, cancer can be curable, and in cases where cure cannot be achieved, it is commonly treated as a chronic disease. As a result, there are approximately 44 million cancer survivors worldwide [1], and this number is expected to increase over time [2]. It has also become apparent that cardiovascular (CV) disease, in general, is the major life-limiting comorbidity in patients previously treated for cancer who survive beyond five years [3]. Given the growing population of patients once treated (or continuing treatment) for cancer, the medical community must learn how to best optimize CV health and minimize the CV complications of cancer treatment.

A growing population of adult survivors of both pediatric and adult-onset cancers are recognized to have an increased incidence of: CV risk factors (hypertension [HTN], dyslipidemia, diabetes, obesity), CV disease (coronary disease, valvular disease, cardiomyopathy, heart failure [HF], and stroke) [3-5], and pulmonary disease compared with the general population [6,7]. Epidemiologic data suggest that common CV risk factors are more strongly associated with risk of incident CV disease in cancer survivors as compared with noncancer controls [8]. Because of the potential for these conditions to result in a high degree of morbidity and mortality, understanding how to improve the prevention, recognition, and treatment of CV and pulmonary disease is an important priority to the overall health of this population.

This section will focus on the long-term CV complications encountered in cancer survivorship and will also cover respiratory issues related to cancer therapy. Since there are a myriad of possible complications of cancer therapy [9], this section will summarize the most important and common cardiopulmonary conditions related to these systems. In each subsection, the diagnosis, treatment, and prognosis will be highlighted, if known, and areas where improvements in understanding are needed will be outlined. Finally, practical recommendations will be made for certain principles that may help guide the optimal treatment of CV effects in cancer survivors.

For readers who desire a broader overview of cancer survivorship, a separate topic that discusses these issues is available. (See "Overview of cancer survivorship care for primary care and oncology providers".)

ATHEROSCLEROSIS

Effect of cancer therapy on atherosclerosis — Various cancer therapies are associated with increased atherosclerosis, such as radiation therapy (RT) and hormonal therapy such as androgen deprivation therapy (ADT).

Radiation therapy — It is well established that RT is associated with an increased risk of coronary [10,11] and carotid artery disease [12-14]. This is believed to be secondary to damage to the microvasculature, which results in endothelial dysfunction, inflammation, oxidative stress, and accelerated atherosclerosis.

The risk from RT has been well characterized in patients with breast cancer or lymphoma [10]. Historical data from breast cancer participants treated from 2005 to 2008 suggested that the incidence of adverse cardiovascular (CV) events was 3.3 percent over a median follow-up time of 7.6 years (range 0.1 to 10.1 years). Each gray (Gy) of radiation delivered to the heart was associated with a 16.5 percent increased risk of adverse events [15]. In childhood cancer survivors, the risk of cardiotoxicity from RT was shown to be dose dependent, with the cumulative incidence of symptomatic coronary artery disease (CAD) at age 50 years increasing to 20 percent in males exposed to >35 Gy [16].

The adverse CV effects of RT are also becoming increasingly recognized in other malignancies, including non-small cell lung cancer where higher heart radiation doses have been associated with worse overall survival [17,18]. Moreover, any vascular location that is in the radiation field is at increased risk for early atherosclerosis. This is particularly relevant among patients with head and neck cancer because neck RT is a major risk factor for significant carotid disease [19,20], and the complexity of atherosclerosis can be quite challenging [21]. Further discussion on the cardiotoxicity, especially valvular disease, associated with RT is discussed separately. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

There may be no symptoms attributable to either CAD or carotid disease in patients previously treated with RT. Therefore, clinicians should be proactive about age-appropriate CV risk factors and disease screening for potentially significant yet asymptomatic disease in these patients [22-24]. This includes periodic surveillance for cardiomyopathy by echocardiography in high-risk individuals and surveillance of coronary disease by noninvasive cardiac stress testing following RT and at least every five years. Moreover, invasive coronary angiography may be indicated to evaluate for CAD. For patients at risk for carotid artery disease, ultrasound is the safest and most effective screening tool. Other modalities may also be recommended depending upon patient characteristics and institutional expertise. (See "Screening for coronary heart disease".)

Beyond screening, aggressive management of known cardiac risk factors is the best prevention for atherosclerosis in a cancer survivor. (See "Overview of primary prevention of cardiovascular disease".)

These include the following [25]:

Adequate blood pressure and glucose control (especially for patients with diabetes mellitus). (See "Overview of general medical care in nonpregnant adults with diabetes mellitus" and "Goal blood pressure in adults with hypertension".)

Daily aspirin in select patients following a discussion of risks and benefits. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

Statin-based lipid-lowering therapy, with further risk stratification aided by coronary artery calcification assessment and atherosclerotic CV disease risk assessment. (See "Statins: Actions, side effects, and administration".)

Antiplatelet therapy in selected patients. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use".)

Regular exercise, tobacco cessation, and healthy dietary habits are also major components of effective management strategies. These are associated with improved survival in all patients, including those treated for cancer [26-28]. (See "The roles of diet, physical activity, and body weight in cancer survivors" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

Androgen deprivation therapy — Androgen deprivation therapy (ADT) is used in the treatment of prostate cancer. ADT utilizes hormonal agents, such as gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, triptorelin) and antagonists (degarelix, relugolix), as well as antiandrogens (flutamide, bicalutamide, enzalutamide). (See "Side effects of androgen deprivation therapy".)

Although previous retrospective studies were inconsistent [29-31], prospective studies and randomized trials have demonstrated the risks of CAD or myocardial infarction (MI) associated with ADT [32-34]. These data suggest that CV adverse events (especially hypertension [HTN], ischemic heart disease, and MI) are frequently encountered safety concerns, and that optimal CV risk factor control and encouragement of regular exercise should be recommended.

We agree with the consensus statement from the American Heart Association (AHA), American Cancer Society, and the American Urologic Association that states patients receiving ADT should be evaluated annually with an examination of blood pressure, serum measurements of lipid profiles, and checks of fasting glucose levels. In addition, patients should undergo primary and secondary preventive measures [35]. Both aggressive cardiac risk factor modification and appropriate screening are the guiding principles of optimal care, and some have proposed an "ABCDE" algorithm addressing awareness and aspirin therapy, blood pressure, cholesterol and cigarette cessation, diet and diabetes, and exercise [36]. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Several randomized trials have attempted to inform the question of optimal strategy for ADT and hormonal-based therapy for prostate cancer [32-34]. As an example, one randomized trial of patients with prostate cancer treated with GnRH agonist or antagonist for one year indicated that GnRH agonists resulted in higher rates of major CV and cerebrovascular events than GnRH antagonists [37]. Prolonged ADT is also highly associated with worsened cardiorespiratory fitness [38] and has negative effects on obesity with resultant worsening CV disease and all-cause mortality [39], visceral adiposity, insulin sensitivity, metabolic syndrome, and dyslipidemia [40].

Examples of the retrospective data on ADT and CV risk include the following:

A retrospective analysis of the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database examined 22,816 prostate cancer patients who had survived for one year after diagnosis. Patients who received ADT had a 20 percent increased incidence of CAD over a mean follow-up period of five years, compared with those who were not treated with ADT (hazard ratio [HR] 1.20, 95% CI 1.15-1.26) [30].

In contrast, a meta-analysis that included randomized trials with follow-up ranging from 7.6 to 13.2 years did not show an association between ADT and an increased risk of CV mortality [31].

However, potential concerns have been raised over these analyses, including:

A lack of generalizability of clinical trial participants to the general population

The presence of competing risks

The potential for outcomes misclassification, resulting in underreporting of CV deaths

Any of these may have resulted in an underestimation the CV risk among males using ADT. Moreover, data support that CV risk factors are underassessed and undertreated in males receiving ADT [41].

Childhood cancer survivors — Cardiovascular disease is a leading noncancer contributor to early morbidity and mortality in survivors of childhood cancer [42-48]. The risk of CV disease is substantially increased in childhood cancer survivors [16,49]. On average, survivors of childhood cancer have a greater than 10-fold risk of ischemic heart disease and stroke compared with siblings [8,46]. Risk of ischemic heart disease among treated childhood cancer survivors remains for at least four decades after completion of therapy [5]. Long-term follow-up studies in this cohort have led to the development of cardiac risk calculators as well as surveillance guidelines for cardiac disease [50], and they support advances in cancer treatment that limit cardiotoxicity:

Cardiac-specific risk was addressed in a review of 13,060 participants in the Childhood Cancer Survivor Study (CCSS) who were diagnosed and treated for cancer prior to age 21 and were observed through the age of 50 [51]. Ischemic heart disease and stroke occurred in 265 (2 percent) and 295 (2.25 percent), respectively; the risk could be predicted based on factors that were available at the end of treatment.

In a subsequent analysis of an expanded CCSS cohort of 24,214 participants followed for up to 39 years, RT with cardiac exposure was associated with an elevated risk of cardiac disease, regardless of radiation dosing or cardiac volume [5]. Patients with low to moderate RT doses (5 to 20 Gy) to large cardiac volumes (greater than 50 percent) were at increased risk for cardiac disease when compared with patients without cardiac RT exposure (relative risk [RR] 1.6, 95% CI 1.1-2.3). Similarly, patients with high RT doses (≥20 Gy) to small cardiac volumes (0.1 to 30 percent) were also at increased risk for cardiac disease (RR 2.4, 95% CI 1.4-4.2).

These results add to the growing body of work supporting RT delivery techniques that reduce cardiac radiation exposure [52].

Cardiac risk factor prediction model — A prediction model was developed based on the CCSS cohort that included sex; age at cancer diagnosis; use of alkylating agents, anthracyclines, and/or vinca alkaloids; and cranial, neck, chest, and abdominal RT. Risk scores were then summed to create low-, intermediate-, and high-risk groups for both outcomes. The cumulative incidence of both ischemic heart disease and stroke at age 50 years among low-risk groups was <5 percent, compared with approximately 20 percent for the high-risk groups; cumulative incidence was only 1 percent for controls not treated for a childhood cancer (siblings). The CV risk calculator for the prediction of heart failure (HF), ischemic heart disease, and stroke is available online.

Surveillance guidelines for cardiac disease — Long-term follow-up guidelines are available from the Children's Oncology Group for survivors of childhood, adolescent, and young adult cancer that include specific recommendations for CV monitoring after chemotherapy and RT. A specific recommendation to consider cardiology consultation 5 to 10 years after RT is made for individuals who received ≥35 Gy of chest irradiation, or ≥15 Gy chest irradiation plus an anthracycline, and for those who received ≥40 Gy of RT to the neck to consider a color Doppler examination of the carotids 10 years after completion of RT to the neck as a baseline.

Surveillance guidelines for cardiomyopathy in childhood cancer survivors are discussed separately. (See 'Surveillance guidelines for myocardial dysfunction' below.)

HYPERTENSION

Effect of cancer therapy on hypertension — Hypertension (HTN) is a long-term consequence of many cancer therapies, including both chemotherapy and targeted agents.

Chemotherapy — Alkylating and alkyl-like agents such as cisplatin, cyclophosphamide, and ifosfamide are associated with HTN, with effects mediated by vascular endothelial injury and nephrotoxicity [53]. For example, cisplatin exerts cytotoxic effects via the formation of covalent adducts with DNA purine bases and inter- and intra-strand cross-links, which can persist in multiple organ systems and circulate for many years after exposure [54-56]. At the vascular level, cisplatin appears to abolish capillary beds [57]. Furthermore, animals treated with cisplatin demonstrate increased levels of TNF alpha and multiple cytokines [58] and markers of oxidative stress [59]. Although speculative, these factors may help to explain long-standing toxicities related to cisplatin, including HTN.

Among chemotherapeutic agents, cisplatin has been associated with HTN, based on preclinical data and from the evaluation of males treated for testicular cancer [60,61]. Unfortunately, limited data exist in females treated with a platinum agent. Clinical data on cisplatin and HTN include the following:

In one study in which these survivors were followed for a median duration of 11.2 years, major results included that [60]:

Survivors of testicular cancer had significant increases in age, testosterone, and body mass index-adjusted blood pressure, on the order of 2.3 mmHg for systolic and 1.8 mmHg for diastolic blood pressure.

Compared with healthy controls, the risk of incident HTN was significantly elevated in testicular cancer survivors (odds ratio [OR] 1.4, 95% CI 1.2-1.7). Subgroup analyses demonstrated that the age-adjusted odds of HTN were greatest in the cisplatin treated group, particularly at dosages >850 mg (OR 2.4, 95% CI 1.4-4).

In another study of testicular cancer survivors who were followed for a median time of 19 years, males who had received chemotherapy (n = 364) had an increased prevalence of antihypertensive medication use compared with the general population (OR 3.7, 95% CI 1.9-5.2) [61].

Targeted therapy — In addition to chemotherapeutic agents, inhibitors that target the vascular endothelial growth factor receptor (VEGFR) signaling pathways are highly associated with significant HTN, especially during active therapy [62-66]. Mechanistically, VEGFR inhibitor therapy causes HTN through increased vascular resistance mediated by a reduction in nitric oxide production and angiogenesis, in addition to impaired natriuresis, endothelin-1-mediated vasoconstriction, capillary rarefaction, and systemic thrombotic microangiopathy [67]. However, the long-term effects on blood pressure and the vasculature are unknown. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Hypertension'.)

Clinical data on VEGFR and tyrosine kinase inhibitors (TKIs) include the following:

A systematic review and meta-analysis of 77 studies of angiogenesis inhibitors concluded that the OR for HTN was 5.28 (95% CI 4.53-6.15) with angiogenesis inhibitors compared with routine care with a number needed to harm of six. Additionally, the OR for severe HTN, defined as blood pressure ≥160/100 mmHg, was 5.59 (95% CI 4.67-6.69) with a number needed to harm of 17 [68].

A meta-analysis of 71 randomized controlled trials comprising over 29,000 patients concluded that the relative risk (RR) of HTN with TKI therapy was 3.78 (95% CI 3.15-4.54) [69].

A retrospective, single-center study of 228 patients with metastatic renal cell carcinoma treated with VEGFR TKIs demonstrated a significant increase in blood pressure relative to baseline. The use of calcium channel blockers and potassium-sparing diuretics significantly lowered blood pressure during therapy [70].

Risks of hypertension in cancer survivors — HTN and other common cardiovascular (CV) risk factors significantly promote the development of CV disease in cancer survivors. The prevalence of HTN in childhood cancer survivors is approximately 2.5 times higher than in noncancer survivors. Active areas of investigation include the role of genetics, in addition to treatment-related risk factors, in identifying childhood cancer survivors at increased risk of developing HTN [71].

An analysis of 10,725 five-year survivors and 3159 siblings in the Childhood Cancer Survivor Study (CCSS) determined that two or more CV risk factors were reported in a greater number of survivors than siblings, and HTN increased the risk for coronary artery disease (CAD), heart failure (HF), valvular disease, and arrhythmia [8]. Moreover, the combined effect of chest radiation therapy (RT) and HTN, as well as anthracyclines and HTN, resulted in a more than additive increased risk of subsequent CV events (table 1) [8].

HTN was furthermore associated with an increased risk of CV mortality in this population. In survivors of adult-onset cancers, findings have been similar [72]. Cancer survivors with CV risk factors have a higher risk of CV disease, and those who develop CV disease have worse survival (figure 1) [4].

Management recommendations for cancer therapy-induced hypertension — The available medications to treat HTN are described in the Joint National Committee guidelines [73]. The American College of Cardiology/American Heart Association (ACC/AHA) HF guidelines also recommend blood pressure control as a major strategy to prevent overt HF. In addition, patients treated with cardiotoxic chemotherapy are considered to have stage A HF [74]. (See "Asymptomatic left ventricular diastolic dysfunction", section on 'Definitions'.)

For HTN screening and monitoring of treated HTN in patients with cancer therapy-related HTN, we follow established guidelines for the general population. (See "Blood pressure measurement in the diagnosis and management of hypertension in adults" and "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".)

Specific approaches for managing HTN induced by cancer therapy are as follows:

Assess for modifiable drivers of hypertension – In all patients with cancer therapy-related HTN, especially for those with HTN refractory to multiple agents, it is important to address modifiable drivers of elevated blood pressure, such as cancer-related pain. In patients with refractory HTN receiving cancer therapy, it may be reasonable to consider dose reduction or temporary discontinuation of chemotherapeutic agents or other medications that may contribute to HTN, in consultation with the patient's oncologist. Examples include nonsteroidal antiinflammatory drugs, high-dose corticosteroids, and erythropoietin-stimulating agents [67].

White coat and masked hypertension – White coat HTN (elevated office-based blood pressure with normal out-of-office blood pressure) and masked HTN (normal office-based blood pressure with elevated out-of-office blood pressure) are both associated with increased risk of adverse CV outcomes and transition to sustained HTN. White coat HTN may be more common in patients receiving cancer treatment compared with the general population, due to increased anxiety surrounding cancer diagnosis and prognosis. In addition, masked HTN may also be more common in patients receiving cancer therapy, potentially due to delayed cancer therapy-induced HTN [67]. This makes out-of-office ambulatory blood pressure monitoring especially important in this patient population. (See "White coat and masked hypertension".)

Lifestyle measures – Management of HTN typically consists of lifestyle measures including counseling on a low-sodium diet and exercise in all patients. (See "Diet in the treatment and prevention of hypertension" and "Exercise in the treatment and prevention of hypertension".)

Choice of antihypertensive agent(s) – The initial choice of antihypertensive agents for cancer therapy-mediated HTN often includes renin-angiotensin system blockers (eg, angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARB]) and beta blockers (BB), as these agents prevent adverse cardiac remodeling. Since HTN may result from nephrotoxicity following cancer treatment, we assess for proteinuria (spot protein to creatinine ratio of ≥500 mg/g or albuminuria to creatinine ratio of ≥300 mg/g). If proteinuria is present, we suggest preferentially initiating or titrating an ACE inhibitor or ARB [67]. Once the maximum tolerated dose of a single agent has been attained, additional first-line antihypertensive medications may be added for blood pressure control as necessary.

Other available agents for cancer therapy-related HTN include mineralocorticoid antagonists and diuretics. If patients are being evaluated for these therapies, it is important to account for the risk of volume depletion and electrolyte abnormalities in patients likely to experience adverse effects from cancer therapies including reduced oral intake and gastrointestinal losses. (See "Choice of drug therapy in primary (essential) hypertension".)

Calcium channel blockers are also an option. Depending upon the mechanism of HTN (ie, impact on arterial stiffness, pulsatile or resistive load), particularly with VEGFR inhibitors, medications with a primary vasodilator effect may be more effective at controlling blood pressure. However, we typically avoid non-dihydropyridine calcium channel blockers (verapamil and diltiazem). These agents inhibit cytochrome P450 3A4 (table 2), a family of enzymes involved in the metabolism of many chemotherapeutic agents, and their use may worsen chemotherapy-related toxicity [67]. (See "Major side effects and safety of calcium channel blockers", section on 'Types of calcium channel blockers'.)

HYPERLIPIDEMIA

Effect of cancer therapy on hyperlipidemia — Treatments for cancer may increase lipid levels among cancer survivors. Examples of this include:

Patients with breast cancer on aromatase inhibitors – Aromatase inhibitors (AIs) block the conversion of androgens to estrogen and have variable effects on lipids [75-77]. An analysis of pooled data from seven clinical trials (n = 30,023 patients) demonstrated that longer duration of AI use was associated with a statistically significant increase in the odds of hypercholesterolemia as compared with tamoxifen [75].

In addition, there may be a slight difference on lipid profiles between the different AIs. Four-year follow-up of participants in one randomized trial reported that patients who took anastrozole had a slightly higher incidence of hypertriglyceridemia (3 versus 2 percent, respectively) and hypercholesterolemia (18 versus 15 percent) compared with those who took exemestane [76]. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Comparison between AIs'.)

Patients after allogeneic hematopoietic stem cell transplantation – In a retrospective study of 761 patients who underwent transplant at a single institution from 1998 to 2008 and survived at least 100 days, 73.4 percent developed hypercholesterolemia and 72.5 percent developed hypertriglyceridemia in the first two years. Acute graft-versus-host disease (GVHD) was independently associated with hypercholesterolemia and hypertriglyceridemia [78]. A retrospective study of 194 transplant patients at another institution from 1995 to 2008 revealed 42.8 percent developed hypercholesterolemia and 50.8 percent hypertriglyceridemia. Similarly, chronic GVHD and steroid use were independently associated with hypercholesterolemia [79].

Survivors of testicular cancer treated with radiation therapy (RT) and/or chemotherapy – There is an increased incidence of hyperlipidemia among males treated for testicular cancer, which appears to be associated with RT and/or chemotherapy. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Hyperlipidemia'.)

In one study, testicular cancer survivors previously treated with RT and chemotherapy had significantly lower levels of high-density lipoprotein (HDL) compared with patients treated with surgery only [61]. Testicular cancer survivors had an increased odds of being on lipid-lowering medication compared with normal controls (odds ratio [OR] between 1.8 and 2.6), regardless of treatment type at diagnosis (surgery, RT, chemotherapy).

Survivors of prostate cancer treated with ADT – Males treated with ADT for prostate cancer can experience persistent changes in their body composition, including decreases in lean body mass, increases in fat mass [80], and alterations in insulin sensitivity [81]. For example, in one study of patients who had received ADT for 12 months, significant increases in total cholesterol, low-density lipoprotein, and non-HDL were noted [81]. (See "Side effects of androgen deprivation therapy", section on 'Potential cardiovascular harm'.)

Management guidelines — For patients with hyperlipidemia as a result of cancer-related treatment, the current accepted standards are to use lipid-lowering guidelines, which are described separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

CARDIAC STRUCTURAL COMPLICATIONS

Effect of cancer therapy on cardiac structure — Cancer therapy can potentially result in damage to multiple cardiac structures as a late complication. However, this may not be manifest for years after treatment has completed. For patients who experience issues related to structural damage to the heart, close monitoring is essential [82]. In addition, a medical evaluation is necessary to determine if other causes of cardiac dysfunction are present.

Close monitoring is important because the timing of surgical or medical treatment can be critical for optimal outcomes. The American Society of Oncology has led an effort in publishing a clinical practice guideline in the "Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers." Briefly, this review and expert consensus statement summarized key recommendations for cardiac monitoring and treatment of dysfunction and also provided the definition of risk factors for cardiac dysfunction, components of comprehensive cardiovascular (CV) assessment, various strategies for minimizing cardiac risk during treatment, and monitoring strategies during and after cancer therapy (table 3) [83]. The European Society of Cardiology has also provided a position paper on cancer treatments focused on a comprehensive overview of cardiotoxicities with cancer therapies before, during, and after treatment [84]. The European Society of Medical Oncology also provided a consensus document for the management of CV disease throughout the spectrum of cancer treatment [85].

The impact of prior cancer treatment has been well illustrated in adult survivors of childhood cancers. Compared with siblings, adult survivors of childhood cancers have an increased age-adjusted rate of valvular abnormalities, pericardial disease, and heart failure (HF) over a time from of 7 to 50 years [86]. In a study of 1853 adult survivors of childhood cancers, cardiomyopathy was detected in 7.4 percent of survivors, coronary artery disease (CAD) in 3.8 percent, valvular regurgitation or stenosis in 28 percent, and conduction abnormalities in 4.4 percent. Nearly all were asymptomatic and the prevalence of abnormalities increased with age, and were associated with anthracycline dose and radiation exposure [42]. Similarly, additional data suggest that cancer survivors may have an increased prevalence of both overt and subclinical abnormalities in cardiac function, in sensitive measures of cardiac mechanics [87]. In a study of 1820 adult survivors of childhood cancers from the same group, abnormal global longitudinal strain existed in 28 percent of patients and was associated with prior exposure to chest radiation therapy (RT), anthracycline dose, and metabolic syndrome. Abnormalities in circumferential strain have also been noted with anthracycline and/or trastuzumab exposure in adult breast cancer patients [88].

Valvular degeneration and calcification — Valvular issues resulting in stenosis and/or regurgitation are established long-term consequences of mediastinal radiation [89-91]. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

For patients in whom a valvular condition has been detected, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for valvular heart disease can be used to help direct care. (See "Clinical manifestations and diagnosis of aortic stenosis in adults" and "Clinical manifestations and diagnosis of rheumatic mitral stenosis" and "Clinical manifestations and diagnosis of chronic mitral regurgitation" and "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults".)

Echocardiography is an essential tool that is used to define disease severity and progression of valvular heart disease, and can be applied in accordance with accepted guidelines and standards [74,92,93]. If structural disease is suspected but the noninvasive work-up is not conclusive, right heart catheterization can also be performed to assess hemodynamics, particularly when intervention is being considered.

The impact of mediastinal radiation on valvular disease is illustrated by the following studies:

In a cross-sectional study of over 1800 adult survivors of childhood cancer who had received cardiotoxic anticancer treatments at least a decade earlier, valvular regurgitation or stenosis was present in 28 percent [42]. Radiation exposure exceeding 1500 centigray (cGy) resulted in the greatest risk for developing valvular disease.

In one study of 415 survivors of Hodgkin lymphoma who received mediastinal irradiation, with a minimum of two years of follow-up, 6.2 percent developed clinically significant valvular disease at a median of 22 years [89]. Patients who developed valvular damage had received higher doses of radiation (37 gray [Gy; 23 to 44 Gy] versus 33 Gy [10 to 47 Gy]). The most common valvular abnormality was aortic stenosis followed by (in order of decreasing frequency) mitral regurgitation, mitral stenosis, tricuspid regurgitation, and aortic regurgitation. These findings have been corroborated by other investigators, including a study of 1279 survivors of Hodgkin lymphoma that demonstrated a cumulative incidence of moderate to severe valvular disease of 0.5 percent at five years that increased to 8.7 percent at 25 years of follow-up, and typically occurred at a median of 15 years after RT [94].

In a cross-sectional study of 82 survivors of Hodgkin lymphoma, severe valvular disease was seen more frequently in those that received mediastinal radiation compared with those who did not (24.5 versus 3.4 percent). The most common valvular abnormality was aortic regurgitation [95].

Pericardial disease — Pericardial disease, usually manifest as pericardial effusion with or without tamponade, or pericardial constriction may be particularly difficult clinical conditions encountered in cancer survivors [96]. Although pericardial effusions are typically seen in the active treatment phase of solid tumors, this can be as a late consequence of chest RT, although it is uncommon [97]. In many instances, a pericardial effusion or constriction can be observed for an extended period of time, and symptoms due to HF may occur late. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies", section on 'Pericarditis'.)

For patients in whom pericardial disease is suspected, monitoring is best done by echocardiography and periodic clinical assessment [98,99]. (See "Echocardiographic evaluation of the pericardium".)

Conduction disease — Dysfunction of cardiac conduction is indicative of structural damage. Sick sinus syndrome, bradycardia, and heart block have been reported among patients treated for lymphoma, especially following treatment with mediastinal or chest wall RT [94,100]. In addition, there are reports of persistent tachycardia and loss of circadian variability in heart rate. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies", section on 'Palpitations, syncope, and sudden death'.)

For patients who received chest wall RT, surveillance is suggested. If asymptomatic, this can be done with a routine electrocardiogram (ECG). For symptomatic patients (eg, lightheadedness, syncope, or palpitations), noninvasive or electrophysiologic studies may be required, especially if the ECG is nondiagnostic. (See "Arrhythmia management for the primary care clinician" and "Sinus node dysfunction: Treatment".)

MYOCARDIAL DYSFUNCTION, CARDIOMYOPATHY, AND HEART FAILURE

Cancer populations at risk for cardiomyopathy — The development of a cardiomyopathy as a late effect of cancer therapy is a devastating consequence leading to myocardial dysfunction, heart failure (HF), and higher rates of mortality and significant morbidity [3,43]. The outcomes of cancer survivors who develop cardiomyopathy (whether due to chemotherapy or radiation therapy [RT]) are generally poor [101]. Therefore, efforts to detect cardiac dysfunction at the earliest possible time and provide cardiac-specific therapy to prevent progression are of paramount importance [102].

The American College of Cardiology and American Heart Association (ACC/AHA) classify patients who have received cardiotoxic chemotherapy as having stage A HF [74]. (See "Asymptomatic left ventricular diastolic dysfunction", section on 'Definitions'.)

Moreover, the American Society of Clinical Oncology classifies specific patients as higher risk for developing cardiac dysfunction (table 3). These include patients receiving high-dose cardiotoxic chemotherapy; RT to a field that includes the heart; combination cardiotoxic chemotherapy and chest RT; age >60 years at time of treatment; and those with cardiac risk factors or existing cardiac history [83]. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies", section on 'Heart failure' and "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Risk assessment and monitoring'.)

In one retrospective cohort study of 126,120 cancer survivors followed for a median of approximately five years, the risk of HF or cardiomyopathy was increased at one year, and continued to rise over a decade of follow-up, relative to those without a cancer diagnosis [3]. These results, obtained from linked electronic health record databases, were noted in patients with a history of treated hematologic malignancies (eg, non-Hodgkin lymphoma [hazard ratio (HR) 1.94, 95% CI 1.66-2.25], leukemia [HR 1.77, 95% CI 1.50-2.09], and multiple myeloma [HR 3.29, 95% CI 2.59-4.18]) and solid tumors (eg, esophageal [HR 1.96, 95% CI 1.46-2.64], lung cancer [HR 1.82, 95% CI 1.52-2.17], kidney cancer [HR 1.73, 95% CI 1.38-2.17], and ovarian cancer [HR 1.59, 95% CI 1.19-2.12]). In addition, the magnitude of the increased risk, relative to age-matched controls, was higher among patients <60 years of age and those with no previous history of cardiovascular (CV) disease or hypertension (HTN), specifically among those with non-Hodgkin lymphoma, breast cancer, and lung cancer.

Effect of cancer therapy on cardiomyopathy

Anthracyclines — The chemotherapeutic agents most commonly associated with cardiotoxicity are the anthracycline analogues (doxorubicin, epirubicin, pegylated liposomal doxorubicin, mitoxantrone, as well as others (table 4)). In adult cancer survivors, anthracyclines are associated with both systolic and diastolic dysfunction [52,103-105]. In childhood cancer survivors, anthracyclines can lead to congestive HF, one of the most common late cardiac effects in this population [105]. (See 'Childhood cancer survivors' below.)

Data suggest that cardiotoxicity may occur in the first one to two years post-anthracycline exposure [88,106].

The risk of cardiotoxicity differs by the type of anthracycline administered. For example, in one study of 28,423 childhood cancer survivors, relative to doxorubicin, daunorubicin was associated with decreased cardiomyopathy risk [107]. Of note, mitoxantrone is considered 10 times more cardiotoxic than doxorubicin. Additionally, while mitoxantrone has traditionally been classified as an anthracycline, it may in fact result in cardiotoxicity through a distinct mechanism where it exhibits a nonlinear dose-response relationship with HF risk [105].

The total dose of anthracycline received is an important risk factor for long-term, subsequent cardiac dysfunction. The typical belief is that large doses (>450 mg/m2) induce cardiotoxicity [42,86]. For example, in one study, the frequency of doxorubicin-related HF was estimated to be 5 percent at a cumulative dose of 400 mg/m2, increasing to 26 percent at 500 mg/m2 and 48 percent at 700 mg/m2 [108]. (See "Prevention and management of anthracycline cardiotoxicity", section on 'Approach to prevention' and "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity".)

However, patients can be susceptible to cardiomyopathy at lower doses. For example, detailed echocardiographic data from adult patients with breast cancer suggest that with anthracyclines (doxorubicin 240 mg/m2), there are modest but persistent declines in left ventricular ejection fraction (LVEF; approximately 4 percent) [88], as well as persistent worsening in diastolic function [109].

Genetic variation also contributes significantly to chemotherapy-related cardiotoxicity and can modify the relationship between anthracycline dose and cardiotoxicity risk. Systematic reviews and meta-analyses suggest that there is a genetic basis for anthracycline-mediated cardiac dysfunction across multiple patient populations, including those with childhood cancer, adult-onset cancer, and across the age spectrum [110]. Further details on the pathophysiology and risk factors of anthracycline-induced cardiotoxicity are discussed separately. (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Mechanisms'.)

As examples:

In a case-control study of 170 cancer survivors with cardiomyopathy compared with 317 survivors without cardiomyopathy, the risk of cardiomyopathy was increased in patients with the myocardial cytosolic carbonyl reductase 3 (CBR3) homozygous GG genotype (odds ratio [OR] 1.79) [111]. Furthermore, in patients with GG versus the GA/AA genotype, there was a 3.30-fold increased risk of cardiomyopathy when exposed to low dose anthracycline (1 to 250 mg/m2). At doses greater than 250 mg/m2, there was no significant interaction by genotype, with an increased risk of cardiomyopathy irrespective of CBR3 genotype status.

Other genomic studies have identified pathogenic variants which were shown to modulate the risk of anthracycline-related cardiomyopathy [110,112]. Examples include key drug biotransformation genes (SLC28A3, SLC22A17, UGT1A6), glutathione S-transferase 1 (GSTM1) which is responsible for anthracycline elimination, antioxidant pathways (HAS3), topoisomerase-2B mediated DNA damage (RARG) and Titin-truncating variants (TTNtvs).

Other therapies — Other cancer-related therapies associated with cardiac dysfunction include the following:

Trastuzumab and other human epidermal growth factor receptor 2 (HER-2) targeted agents Trastuzumab is a humanized monoclonal antibody targeting the ErbB2 receptor and is routinely administered in selected patients with breast cancer overexpressing HER2. Treatment with trastuzumab is associated with a risk of cardiac toxicity that is mechanistically distinct from that caused by anthracyclines. Trastuzumab-related cardiotoxicity is typically manifested by an asymptomatic decrease in the LVEF and is less commonly manifested by clinical HF. This is discussed in more detail separately. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

Radiation therapy – RT to myocardial tissues can also result in restrictive cardiomyopathy, although less common. Data suggest an increased risk of HF with preserved ejection fraction, however [113]. Mediastinal RT certainly sensitizes the myocardial tissue to the toxic effects of chemotherapy and would result in a patient being highly susceptible to myocardial dysfunction. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

RT and doxorubicin may induce synergistic cardiotoxic effects with each other and with other chemotherapeutic agents, resulting in subsequent cardiac toxicity in cancer survivors [114]. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies", section on 'Incidence of cardiovascular disease' and "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Cardiovascular disease' and "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity".)

Hematopoietic cell transplantation (HCT) – Survivors of HCT have a higher incidence of CV disease when compared with their nontransplant siblings. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Cardiovascular'.)

Antiangiogenic agents – The natural history of cardiomyopathy secondary to antiangiogenic-based cancer therapy is still unclear, with few long-term data describing the outcomes. Some subsequent data suggest that in the short-term, declines in LVEF occur early and are manageable with close CV monitoring and follow-up [115]. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Left ventricular dysfunction and myocardial ischemia'.)

Childhood cancer survivors — Childhood cancer survivors are at increased risk for CV risk factors (eg, HTN) as well as CV disease (eg, cardiomyopathy and HF). Compared with siblings and the general population, the risk ratios range from 5 to 15 [8,44,46,116]. In pediatric-age childhood cancer survivors, one retrospective case-control study suggests that early longitudinal changes in functional and structural parameters on echocardiography are associated with the subsequent development of cardiomyopathy [117].

Risk of HF among treated childhood cancer survivors remains for at least four decades after completion of therapy, with the youngest children at diagnosis exhibiting the most vulnerability to long-term treatment-related cardiotoxicity [5].

The specific risk was addressed in a review of over 13,000 participants in the Childhood Cancer Survivor Study (CCSS) who were diagnosed and treated for cancer prior to age 21 years and were observed through age 40 years [118]. HF occurred in 285 (2.2 percent), with a subsequent CCSS study suggesting an incidence of being waitlisted for or undergoing cardiac transplantation of approximately 0.5 percent after at least 35 years following initial cancer diagnosis [119]; the risk could be predicted based on factors that were available at the end of treatment, including cumulative anthracycline exposure and cardiac RT dose.

A subsequent analysis of an expanded CCSS cohort of 24,214 participants followed for up to 39 years demonstrated a dose-response relationship between anthracycline chemotherapy and HF, with children <13 years of age at highest risk for HF [5]. Young children (<4 years) exposed to low and intermediate lifetime cumulative anthracycline-based chemotherapy (<250 mg/m2) had a twofold increased risk of HF relative to older children (>13 years). This risk increased fourfold with higher cumulative anthracycline-based chemotherapy (≥250 mg/m2).

Similar results were seen in another study of nearly 6000 childhood cancer survivors. In this study, approximately 40 years after diagnosis, the cumulative incidence of developing HF was 11 percent among those who received cardiotoxic chemotherapy and 29 percent among those who received both cardiotoxic chemotherapy and radiotherapy involving the heart [105].

Heart failure risk calculator — A prediction model for HF risk was developed based on the CCSS cohort that included sex; age at cancer diagnosis; use of alkylating agents, anthracyclines, and/or vinca alkaloids; and cranial, neck, chest, and abdominal RT. Risk scores were then summed to create low-, intermediate-, and high-risk groups. The cumulative incidences of HF at age 40 years among low-, intermediate-, and high-risk groups were 0.5, 2.4, and 11.7 percent, respectively; cumulative incidence was 0.3 percent for controls not treated for a childhood cancer (siblings). An online calculator to estimate the risk of HF is available.

The addition of surveillance LVEF to a clinical risk score may also improve the prediction of LVEF <40 percent, although further validation data are necessary [103]. In one study of 299 childhood cancer survivors, the addition of surveillance LVEF to a clinical risk score improved the 10-year prediction for subsequent development of LVEF <40 percent [103]. More specifically, a mid-range LVEF 40 to 49 percent on initial surveillance echocardiogram increased the risk of developing LVEF <40 percent by approximately eightfold relative to those with preserved LVEF >50 percent. (See "Treatment and prognosis of heart failure with mid-range ejection fraction".)

Surveillance guidelines for myocardial dysfunction — Long-term follow-up guidelines are available from the Children's Oncology Group for survivors of childhood, adolescent, and young adult cancer that include specific recommendations for CV monitoring after chemotherapy and RT. In addition, the International Late Effects of Childhood Cancer Guideline Harmonization Group has published recommendations regarding cardiomyopathy surveillance in childhood cancer survivors (table 5) [120,121].

Prevention of cardiac dysfunction and heart failure — In oncology patients receiving anthracyclines, various cardioprotective measures may be used to prevent cardiac dysfunction such as dexrazoxane, liposomal anthracyclines, or infusional rather than bolus dosing of anthracyclines. Some studies have demonstrated improvement in survival with these strategies, although longer follow-up data are needed [16]. These preventative measures are discussed in detail separately. (See "Prevention and management of anthracycline cardiotoxicity".)

In addition, among cancer patients receiving chemotherapy, prophylactic neurohormonal therapies including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta blockers, and mineralocorticoid receptor antagonists have been associated with an attenuation of LVEF declines on the order of 3.96 percent. However, in one meta-analysis, the absolute changes in LVEF were small, and significant heterogeneity across studies was observed for the prophylactic efficacy of neurohormonal therapies on chemotherapy-related cardiotoxicity [122]. Further prospective studies and randomized clinical trials of prophylactic cardioprotective strategies in cancer patients are necessary [123]. (See "Prevention and management of anthracycline cardiotoxicity".)

Management of cardiac dysfunction and heart failure — While cardiotoxicity related to anthracyclines was previously thought to be completely irreversible [124], contemporary data suggest that early identification of cardiotoxicity and prompt therapy for HF can lead to substantial improvement in LVEF to even normal levels [125,126]. One study suggested that, if subclinical left ventricular dysfunction is left untreated for six months or longer, there may be a lower likelihood of recovery [126]. In a follow-up study by this same group, LVEF assessment in cancer patients exposed to anthracyclines suggested that the incidence of cardiotoxicity, as defined by a decline in LVEF of >10 percent to <50 percent, occurred in 9 percent of patients with the majority occurring the first year after the completion of chemotherapy. A nontrivial proportion of patients did demonstrate recovery of LVEF to varying degrees [106].

With this principle in mind, cardiac biomarkers such as troponin I, B-type natriuretic peptide (BNP), and n-terminal proBNP (NT-proBNP) have shown some potential utility in the early detection of cardiotoxicity [127]. In addition, the optimization of cardioprotective medications may help prevent or ameliorate damage that may occur during cancer treatment [128,129]. This proactive process can potentially eliminate cardiotoxicity as a substantial late cardiac effect for cancer survivors, although studies are needed to be validated their use in this population [84]. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity", section on 'Investigational tests'.)

Cardiac dysfunction related to therapy can recover when treated optimally with appropriate, guideline-directed medications for HF, including neurohormonal antagonists, beta blockers (BB), or diuretics when appropriate [130]. However, it is not always reversible, and useful clinical factors to predict the risk of serious HF have not been elucidated [131].

In the absence of data, it would be prudent to exercise extreme caution when withdrawing ACE-I or BB in patients with a history of transient treatment-related HF and/or left ventricular dysfunction. We advise only doing so potentially after a long period of stability has passed and provided the patient is no longer being actively treated for cancer.

For patients undergoing antiangiogenic therapy, appropriate cardiac risk factor management is imperative for optimal outcomes. This includes utilizing antihypertensive therapies that control blood pressure (eg, dihydropyridine calcium channel blockers such as amlodipine) and prevent adverse cardiac remodeling (eg, ACE-I, ARB, or BB). Other important management principles potentially include aspirin, statin therapy, dietary sodium restriction, regular exercise, and weight control if possible. (See 'Management recommendations for cancer therapy-induced hypertension' above and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

PULMONARY TOXICITY — Cancer survivors are at increased risk for pulmonary disease that results from treatment with chemotherapy and radiation therapy (RT). These are reviewed below.

Pneumonitis — Several chemotherapeutic agents are associated with interstitial pneumonitis, including bleomycin, cyclophosphamide, methotrexate, melphalan, and carmustine. There also appears to be an increased incidence of pneumonitis with checkpoint inhibitors, the long-term consequences of which are unclear [132]. Pneumonitis has been also reported with other agents, such as those targeting the mTOR pathway [133]. Of these, the pulmonary complications associated with bleomycin (an agent commonly used to treat Hodgkin lymphoma and testicular cancer) have been best characterized.

While this drug can cause a variety of insults, bleomycin interstitial pneumonitis (BIP) is the most common. Depending on the definition used, BIP has been reported to occur in up to 46 percent of patients [134]. BIP is of particular relevance to the long-term care of cancer survivors, given its potential progression to pulmonary fibrosis and associated increased mortality. For example, a study of 38,907 survivors of testicular cancer treated with bleomycin in the past revealed an increased standardized mortality ratio of 2.53 (95% CI 1.26-4.53) for respiratory diseases alone [135]. Late onset BIP typically develops more than six months after treatment [136,137], presenting as a nonproductive cough, dyspnea, tachypnea, fever, and cyanosis. Radiographic imaging demonstrates variable findings but can show bilateral bibasilar infiltrates [134]. Patients with BIP tend to respond to corticosteroids [136,138]. (See "Bleomycin-induced lung injury".)

Pneumonitis can also occur with RT and typically occurs at least one to three months after completion of RT for lung, breast, esophageal cancers and bone metastases, Hodgkin and non-Hodgkin lymphoma, or total body irradiation for leukemia. The incidence and extent of radiation damage depends on the volume of lung irradiated, total radiation dose, and radiation fractions [139]. Again, common symptoms include dyspnea, hypoxia, nonproductive cough, and fever. Radiographic imaging tends to show changes confined to the outlines of radiation fields [139]. Steroids can be helpful and patients can have complete resolution of symptoms after six to eight weeks of treatment. Like BIP, however, radiation pneumonitis can progress to fibrosis, making this particularly relevant to the care of long-term survivors. (See "Radiation-induced lung injury".)

Fibrosis — Pulmonary fibrosis is a dreaded complication of certain chemotherapies, including bleomycin, busulfan, and carmustine, and radiation treatment. In a small study of 17 children who received carmustine to treat brain neoplasms, 25-year follow-up revealed that nine (53 percent) died of pulmonary fibrosis. Of the eight survivors, follow-up was available on seven patients, who all showed signs of upper zone pulmonary fibrosis [140]. (See "Bleomycin-induced lung injury".)

Radiation-induced pulmonary fibrosis develops at least 6 to 24 months after exposure to radiation, with patients presenting with progressive dyspnea and cough. In some cases, fibrosis is observed on imaging alone and patients are asymptomatic [141]. Steroids typically are associated with little benefit. The Childhood Cancer Survivor Study (CCSS) demonstrated that patients exposed to chest RT were 4.3 times more likely than their siblings to have pulmonary fibrosis five years post-diagnosis. Chest RT was also associated with a 3.5 percent cumulative incidence of pulmonary fibrosis 20 years postdiagnosis [142]. (See "Radiation-induced lung injury".)

Bronchiolitis obliterans syndrome — Bronchiolitis obliterans syndrome (BOS) is a pulmonary complication that can be a significant source of morbidity and mortality in patients receiving allogeneic hematopoietic cell transplantation (HCT) [143]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Overview of bronchiolar disorders in adults" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

BOS is a complication seen after allogeneic HCT and is observed in the presence of chronic graft-versus-host disease (GVHD). This syndrome causes airflow obstruction secondary to progressive circumferential fibrosis with eventual scarring of terminal bronchioles [144]. Further details on the etiology and clinical presentation of BOS are discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Etiology and risk factors' and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Clinical presentation'.)

Since patients with BOS can present asymptomatically and insidiously, screening pulmonary function testing (PFT) is used to monitor for BOS at various intervals in those post-HCT and those diagnosed with chronic GVHD [145]. The frequency of such screening is discussed separately. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease", section on 'Lung'.)

The diagnosis of BOS can be made conditionally on the basis of PFTs demonstrating increasing airflow limitations, and pulmonary biopsy is generally not needed; a new onset obstructive lung defect typifies BOS [145,146]. In addition to PFTs, a high-resolution computed tomography (CT) is also recommended for evaluation [145]. These and other diagnostic testing for BOS are discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Evaluation for BO and BOS'.)

Long-term survival was initially poor [147] but is improving. Among patients with BOS, two to three-year overall survival ranges from 60 to 75 percent and five-year overall survival ranges from 40 to 50 percent [148]. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Prognosis'.)

Pulmonary hypertension — Though not as clearly established, there are emerging data that chest RT may be associated with pulmonary hypertension (HTN). Among 498 adult survivors of childhood cancer exposed to anthracyclines or chest RT, 15 percent had an increased tricuspid regurgitant jet velocity. Increased tricuspid regurgitant jet velocity was also present in 25.2 percent of patients exposed to chest RT, and 30.8 percent in patients who received doses greater than 30 gray (Gy). Survivors with increased tricuspid regurgitant jet velocity also had an odds ratio (OR) of 5.2 (95% CI 2.5-11.0) of being limited on a six-minute walk test compared with counterparts with a normal tricuspid regurgitant jet velocity [149]. These findings suggest the possibility of pulmonary vascular damage from chest RT. There are some data to suggest the utility of invasive hemodynamics in survivors with an increased tricuspid regurgitant velocity by echocardiography [150].

Although the incidence is unclear, pulmonary HTN has been reported in children and adults after HCT [151]. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Pulmonary vascular disease'.)

Several tyrosine kinase inhibitors (TKI) used in cancer treatment (eg, nilotinib, ponatinib, carfilzomib, ruxolinitib) are associated with pulmonary arterial HTN. Dasatinib has the strongest evidence for causing drug-induced pulmonary HTN [152]. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Dasatinib'.)

Secondary lung cancer — RT to the chest increases the risk of subsequent lung cancer. Among 64,782 breast cancer survivors who had surgery, at 10 to 14 years and >15 years from their initial diagnosis, patients who received RT were at a significantly higher relative risk (RR) of lung cancer than those who did not (RR 1.62, 95% CI 1.05-2.54 and RR 1.49, 95% CI 1.05-2.14, respectively) [153]. Other populations who receive chest RT appear to also be at risk; in another study of survivors of Hodgkin lymphoma, those treated with chest RT had an RR of 2.7 to 7 of developing lung cancer [154]. (See "Overview of cancer survivorship care for primary care and oncology providers", section on 'Screening for subsequent primary cancers'.)

Monitoring pulmonary function and follow-up — For patients suspected of having symptoms attributable to pulmonary toxicity, pulmonary function tests can be used to aid in the diagnosis of subclinical, asymptomatic disease.

In a study of 1713 survivors of childhood cancer, 65.2 percent (95% CI 60.4-69.8) had abnormal pulmonary function tests with the highest prevalence in those treated with lung RT (74.4 percent [95% CI 69.1-79.2], bleomycin (73.5 percent [95% CI 61.9-82.9], and thoracotomy (53.2 [95% CI 44.1-62]) [155].

In another study that included 220 five-year childhood cancer survivors who received potentially pulmonary toxic chemotherapy, 44 percent had abnormal pulmonary function tests at a median follow-up of 18 years. Restrictive lung disease and decreased carbon monoxide diffusion capacity were the most common abnormality [156].

Long-term follow-up with spirometry and questionnaires of 1049 testicular cancer survivors showed that 8 percent had restrictive lung disease. In this study, patients treated with a cumulative cisplatin dose greater than 850 mg and patients treated with cisplatin and pulmonary surgery had increased odds of developing restrictive lung disease compared with patients treated with surgery alone. Interestingly, of the patients diagnosed with restrictive lung disease, only 9.5 percent had self-reported dyspnea and 7.5 percent had prevalent asthma [157].

Despite the potential discrepancy between pulmonary function tests and overt clinical symptoms, early identification for pulmonary disease is important given it is a significant cause of mortality in adult survivors. In a CCSS which included 20,483 five-year survivors of childhood cancer, the cumulative mortality at 30 years from diagnosis was 18.1 percent (95% CI, 17.3-18.9) and survivors were 8.8 times more likely to die from a pulmonary cause [149].

SUMMARY

Radiation therapy and cardiovascular (CV) disease – Radiation therapy (RT) is associated with an increased risk of CV disease, including coronary atherosclerosis and carotid disease, as well as cardiac structural abnormalities such as valvular and pericardial disease. (See 'Effect of cancer therapy on atherosclerosis' above and 'Cardiac structural complications' above.)

Cancer therapy and hypertension (HTN) – Testicular cancer survivors have an increased risk of HTN, hyperlipidemia, coronary disease, and metabolic syndrome, as do prostate cancer patients undergoing long-term therapy with androgen deprivation therapy (ADT). (See 'Hypertension' above and 'Androgen deprivation therapy' above.)

Although vascular endothelial growth factor (VEGF) signaling pathway inhibitors (antiangiogenic therapy) are strongly associated with HTN and CV dysfunction during therapy, the long-term effects of these agents remain undefined. However, judicious blood pressure control and aggressive CV risk factor modification are important guiding principles. (See 'Targeted therapy' above and "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".)

Antihypertensive therapy is crucial to manage HTN during certain chemotherapy and those agents known to prevent heart failure (HF) are preferred. (See 'Management recommendations for cancer therapy-induced hypertension' above.)

Myocardial dysfunction – Several classes of chemotherapy agents used commonly are known to have myocardial dysfunction and HF as important consequences in a growing survivor population (anthracyclines, human epidermal growth factor receptor 2 [HER2] receptor antagonists). (See 'Effect of cancer therapy on cardiomyopathy' above and "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents".)

Prediction models for CV disease – Models have been developed to predict the risk of HF, ischemic heart disease, and stroke among survivors of childhood cancer. (See 'Cardiac risk factor prediction model' above and 'Heart failure risk calculator' above.)

Management of cardiac dysfunction – Once a patient develops cardiac dysfunction related to chemotherapy, appropriate HF-based therapy should be used promptly. Early discontinuation of cardioprotective HF therapy is not advised. (See 'Management of cardiac dysfunction and heart failure' above.)

Cancer therapy and pulmonary toxicity – Pulmonary effects of chemotherapy, chest RT, and hematopoietic cell transplant (HCT) can have an insidious onset and devastating consequences. Providers should be aware of conditions that can present years after cancer treatment and are associated with increased mortality. (See 'Pulmonary toxicity' above.)

Diagnostic evaluation can include pulmonary function tests, echocardiograms to assess pulmonary pressures, and chest radiographic imaging in patients who have been exposed to pulmonary toxic chemotherapy or chest RT. (See 'Monitoring pulmonary function and follow-up' above.)

Tobacco cessation – Cancer survivors who continue to smoke tobacco should be counseled to discontinue tobacco use, as smoking increases the risk of a second malignancy. (See "Treatment of alcohol use and smoking for cancer survivors" and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Screening for subsequent primary cancers'.)

Lifestyle modifications – Cancer survivors should also be counseled to engage in a daily exercise regimen to promote CV fitness as well as a heart-healthy diet. (See "The roles of diet, physical activity, and body weight in cancer survivors".)

  1. World Fact Sheet. International Agency for Research on Cancer. Available at: http://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.pdf (Accessed on March 14, 2019).
  2. Cancer Facts & Figures 2017. American Cancer Society. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf (Accessed on September 07, 2017).
  3. Strongman H, Gadd S, Matthews A, et al. Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases. Lancet 2019; 394:1041.
  4. Armenian SH, Xu L, Ky B, et al. Cardiovascular Disease Among Survivors of Adult-Onset Cancer: A Community-Based Retrospective Cohort Study. J Clin Oncol 2016; 34:1122.
  5. Bates JE, Howell RM, Liu Q, et al. Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study. J Clin Oncol 2019; 37:1090.
  6. van Laar M, Feltbower RG, Gale CP, et al. Cardiovascular sequelae in long-term survivors of young peoples' cancer: a linked cohort study. Br J Cancer 2014; 110:1338.
  7. Scholz-Kreisel P, Spix C, Blettner M, et al. Prevalence of cardiovascular late sequelae in long-term survivors of childhood cancer: A systematic review and meta-analysis. Pediatr Blood Cancer 2017; 64.
  8. Armstrong GT, Oeffinger KC, Chen Y, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 2013; 31:3673.
  9. Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25:3991.
  10. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013; 368:987.
  11. van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma. J Clin Oncol 2016; 34:235.
  12. Dubec JJ, Munk PL, Tsang V, et al. Carotid artery stenosis in patients who have undergone radiation therapy for head and neck malignancy. Br J Radiol 1998; 71:872.
  13. Steele SR, Martin MJ, Mullenix PS, et al. Focused high-risk population screening for carotid arterial stenosis after radiation therapy for head and neck cancer. Am J Surg 2004; 187:594.
  14. King LJ, Hasnain SN, Webb JA, et al. Asymptomatic carotid arterial disease in young patients following neck radiation therapy for Hodgkin lymphoma. Radiology 1999; 213:167.
  15. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures. J Clin Oncol 2017; 35:1171.
  16. Leerink JM, de Baat EC, Feijen EAM, et al. Cardiac Disease in Childhood Cancer Survivors: Risk Prediction, Prevention, and Surveillance: JACC CardioOncology State-of-the-Art Review. JACC CardioOncol 2020; 2:363.
  17. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015; 16:187.
  18. Wang K, Eblan MJ, Deal AM, et al. Cardiac Toxicity After Radiotherapy for Stage III Non-Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy. J Clin Oncol 2017; 35:1387.
  19. Protack CD, Bakken AM, Saad WE, et al. Radiation arteritis: a contraindication to carotid stenting? J Vasc Surg 2007; 45:110.
  20. Moritz MW, Higgins RF, Jacobs JR. Duplex imaging and incidence of carotid radiation injury after high-dose radiotherapy for tumors of the head and neck. Arch Surg 1990; 125:1181.
  21. Correa CR, Litt HI, Hwang WT, et al. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol 2007; 25:3031.
  22. Zagar TM, Marks LB. Breast cancer radiotherapy and coronary artery stenosis: location, location, location. J Clin Oncol 2012; 30:350.
  23. Nilsson G, Holmberg L, Garmo H, et al. Distribution of coronary artery stenosis after radiation for breast cancer. J Clin Oncol 2012; 30:380.
  24. Witteles RM. Radiation therapy for breast cancer: buyer beware. J Am Coll Cardiol 2011; 57:453.
  25. Ganatra S, Chatur S, Nohria A. How to Diagnose and Manage Radiation Cardiotoxicity. JACC CardioOncol 2020; 2:655.
  26. Jones LW, Haykowsky MJ, Swartz JJ, et al. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 2007; 50:1435.
  27. Alfano CM, Ganz PA, Rowland JH, Hahn EE. Cancer survivorship and cancer rehabilitation: revitalizing the link. J Clin Oncol 2012; 30:904.
  28. McCullough LE, Eng SM, Bradshaw PT, et al. Fat or fit: the joint effects of physical activity, weight gain, and body size on breast cancer risk. Cancer 2012; 118:4860.
  29. Collier A, Ghosh S, McGlynn B, Hollins G. Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review. Am J Clin Oncol 2012; 35:504.
  30. Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007; 110:1493.
  31. Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011; 306:2359.
  32. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2020; 382:2197.
  33. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2019; 37:2974.
  34. Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med 2020; 382:2187.
  35. Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation 2010; 121:833.
  36. Bhatia N, Santos M, Jones LW, et al. Cardiovascular Effects of Androgen Deprivation Therapy for the Treatment of Prostate Cancer: ABCDE Steps to Reduce Cardiovascular Disease in Patients With Prostate Cancer. Circulation 2016; 133:537.
  37. Margel D, Peer A, Ber Y, et al. Cardiovascular Morbidity in a Randomized Trial Comparing GnRH Agonist and GnRH Antagonist among Patients with Advanced Prostate Cancer and Preexisting Cardiovascular Disease. J Urol 2019; 202:1199.
  38. Gong J, Payne D, Caron J, et al. Reduced Cardiorespiratory Fitness and Increased Cardiovascular Mortality After Prolonged Androgen Deprivation Therapy for Prostate Cancer. JACC CardioOncol 2020; 2:553.
  39. Troeschel AN, Hartman TJ, Jacobs EJ, et al. Postdiagnosis Body Mass Index, Weight Change, and Mortality From Prostate Cancer, Cardiovascular Disease, and All Causes Among Survivors of Nonmetastatic Prostate Cancer. J Clin Oncol 2020; 38:2018.
  40. Narayan V, Ky B. Common Cardiovascular Complications of Cancer Therapy: Epidemiology, Risk Prediction, and Prevention. Annu Rev Med 2018; 69:97.
  41. Sun L, Parikh RB, Hubbard RA, et al. Assessment and Management of Cardiovascular Risk Factors Among US Veterans With Prostate Cancer. JAMA Netw Open 2021; 4:e210070.
  42. Mulrooney DA, Armstrong GT, Huang S, et al. Cardiac Outcomes in Adult Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy: A Cross-sectional Study. Ann Intern Med 2016; 164:93.
  43. van der Pal HJ, van Dalen EC, van Delden E, et al. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 2012; 30:1429.
  44. Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation 2013; 128:1927.
  45. Haddy N, Diallo S, El-Fayech C, et al. Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study. Circulation 2016; 133:31.
  46. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355:1572.
  47. Mueller S, Kline CN, Buerki RA, et al. Stroke impact on mortality and psychologic morbidity within the Childhood Cancer Survivor Study. Cancer 2020; 126:1051.
  48. Suh E, Stratton KL, Leisenring WM, et al. Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol 2020; 21:421.
  49. Schindera C, Zürcher SJ, Jung R, et al. Physical fitness and modifiable cardiovascular disease risk factors in survivors of childhood cancer: A report from the SURfit study. Cancer 2021; 127:1690.
  50. Chen Y, Chow EJ, Oeffinger KC, et al. Traditional Cardiovascular Risk Factors and Individual Prediction of Cardiovascular Events in Childhood Cancer Survivors. J Natl Cancer Inst 2020; 112:256.
  51. Chow EJ, Chen Y, Hudson MM, et al. Prediction of Ischemic Heart Disease and Stroke in Survivors of Childhood Cancer. J Clin Oncol 2018; 36:44.
  52. Mulrooney DA, Hyun G, Ness KK, et al. Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort. BMJ 2020; 368:l6794.
  53. Kooijmans EC, Bökenkamp A, Tjahjadi NS, et al. Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer. Cochrane Database Syst Rev 2019; 3:CD008944.
  54. Travis LB, Beard C, Allan JM, et al. Testicular cancer survivorship: research strategies and recommendations. J Natl Cancer Inst 2010; 102:1114.
  55. Tothill P, Klys HS, Matheson LM, et al. The long-term retention of platinum in human tissues following the administration of cisplatin or carboplatin for cancer chemotherapy. Eur J Cancer 1992; 28A:1358.
  56. Gietema JA, Meinardi MT, Messerschmidt J, et al. Circulating plasma platinum more than 10 years after cisplatin treatment for testicular cancer. Lancet 2000; 355:1075.
  57. Kirchmair R, Walter DH, Ii M, et al. Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. Circulation 2005; 111:2662.
  58. Jansson T, Persson E. Placental transfer of glucose and amino acids in intrauterine growth retardation: studies with substrate analogs in the awake guinea pig. Pediatr Res 1990; 28:203.
  59. El-Awady el-SE, Moustafa YM, Abo-Elmatty DM, Radwan A. Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies. Eur J Pharmacol 2011; 650:335.
  60. Sagstuen H, Aass N, Fosså SD, et al. Blood pressure and body mass index in long-term survivors of testicular cancer. J Clin Oncol 2005; 23:4980.
  61. Haugnes HS, Wethal T, Aass N, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol 2010; 28:4649.
  62. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008; 26:5204.
  63. Mellor HR, Bell AR, Valentin JP, Roberts RR. Cardiotoxicity associated with targeting kinase pathways in cancer. Toxicol Sci 2011; 120:14.
  64. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 2007; 370:2011.
  65. Girardi F, Franceschi E, Brandes AA. Cardiovascular safety of VEGF-targeting therapies: current evidence and handling strategies. Oncologist 2010; 15:683.
  66. Di Lorenzo G, Autorino R, Bruni G, et al. Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol 2009; 20:1535.
  67. Cohen JB, Geara AS, Hogan JJ, Townsend RR. Hypertension in Cancer Patients and Survivors: Epidemiology, Diagnosis, and Management. JACC CardioOncol 2019; 1:238.
  68. Abdel-Qadir H, Ethier JL, Lee DS, et al. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis. Cancer Treat Rev 2017; 53:120.
  69. Totzeck M, Mincu RI, Mrotzek S, et al. Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: A meta-analysis of approximately 29,000 cancer patients. Eur J Prev Cardiol 2018; 25:482.
  70. Waliany S, Sainani KL, Park LS, et al. Increase in Blood Pressure Associated With Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor. JACC CardioOncol 2019; 1:24.
  71. Sapkota Y, Li N, Pierzynski J, et al. Contribution of Polygenic Risk to Hypertension Among Long-Term Survivors of Childhood Cancer. JACC CardioOncol 2021; 3:76.
  72. Simon MS, Hastert TA, Barac A, et al. Cardiometabolic risk factors and survival after cancer in the Women's Health Initiative. Cancer 2021; 127:598.
  73. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311:507.
  74. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017; 70:252.
  75. Amir E, Seruga B, Niraula S, et al. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst 2011; 103:1299.
  76. Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol 2013; 31:1398.
  77. McCloskey EV, Hannon RA, Lakner G, et al. Effects of third generation aromatase inhibitors on bone health and other safety parameters: results of an open, randomised, multi-centre study of letrozole, exemestane and anastrozole in healthy postmenopausal women. Eur J Cancer 2007; 43:2523.
  78. Blaser BW, Kim HT, Alyea EP 3rd, et al. Hyperlipidemia and statin use after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012; 18:575.
  79. Kagoya Y, Seo S, Nannya Y, Kurokawa M. Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on prognosis. Clin Transplant 2012; 26:E168.
  80. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002; 87:599.
  81. Kintzel PE, Chase SL, Schultz LM, O'Rourke TJ. Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Pharmacotherapy 2008; 28:1511.
  82. Children's Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, Version 3.0, 2008. http://www.survivorshipguidelines.org/pdf/XRT%20Reference%20Guide%20v3.0.pdf (Accessed on March 07, 2014).
  83. Armenian SH, Lacchetti C, Barac A, et al. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017; 35:893.
  84. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines:  The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37:2768.
  85. Curigliano G, Lenihan D, Fradley M, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol 2020; 31:171.
  86. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009; 339:b4606.
  87. Armstrong GT, Joshi VM, Ness KK, et al. Comprehensive Echocardiographic Detection of Treatment-Related Cardiac Dysfunction in Adult Survivors of Childhood Cancer: Results From the St. Jude Lifetime Cohort Study. J Am Coll Cardiol 2015; 65:2511.
  88. Narayan HK, Finkelman B, French B, et al. Detailed Echocardiographic Phenotyping in Breast Cancer Patients: Associations With Ejection Fraction Decline, Recovery, and Heart Failure Symptoms Over 3 Years of Follow-Up. Circulation 2017; 135:1397.
  89. Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy. JAMA 2003; 290:2831.
  90. Heidenreich PA, Hancock SL, Lee BK, et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol 2003; 42:743.
  91. van der Pal HJ, van Dijk IW, Geskus RB, et al. Valvular abnormalities detected by echocardiography in 5-year survivors of childhood cancer: a long-term follow-up study. Int J Radiat Oncol Biol Phys 2015; 91:213.
  92. American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance American College of Chest Physicians. J Am Soc Echocardiogr 2011; 24:229.
  93. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63:e57.
  94. Galper SL, Yu JB, Mauch PM, et al. Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 2011; 117:412.
  95. Bijl JM, Roos MM, van Leeuwen-Segarceanu EM, et al. Assessment of Valvular Disorders in Survivors of Hodgkin's Lymphoma Treated by Mediastinal Radiotherapy ± Chemotherapy. Am J Cardiol 2016; 117:691.
  96. Maisch B, Ristic A, Pankuweit S. Evaluation and management of pericardial effusion in patients with neoplastic disease. Prog Cardiovasc Dis 2010; 53:157.
  97. Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 2004; 109:3122.
  98. Little WC, Freeman GL. Pericardial disease. Circulation 2006; 113:1622.
  99. Khandaker MH, Espinosa RE, Nishimura RA, et al. Pericardial disease: diagnosis and management. Mayo Clin Proc 2010; 85:572.
  100. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 2004; 22:3139.
  101. Jefferies JL, Mazur WM, Howell CR, et al. Cardiac remodeling after anthracycline and radiotherapy exposure in adult survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study. Cancer 2021; 127:4646.
  102. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000; 342:1077.
  103. Leerink JM, van der Pal HJH, Kremer LCM, et al. Refining the 10-Year Prediction of Left Ventricular Systolic Dysfunction in Long-Term Survivors of Childhood Cancer. JACC CardioOncol 2021; 3:62.
  104. Chellapandian D, Pole JD, Nathan PC, Sung L. Congestive heart failure among children with acute leukemia: a population-based matched cohort study. Leuk Lymphoma 2019; 60:385.
  105. Feijen EAML, Font-Gonzalez A, Van der Pal HJH, et al. Risk and Temporal Changes of Heart Failure Among 5-Year Childhood Cancer Survivors: a DCOG-LATER Study. J Am Heart Assoc 2019; 8:e009122.
  106. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015; 131:1981.
  107. Feijen EAM, Leisenring WM, Stratton KL, et al. Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. JAMA Oncol 2019; 5:864.
  108. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97:2869.
  109. Upshaw JN, Finkelman B, Hubbard RA, et al. Comprehensive Assessment of Changes in Left Ventricular Diastolic Function With Contemporary Breast Cancer Therapy. JACC Cardiovasc Imaging 2020; 13:198.
  110. Bhatia S. Genetics of Anthracycline Cardiomyopathy in Cancer Survivors: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2020; 2:539.
  111. Blanco JG, Sun CL, Landier W, et al. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group. J Clin Oncol 2012; 30:1415.
  112. Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, et al. Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy. Circulation 2019; 140:31.
  113. Saiki H, Petersen IA, Scott CG, et al. Risk of Heart Failure With Preserved Ejection Fraction in Older Women After Contemporary Radiotherapy for Breast Cancer. Circulation 2017; 135:1388.
  114. Myrehaug S, Pintilie M, Tsang R, et al. Cardiac morbidity following modern treatment for Hodgkin lymphoma: supra-additive cardiotoxicity of doxorubicin and radiation therapy. Leuk Lymphoma 2008; 49:1486.
  115. Narayan V, Keefe S, Haas N, et al. Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma. Clin Cancer Res 2017; 23:3601.
  116. Tukenova M, Guibout C, Oberlin O, et al. Role of cancer treatment in long-term overall and cardiovascular mortality after childhood cancer. J Clin Oncol 2010; 28:1308.
  117. Border WL, Sachdeva R, Stratton KL, et al. Longitudinal Changes in Echocardiographic Parameters of Cardiac Function in Pediatric Cancer Survivors. JACC CardioOncol 2020; 2:26.
  118. Chow EJ, Chen Y, Kremer LC, et al. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol 2015; 33:394.
  119. Dietz AC, Seidel K, Leisenring WM, et al. Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study. Lancet Oncol 2019; 20:1420.
  120. Armenian SH, Hudson MM, Mulder RL, et al. Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 2015; 16:e123.
  121. Ehrhardt MJ, Ward ZJ, Liu Q, et al. Cost-Effectiveness of the International Late Effects of Childhood Cancer Guideline Harmonization Group Screening Guidelines to Prevent Heart Failure in Survivors of Childhood Cancer. J Clin Oncol 2020; 38:3851.
  122. Vaduganathan M, Hirji SA, Qamar A, et al. Efficacy of Neurohormonal Therapies in Preventing Cardiotoxicity in Patients with Cancer Undergoing Chemotherapy. JACC CardioOncol 2019; 1:54.
  123. Jessup M, Abraham WT, Casey DE, et al. 2009 focused update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119:1977.
  124. Ewer MS, Von Hoff DD, Benjamin RS. A historical perspective of anthracycline cardiotoxicity. Heart Fail Clin 2011; 7:363.
  125. Noori A, Lindenfeld J, Wolfel E, et al. Beta-blockade in adriamycin-induced cardiomyopathy. J Card Fail 2000; 6:115.
  126. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol 2010; 55:213.
  127. Dixon SB, Howell CR, Lu L, et al. Cardiac biomarkers and association with subsequent cardiomyopathy and mortality among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. Cancer 2021; 127:458.
  128. Cardinale D, Colombo A, Sandri MT, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006; 114:2474.
  129. Cardinale D, Colombo A, Cipolla CM. Prevention and treatment of cardiomyopathy and heart failure in patients receiving cancer chemotherapy. Curr Treat Options Cardiovasc Med 2008; 10:486.
  130. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 2005; 23:7820.
  131. Telli ML, Hunt SA, Carlson RW, Guardino AE. Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 2007; 25:3525.
  132. Nishino M, Sholl LM, Hodi FS, et al. Anti-PD-1-Related Pneumonitis during Cancer Immunotherapy. N Engl J Med 2015; 373:288.
  133. Haustraete E, Obert J, Diab S, et al. Idelalisib-related pneumonitis. Eur Respir J 2016; 47:1280.
  134. Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001; 120:617.
  135. Fosså SD, Gilbert E, Dores GM, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 2007; 99:533.
  136. White DA, Stover DE. Severe bleomycin-induced pneumonitis. Clinical features and response to corticosteroids. Chest 1984; 86:723.
  137. Uzel I, Ozguroglu M, Uzel B, et al. Delayed onset bleomycin-induced pneumonitis. Urology 2005; 66:195.
  138. Maher J, Daly PA. Severe bleomycin lung toxicity: reversal with high dose corticosteroids. Thorax 1993; 48:92.
  139. Abid SH, Malhotra V, Perry MC. Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol 2001; 13:242.
  140. Lohani S, O'Driscoll BR, Woodcock AA. 25-year study of lung fibrosis following carmustine therapy for brain tumor in childhood. Chest 2004; 126:1007.
  141. Williams JP, Johnston CJ, Finkelstein JN. Treatment for radiation-induced pulmonary late effects: spoiled for choice or looking in the wrong direction? Curr Drug Targets 2010; 11:1386.
  142. Mertens AC, Yasui Y, Liu Y, et al. Pulmonary complications in survivors of childhood and adolescent cancer. A report from the Childhood Cancer Survivor Study. Cancer 2002; 95:2431.
  143. Patriarca F, Skert C, Bonifazi F, et al. Effect on survival of the development of late-onset non-infectious pulmonary complications after stem cell transplantation. Haematologica 2006; 91:1268.
  144. Williams KM, Chien JW, Gladwin MT, Pavletic SZ. Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. JAMA 2009; 302:306.
  145. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21:389.
  146. Hildebrandt GC, Fazekas T, Lawitschka A, et al. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant 2011; 46:1283.
  147. Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant 2003; 9:657.
  148. Williams KM. How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Blood 2017; 129:448.
  149. Armstrong GT, Liu Q, Yasui Y, et al. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol 2009; 27:2328.
  150. Armstrong GT, Tolle JJ, Piana R, et al. Exercise right heart catheterization for pulmonary hypertension identified on screening echocardiography in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. Pediatr Blood Cancer 2018; 65.
  151. Dandoy CE, Hirsch R, Chima R, et al. Pulmonary hypertension after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19:1546.
  152. McGee M, Whitehead N, Martin J, Collins N. Drug-associated pulmonary arterial hypertension. Clin Toxicol (Phila) 2018; 56:801.
  153. Roychoudhuri R, Evans H, Robinson D, Møller H. Radiation-induced malignancies following radiotherapy for breast cancer. Br J Cancer 2004; 91:868.
  154. Lorigan P, Radford J, Howell A, Thatcher N. Lung cancer after treatment for Hodgkin's lymphoma: a systematic review. Lancet Oncol 2005; 6:773.
  155. Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 2013; 309:2371.
  156. Mulder RL, Thönissen NM, van der Pal HJ, et al. Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer. Thorax 2011; 66:1065.
  157. Haugnes HS, Aass N, Fosså SD, et al. Pulmonary function in long-term survivors of testicular cancer. J Clin Oncol 2009; 27:2779.
Topic 17017 Version 33.0

References