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 — Childhood cancer survivors are at increased risk of cardiovascular disease [16,42,43]. On average, survivors of childhood cancer have a greater than 10-fold risk of ischemic heart disease and stroke compared with siblings [8,44]. This risk can persist for at least four decades after treatment completion [5].
Cardiovascular disease is also a leading contributor to morbidity and mortality in survivors of childhood cancer [44-51]. In an observational study from the Childhood Cancer Survivor Study Cohort (CCSS) of 34,230 childhood cancer survivors, the 40-year cumulative all-cause mortality was 23 percent, over half of which were due to health-related causes [51]. Cancer survivors 40 years or more from diagnosis had 131 excess health-related deaths per 10,000-person years, with heart disease and cerebrovascular disease (absolute excess risk of 27 and 10 per 10,000-person years, respectively) among the most common causes. Cancer survivors were also at significantly increased risk of death due to heart disease (standardized mortality ratio [SMR] 4.3) and cerebrovascular disease (SMR 5.1) compared with the general population. Notably, healthy lifestyle and absence of hypertension and diabetes were associated with reduced health-related mortality. These data suggest the importance of long-term surveillance, recognition, and treatment of cardiovascular disease in childhood cancer survivors as they transition into adults. (See 'Surveillance guidelines for cardiovascular disease' below.)
Long-term follow-up studies in cohorts of childhood cancer survivors have led to the development of cardiac risk calculators as well as surveillance guidelines for cardiac disease [52]. These studies also support advances in cancer treatment that limit cardiotoxicity, such as RT techniques that reduce cardiac radiation exposure [5,53].
Cardiac risk factor prediction model — Cardiac risk factor prediction models are available that have been validated in cancer survivors [43,54]. As an example, one 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 CV risk calculator for the prediction of heart failure (HF), ischemic heart disease, and stroke is available online.
This cardiac risk factor prediction model was based on 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 [43]. Ischemic heart disease and stroke occurred in 265 (2 percent) and 295 (2.25 percent), respectively; the risk could be predicted based on clinical factors that were available at the end of treatment. 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. By contrast, the cumulative incidence was only 1 percent for controls not treated for a childhood cancer (siblings).
Surveillance guidelines for cardiovascular 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.
Cancer survivors should also be screened for cardiovascular disease by reviewing available computed tomography (CT) chest imaging (eg, studies previously performed for cancer staging or surveillance) for calcifications in any coronary or vascular bed exposed to RT. For patients with such calcifications, a coronary artery calcium score (CAC) can be obtained to screen for high-risk coronary artery disease [55]. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)
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 [56]. 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 [57-59]. At the vascular level, cisplatin appears to abolish capillary beds [60]. Furthermore, animals treated with cisplatin demonstrate increased levels of TNF alpha and multiple cytokines [61] and markers of oxidative stress [62]. 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 [63,64]. 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 [63]:
•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) [64].
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 [65-69]. 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 [70]. However, the long-term effects on blood pressure and the vasculature are unknown. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", 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 [71].
●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) [72].
●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 [73].
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. Nevertheless, cancer survivors are at risk for undertreatment of HTN, along with other modifiable CV risk factors [74]. 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 [75].
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 [76]. 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 [77]. 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 [78]. (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 [70].
●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 [70]. 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 [70]. 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 [70]. (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 [79-81]. 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 [79].
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 [80]. (See "Adjuvant endocrine and targeted 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 [82]. 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 [83].
●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 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 [64]. 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 [84], and alterations in insulin sensitivity [85]. 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 [85]. (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 [86]. For patients who experience issues related to structural damage to the heart, close monitoring is essential [87]. 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) [88]. 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 [89]. The European Society of Medical Oncology also provided a consensus document for the management of CV disease throughout the spectrum of cancer treatment [90].
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 [91]. 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 [45]. 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 [92]. 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 [93].
Valvular degeneration and calcification — Valvular issues resulting in stenosis and/or regurgitation are established long-term consequences of mediastinal radiation [94-96]. (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 "Rheumatic mitral stenosis: Clinical manifestations and diagnosis" 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 [78,97,98]. 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 [45]. 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 [94]. 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 [99].
●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 [100].
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 [101]. 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 [102]. 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 [103,104]. (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 [99,105]. 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 'Arrhythmias'.)
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 — Cancer survivors are at higher risk of myocardial (cardiac) dysfunction, cardiomyopathy, and heart failure (HF) compared with populations without cancer [3,106-108]. These conditions are typically late effects of cancer therapy from both solid and hematologic malignancies [3]. Cancer survivors who develop cardiomyopathy or HF are at risk for significant morbidity and mortality [46,109,110]. Therefore, it is important to detect cardiac dysfunction early and provide cardiac-specific therapy to prevent progression [111,112].
The American College of Cardiology and American Heart Association (ACC/AHA) classify patients who have received cardiotoxic chemotherapy as having stage A HF [78]. (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 [88]. (See "Cardiotoxicity of radiation therapy for Hodgkin lymphoma and pediatric malignancies", section on 'Heart failure' and "Risk and prevention of anthracycline cardiotoxicity".)
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 [53,113-115]. In childhood cancer survivors, anthracyclines can lead to congestive HF, one of the most common late cardiac effects in this population [115]. (See 'Childhood cancer survivors' below.)
Data suggest that cardiotoxicity may occur in the first one to two years post-anthracycline exposure [93,116].
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 [117]. 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 [115].
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 of doxorubicin) induce cardiotoxicity [45,91]. 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 [118]. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Cumulative dose'.)
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) [93], as well as persistent worsening in diastolic function [119].
Genetic variation also contributes significantly to chemotherapy-related cardiotoxicity and can modify the relationship between anthracycline dose and cardiotoxicity risk. Data suggest a genetic basis for anthracycline-mediated cardiac dysfunction across multiple patient populations, including those with childhood cancer, survivors of childhood cancer [120-122], adult-onset cancer, and across the age spectrum [123,124]. Further details on pathogenic variants associated with anthracycline-induced cardiotoxicity are discussed separately. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Other factors' and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)
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 – Patients with RT exposure to myocardial tissues are at increased risk of HF with preserved ejection fraction and restrictive cardiomyopathy. (See "Pathophysiology of heart failure with preserved ejection fraction", section on 'Myocardial ischemia' and "Restrictive cardiomyopathies", section on 'Etiology'.)
Further details on the cardiotoxicities of RT in patient with cancer are discussed separately. (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 [125]. (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 "Risk and prevention of anthracycline cardiotoxicity", section on 'Combined treatment with other cancer therapies'.)
●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 [126]. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Left ventricular dysfunction and myocardial ischemia'.)
●Immune checkpoint inhibitors – Immune checkpoint inhibitors, or immunotherapy, can be associated with cardiovascular toxicity, including myocarditis and HF. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Cardiovascular toxicity'.)
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 [8,44,47,127]. 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 [128].
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 [5,129].
●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 [130]. 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 [131]; the risk could be predicted based on factors that were available at the end of treatment, including cumulative anthracycline exposure and cardiac RT dose. (See 'Heart failure risk calculator' below.)
●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 [115].
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 [130]. 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 [113]. 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 [113]. 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 mildly reduced 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 [132,133].
Prevention of cardiac dysfunction and heart failure — In patients receiving anthracyclines, various cardioprotective measures may be used to prevent long-term cardiac dysfunction such as dexrazoxane [134,135], 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 "Risk and prevention of anthracycline cardiotoxicity", section on 'Primary prevention with cardiovascular drugs'.)
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 [136]. Further prospective studies and randomized clinical trials of prophylactic cardioprotective strategies in cancer patients are necessary [137]. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Approaches to cardiotoxicity mitigation'.)
Management of cardiac dysfunction and heart failure — While cardiotoxicity related to anthracyclines was previously thought to be completely irreversible [138], contemporary data suggest that early identification of cardiotoxicity and prompt therapy for HF can lead to substantial improvement in LVEF to even normal levels [139,140]. 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 [140]. 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 [116].
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 [141]. In addition, the optimization of cardioprotective medications may help prevent or ameliorate damage that may occur during cancer treatment [142,143]. 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 [89]. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Risk and prevention of anthracycline cardiotoxicity", section on 'Preventive management of anthracycline therapy' and "Risk and prevention of anthracycline cardiotoxicity", section on 'Approaches to cardiotoxicity mitigation'.)
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 [144]. However, it is not always reversible, and useful clinical factors to predict the risk of serious HF have not been elucidated [145].
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 "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
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 [146]. Pneumonitis has been also reported with other agents, such as those targeting the mTOR pathway [147]. 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 [148]. 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 [149]. Late onset BIP typically develops more than six months after treatment [150,151], presenting as a nonproductive cough, dyspnea, tachypnea, fever, and cyanosis. Radiographic imaging demonstrates variable findings but can show bilateral bibasilar infiltrates [148]. Patients with BIP tend to respond to corticosteroids [150,152]. (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 [153]. Again, common symptoms include dyspnea, hypoxia, nonproductive cough, and fever. Radiographic imaging tends to show changes confined to the outlines of radiation fields [153]. 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 [154]. (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 [155]. 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 [156]. (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) [157]. (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 [158]. 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 [159]. 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 [159,160]. In addition to PFTs, a high-resolution computed tomography (CT) is also recommended for evaluation [159]. These and other diagnostic testing for BOS are discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Evaluation for CLAD'.)
Long-term survival was initially poor [161] 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 [162]. (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 [163]. 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 [164].
Although the incidence is unclear, pulmonary HTN has been reported in children and adults after HCT [165]. (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, ruxolitinib) are associated with pulmonary arterial HTN. Dasatinib has the strongest evidence for causing drug-induced pulmonary HTN [166]. (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) [167]. 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 [168]. (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]) [169].
●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 [170].
●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 [171].
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 [163].
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 "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
•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, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention 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.)
●Surveillance guidelines for cardiovascular disease and cardiomyopathy – There are available surveillance guidelines for cardiovascular disease and cardiomyopathy in childhood, adolescent, and young adult cancer survivors. (See 'Surveillance guidelines for cardiovascular disease' above and 'Surveillance guidelines for myocardial dysfunction' 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".)
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