Overview
The last 40 years have brought us to an 80% five-year-survival rate for childhood cancers (diagnosed prior to age 21).1-3 Despite the welcome news, survival rate among long-term survivors falls short of gender-matched population controls, most likely because 40% of those who survive over 30 years have serious or life-threatening medical issues.1-3 Cardiovascular [CV] complications—congestive heart failure [CHF] in particular—are leading causes of death in long-term survivors of childhood cancer.1-3 Many survivors develop cardiomyopathy, which leads to CHF, a progressive “late effect” (see Box 1) of both radiation and anthracycline cancer treatments.1-3
Clinical Significance
Sixty percent of childhood cancer survivors received anthracycline chemotherapy and/or radiation therapy [RT], treatments that cure cancer but damage the heart.2 Following treatments, the risk for cardiac complications increases with each year of survival.1-3 Cardiotoxicity often goes unrecognized because cardiovascular professionals lack training in the field of cardio-oncology and survivors may be asymptomatic for years.4 Data Chow et al3 studied revealed a significant number of CHF events occurred within five to 15 years of diagnosis. Often physicians and nurses don’t obtain a person’s childhood cancer treatment history; even when they do, they underestimate its significance.1 As a result, they miss the connection between a cardiac event and the survivor’s treatment history and misidentify the cause of the event.1 Another point to consider is patients in this long-term survivor population may present with non-cardiac medical problems that require aggressive hydration, such as sepsis and dehydration. They might spend time in emergency and surgical units, where they receive IV fluids and blood transfusions. If clinicians don’t consider prior cancer-treatment histories, they risk throwing these patients over the “fluid cliff,” subjecting them to pulmonary edema or even death.
Late Cardiac Effects
Anthracycline chemotherapy agents, such as doxorubicin, epirubicin, and daunorubicin, cause “progressive and irreversible” cardiomyopathy, the severity and risk of which depends on cumulative treatment doses, “patient-related risk factors” —age, gender, genetics—and the usual culprits of CV risk: diabetes, hypertension, smoking, etc.1-4 Radiation therapy worsens the toxic cardiac effects of anthracycline; when used together, the patient’s risk for heart failure and cardiac morbidity increases.1-2 According to Chen et al,1 given to a person whose baseline heart condition is normal, anthracycline affects cardiomyocytes and endothelial cells. Damage to the former thins the heart wall thus increasing the stress on it; damage to the latter decreases heart contractility. Given to a person with existing cardiac stress or injury, anthracycline assaults fibroblasts and progenitor cells, hindering the heart’s ability to recover from stressors or injuries. Heart biopsy specimens reveal cell loss, compensatory hypertrophy, and interstitial fibrosis. Cardiomyopathy associated with anthracycline toxicity tends to be dilated, with mainly systolic dysfunction and decreased left ventricular ejection fraction [LVEF], a condition that predisposes survivors to heart failure.1-2
Radiation directly damages heart muscle, valves, and coronary arteries; >20 years after treatment, 60% Hodgkin Lymphoma survivors treated with it manifest moderate to severe valvular dysfunction.1 Traditional CV risk factors present at the time of treatment could make the heart more susceptible to RT damage. Endothelial-cell damage possibly compromises arterial functioning; the mechanism of valvular dysfunction hasn’t been pinpointed.1 Altered ventricular structure and cardiac functioning secondary to RT is possibly due to arterial stenosis, progressive deterioration of valvular function, or constrictive pericarditis.2 Restrictive cardiomyopathy leads to mainly diastolic dysfunction with normal to mildly decreased LVEF.1 While RT primarily causes restrictive cardiomyopathy, radiation-induced fibrosis of the heart’s vasculature can add an element of dilated cardiomyopathy.2
Detection and Treatment
The International Late Effects of Childhood Cancer Guideline Harmonization Group—an international collaboration of oncology professionals—established evidenced-based, clinical-practice guidelines using standardized definitions2 (Table 1) to help detect and treat asymptomatic cardiomyopathy in survivors of childhood cancer and young adult cancer.
Table1. Standardized Definitions by Harmonization Group
| Term | Standardized Definition |
|---|---|
| childhood cancer survivor | individuals treated for cancer up to 21 years of age, regardless of current age |
| anthracycline chemotherapy | doxorubicin, daunorubicin, epirubicin, idarubicin; anthraquinone mitoxantrone (included because of its similar cardiotoxic nature) |
| chest radiation | any radiation field in which the heart is situated: mediastinal, thoracic, spinal, left or whole upper abdominal, or total body |
| asymptomatic cardiomyopathy | decline in left ventricular systolic function or diastolic dysfunction in the presence of preserved ejection fraction;no associated heart failure symptoms |
| CHF | defineda per American College of Cardiology [ACC]/American Heart Association [AHA] guidelines; correlated with symptomatic cardiomyopathy evidenced by imaging studies reflecting cardiac dysfunction |
aACC/AHA description of heart failure per Armenian et al2: “a progressive disorder, with a variable period of asymptomatic cardiac dysfunction which precedes clinically overt signs and symptoms.”
Armenian et al2 list the harmonized recommendations for cardiomyopathy surveillance in their entirety. Each recommendation comes with varying degrees of certainty, based on evidence quality. Strong recommendations (Table 2) are supported by “high quality evidence.”
Table 2. Strong Cardiomyopathy Surveillance Recommendations with High-Quality Evidence
| General Recommendations | Survivors treated w/ anthracyclines and/or chest radiation, as well as their healthcare providers, need to be aware of cardiomyopathy risk. |
| Identified as needing cardiomyopathy surveillance: | |
| Patients treated w/ anthracyclines | Survivors treated with high dose (≥250 mg/m2) anthracyclines need cardiomyopathy surveillance. |
| Patients treated w/ chest radiation | Survivors treated with high dose (≥35 Gy) chest radiation need cardiomyopathy surveillance. |
| Patients treated w/ anthracyclines + chest radiation | Survivors treated with moderate to high dose anthracyclines (≥100 mg/m2) and moderate to high dose chest radiation (≥15 Gy) need cardiomyopathy surveillance. |
| Surveillance modality | Echocardiography is primarily recommended for assessing left ventricular systolic function in survivors treated with anthracyclines or chest radiation. |
| When do high risk survivors need surveillance? | Begin no later than 2 years after finishing cardiotoxic therapy; repeat 5 years after diagnosis; continue every 5 years following that. |
| Recommended action when abnormalities are identified | Survivors with asymptomatic cardiomyopathy should see a cardiologist following treatment with anthracyclines or chest radiation. |
| Advice regarding physical activity and modifiable cardiovascular risk factors | Survivors who had anthracylines or radiation and have normal left ventricular systolic function: regular exercise per AHA & European Society of Cardiology [ESC] guidelines may reap benefits. Cardiology consultation is recommended for survivors with asymptomatic cardiomyopathy—discuss with cardiologist limits and precautions for exercise. |
Prevention
Prevention of long-term CV disease in cancer survivors focuses on modifying cancer treatments at the time of their delivery: reducing chemotherapy dose and limiting the radiation-portal size.1 More studies are needed to establish the efficacy of cardioprotective drugs, such as dexrazo-xane.2 Respiratory maneuvers during RT possibly reduce RT damage to the heart because anatomical changes due to inspiration move the heart away from the left breast,1 but the measure is not effective for all chest RT fields. Several large cancer centers have comprehensive cardio-oncology programs that aim to prevent, screen, and treat the cardiovascular effects of cancer treatments while providing “comprehensive [cardiovascular] care for current cancer patients and cancer survivors.4”Vital to to developing preventative strategies, Chen et al1 assert, is a “[g]reater understanding of mechanisms of late cardiovascular effects,” wisdom further research could unveil.
Childhood cancer survivors have an increased risk for modifiable cardiovascular risk factors, two of which can exacerbate the effects of anthracycline and radiation therapy: diabetes and hypertension.1-2 Therefore, health care providers should educate this patient population about how to live a heart-healthy lifestyle, including eating “five servings of fresh fruits and vegetables per day”2 and exercising per AHA and ESC recommendations. (See Table 2, physical activity advice.) As evidenced in studies of non-cancer populations, people reduce their risk for CV problems when they decrease modifiable risk factors, such as smoking, diabetes, and dyslipidemia.2
Fluid Replacement: Take a Cautious Approach
Patients at risk for CHF require diligent assessment when receiving intravenous fluids. Take a patient’s cancer-treatment history, and note other cardiac risk factors. Establish a baseline: assess childhood cancer survivors before administering IV fluids whenever possible, checking breath and heart sounds, vital signs, and oxygen saturation. Look for signs of heart failure (which may or may not be present, even in the presence of CHF5): orthopnea, dyspnea, tachypnea, tachycardia (or palpitations), decreased activity tolerance/shortness of breath, edema of feet/ankles, crackles (rales) upon auscultation of breath sounds, S3 heart sound, and jugular-vein distension.2,5 While administering fluids intravenously, monitor fluid intake and output, periodically reassessing the patient. Validate subjective complaints with objective clues evidencing hypervolemia—symptoms as noted above, as well as decreasing oxygen saturation. Check radiographic tests for pleural and/or cardiac effusions. Natriuretic peptides [NPs]—serum NT-pro-B-type natriuretic peptide [BNP], BNP, and atrial natriuretic[ANP]—are established biomarkers for CHF.2 When increased fluid volume stresses the heart to the point of decompensation, values of NPs rise because the stretched myocardial walls release them.2
Conclusion
Childhood cancer survival rates are encouraging, but common treatments can damage the heart. Patients who received anthracycline and/or radiation therapy need to be monitored for signs of cardiomyopathy, a progressive condition that may be asymptomatic at first but later could manifest valvular disfunction and heart failure. Patients should be educated early on about the importance of a healthy diet and exercise in order to reduce modifiable risk factors for heart disease. Medical personnel should consider their patients’ cancer-treatment histories and potential for CHF when administering intravenous fluids—deliver with caution. Childhood cancer treatment protocols can be modified to reduce the potential for heart damage, but vital to this strategy is a better understanding of the “mechanisms of late cardiovascular effects,” as Dr. Chen puts it. This means more research needs to be done to improve the quality of life for long-term survivors, whose numbers are growing, a sure sign we’re headed in the right direction in the battle against childhood cancer.
References
1. Chen MH, Colan SD, Diller L. Cardiovascular Disease: Cause of Morbidity and Mortality in Adult Survivors of Childhood Cancers [published correction appears in 2011;108:e11. doi:10.1161/RES.0b013e31821bc2f1]. Circ Res. 2011;108:619-628. doi:10.1161/CIRCRESAHA.110.224519.
2. Armenian SH, Hudson MM, Hulder 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(3):e123-e136. doi:10.1016/S1470-2045(14)70409-7.
3. Chow EJ, Chen Y, Kremer LC, et al. Individual prediction of heart failure among childhood cancer survivors. J Clin Oncol. 2015;33(5):394–402. Published online 2014 Oct 6. doi: 10.1200/JCO.2014.56.1373. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314592/.
4. Barac A, Murtagh G, Carver JR, et al. Council Clinical Perspective: Cardiovascular Health of Patients with Cancer and Cancer Survivors: A Roadmap to the Next Level. J Am Coll Cardiol. 2015;65(25):2739-2746. doi:10.1016/j.jacc.2015.04.059.
5. Albert, NM. Fluid management strategies in heart failure. Crit Care Nurse. 2012;32(2):20-32. doi: 10.4037/ccn2012877