Cardiac toxicity associated with anthracyclines

Cancer patients receiving anthracycline therapy are at an increased risk of developing cardiotoxicity, including cardiomyopathy and congestive heart failure (CHF).

Definition

Anthracyclines are the most frequently implicated antineoplastic agents associated with cardiotoxicity. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive, and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses. Anthracycline-induced cardiotoxicity typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF.

Diagnostic criteria for cardiac dysfunction due to antitumour medication is defined as a decrease in LVEF >10% from baseline to a final LVEF <53% (lower limit of normal).^rr

Incidence/prevalence

A meta-analysis of 8 trials showed that the use of anthracyclines was associated with a significantly increased risk of both clinical (odds ratio [OR] 5.43, 95% CI 2.34-12.62) and subclinical cardiotoxicity (OR 6.25, 95% CI 2.58-15.13). The rate of cardiac-related deaths, though infrequent, was also significantly higher when an anthracycline was used (OR 4.94, 95% CI 1.23-19.87).^r

In a separate meta-analysis which included over 49,000 patients, the incidence of clinically overt cardiotoxicity and subclinical cardiotoxicity was 6% and 18% respectively after a median follow up of 9 years.^r

Onset/duration

• Acute anthracycline cardiotoxicity – occurs during or immediately after a single dose of an anthracycline and occurs in <1% of patients.^r It may manifest as ventricular dysfunction, ECG abnormalities, arrhythmias and pericarditis-myocarditis syndrome. Most of these events are transient and normally resolve within a week and are not dose related.
• Early onset chronic progressive anthracycline cardiotoxicity – typically presents early, either during treatment or within one year after termination of treatment occurring in 1.6-2.1% of patients typically presenting as cardiomyopathy which can be progressive.^r
• Late onset chronic progressive anthracycline cardiotoxicity – presenting at least one year after completion of treatment up to 20 years since the first dose. Occurring in 1.6-5% of patients manifestations include reduced LVEF, cardiomyopathy or symptomatic CHF.^r Chronic cardiotoxicity is dose-related and the risk may be minimised by ensuring the total lifetime cumulative dose of an anthracycline administered to a patient is not exceeded.

Risk factors^rr

Demographics:

• female
• age <15 or >65 years

Cancer treatments:

• cumulative anthracycline dose (e.g. >250 mg/m² doxorubicin or equivalent)
• high-dose (>30 Gy) thoracic radiation therapy (particularly left-sided)
• lower-dose anthracyclines in combination with thoracic radiation therapy or trastuzumab (sequential therapy)
• intravenous bolus administration of anthracyclines
• previous, concurrent or planned treatment with other potentially cardiotoxic drugs may increase risk e.g. trastuzumab, paclitaxel, streptozocin, cyclosporin, dacarbazine, dactinomycin, etoposide, cyclophosphamide, ifosfamide, mitomycin, melphalan, vincristine, and bleomycin

Multiple cardiac risk factors (≥2):

• hypertension
• diabetes mellitus
• dyslipidaemia
• smoking
• obesity
• peripheral vascular disease
• sedentary lifestyle

Non-cardiac conditions that may increase cardiotoxicity risk:

• thyroid dysfunction
• electrolyte abnormalities
• chronic kidney disease
• very high or very low weight and possibly malnutrition, especially vitamin E deficiency

Prior heart diseases:

• borderline low LVEF (50-55%)
• history of:
  • heart failure
  • cardiomyopathy
  • myocardial infarction
  • clinically relevant cardiac arrhythmias (atrial fibrillation, prolonged QT interval, supraventricular tachycardia, ventricular tachycardia)
  • moderate or severe valvular heart disease

Other:

• increase in cardiac biomarkers (troponins and natriuretic peptides) during and after administration
• increased length of time since completion of chemotherapy

Anthracyclines in breast cancer

For patients with risk factors for cardiac impairment, less cardiotoxic regimens should be considered e.g. TC (docetaxel/cyclophosphamide) or CMF (cyclophosphamide/methotrexate/fluorouracil). For those who require trastuzumab, a non-anthracycline containing chemotherapy regimen could be considered such as TCarboH (docetaxel/carboplatin/trastuzumab) or TCycloH (docetaxel/cyclophosphamide/trastuzumab).

Trastuzumab has been used concurrently with anthracyclines in the metastatic^r and the neoadjuvant setting,^r with cardiotoxicity rates up to 27%.^r It is recommended that where this combination is used, extended administration is avoided (i.e. limited to 3 cycles) and patients counselled about the potential for increased risk of cardiotoxicity. Consideration should be given to closer cardiac monitoring in this setting. There is evidence that liposomal doxorubicin does not increase trastuzumab associated cardiotoxicity.^r There is currently no data suggesting any difference in efficacy whether trastuzumab is given concurrently or sequentially with anthracyclines.

Strategies to prevent anthracycline-induced cardiotoxicity traditionally include use of a liposomal formulation for high-dose (e.g. ≥250 mg/m² doxorubicin), continuous infusion or use of cardioprotectant dexrazoxane.^rr

ACE inhibition, angiotensin inhibition and β-blockade are also protective and appear to prevent the development of left ventricular dysfunction when given prior to or during chemotherapy in patients exhibiting early signs of cardiotoxicity.^rr However, universal primary prevention with standard heart failure medication is controversial, with only a few small studies demonstrating clinical benefit in high-risk populations.^rrrrr

Specific cardiovascular risk factors and suggested treatment targets^r

^* Source: www.heartscore.org/en_GB/access

Investigations and diagnosis

All patients should have a baseline cardiac history, physical examination and ECG and be considered for assessment of LVEF with either echocardiogram (ECHO) or gated heart pool scan (GHPS). Imaging could be omitted at physician discretion for patients not receiving trastuzumab who are under 60 years of age with no cardiac risk factors. ECHO is the preferred method of measuring cardiac function because of the ability to assess both systolic and diastolic dysfunction. However, limitations include operator dependency, reduced accuracy due to enlarged body habitus and variable methods for LVEF assessment. The threshold for monitoring cardiac function may be different for patients treated with curative versus palliative intent and clinician judgement is required especially in palliative settings.

Guideline for monitoring anthracycline cardiac toxicity

© ESMO Clinical Practice Guidelines 2010 ^r

Recommended maximum cumulative anthracycline doses^rrrrr

* Liposomal doxorubicin has been shown to be less cardiotoxic than conventional doxorubicin with larger cumulative doses reached in some studies.^r For cumulative doses >700 mg/m² it is recommended to monitor cardiac function.

Treatment

• Onset of acute cardiac symptoms, such as shortness of breath or chest pain, is a medical emergency
  • stop any infusion of an anthracycline
  • refer to emergency department or manage as per local hospital policy.
• Chronic cardiac symptoms
  • refer to a cardiologist for ongoing management and advice
  • management of asymptomatic left ventricular dysfunction (LVD) and heart failure may include the use of an angiotensin converting enzyme inhibitor (ACEI) agent, angiotensin receptor blocker (ARB) and/or beta blocker.^rr

All patients undergoing antineoplastic therapy should be encouraged to reduce their cardiovascular risk by controlling blood pressure and lipid levels, smoking cessation and implementing lifestyle changes. Patients receiving anthracycline therapies should be encouraged to continue exercising. 

Discontinuation

There is currently no compelling evidence to determine the optimal selection of patients who can continue cancer therapy despite LV dysfunction.^r Any decision to discontinue cancer therapy should be multidisciplinary and weigh the risks and benefits of the current treatment as well as alternative regimens. Other causes of LV dysfunction should be considered.

Educate the patient:

• about the risk of developing heart failure
• about the importance of ongoing monitoring
• to immediately report any cardiac symptoms, or changes, to the treating team:
  • any alteration in breathing patterns
  • swelling in the extremities
  • palpitations, chest pain
• to go to the nearest hospital emergency department or call an ambulance if they develop chest pain or shortness of breath at home.

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Bibliography

Berardi, R., M. Caramanti, A. Savini, et al. 2013. "State of the art for cardiotoxicity due to chemotherapy and to targeted therapies: a literature review." Crit Rev Oncol Hematol 88(1):75-86.

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Cardiotoxicity is a common complication of many anti-cancer agents and it remains a major limitation, strongly impacting the quality of life and the overall survival, regardless of the oncologic prognosis. Cardiotoxicity may occur during or shortly after treatment (within days or weeks), or it may become evident months, and sometimes years, after completion of chemotherapy. Cardiotoxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes. The aim of this review is to summarize potential cancer chemotherapeutics-related cardiovascular toxicities in adult cancer-patients and to suggest monitoring and treatment options for each agent, that can serve as a tool in the clinical practice.

Keefe, D. L. 2001. "Anthracycline-induced cardiomyopathy." Semin Oncol 28(4 Suppl 12):2-7.

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The highly active chemotherapeutic agents doxorubicin, duanorubicin, idarubicin, epirubicin, and mitoxantrone are also associated with acute, largely reversible cardiotoxic effects and a dose-related cardiomyopathy. This cardiomyopathy is characterized by minimal left ventricular enlargement and global systolic dysfunction, usually with associated mild to moderate mitral insufficiency. Historically, this was characterized by myocardial biopsy and radionuclide angiography. More recently, echocardiography has become the most widely available and cost-efficient tool for diagnosis. The precise mechanism of this toxicity has not been fully defined. However, the maximum tolerated cumulative dose can by increased by reducing peak drug levels and concurrent administration of the iron chelator, dexrazoxane. Because anthracycline-induced cardiomyopathy is largely irreversible and cumulative, prevention is the preferred strategy. Monitoring by assessment of left ventricular function by the most reproducible method available as patients approach potentially toxic doses can substantially reduce toxicity. Stress studies before major procedures such as bone marrow or stem cell transplants may be of benefit. This syndrome responds well to conventional therapy for congestive heart failure with angiotensin-converting enzyme inhibitors, digoxin, and diuretics. The beta-blocker carvedilol is often associated with significant improvement in ejection fraction and symptoms and spironolactone is well tolerated and often of benefit. The long-term outlook of the syndrome is much better than previously reported because of advances in therapy and prevention.

O'Hare, M., K. Murphy, F. Mookadam, et al. 2015. "Cardio-oncology Part II: the monitoring, prevention, detection and treatment of chemotherapeutic cardiac toxicity." Expert Rev Cardiovasc Ther 13(5):519-527.

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Cancer treatment has advanced in recent years with new drugs, complex regimes and multiple modalities of treatment; which has improved survival of cancer patients. Cardiotoxicity from chemotherapy is an emerging, important issue. Currently, echocardiographic evaluation of ejection fraction is the most commonly employed diagnostic tool for detecting chemotherapy-induced cardiotoxicity. However, novel echocardiographic techniques assessing myocardial mechanics using strain imaging can detect earlier changes. New imaging techniques and biomarkers can risk stratify patients to identify those requiring closer monitoring. Cardiologists collaborating with oncologists can detect and treat cardiovascular chemotherapeutic complications earlier, reducing morbidity and mortality. While cardiac MRI and multigated acquisition nuclear scanning are alternatives, echocardiography has become the mainstream for assessing cardiac function due to its portability, efficiency and low cost. Current recommendations regarding cardiac monitoring of cancer patients are based on expert consensus opinion. There is a need for prospective controlled trials to support specific guidelines.

O'Hare, M., A. Sharma, K. Murphy, et al. 2015. "Cardio-oncology Part I: chemotherapy and cardiovascular toxicity." Expert Rev Cardiovasc Ther 13(5):511-518.

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Cancer and cardiovascular disease are the most common causes of mortality in the US, causing approximately 1.2 million deaths annually. The incidence of cancer is expected to increase as the population ages. The prognosis of cancer patients has improved over the last few decades primarily because of newer chemotherapeutic drugs; however, many of these drugs have cardiotoxic side effects. The short-term cardiovascular toxicities of more established drugs are well described; however, understanding of the underlying pathogenesis is increasing. The delayed cardiotoxic effects of cancer treatments have become an important issue contributing to mortality and morbidity as cancer survivorship increases. Chemotherapy-induced cardiotoxicity can manifest in many ways, from asymptomatic decreases in left ventricular ejection fraction to congestive heart failure. Hypertension is commonly seen both as a co-morbidity and a side effect of chemotherapy. In this article, we discuss the pathogenesis, scope, presentation and potential prevention of these toxicities.

Shank Coviello, J. 2014. "Cardiac side effects of targeted therapies." Semin Oncol Nurs 30(3):175-182.

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OBJECTIVES: To review common cardiac side effects, their clinical presentation, and recommendations for assessment and management of patients receiving molecularly targeted cancer therapies. DATA SOURCES: Peer-reviewed literature. CONCLUSION: Although there is no established guideline for pretreatment cardiac evaluation and monitoring of patients receiving molecularly targeted agents, data currently supports the need for early risk identification and prevention/reduction strategies. IMPLICATIONS FOR NURSING PRACTICE: As nurses, we have a unique opportunity to help improve and maintain the quality of life of cancer survivors. Cardiovascular assessment and prevention/reduction strategies are essential to reduce risk of cardiovascular disease, promote optimal quality of life, and improve survival outcomes in patients receiving molecularly targeted cancer treatment.

Theodoulou, M. and A. D. Seidman. 2003. "Cardiac effects of adjuvant therapy for early breast cancer." Semin Oncol 30(6):730-739.

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Adjuvant chemotherapy is an established standard of care for most patients diagnosed with early breast cancer, and its popularity is gaining worldwide. The systemic armamentarium presently includes anthracyclines and taxanes, alkylating agents, fluoropyrimidines, and antimetabolites; in the future, it may include platinum compounds and the recombinant humanized anti-HER2 monoclonal antibody, trastuzumab, as well. Anti-estrogens continue to play an important role in the adjuvant setting for hormone-sensitive primary breast cancer. Adjuvant radiotherapy is common in the setting of early-stage disease as breast conservation gains popularity, and radiation is often employed in the postmastectomy setting as well. As treatment guidelines continue to evolve with newer data, the relative benefits of treatment in many situations continues to grow. Refinement of the optimal identification of patients at risk for local and distant relapse is a continued challenge facing the treating clinician. Parallel to this effort, and of equal importance, is the ability to shield patients that will gain little, if any, benefit from treatment and to identify those who may be at greater risk to suffer from potential toxicities. Until these factors are better defined, the recognition by clinicians of long-term side effects associated with adjuvant therapy is obligatory. Acute toxicities from treatment are often reversible, but late onset adverse effects of therapy can increase morbidity and mortality in long-term survivors, and continue to be of concern. One of the most serious side effects of adjuvant therapy of early breast cancer is cardiac toxicity. This article will provide an overview of the cardiac effects of adjuvant therapy in the treatment of early breast cancer.

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