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Cardiac Effects of Doxorubicin
December  2018

A 53-year-old woman applied for life insurance. She had a 10-year history of hypertension. Her BMI was 32. She reported being diagnosed with stage II HER2-positive breast cancer four years prior, and she underwent a mastectomy followed by adjuvant chemotherapy.

This adjuvant therapy was doxorubicin (60 mg/m2) given every three weeks for four cycles. Shortly after receiving her final planned dose of doxorubicin, she developed shortness of breath and marked fatigue. An echocardiogram was performed and revealed her left ventricular ejection fraction (LVEF) to be approximately 40%. This had significantly changed from a pre-treatment evaluation showing a normal LVEF of 55-60%.

A beta blocker and an angiotensin converting enzyme (ACE) inhibitor were begun. She had a rapid clinical response to treatment with all symptoms abating. Holter monitor testing revealed no arrhythmias. A follow-up echocardiogram a few weeks later showed the ejection fraction to have returned to the pre-treatment range of 55-60%.

She has had annual echocardiograms since then (including eight weeks ago), and the ejection fraction has remained normal. She remains on an ACE inhibitor for BP control. She has had no further cardiac symptoms. She completed her planned chemotherapy prior to the onset of symptoms so no change in therapy was needed. She has had good breast cancer follow up and has had no evidence of recurrence. Current electrocardiogram is within normal limits.

What are the cardiotoxicity concerns with use of anthracyclines?
Doxorubicin (trade name Adriamycin), the medication mentioned in the case above, is one of the anthracycline types of medications. Other common medication in this class include daunorubicin, mitoxantrone, epirubicin and idarubicin.

Anthracyclines are a potent class of cancer chemotherapeutic medications and have been available since the 1960s. They are used effectively to treat many types of cancers, including carcinomas (bladder, breast, esophagus, liver, lung, stomach and thyroid), sarcomas (Ewing, osteogenic bone and soft tissue) and lymphomas (Hodgkin’s and non-Hodgkin’s). They are used in both pediatric and adult patients.

While being extremely effective in treating malignancy there are several potential serious adverse complications associated with anthracycline use. One of these complications is cardiotoxicity. Anthracyclines can cause direct damage to cardiomyocytes.

Research continues to shed light on the mechanism of injury, but currently the evidence points to a variety of contributing factors including DNA damage from interaction of the medication with an enzyme named topoisomerase-II, induction of apoptosis (programmed cell death), mitochondrial iron accumulation, oxidative stress and decreased protein synthesis.

Although other complications of anthracycline toxicity (e.g. arrhythmias) are described, cardiac toxicity is frequently identified as a decreased left ventricular ejection fraction, with or without symptoms or signs of heart failure. The incidence of this myocardial dysfunction appears to vary based upon the cumulative dose and the presence of various risk factors in the individual.

Below are risk factors for cardiotoxicity with anthracycline use.

  • Cumulative dose
  • Age (<4 or >65)
  • Obesity
  • Hypertension
  • Concomitant radiation exposure
  • Valvular disease
  • Female sex
  • Diabetes
  • Pre-existing low LVH ejection fraction
  • Renal failure
  • Concomitant exposure to trastuzamab
  • Smoking

The cumulative dose risk factor is especially important. The incidence of cardiotoxicity has been estimated to vary from 5% for cumulative doses of 400 mg/m2 to 48% in those exposed to 700 mg/m2.

The dosage of doxorubicin, for example, varies based upon the type of cancer being treated. Dosage can depend upon whether doxorubicin is used as a single agent versus part of a combination therapy with other chemotherapeutic medications. Breast cancer frequently has a lower cumulative dose than other cancers.

Considerations prior to anthracycline use
When clinicians are evaluating a cancer patient for potential anthracycline chemotherapy they typically consider the cardiac condition and cardiac risk factors of the individual patient. Frequently this evaluation includes obtaining an echocardiogram for evaluation of the LVEF and detection of valvular issues or other structural and functional issues.

Once evaluated, they weigh the risk of therapy versus the potential benefit. Prevention of toxicity is sometimes best done by identifying the risk and avoiding anthracyclines altogether when there is a readily acceptable alternative chemotherapy. When anthracyclines are considered the best alternative, modifiable risk factors are aggressively treated.

Figure 1 – Treatment alternatives for Anthracycline

  • Stop the anthacycline
  • ACE inhibiter?
  • ARB
  • B-blocker?
  • Dexrazoxane
  • Statin?

At times initiation of an ACE inhibitor, an angiotensin II receptor blocker (ARB) and/or a beta blocker prior to anthracycline therapy is helpful. Cessation of smoking, ideal weight maintenance, adequate BP control and excellent diabetic sugar control are all strongly encouraged. Using a different delivery formulation of anthracycline (liposomal formulation) and a modified delivery infusion rate (infusional rather than bolus) also has been shown to have a favorable impact. These maneuvers are considered important in mitigating the cardiotoxicity impact of the anthracyclines.

In addition, there is one FDA-approved medication (dexrazoxane) that is sometimes used for cardio-protection. Currently the FDA recommends using this medication only for those with metastatic breast cancer when >300 mg/m2 of doxorubicin is required for cancer control. However, it is occasionally used in an off-label way for other malignancies.

Cardiotoxicity timing
Anthracyclines can induce cardiac damage very early in treatment or at times can have a delayed effect. Myocardial dysfunction can develop years or even decades later in some individuals. For instance, adult survivors of cancer who were exposed to anthracyclines as children have been identified years later with markedly reduced ejection fractions.

In 2015 one group of investigators (Cardinale, D. et al) prospectively evaluated the timing and outcome of anthracycline induced cardiotoxicity in 2,625 patients and reported the results in the journal Circulation. In this study cardiotoxicity was defined as having both a LVEF decrease >10 absolute points from baseline and the absolute value being <50%.

In this study, LVEF was measured at baseline every three months during chemotherapy, every three months during the following year, every six months over the next four years and then yearly afterwards. The median follow-up was 5.2 years.

The overall incidence of cardiotoxicity was 9% (9.7% in breast cancer patients, 6.2% in non-Hodgkin disease). The median time for cardiotoxicity discovery was 3.5 months.

In 98% of cases cardiotoxicity occurred within one year. Of patients with cardiotoxicity, 11% had complete recovery, 71% had partial recovery. In their conclusions they mentioned that in their study “early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.”

The finding that 98% of all the cases of cardiotoxicity occurred within the first year is especially interesting. Late reductions in LVEF did occur >5 years after treatment, but the degree of anthracycline causation of this LVEF decline is difficult to ascertain. A “double hit” phenomenon is speculated to possibly occur after the original insult by anthracycline chemotherapy.

Monitoring for cardiotoxicity
While on the anthracycline therapy and following the completion of therapy, patients are frequently monitored for signs of cardiotoxicity. Clinicians have keen clinical interest in obtaining baseline measurements and monitoring patients who are undergoing chemotherapy, because early detection of cardiotoxicity can result in a change in treatment which can favorably impact long-term (including mortality) outcomes.

Several clinical guidelines have been developed expressing general agreement of the importance of monitoring asymptomatic patients who are undergoing anthracycline chemotherapy for cardiotoxicity. However, there is no consensus regarding the specifics of how to do this.

Monitoring therefore is frequently individualized and depends on the presence of risk factors as well as the development of any cardiac signs. Clinical assessment includes evaluation for symptoms and signs of congestive heart failure such as dyspnea, edema, orthopnea and extreme fatigue.

Transthoracic echocardiography is typically used for imaging. It is not uncommon for clinicians to obtain a baseline echocardiogram followed by additional echocardiograms during and/or immediately following therapy. Repeat imaging is then considered 6-12 months later even if there are no cardiac symptoms.

Significant drop in LVEF with or without cardiac symptoms is a sign of cardiotoxicity. Cardiac MRI and/or nuclear imaging are sometimes performed in place of or in addition to echocardiograms. They are frequently ordered when the echocardiogram is equivocal.

Some investigators are evaluating other forms of cardiac damage detection such as measuring troponin or natriuretic peptides (brain natriuretic peptide; N-terminal pro-brain natriuretic peptide) levels. A rise in the troponin levels or natriuretic peptide levels can be seen with cardiotoxicity and is an early marker of cardiac damage.

Electrocardiograms (EKG) are frequently performed but are not very sensitive in detecting early cardiac problems. However, supraventricular or ventricular arrhythmias, atrioventricular block and pericarditis findings on an EKG can be indicative of early cardiotoxicity.

When cardiotoxicity is discovered
If anthracycline induced cardiotoxicity is discovered during therapy, clinicians evaluate the need for additional anthracycline and frequently discontinue the treatment and rely on other treatment choices, if possible. For instance, in breast cancer there are several other options such as docetaxel and cyclophosphamide which have comparable results.

If ongoing doxorubicin is needed, then dexrazoxane can be given prior to each future dose. Treatment of cardiotoxicity includes beta blockers, ACE inhibitors, ARBs and statins alone or in combinations. Some but not all patients respond nicely to these treatments.

Cardiac function returns to normal in many individuals. However, some impacted individuals have persistent cardiotoxicity concerns. Long-term cardiac dysfunction and chronic congestive heart failure can occur.

Chronic congestive heart failure has serious long-term mortality concerns. Typically, those with a chronically decreased ejection fraction have the worst mortality outcomes, and the degree of LVEF loss correlates directly with the mortality concern. Other cardiac toxicity complications, such as recurrent arrhythmias, are also associated with adverse long-term results.

Returning to the case
The proposed insured had several risk factors for anthracycline induced cardiotoxicity and indeed had evidence of a significant adverse event with treatment. However, it is very encouraging that she had a nice response to treatment with a quick return of her left ventricular ejection fraction back to normal.

Her current echocardiogram shows no significant abnormalities with a normal ejection fraction. Her clinicians have documented that the breast cancer is in remission, and no further treatment is planned.

Late term cardiotoxicity could still occur. Recall that in the large prospective study by Cardinale et al approximately two percent of individuals that ever experienced cardiotoxicity had a delayed toxicity that developed after one year.

In this unique case, where early toxicity occurred but with a prompt and effective response by the clinical team, it is difficult to know what the long-term outcome will be. However, it is encouraging that this individual has had close follow up and has been asymptomatic without arrythmia, and with a normal ejection fraction for several years. There appears to be minimal cardiac risk in this case.

Asnani, A et al. Clinical manifestations, monitoring, and diagnosis of anthracyline-induced cardiotoxicity. UpToDate. Topic updated Jul 2, 2018. Last accessed Nov 16, 2018.

Cardinale, D, et al. Early Detection of Anthracycline Cadiotoxicity and Improvement With Heart Failure Therapy. Circulation. 2015 Jun;131(22) 1981-8.

Neilan, T et al. Prevention and management of anthracycline cardiotoxicity. UpToDate. Topic updated Jul 2, 2018. Last accessed Nov 16, 2018.

Smith, LA et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and metaanalysis of randomised controlled trials. BMC Cancer. 2010;10:337.

Tan, C et al. Cardiovascular toxicity in cancer survivors: Current Guidelines and future directions. American College of Cardiology. 2018;June 29.

Zamorano, JL, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016; 37(36) Aug 26.