What is Anthracycline Toxicity?
Anthracycline toxicity refers to harmful effects caused by a group of drugs known as anthracyclines. These medicines, like doxorubicin and epirubicin, are strong chemotherapy drugs used to treat different types of blood and solid cancers. Doxorubicin, in particular, is widely used in chemotherapy treatments for lymphoma, included in protocols such as CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin® [vincristine], prednisone) and ABVD (Adriamycin® [doxorubicin], bleomycin, vinblastine, dacarbazine).
Anthracyclines work primarily by disrupting the activity of the enzyme topoisomerase-II (TOP2), which results in increasing damage to DNA. Other processes, like creating reactive oxygen species, interfering with intercalation, and causing chromatin damage, might also contribute to their cancer-fighting ability. These processes trigger programmed cell death, particularly in cells that multiply rapidly, and have less of an effect on slower-replicating cells.
The most notable and worrisome harmful effect linked to anthracycline chemotherapy is type-1 cardiotoxicity. This is a cumulative, irreversible, and dose-dependent condition that causes heart muscle cell death, leading to a type of heart disease known as dilated cardiomyopathy and subsequently, heart failure. These drugs may also elevate the risk of getting another cancer and cause reproductive system failure, but these effects are not as well recorded. Other potential negative effects include damage to the liver, gastrointestinal tract, kidneys, and bone marrow. While these effects are usually reversible, high doses of anthracyclines can cause liver necrosis (liver cell death) which might develop into a chronic condition.
As more and more people survive cancer, the issues caused by anthracycline toxicity are becoming more prevalent, leading to an increase in related health problems and deaths. Therefore, it’s vital to gain an understanding of the causes, signs and symptoms, evaluation, and treatment of anthracycline-induced heart toxicity. It’s also equally essential to highlight the importance of a team-based approach in caring for patients receiving anthracycline chemotherapy.
What Causes Anthracycline Toxicity?
The details of how anthracycline, a type of chemotherapy drug, causes harm are still being uncovered. It appears to involve a complex web of interactions and factors. Currently, we believe that anthracycline damage can happen in two different ways: a nuclear-mediated pathway and a mitochondrial-mediated pathway. The toxicity of anthracycline seems to increase with higher doses and accumulates over time. This could be due to energy production failures in the mitochondria, dying heart muscle cells, the disruption of genes’ normal behavior caused by a mixture of nuclear and mitochondrial damage, or a combination of these.
Nuclear-Mediated Heart Muscle Cell Death:
The main anti-cancer action of anthracycline chemotherapy drugs is thought to be disrupting a molecule known as topoisomerase II (TOP2), specifically TOPIIβ. This molecule is usually involved in managing DNA breaks, so if it’s disrupted, it can lead to DNA damage that can’t be fixed, stopping normal cell activities. This also leads to a downstream effect of mitochondrial dysfunction due to altered gene expression. The combined effects of damage from TOP2, direct incorporation of anthracycline into the DNA, and this mitochondrial problem bring about cell death. If the anthracycline molecules can’t get into the cell nucleus and interfere with gene regulation, there’s less toxicity and cell death. Interestingly, even if anthracycline can’t get into the nucleus, the cell can still die, showing that both nuclear and mitochondrial pathways contribute to heart muscle cell death.
Mitochondrial-Mediated Heart Muscle Cell Death:
Reactive oxygen species (ROS), which is potentially part of the anti-cancer properties of anthracycline, may cause mitochondrial dysfunction in cells with high energy requirements and weaker protection against oxidation, such as heart muscle cells. When a heart muscle cell quickly absorbs an anthracycline molecule, it triggers a process that produces ROS and semiquinone free radicals. When this happens excessively within the mitochondria of heart muscle cells, it significantly increases oxidative stress. The Fenton cycle, which occurs in the presence of mitochondrial iron, can worsen this situation. This enhanced oxidative stress damages lipids and proteins, impairing enzyme function and energy production. Specifically, anthracyclines in the mitochondria promote the separation of a molecule called cardiolipin from another molecule, cytochrome-C, which can cause the cell to self-destruct.
Lastly, anthracyclines can alter the permeability of the mitochondrial membrane in a way that depends on dose, calcium, and redox, with mitochondrial iron playing a crucial role. As this permeability increases, the mitochondria struggle to maintain their function, which leads to cellular breathing failure and a type of cell death called necroptosis. This increase in permeability also triggers the release of a molecule that promotes cell death apart from the cytochrome-C mechanism mentioned earlier; this is known as ferroptosis.
Risk Factors and Frequency for Anthracycline Toxicity
Anthracycline toxicity, a harmful side effect of a particular type of cancer treatment, shows up in people differently. This variation is influenced by many factors such as dosages, individual’s general health status, their genetics, and their environment. How doctors measure heart function can also bring differences in the data. The toxicity is characterized by a drop in the heart’s efficiency, which can be measured as left ventricular ejection fraction (LVEF). It is called anthracycline toxicity when the LVEF level falls below 40% or reduces by more than 10% from the initial level before treatment.
Among patients, kids, and adults, experience the toxicity differently. Both the incidence and effects of the toxicity are often related to the dosages of the drug doxorubicin, a famous anthracycline chemotherapy drug.
- Over 50% of children with cancer receive this type of chemotherapy. Kids getting more than 250 mg/m2 dose have a 10% chance of experiencing toxicity. This risk increases to 30% if the total dosage goes beyond 600 mg/m2. Also, a child who receives less than 250 mg/m2 in total has about 0.5% chance of having heart failure by the age of 40, while for those with a total dosage above 250 mg/m2, the risk jumps to 11.7%. The chance of toxicity is particularly higher in children under 5, girls, and those with conditions like diabetes or hypertension.
- More and more adults are getting different types of chemotherapy now. However, up to 70% of older adults with a type of cancer called lymphoma still use anthracycline chemotherapy. Again, the risk of heart failure in adults increases with the dosage: 3-5% with 250-400 mg/m2, 7-26% with 550 mg/m2, and up to 48% with 700 mg/m2. Medical professionals usually advise against using dosages beyond 400-450 mg/m2. Advanced imaging techniques show that even without symptoms, more than 90% of patients receiving a dosage of 240 mg/m2 or more experience changes in their hearts. When the dosage goes above 400 mg/m2 symptoms or not, the average decrease in heart efficiency (LVEF) reached 15%. A previous reduction in LVEF or treatments alongside cyclophosphamide, paclitaxel, or human epidermal growth factor receptor 2 (HER2) therapies also increase the risk of toxicity in adults.
Signs and Symptoms of Anthracycline Toxicity
Anthracycline cardiotoxicity generally shows up as heart failure symptoms. Two main types of symptoms can occur: those related to congestion and those associated with a reduction in muscle contraction force in the heart (inotropy). Congestion symptoms can include unexplained weight gain, shortness of breath, nightly shortness of breath, swelling of the extremities, abdominal fluid buildup, cough, and difficulty breathing when lying flat. Symptoms due to reduced inotropy are often more general, including a decrease in physical stamina, loss of appetite, and fatigue. It’s possible, though, to have anthracycline cardiotoxicity without experiencing symptoms. In such cases, it’s crucial to figure out the total exposure to anthracycline and when the drug was administered.
Understanding cardiac risk factors is critical as symptoms of anthracycline toxicity can easily be confused with cancer symptoms or effects of chemotherapy. Other possible causes, including heart attack, lung clots, and myocarditis, should not be overlooked. Rapid heartbeat can be a sign of anthracycline toxicity; an irregular heartbeat could be an early symptom.
People with non-obvious anthracycline cardiotoxicity may not show significant physical symptoms. The early symptoms are usually mild and can include a rise in jugular vein pressure, slight weight gain, and foot swelling. Heart-related congestion could result in high blood pressure or fast heartbeat. Patients without congestive symptoms may have normal or low blood pressure. Increased urination at night and reduced in the day may be reported. Weight gain due to fluid retention and third spacing (fluid shift) is common.
A diagnosis of anthracycline-induced cardiotoxicity is easier to make when there are clear signs of heart failure. These could include increased jugular vein pressure, rapid breathing and heartbeat, and foot swelling. Additionally, swelling in the lower back, abdominal fluid buildup, fluid accumulation in the chest and lungs with related breathing difficulties and blueness may be present. During a heart checkup, an extra heart sound might be heard. A point-of-care ultrasound may show reduced overall heart muscle activity with enlarged heart chambers and other associated features such as an enlarged inferior vena cava, increased bloodstream to the liver, and an inverted liver Doppler waveform.
Testing for Anthracycline Toxicity
Some patients are at a higher risk of heart damage from a type of chemotherapy drug called anthracyclines. To determine this risk, doctors conduct a variety of tests before starting treatment. These tests include an EKG, a heart ultrasound, blood tests for certain proteins (troponin and NT-proBNP), and advanced heart imaging using 3D ultrasound, CT scan, or MRI.
Doctors also assess risk using online calculators developed by leading heart disease and cancer organizations, which take into account several risk factors like smoking, obesity, previous chemotherapy treatment, diabetes, kidney disease, and certain heart conditions among others.
Regular check-ups during and after treatment are crucial too. A substantial reduction in the heart’s ability to pump blood or a drop to a certain level can indicate heart damage from the drug. In such cases, further examination may be needed. It is also recommended to conduct heart imaging after a certain cumulative dose of the drug.
Blood tests for heart damage markers and additional heart imaging should be conducted for high-risk patients during treatment. For patients treated with anthracyclines and stem cell transplants, doctors should monitor them for longer periods as they may develop late heart damage.
Special populations, such as adult survivors of childhood cancer, require careful risk assessment and regular heart imaging as a part of their follow-up care, with additional care taken during special situations like pregnancy. Children undergoing treatment with anthracyclines are also recommended to have regular heart imaging performed during treatment and every five years thereafter.
Treatment Options for Anthracycline Toxicity
Patients getting anthracycline chemotherapy who are at high or very high risk for heart damage caused by the drug should receive the lowest possible dose. To reduce the heart damage, consideration should be given to starting high-dose statin therapy and certain heart medications before the chemotherapy begins. These heart medications include angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), or beta-blockers. This strategy is also used when blood tests show signs of heart damage. Beta-blockers with antioxidant activity, like nebivolol and carvedilol, might be the better choice. Additional protective therapies might be needed for patients with significant risk of toxicity.
The severity and treatment of anthracycline toxicity come down to the symptoms the patient has and the results of cardiac imaging. The heart damage is ranked as mild, moderate, or severe:
* Mild damage: This happens when LVEF, a measure of how well the heart is pumping, is reduced but still above 50%, or GLS, another measure of heart function, is decreased by more than 15%.
* Moderate damage: When the LVEF is between 40% and 50%.
* Severe damage: When the LVEF is less than 40%.
If the patient doesn’t show symptoms of anthracycline toxicity:
* Mild toxicity is treated with protective heart therapy with ACEi/ARB and beta-blockers, and the patient’s condition should be closely monitored while continuing with chemotherapy.
* Moderate toxicity means anthracycline chemotherapy should be paused and special heart failure treatment should start.
* Severe toxicity also requires the chemotherapy to be stopped and heart failure treatment to begin.
If the patient does show symptoms of anthracycline toxicity:
* Mild toxicity suggests that chemotherapy might need to be paused, and heart failure treatment should begin.
* Moderate toxicity means chemotherapy should be stopped immediately and not restarted until LVEF improves with heart failure therapy.
* Severe toxicity requires the immediate stop of chemotherapy and it should no longer be considered.
Any patient with symptoms of heart failure, or a patient without symptoms but with a significant drop in LVEF, needs to start heart failure therapy. This involves starting with ACEi/ARB and beta-blockers that affect the RAAS pathway and control neurohormonal dysregulation in heart failure. In addition, unless contraindicated, patients should also start the following treatment that does not include water pills (diuretics) which may be required to manage symptoms of heart congestion:
* Treatments that block the effect of mineralocorticoid hormones.
* Drugs called angiotensin receptor-neprilysin inhibitors (these must not be given with ACEi/ARB therapy).
* Nose inhibitors that lower blood sugar by making the kidneys get rid of glucose in the urine (SGLT2i).
Patients with severe heart failure require specialist evaluation. Other medication like ivabradine or digoxin may be necessary. If the patient has serious heart failure and unusual heart rhythms, a device for cardiac resynchronization therapy might be necessary to assist the heart in beating more efficiently, although this is uncommon. Devices to assist heart pumping (left ventricular assist devices) and heart transplants are rarely given to patients with anthracycline toxicity due to their ongoing risk of cancer.
Cardiac rehabilitation through high-intensity interval training can improve health outcomes for patients with anthracycline toxicity and can be offered to all suitable patients. There are no specialized cardiac rehabilitation programs for anthracycline toxicity. Managing risk factors for heart disease before, during, and after anthracycline toxicity helps improve health outcomes. Everyone should be informed about the benefits of quitting tobacco and reducing alcohol consumption, managing chronic diseases properly, and diet and exercise.
What else can Anthracycline Toxicity be?
Dilated cardiomyopathy, a condition where the heart’s ability to pump blood is lessened due to an enlarged and weakened heart muscle, can result from something called anthracycline toxicity. This happens when a drug class known as anthracyclines, which are used in chemotherapy, harm the heart. However, diagnosing this condition can be tricky unless it’s connected with a patient’s medical history. This is because the changes to the heart muscle seen on heart tissue samples and MRI scans could also be due to several other conditions.
Just like this, there are other medical conditions that can cause dilated cardiomyopathy and may potentially confuse the diagnosis. Some of these include myocarditis (heart muscle inflammation), thyrotoxic cardiomyopathy (a heart condition due to a hyperactive thyroid), ischemic cardiomyopathy (a weak heart muscle due to poor blood supply), and alcohol-induced cardiomyopathy (damage to the heart muscle from excessive alcohol use).
The process of diagnosis can also be complicated if the patient is taking other heart-damaging chemotherapy drugs besides anthracyclines. Such chemotherapy agents include HER2 therapies and immune checkpoint inhibitors. Other possible causes of heart problems that need to be considered include the chemotherapy drug cyclophosphamide, and radiation therapy to the chest, both of which can harm the heart in different ways. Because cancer treatments are often given one after the other, figuring out the exact cause of dilated cardiomyopathy can be a real challenge. Such cases may need the involvement of various specialists and a team-based approach.
Doctors usually suspect anthracycline toxicity if the patient has recently been treated with anthracyclines and there is a noticeable decrease in the heart’s performance when compared to previous medical images of the heart. Because of evolution in medicine that improved how we track patients’ heart conditions before, during, and after using anthracyclines, discovering anthracycline toxicity after a long time since treatment is unlikely. However, in cases where the cause of dilated cardiomyopathy can’t be determined, it would be wrong to jump to the conclusion of it being idiopathic (having no known cause) if heart-damaging medicines had recently been used and the heart was normal in earlier checks.
What to expect with Anthracycline Toxicity
Patients receiving a type of chemotherapy known as anthracycline are generally more likely to succumb to their cancer before the side effects of the drug become life-threatening. In fact, over 95% of cancer patients treated with this therapy die from their cancer, not from the drug’s toxicity. Only 0.7% of deaths among these patients are linked to heart-related complications.
Interestingly, one year after receiving anthracycline treatment, about 98% of patients will show signs of toxicity. Though a small percentage fully recover their heart function, the majority either see incomplete recovery (71%) or no significant recovery (18%). Those who experience partial to no recovery can have a worse prognosis, including higher heart disease classifications, decreased quality of life, and an increased risk of heart-related death.
In instances of high-dose anthracycline treatment, where severe heart toxicity symptoms appear during therapy, heart failure is a related cause of death in up to 38% of patients. The average survival time in these cases is about 162 days.
When comparing long-term survival versus heart-related outcomes, it takes about nine years after a patient’s first cancer diagnosis for the risk of dying from heart-related issues to surpass the risk of dying from the cancer itself. This includes cases of cancer recurrence and secondary cancers. In terms of prognosis, patients experiencing heart toxicity from anthracycline treatment fare similarly to those with dilated cardiomyopathy, regardless of the cause; the five-year survival rate for both groups is around 86%.
For patients who were treated for cancer during their childhood, heart-related deaths due to anthracycline toxicity are quite rare, occurring in less than 0.5% of cases. This remains true even among those who received high doses of the drug and showed signs of heart toxicity on imaging scans. In fact, even after 30 years, the incidence of heart-related death for survivors of childhood cancer remains low at 0.14%, even among those who received high doses of anthracycline and showed impaired heart function.
Possible Complications When Diagnosed with Anthracycline Toxicity
Complications due to heart toxicity from anthracycline (a type of chemotherapy drug) often resemble those from dilated cardiomyopathy, a condition where the heart’s ability to pump blood is decreased.
Some patients who have undergone anthracycline chemotherapy have experienced pericardial effusions, a low-incidence condition where fluid gathers around the heart. The exact cause of these effusions, however, isn’t known. Heart toxicity from anthracycline can also lead to certain heart rhythm problems, such as atrial fibrillation and atrial flutter. Such rhythm issues are found in around 10% to 15% of patients with below-the-surface heart toxicity from anthracycline and are comparable to those of other forms of dilated cardiomyopathy. The risk of these rhythm problems rises with the severity of anthracycline toxicity. Severe and life-threatening rhythm problems, however, are rare.
Contrary to other chemotherapy-induced toxicities, anthracycline toxicity doesn’t seem to increase the risk of ischemic or valvular heart disease.
Pregnant patients who have experienced anthracycline-induced heart toxicity have a very high chance of experiencing heart-related events. However, in situations where heart failure occurs around childbirth (peripartum cardiomyopathy) regardless of the cause, the complication rates are markedly high. Nevertheless, there’s no increase in maternal deaths linked to anthracycline toxicity compared to other causes of peripartum cardiomyopathy.
Preventing Anthracycline Toxicity
It’s crucial for patients receiving chemotherapy, such as anthracycline chemotherapy, to fully understand the risks and benefits of the treatment. The medical team in charge should actively participate in decision-making with the patients to develop a tailored treatment plan. If the patient is to receive a type of medication classified as anthracycline, they should be informed about symptoms of heart-related side effects. They should also understand the necessity of regularly checking their health and taking their prescribed medicines as directed.
Managing risk factors linked to anthracycline toxicity, like diabetes, quitting smoking, and losing weight, can significantly improve the overall effectiveness of the treatment. Patients should always be reminded of how important it is to manage the risk factors they can control.
