Safety of Anthracyclines Chemotherapy

Edita Bronė Juodžbalienė
LSMU MA Oncology and Hematology Clinic

Various groups of cytostatic drugs are used for cancer chemotherapy. They differ in effectiveness and side effects. One of them - anthracyclines - has been used for 30 years. The most important and dangerous side effect caused by anthracyclines is damage to the heart muscle, leading to a weakening of the heart's contraction function. This phenomenon is called anthracycline-induced cardiomyopathy in medical literature. Anthracycline-induced cardiomyopathy can sometimes occur even many years after treatment.

Anthracyclines are a class of cytostatic drugs created from the streptomyces bacteria Streptomyces peucetius var. caesius. The antineoplastic effect of anthracyclines was observed as early as 1960 [1]. The basis of their cytostatic effect is the inhibition of DNA and RNA synthesis in cancer cells. Although knowledge about the division of cancer cells and the mechanisms of action of chemotherapeutic drugs is constantly increasing, they are not yet fully understood. Drugs developed in 1990 quickly replaced many older chemotherapeutic agents and became established in modern antineoplastic treatment regimens. The first drug in this group was daunorubicin, naturally extracted from Streptomyces peucetius, later other analogues were created. Currently, the most widely used anthracycline is doxorubicin. Cardiotoxicity, although of varying degrees, is characteristic of all these preparations.
This so-called red chemotherapy has proven to be truly effective. For example, in a meta-analysis of 11 clinical studies in 1998 (Early Breast Cancer Trialists' Collaborative Group, EBCTCG), it was found that using anthracyclines in breast cancer chemotherapy extended the time to disease recurrence and improved overall survival. To this day, anthracyclines are among the most effective cytostatic drugs for the treatment of early and advanced breast cancer.

The most important side effect of anthracyclines
The side effects of cytostatic drugs during treatment are determined by their effect on rapidly dividing cells. Drugs affect not only cancer cells - they also affect bone marrow, mucous membranes, and hair follicle cells. Anthracyclines, like other cytostatic drugs, can cause nausea, vomiting, alopecia, myelosuppressive effects on bone marrow (neutropenia, thrombocytopenia), but their cardiotoxic effect is stronger than many other drugs. In addition, improperly administered anthracycline can cause tissue necrosis, so chemotherapy is only prescribed by experienced doctors (chemotherapists).
Heart failure can occur in individuals treated with chemotherapeutic agents even after many years. Two years after cancer treatment, cardiotoxic effects were found in 2% of patients, and after 15 years - 5%. It is important to consider this when treating adult patients, especially children, as many childhood cancers can be cured [2].
Anthracyclines have a certain cumulative dose that cannot be exceeded throughout the patient's life. Therefore, oncologists calculate the cumulative dose received by the patient throughout the treatment and try not to exceed the limits. If a patient is prescribed treatment with cardiotoxic cytostatic drugs, the condition of the heart is assessed before starting treatment and during treatment, and after completion - the late cardiotoxic side effect is evaluated. It is very important to protect cancer patients from the cardiotoxic effects of drugs, as the cause of death of many cancer survivors is often chronic heart failure caused by antineoplastic treatment. The prognosis for anthracycline-induced cardiomyopathy is very poor - the mortality rate over 5 years reaches 40% [3].

Clinical manifestation of cardiotoxic effect
The cardiotoxic effect of drugs is indicated by certain characteristic preclinical signs:
• decrease in systolic function (13% of patients);
• decrease in heart mass (52% of patients);
• intolerance to physical exertion (80% of patients);
• abnormal diastolic function (80% of patients).
Heart damage caused by antineoplastic drugs is divided into two types. The first type of cardiotoxic damage is caused by doxorubicin - it results in the death of heart cells. Cardiotoxic effects start from the first dose, characteristic changes are seen in biopsy material, and the severity of the damage depends on the cumulative dose of the drug. Certain risk factors influence this type of heart damage (combined radiation therapy, previous or concomitant radiation therapy, age, pre-existing heart disease, hypertension).
The first type of cardiotoxic effect is traditionally divided into acute and chronic. Acute damage manifests in the first days or weeks of treatment: changes in ECG are recorded (repolarization disturbance), the patient feels chest pain, but usually, this is not paid attention to. A few years ago, it was discovered that during the acute damage phase, troponins are released into the bloodstream, indicating cardiomyocyte death. Therefore, it is now believed that the chronic course, characterized by constant tachycardia after exertion, tachycardia at rest, decreased functional capacity, shortness of breath, signs of heart failure, reflects advanced-stage heart damage, and the most significant changes occur precisely in the acute phase. Unfortunately, acute damage is usually not detected, and acute cardiotoxicity is still underappreciated.
Most new antineoplastic agents, as well as biological therapies (trastuzumab, lapatinib, sunitinib, etc.), cause the second type of cardiotoxic damage - dysfunction of heart cells. In this case, biopsy results do not show typical damage. Moreover, this type of damage is not dependent on the cumulative dose and is essentially temporary.

Dose size and frequency of complications of anthracyclines
The doses of cytostatic drugs are calculated based on body surface area. All patients receiving anthracycline therapy should undergo ECG, echocardiography, and possibly radionuclide angiography. Left ventricular ejection fraction (LVEF) shows how much blood is pumped out of the left ventricle of the heart. In 2009, the British Journal of Cardiology presented an LVEF monitoring algorithm (Table 1), but in our clinical practice, the treatment with doxorubicin is often refused when LVEF does not reach 45-50% (other treatment alternatives are sought).
On average, during one course of chemotherapy, 60-75 mg/m2 of doxorubicin is usually administered. During treatment, a patient can receive 4-6 courses of chemotherapy with doxorubicin, and in a lifetime - 6-8. It has been described that the lowest doxorubicin dose that caused myocardial damage was 180 mg/m2 (about 3 courses) - the cardiotoxic effect of the drug caused myocardial degeneration. It is detected in almost all patients treated with a dose of doxorubicin greater than 240 mg/m2.
When the cumulative dose of anthracyclines (doxorubicin) exceeds 550 mg/m2, the likelihood of acute heart failure steadily increases. Comparing patients treated with up to 550 mg/m2 and more than 550 mg/m2 of doxorubicin, it was found that the latter experienced heart failure twice as often. Cardiotoxicity manifested as follows:
•    9% of patients when the cumulative dose was 501-550 mg/m2;
•    20% - when 551-600 mg/m2;
•    41% - > 600 mg/m2.

Table 1. Left ventricular ejection fraction monitoring algorithm

When initial LVEF >50%	When initial LVEF
Repeat LVEF test when Dox 250-300 mg/m2	Do not administer Dox if LVEF
Repeat LVEF test when Dox 400 mg/m2, if: •    there is heart disease •    radiation therapy was applied to the chest •    abnormal ECG •    cyclophosphamide is administered concomitantly	If LVEF is between 30% and 50%, repeat LVEF test before each course
Repeat LVEF test when Dox 450 mg/m2 and there are no risk factors	Do not administer Dox if LVEF decreases >10%, and/or LVEF is
Continue to monitor LVEF before each course
Discontinue Dox if LVEF decreases by 15% and LVEF is

Dox - doxorubicin.

Risk factors for cardiotoxicity
Higher cumulative doses of cardiotoxic drugs are more harmful to the hearts of women, young people, and those previously treated with ionizing radiation in the chest area. Risk factors are listed in Table 2.

Table 2. Risk factors for cardiotoxicity [7, 8]

Administration method	Harmful effect increases if a large single dose is administered quickly (bolus) and infrequently (every 3 weeks)
Chest irradiation	This is an important factor as ionizing radiation could harm the myocardium
Previous heart diseases	Significance is present, but the mechanism is unclear
Age	Risk is higher in children, young people, and those over 60 years old
Most dangerous - Herceptin and Cyclophosphamide.	Risk increases when combined with etoposide, mitomycin, melphalan, vincristine, bleomycin, and dacarbazine
Cumulative dose	Risk does not exceed 10% when doxorubicin dose 450 mg/m2. Risk suddenly increases when doxorubicin dose ≥ 550 mg/m2

Ways to reduce the side effects of anthracyclines
• Evaluate risk factors, do not exceed the maximum dose during treatment, and monitor the heart. Cardiotoxicity is observed by performing echocardiography before treatment and repeating LVEF testing during treatment. If LVEF decreases and no longer reaches 50%, treatment with anthracyclines (or other chemotherapeutic agents) may be discontinued. If heart disorders occur in cancer patients, the family doctor should suspect a possible cardiotoxic effect of previous chemotherapy. Treatment of diagnosed heart diseases during chemotherapy should not be discontinued.
• Prolonging the infusion time of doxorubicin reduces cardiotoxicity. Instead of rapid infusion, a slow infusion lasting 24, 48, or 96 hours is given (Prolonging the time increases the risk of mucositis!).
• Reduce the single dose: divide it over several days, not every 3 weeks, but weekly in 3 or 4 doses.
• Choose other less cardiotoxic anthracycline derivatives for treatment, for example, the cumulative dose of epirubicin is 900–1000 mg/m2.
• In practice, new forms of liposomal anthracyclines (pegylated liposomal doxorubicin Caelyx and non-pegylated liposomal doxorubicin Myocet) have been started and positively evaluated by oncologists. Liposomal encapsulated doxorubicin releases slowly, acts longer on cancer cells, and causes less damage to the heart muscle. The cumulative doses of these effective liposomal anthracyclines are much higher, and the side effects are milder and less frequent [9].
• A cardioprotective drug dexrazoxane can be used. Unfortunately, it is not part of our daily practice.
• Treatment is more effective and anthracycline toxicity is lower when multiple chemotherapeutic agents are used in combination (lower doses of individual drugs, and toxicity varies).
• New drugs, including biological ones, can cause a type II cardiotoxicity - dysfunction of heart cells - which does not depend on the cumulative dose, is essentially temporary, and should disappear without any consequences. However, it does not always go away. This phenomenon can be explained as follows: the administration of new drugs after treatment with anthracyclines, which have already caused necrosis of myocytes, or if the patient's heart was already damaged by previous heart diseases.
• No matter how many years ago the patient was treated with anthracyclines, when the disease recurs, the same doses cannot be administered again. This is unsafe because it is likely that the toxic effect will accumulate and manifest as cardiotoxicity (acute, subacute, chronic, or late). Therefore, it is important not to lose the data on past illnesses and treatments (especially cancer).

Review of the effects of liposomal anthracyclines
These are new, less known forms of antineoplastic drugs. Liposomal chemotherapeutics began to be studied in clinical trials in 1980. Conventional cytostatic drugs, when they enter tissues, are affected by the body fluids, so the pharmacological effect and toxic effects are unpredictable. Liposomes, into which various chemical substances are inserted, protect them from sudden breakdown in the serum and deliver them to the target. The distribution of the drug in tissues (especially in tumors) improves significantly, and toxicity decreases. If the drug can be administered for a longer period, then the treatment will be more effective. This is particularly important in oncology, as cancer patients need to be treated for a long time (cancer is considered a chronic disease). Liposomes differ in size, structure, composition, and therefore properties, for example, liposomal paclitaxel is less neurotoxic, liposomal doxorubicin has less cardiotoxicity. By improving an existing drug, it is expected to be superior - more effective or safer for the patient. Liposomal forms of drugs are truly promising, not only in oncology.
In Lithuania, there is already experience in treating with two liposomal doxorubicin preparations. One of them, pegylated doxorubicin, is used to treat progressive ovarian cancer, while non-pegylated doxorubicin with cyclophosphamide is used for the first-line treatment of metastatic breast cancer in adult women. Currently, these drugs are not reimbursed, but the experience is optimistic because the drugs are effective and very well tolerated.
Mechanism of action of liposomal anthracyclines:
 Relaxation. Due to the liposomal envelope, the active substance relaxes slowly: the peak concentration of the free drug in the blood decreases, the tumor is affected for a longer time. Liposomal doxorubicin circulates in the blood for a longer time because it retains doxorubicin inside until it reaches the tumor.
 Distribution. Due to the liposomal envelope, doxorubicin penetrates less easily through normal blood vessel walls but easily passes through newly formed permeable tumor blood vessels. Therefore, the accumulated drug will affect healthy tissues for a shorter time, there will be fewer unwanted side effects, and the effect on the target, the malignant tumor, will be stronger.
 Toxic effects, as when treating with all cytostatic drugs, may occur, but in clinical practice, it is seen that they are significantly milder. Unlike the "ancestor" doxorubicin, pegylated liposomal doxorubicin does not cause complete alopecia, so a wig is not needed. However, pegylated liposomal doxorubicin is characterized by the hand-foot syndrome or hand-foot erythrodysesthesia (HFS). It occurs when liposomes with doxorubicin enter the skin from the blood vessels due to pressure. This phenomenon is reversible and easy to prevent (patients are recommended not to do heavy work and not to wear tight shoes).
 When treating with liposomal anthracyclines, myelosuppression is mild (febrile neutropenia has not been observed), and cardiotoxicity is significantly weaker (see clinical case). For example, the median cumulative doses of non-pegylated liposomal doxorubicin are much higher than those of conventional doxorubicin (respectively >1260 mg/m2 and 480 mg/m2).
Numerous studies are being conducted with liposomal anthracyclines as they are safer, tested in various combinations. They are already included in first-line chemotherapy regimens. These drugs are highly anticipated by oncologists due to their safety, which could ease the treatment of patients with multiple comorbidities. This is another alternative for long-term treatment of oncological diseases.

Clinical case: successful treatment of a patient with severe heart disease with non-pegylated liposomal doxorubicin Myocet
In April 2012, a 50-year-old patient experienced a myocardial infarction. After 2 months of rehabilitation, she was diagnosed with stage IIB breast cancer. Ischemic symptoms appeared while planning the breast operation, and in July 2012, the patient underwent coronary artery bypass surgery. The breast cancer operation was successful only 5 months after the diagnosis (Carcinima mammae sin pT2N1aM0 L1V0R0G3 ER(3+) PR(3+) HER2(0)) was established in November 2012.
The patient felt unwell as postoperative chemotherapy could not be applied, and hormone therapy was prescribed. When the cancer marker CEA levels increased, a chest CT scan revealed spread to the pleural cavity. Since the disease progressed rapidly during hormone therapy, the patient required intensive chemotherapy, but conventional doxorubicin could not be administered due to heart muscle damage. Inadequate treatment would yield no results. The patient was treated with first-line metastatic disease therapy Myocet and cyclophosphamide.
To our surprise, the patient, who had many heart complaints, tolerated all treatment courses very well, experienced no adverse effects, and her heart function was never impaired. CEA levels normalized. No lung metastases were visible on the chest X-ray, awaiting repeat chest CT data.

Tips on how a family doctor can help a cancer patient
•    If chemotherapy is planned for the patient, send them for an echocardiogram in advance, preferably provide the patient with a copy of the test results.
•    Pay attention to the oncologists' recommendations, as the patient may need to undergo an echocardiogram regularly (often every 3-4 months).
•    Under no circumstances should essential cardiological medication be discontinued during chemotherapy (on the contrary, more intensive treatment may be needed).
•    Continue monitoring the heart condition of individuals treated with anthracyclines even after treatment. Maintain the oncology patient's data on the cancer treatment applied, drug doses.

Anthracyclines will continue to be used in oncology practice for many years, so cardiotoxicity has been, is, and will remain a relevant issue. Nevertheless, when the causes and protective measures are known, patients can be greatly helped through close collaboration between oncologists, cardiologists, and family doctors.

LI/MYO/14/0001
References

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