Anthracyclines

Mechanism of Action

The explanations of cytostatic and cytotoxic actions of anthracyclines point to a number of different mechanisms, including free radical formation, lipid peroxidation, direct membrane effects, and enzyme interactions. The following elucidates some of these theories:

Enzyme Interaction

The most widely accepted explanation for the action of anthracyclines is their interaction with topoisomerase-II. The ternary complex thus formed prevents the re-ligation of the ds-DNA breaks. Subsequently, it promotes growth arrest and apoptotic cell death.[6] 

DNA Intercalation

Anthracyclines have a chromophore moiety that has an intercalating function and inserts between adjacent base pairs of DNA when localized to the cell's nucleus; this inhibits DNA and RNA synthesis, especially in highly replicating cells blocking cell division.[6]

Reactive Oxygen Species (ROS)

Redox reactions generate reactive oxygen species in the presence of cytochrome P450 reductase, NADH dehydrogenase, and xanthine oxidase. The excess ROS cannot be detoxified, resulting in oxidative stress, DNA damage, and lipid peroxidation triggering cell apoptosis.[6]

DNA Adduct Formation

These drugs are known to form adducts with DNA promoted by formaldehyde-releasing pro-drugs. The adducts block specific transcription factors and eventually initiate apoptosis.[6]

Administration

Anthracyclines administration is generally by injection or via an intravenous infusion. The type of cancer and its stage will influence the dose and duration of chemotherapy. As an example, treatment may be daily for two weeks followed by an off week to permit the body to recover and regenerate new cells. This 3-week cycle may then be repeated. There are numerous time and administration sequences used; this one given is only an example. Clinicians need to explain the administration process to the patient so they can understand the schedule, and also receive counsel on factors that may alter the administration regimen.

Mode of Administration

• Injectable
• Intravenous
• Intraarterial - Not FDA approved for chemotherapy; used for hepatic artery chemoembolization
• Intravesical - Used in early bladder cancer

Dosage

The dosing of anthracyclines is by body surface area and varies with indication and type of anthracycline. general dose ranges for anthracyclines are listed below; specific indications will vary the dose. Clinicians should consult facility-specific dosing regimens and consult package inserts for specific agents.

The following shows the dosing regimens for doxorubicin, as an example of how agents in this class may be dosed and administered.

IV Route

Acute Lymphoblastic Leukemia

• 60 to 75 mg/m repeated every 21 days as a single agent
• 40 to 75 mg/m repeated every 21 days if combined with other chemotherapeutic agents
• Cumulative dose not to exceed 550 mg/m
• The dosing is the same for adults, adolescents, and children

Acute Myelogenous Leukemia

• 60 to 75 mg/m repeated every 21 days as a single agent
• 40 to 75 mg/m repeated every 21 days if combined with other chemotherapeutic agents
• Cumulative dose not to exceed 550 mg/m
• The dosing is the same for adults, adolescents, and children

Hodgkin Lymphoma

• Stanford V regimen
  • 25 mg/m^2 on weeks 1,3,5,7,9, and 11 in combination with mechlorethamine, vinblastine, vincristine, bleomycin, and prednisone. The total duration of treatment is 12 weeks
• BEACOPP regimen
  • Adults and adolescents 15 years or older: 25 mg/m on day 1 in combination with bleomycin, etoposide, cyclophosphamide, vincristine, procarbazine, and prednisone
• ABVD/MOPP regimen
  • 25 mg/m^2 on days 1 and 15 repeated every 28 days in combination with vinblastine, bleomycin, and dacarbazine
  • It is also used with vinblastine, brentuximab vedotin, and dacarbazine as well.
• The dosing is the same for adults, adolescents, and children

Intravesical

• Rapidly recurrent (stage Ta or T1) or in situ transitional cell bladder cancer
• 50 to 150 mg  in 150 ml of normal saline is instilled into the bladder and retained for at least 30 minutes

Adverse Effects

Although anthracyclines are among the most widely used chemotherapeutic agents, their therapeutic potential is limited by their extensive adverse event profile, ranging from mild to severe. The incidence rates of these reactions, however, are largely unknown.[7][8]

Mild

• Chills - Rapid
• Urticaria - Rapid
• Pruritis - Rapid
• Injection site reaction - Rapid
• Rash -  Early 
• Infection -  Early
• Nausea and vomiting -  Early
• Fever -  Early
• Diarrhea -  Early
• Abdominal pain -  Early
• Urine discoloration -  Early
• Lacrimation -  Early
• Malaise -  Early
• Anorexia - Delayed
• Photosensitivity - Delayed
• Nail discoloration - Delayed
• Skin hyperpigmentation - Delayed
• Amenorrhea - Delayed
• Oligospermia - Delayed
• Azoospermia - Delayed
• Gonadal suppression - Delayed
• Spermatogenesis inhibition - Delayed
• Asthenia - Delayed
• Co-enzyme Q10 deficiency - Delayed

Moderate

• Bleeding - Early
• Bone marrow suppression - Delayed
• Neutropenia - Delayed
• Dehydration - Delayed
• Stomatitis - Delayed
• Esophagitis - Delayed
• Colitis - Delayed
• Erythema - Delayed
• Palmar-plantar erythrodysesthesia - Delayed
• Conjunctivitis - Delayed
• Phlebitis - Delayed
• Skin ulcer - Delayed
• Radiation recall reaction - Delayed
• Skin ulcer - Delayed
• Elevated hepatic enzymes - Delayed
• Peripheral neuropathy - Delayed

Severe

• Anaphylactoid reactions - Rapid
• Tissue necrosis - Early 
• Coma - Early
• Leukopenia - Delayed
• Thrombocytopenia - Delayed
• Heart Failure - Delayed
• Cardiomyopathy - Delayed
• Cardiotoxicity - Delayed
• Pericarditis - Delayed
• Myocarditis - Delayed
• Typhlitis - Delayed
• Peptic ulcer - Delayed
• GI bleeding - Delayed
• Keratitis - Delayed
• Tumor lysis syndrome - Delayed
• New primary malignancy - Delayed
• Seizures - Delayed

Researchers are studying ways to mitigate the toxicity of anthracyclines through newer technologies, including nanoparticle delivery systems.[5][9][10] The effectiveness of cardioprotective agents remains ambiguous; there is no high-quality evidence supporting their effectiveness.[10]

Contraindications

Relative Contraindications

• Anthracycline hypersensitivity
  • Patients with previous anaphylactic reactions following administration of anthracyclines
• Hepatic disease
  • Patients with severe hepatic disease, defined as Child-Pugh class C or serum bilirubin greater than 5 mg/dL. Dosage adjustments are necessary for patients with mild to moderate hepatic disease.
• Pre-existing cardiac conditions
  • Heart failure, cardiomyopathy, myocardial infarction, myocarditis, pericarditis
  • Assessment of cardiac function using a MUGA or echocardiogram is necessary before starting treatment in these patients.
• Gender
  • Females have a higher risk of anthracycline-induced cardiotoxicity
• Age
  • Children and adolescents have a higher risk of developing late cardiovascular dysfunction. They should receive periodic cardiac evaluations.
• Reports of prepubertal growth inhibition/failure and gonadal impairment in children and adolescents
• Pregnancy (category D)
• In animal studies
• Breastfeeding 
• Live vaccines

Monitoring

Maximum Dosage

Adults, Adolescents and, Children

• Doxorubicin - Maximum lifetime cumulative dose of 550 mg/m; 450 mg/m^2 in patients who have received previous mediastinal radiation
• Daunorubicin - 45 mg/m/dose IV (up to 90 mg/m/dose has been used off-label); Maximum lifetime cumulative dose of 550 mg/m^2; 450 mg/m^2 in patients who have received previous mediastinal radiation.
• Epirubicin - 150 mg/m/dose  as a single agent - maximum cumulative dose is  900mg/m^2.
• Valrubicin - 800 mg intravesically in adults - efficacy and safety not established in adolescents and children
• Idarubicin - 12 mg/m^2 IV; maximum cumulative  lifetime dose is 150 mg/m^2 - efficacy and safety not established in adolescents and children
• Mitoxantrone - Maximum cumulative lifetime dosage is 140 mg/m^2

Children with BSA less than 0.5 m should have dose calculated based on body weight.

Dose adjustments are necessary for hepatic impairment.

Drug Interactions

Anthracyclines are major substrates of CYP2D6 and CYP3A4. Caution is necessary when using them concurrently with inhibitors of CYP3A4 and CYP2D6, as this will reduce anthracycline clearance and increase the chances of cardiotoxicity and other adverse effects. Notable interactions exist with taxanes (except docetaxel) and trastuzumab.[11][12]

Toxicity

Anthracycline-Induced Cardiotoxicity

• Cardiotoxicity-induced by anthracyclines is a significant cause of morbidity and mortality. The clinical definition is new-onset heart failure and/or detection of left ventricular dysfunction in exposed individuals; LV ejection fraction is the most commonly used measure.[13]
• Patients at high risk are those receiving any of the following treatments -
  • High dose anthracyclines (e.g., doxorubicin greater than 250 mg/m), high dose radiation therapy (greater than 30 Gy) where the heart is in the radiation field and, lower dose anthracyclines in combination with lower-dose radiation therapy.
• Other risk factors - Age older than 60 years at cancer diagnosis, compromised cardiac function, multiple cardiovascular risk factors including smoking, hypertension, hyperlipidemia and, obesity.[13]

Antidotes for Anthracyclines

Tissue necrosis induced by the extravasation of anthracycline can have many complications. Dexrazoxane is an available antidote to tackle the effects of extravasation and may also help prevent the development of anthracycline-induced cardiotoxicity.[14][15]

Enhancing Healthcare Team Outcomes

The administration of anthracyclines requires the efficient functioning of an interprofessional healthcare team comprised of doctors and other health professionals. A general practitioner, oncologist, physician assistant or nurse practitioner, pharmacist, and nurses are usually involved in the patient's care. A pediatrician and cardiologist may also have involvement as the case may dictate. The primary oncologist usually decides the patient's treatment plan; they will also counsel the patient on the need for this chemotherapeutic agent and the potential risks. During the initial treatment phase, a pharmacist is usually involved in providing the patient information on the dose, adverse effects, monitoring, checking for possible drug interactions, and follow-up.

After the initial phase of treatment, the patient is regularly followed up in the oncology clinic by the oncologist, who assesses response to treatment and also monitors the patient for adverse effects. The oncologist may alternate with the physician assistant or the nurse practitioner to see the patient at shorter intervals. A pediatrician may monitor growth and development in cases of chemotherapy in children. Oncology certified nursing will administer the medication and must be aware of the signs of toxicity or adverse effects so they can effectively monitor the patient and report any issues to the clinician on duty or oncologist. These examples demonstrate the impact of an interprofessional team on patient care, driving outcomes to a positive result while minimizing adverse events.

The most critical component of an interprofessional approach is the involvement of a cardiovascular team in the treatment to prevent anthracycline-induced cardiotoxicity and manage it effectively. Several studies have shown the benefit of this approach, including long-term care and follow-up in the outpatient setting. One such study provides high-level evidence for the development of guidelines.[16] Interprofessional care coordination will derive the best patient outcome while minimizing the not insignificant potential adverse events of anthracycline therapy. [Level 5]