What is anthracycline

Anthracyclines are drugs extracted from Streptomyces spp. used in the treatment of various types of cancers ¹. The different types of anthracycline available for treatment are –

• Daunorubicin
• Doxorubicin
• Epirubicin
• Idarubicin
• Mitoxantrone
• Valrubicin

FDA approved indications ²:

• Acute lymphocytic leukemia
• Acute myelogenous leukemia
• Hodgkin’s lymphoma
• Non-Hodgkin’s lymphoma
• Bladder cancer
  • Rapidly recurrent (Ta or Ti) or in situ transitional cell carcinoma (Intravesical therapy)
  • Neoadjuvant treatment
  • Metastatic transitional cell bladder cancer
• Breast cancer
  • Adjuvant therapy following axillary lymph node resection in primary breast cancer
  • Metastatic breast cancer
• Other metastatic cancers
  • Ovarian cancer
  • Osteogenic sarcoma
  • Ewing’s sarcoma
  • Soft tissue sarcoma
  • Thyroid cancer
  • Neuroblastoma
  • Wilm’s tumor
  • Small cell lung cancer

Non-FDA approved indications include:

• Advanced endometrial carcinoma
• Metastatic hepatocellular cancer
• Multiple myeloma
• Advanced renal cell carcinoma (with sarcomatoid features)
• Thymomas and thymic malignancies
• Uterine sarcoma
• Waldenstrom macroglobulinemia

Anthracycline mechanism of action

The explanations of cytostatic and cytotoxic actions of anthracyclines point to by many 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.

DNA intercalation

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

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.

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.

Anthracycline contraindications

Anthracycline contraindications (relative)

• 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/ml – 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. These children should receive periodic cardiac evaluations
• Prepubertal growth inhibition/failure and gonadal impairment have been reported in children and adolescents
• Pregnancy category D
• In animal studies
• Breastfeeding
• Live vaccines

Anthracycline administration

Pharmacokinetics of anthracycline drugs:

• 75% bound to plasma proteins
• Primarily excreted into the bile
• Does not cross the blood-brain barrier

Mode of anthracycline drugs administration:

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

Anthracycline Dosage

The dosing of anthracyclines is by body surface area and varies with indication and type of anthracycline. The dosage of doxorubicin for common indications are listed below.

IV route

Acute lymphoblastic leukemia

• 60 to 75mg/m² repeated every 21 days as a single agent
• 40 to 75mg/m² repeated every 21 days if combined with other chemotherapeutic agents
• Cumulative dose not to exceed 550mg/m²
• The dosing is the same for adults, adolescents, and children

Acute myelogenous leukemia

• 60 to 75mg/m² repeated every 21 days as a single agent
• 40 to 75mg/m² repeated every 21 days if combined with other chemotherapeutic agents
• Cumulative dose not to exceed 550mg/m²
• The dosing is the same for adults, adolescents, and children

Hodgkin’s lymphoma

• Stanford V regimen: 25mg/m² 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 – 25mg/m² on day 1 in combination with bleomycin, etoposide, cyclophosphamide, vincristine, procarbazine, and prednisone
• ABVD/MOPP regimen: 25mg/m² on day 1 and 15 repeated every 28 days in combination with vinblastine, bleomycin, and dacarbazine
• The dosing is the same for adults, adolescents, and children

Intravesical

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

Anthracycline monitoring

Maximum dosage

Adults, adolescents and, children

• Doxorubicin – Maximum lifetime cumulative dose of 550mg/m²; 450mg/m² in patients who have received previous mediastinal radiation
• Daunorubicin – 45mg/m2/dose IV (up to 90mg/m²/dose has been used off-label); Maximum lifetime cumulative dose of 550mg/m²; 450mg/m² in patients who have received previous mediastinal radiation
• Epirubicin – 150mg/m²/dose as a single agent – maximum cumulative dose is 900mg/m²
• Valrubicin – 800mg intravesically in adults – efficacy and safety not established in adolescents and children
• Idarubicin – 12mg/m2 IV; maximum cumulative lifetime dose is 150mg/m² IV – efficacy and safety not established in adolescents and children
• Mitoxantrone – Maximum cumulative lifetime dosage is 140 mg/m² IV

Children with body surface area less than 0.5m² 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 substrate. Express caution while using it concurrently with inhibitors of CYP3A4 and CYP2D6.

Anthracycline toxicity

Anthracycline-induced cardiotoxicity ³

• 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
• Patients at high risk are those receiving any of the following treatments: High dose anthracyclines (e.g., doxorubicin greater than 250mg/m2), high dose radiation therapy (greater than 30Gy) where the heart is in the radiation field and, lower dose anthracyclines in combination with lower dose radiation therapy.
• Other risk factors: Age greater than 60 years at cancer diagnosis, compromised cardiac function, multiple cardiovascular risk factors including smoking, hypertension, hyperlipidemia and, obesity

Antidote for anthracyclines:

Tissue necrosis induced by extravasation of anthracycline can have many complications. Dexrazoxane is an experimental antidote to tackle the effects of extravasation.

It may also help to prevent the development of anthracycline-induced cardiotoxicity.

Anthracycline side effects

Anthracyclines have many side effects which may range from mild to severe. The incidence rates of these reactions, however, are largely unknown.

Mild side effects

• 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 side effects

• 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 side effects

• 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.

References

1. Venkatesh P, Kasi A. Anthracyclines. [Updated 2019 Feb 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538187
2. Megías-Vericat JE, Martínez-Cuadrón D, Sanz MÁ, Poveda JL, Montesinos P. Daunorubicin and cytarabine for certain types of poor-prognosis acute myeloid leukemia: a systematic literature review. Expert Rev Clin Pharmacol. 2019 Mar;12(3):197-218.
3. Barbosa RR, Bourguignon TB, Torres LD, Arruda LS, Jacques TM, Serpa RG, Calil OA, Barbosa LFM. Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers. Rev Assoc Med Bras (1992). 2018 Aug;64(8):745-754