Continuing Education Activity

Doxorubicin is an anthracycline class medication used to manage and treat various types of malignancies and tumors. This activity will highlight the mechanism of action, adverse event profile, and other factors, including off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions.

Objectives:

• Outline the mechanism of action of doxorubicin.
• Identify the potential adverse reactions of doxorubicin.
• Summarize the required monitoring of patients planning to take or currently taking doxorubicin.
• Review the importance of collaboration and coordination among the interprofessional team to enhance outcomes for patients receiving chemotherapy with doxorubicin.

Indications

Doxorubicin is an anthracycline class medication used to manage and treat various types of malignancies and tumors. It has both FDA-approved and off-label indications.[1][2]

FDA Approved Indications

• Acute lymphocytic leukemia
• Acute myelogenous leukemia
• Hodgkin lymphoma
• Non-Hodgkin lymphoma
• Bladder cancer
• Metastatic breast cancer
• Ewing sarcoma
• Metastatic neuroblastoma
• Metastatic ovarian carcinoma
• Metastatic osteogenic sarcoma
• Small cell lung cancer
• Metastatic soft tissue sarcoma
• Thyroid cancer
• Wilms tumor

Non-FDA Approved Indications

• Advanced endometrial carcinoma
• Metastatic hepatocellular cancer
• Multiple myeloma
• Advanced renal cell carcinoma
• Thymomas and thymic malignancies
• Uterine sarcoma
• Waldenstrom macroglobulinemia

Mechanism of Action

Doxorubicin is one of the cytotoxic anthracycline agents derived from Streptomyces spp. The anthracycline class of agents has similar mechanisms of action and works by intercalating between the DNA base pairs causing uncoiling of the DNA helical structure. This action causes inhibition of DNA synthesis and affects the activity of DNA topoisomerase II.[3] Anthracyclines can also form free radicals, which can target and damage rapidly growing cells.[4]

Doxorubicin is a major substrate of cytochrome P450, CYP3A4, CYP2D6, and P-glycoprotein (Pgp). Several clinically significant interactions have been reported with other inhibitors of CYP3A4, CYP2D6, and/or Pgp that can increase doxorubicin concentration, resulting in more or worsening side effects and toxicity at lower levels dosages.[4]

Administration

Doxorubicin is available as a powder for injection or as a liquid solution [2 mg/mL] administered intravenously (IV) via a central line as a continuous infusion.[5]

Adult Dosing

• 60 to 75 mg/m^2 intravenously (IV) every 21 days OR
• 60 mg/m2 IV every 14 days OR
• 40 to 60 mg/m^2 IV every 21 to 28 days OR
• 20 mg/m^2/dose once/week

Pediatric Dosing

• 35 to 75 mg/m^2 intravenously (IV) every 21 days 
• 20 to 30 mg/m^2/dose once/week
• 60 to 90 mg/m^2 IV over 96 hours every 3 to 4 weeks

Renal Impairment

• No dosage adjustment is necessary

Hepatic Impairment

• Total serum bilirubin less than 1.2 mg/dL: No dosage adjustment is necessary
• Total serum bilirubin 1.2 to 3.0 mg/dL: Decrease dose by 50%
• Total serum bilirubin: 3.1 to 5.0 mg/dL: Decrease dose by 25%
• Severe hepatic impairment: Contraindicated due to toxicity

Due to the side effect profile and toxicity of doxorubicin, patients are only allowed a lifetime dose of 550 mg/m^2. Patients receiving doxorubicin therapy must receive close follow-up and monitoring of blood counts, liver function, and heart function studies.[6]

Adverse Effects

Side Effects[7][8][9][10]

• Allergic reactions (anaphylaxis)
• Severe cough
• Photosensitivity
• Skin and nail hyperpigmentation
• Hoarseness of voice
• Flushing of the face
• Fatigue
• Joint pain
• Painful or difficult urination
• Persistent diarrhea

Less Common Side Effects[4]

• Black/tarry or bloody stools
• Seizures
• Tissue necrosis or death
• Cardiac arrhythmias
• Anemia 
• Neutropenia
• Shortness of breath due to congestive heart failure
• Edema in ankles or feet due to congestive heart failure
• A decrease in left-ventricular ejection fraction (LVEF) of greater than or equal to 10% 
• Cardiomyopathy
• Hepatotoxicity
• Tumor lysis syndrome

Contraindications

• Previous allergic reaction or anaphylaxis
• Pregnancy or if planning to become pregnant (relative contraindication - should be used for cancer treatment during pregnancy when indicated as a first-line agent)
• Current active viral or bacterial infections
• Severe hepatic impairment and/or total serum bilirubin over 5.0 mg/dL
• Myocardial infarction within the last 30 days before treatment
• Prior treatment to a maximum dose of 550 mg/m^2 with doxorubicin or other anthracycline agents
• Systolic dysfunction/cardiomyopathy not optimized on medical therapy
• Intramuscular or subcutaneous administration

Monitoring

Due to the cardiotoxic profile of doxorubicin, baseline left ventricular ejection fraction (LVEF) should be assessed and monitored routinely using an echocardiogram. An LVEF drop of greater than 10% from baseline is considered indicative of cardiotoxicity, and immediate intervention by physicians and the healthcare team is required. An alternative to echocardiogram monitoring is radionuclide ventriculography, such as multi-gated acquisition angiogram (MUGA) or equilibrium radionuclide angiogram (ERNA) scans, although less frequently used.[4][11]

Obtain baseline complete blood counts (CBC), hepatic enzymes, and tests of hepatic function.

Toxicity

The most prevalent toxicities appear below, as reported by several case studies and medication trials.[12][13] 

• Cardiomyopathy/cardiotoxicity: The incidence of myocardial damage from doxorubicin ranges from 1% to 20%, with dosages above 300 mg/m2. LVEF is important to monitor before, during, and after doxorubicin treatment.[4][14]
• Secondary malignancies: Although used to treat various malignancies and tumors, doxorubicin and other anthracyclines are known for causing secondary malignancies such as acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS).
• Tissue necrosis: doxorubicin extravasation can cause severe tissue death and necrosis requiring excision and grafting of the skin. It is important to monitor during intravenous injection or infusion of the agent.
• Hepatotoxicity: Hepatic failure is a strong contraindication to the use of doxorubicin. Trending total bilirubin concentrations and monitoring liver enzyme concentrations is essential.
• Myelosuppression: As with other anthracyclines, doxorubicin is known for causing severe myelosuppression requiring routine monitoring of white blood counts, hemoglobin, and platelets as myelosuppression predisposes to infections, sepsis, hospitalizations, or even death.

 Toxicity Prevention

• Several pharmacological agents have been used and studied to prevent and/or decrease cardiotoxicity in patients receiving anthracyclines, including dexrazoxane, beta-blockers, angiotensin antagonists, statins coenzyme Q-10, and N-acetylcysteine. Most notable studies have taken place testing beta-blockers and dexrazoxane.
• In one randomized study of 25 patients, carvedilol was not better than a placebo at preventing systolic and diastolic heart failure in patients taking anthracyclines.[15]
• Dexrazoxane is a prodrug and potent reversible inhibitor of DNA topoisomerase II, which may decrease topoisomerase II binding by doxorubicin and thus decrease the cytotoxicity of healthy cells. Dexrazoxane is an iron chelator (structurally similar to EDTA) that is thought to decrease free radicals generated by doxorubicin.
• A retrospective study found that dexrazoxane did not significantly affect the mean LVEF after anthracycline administration (56% with dexrazoxane vs. 53% without), but while the authors concluded that it decreased the rate of cardiac events, defined as a reduction of LVEF more than 10%, it is difficult to reconcile that conclusion of this retrospective analysis with the fact that the mean LVEF between the two groups was not different.[16]
• In a meta-analysis reviewing 16 trials, including 1918 patients: dexrazoxane reduced cardiotoxicity after anthracycline treatment by 33%. It specifically decreased heart failure by 58% compared to other agents, including beta-blockers, statins, coenzyme Q-10, and N-acetylcysteine. However, the study determined dexrazoxane did not affect the response rate of malignancies or the risk of death.[17]
• Further studies are in process and have begun to attract attention to minimize the cardiotoxicity risk of doxorubicin. 

Enhancing Healthcare Team Outcomes

Doxorubicin has been a mainstay in treating various cancers for many years, and members of the interprofessional health care team must be aware and up to date on the indications, interaction, adverse effects, and other pharmacodynamic and pharmacokinetic factors that can affect successful therapy implementation, and lead to improved patient outcomes. 

Prescribing and monitoring doxorubicin requires an interprofessional team of healthcare professionals that includes clinicians (MDs, DOs, NPs, PAs), various specialists (e.g., cardiologist, and hematologist/oncologist), nursing staff with specialized oncology and chemotherapy training, laboratory technologists, and pharmacists (preferably also oncology specialized)all working collaboratively and engaging in open communication about the patient's progress, status, and response to treatment.

Proper monitoring for complications, particularly cardiac and hepatic, is indicated as a retrospective study reported cardiotoxicity in 26%, and the 1-year mortality with doxorubicin-induced cardiotoxicity is as high as 50%.[18][19] Research has also shown cardiotoxicity as the leading cause of death in patients taking anthracyclines, as seen by several extensive randomized clinical retrospective studies.[4] [Level 1] 

Regularly monitor complete blood counts and metabolic panels to monitor for myelosuppression. The medical team should respond and assess significant changes to consider halting the drug when indicated. This monitoring function often falls to the clinical pharmacist, who will track the necessary lab work and inform the ordering clinician regarding situations that require alterations in the regimen. Nursing will be well versed in administration and monitoring for side effects, particularly extravasation, and inform the team of any concerns.

Team coordination is also necessary when considering using dexrazoxane to decrease the risk of cardiotoxicity. 

This interprofessional paradigm leads to the best patient result for oncological care with doxorubicin while mitigating risks and preventing adverse events. [Level 5]