Generic Name

Doxorubicin

Mechanism

Doxorubicin is an anthracycline antibiotic that exerts cytotoxic effects through multiple interrelated mechanisms:
• DNA intercalation – inserts between base pairs, preventing proper DNA unwinding and transcription.
• Topoisomerase II inhibition – stabilizes the cleavable complex, leading to double‑strand breaks during replication.
• Generation of reactive oxygen species (ROS) – iron chelation mediates free‑radical production, causing oxidative DNA and cellular damage.
• Disruption of microtubule dynamics – interferes with mitotic spindle assembly, culminating in cell cycle arrest at G₂/M.

These actions culminate in apoptosis of rapidly dividing tumor cells while sparing normal cells to the extent possible.

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Pharmacokinetics

• Absorption – negligible oral bioavailability; administered intravenously (IV) or intrathecally.
• Distribution – extensive tissue penetration; high protein binding (~80‑90 % mainly to albumin). Peaks in breast, liver, and GI tract.
• Metabolism – hepatic conjugation (glucuronidation) and reduction. Reactive metabolites (e.g., doxorubicinol) contribute to cardiotoxicity.
• Elimination – biliary excretion (≈ 90 %) with ~10 % renal clearance. Half‑life ~24 h (commonly ~2½‑3 days due to tissue sequestration).

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Indications

• Breast cancer (primary, metastatic, and postoperative adjuvant).
• Leukemias – acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL).
• Lymphomas – Hodgkin's and non‑Hodgkin's.
• Sarcomas – various soft‑tissue and bone sarcomas.
• Other solid tumors – including ovarian, esophageal, and bladder cancer, often as part of combination regimens.
• Intrathecal therapy for leptomeningeal carcinomatosis (specialized dosing; not for routine use).

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Contraindications

• Absolute: History of severe cardiomyopathy or heart failure; cumulative dose >450 mg/m² (lifelong limit) due to irreversible cardiotoxicity.
• Relative: Pregnancy (category D); lactation; severe hepatic insufficiency; active, uncontrolled infection.
• Warnings:
• Cardiotoxicity – dose‑dependent, cumulative; anthracycline‑induced congestive heart failure (CHF) and arrhythmias.
• Myelosuppression – profound neutropenia, thrombocytopenia, anemia; risk of febrile neutropenia.
• Ototoxicity – rare, mainly at high doses.
• Radiation interaction – concurrent use may potentiate tissue damage; coordinate schedules.

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Dosing

• Resuscitation Diluent – 0.9 % NaCl or 5 % dextrose in normal saline.
• Premedication – antihistamines (diphenhydramine), corticosteroids (dexamethasone) for infusion reactions.
• Infusion Rate – 15‑30 min IV; slower rates reduce hypersensitivity.

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Adverse Effects

• Common (≥10 %)
• Nausea/vomiting
• Cardiac arrhythmias (palpitations, tachycardia)
• Myelosuppression (cytopenias, petechiae)
• Alopecia
• Oral mucositis
• Serious (≥1 %)
• Cumulative cardiotoxicity – CHF, dilated cardiomyopathy, sudden cardiac death.
• Secondary malignancies – therapy‑related acute myeloid leukemia (t‑AML) or myelodysplastic syndrome.
• Severe neutropenia → febrile neutropenia.
• Infections due to neutropenia.
• I/O compromise – hypersensitivity, anaphylaxis.

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Monitoring

• Baseline
• ECG and echocardiogram (LVEF).
• CBC with differential; serum chemistries.
• Pregnancy test if applicable.
• During Therapy
• CBC weekly (or per protocol).
• Echocardiography every 3 months or sooner if symptomatic.
• Liver function tests (ALT/AST) monthly.
• Measure cumulative dose weekly to avoid exceeding 450 mg/m².
• Post‑Treatment
• Annual cardiac screening for survivors.
• Surveillance for secondary malignancies (annual CBC, physical exam).

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Clinical Pearls

• Cumulative Dose Tracking – Use spreadsheet or electronic medication record to enforce the 450 mg/m² limit; most cardiotoxicity manifests after 300–400 mg/m².
• Dexrazoxane Advantage – Cardioprotective agent (25 mg/kg IV 30 min before doxorubicin) recommended after 240 mg/m² cumulative dose or in patients at high cardiac risk; reduces incidence of congestive heart failure by ~30‑40 % without affecting overall response.
• Metronomic Dosing – Low‑dose, continuous oral doxorubicin (e.g., 10 mg BID) has shown efficacy in some refractory cancers with dramatically lower cardiotoxicity; consider in heavily pre‑treated patients.
• Drug–Drug Interaction – Avoid concomitant use of other cardiotoxic agents (e.g., trastuzumab) at peak cardiotoxic windows; stagger administration when possible.
• Intrathecal Use Caveat – Because of higher toxicity and contamination risk, ensure strict adherence to WHO guidelines and use dedicated syringes/scalpel for CSF penetration.
• Top‑thing Study – In clinical trials, continuous cardiac monitoring (telemetry) after each infusion improves early detection of arrhythmias; may be practical in high‑dose regimens.

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• Doxorubicin remains a cornerstone of multi‑agent chemotherapy, but its utility hinges on vigilant cardiac monitoring, cumulative‑dose management, and thoughtful combination strategies.