5.2 Cytotoxic Chemotherapy Classes & Adverse Effect Management

3.2 Cytotoxic Chemotherapy Classes & Adverse Effect Management

Clinical Pearl: Intrathecal administration of vincristine is uniformly fatal, inducing progressive ascending radiculomyeloencephalopathy. To prevent accidental intrathecal administration, vincristine must never be prepared in a syringe; ONS guidelines mandate dispensing vincristine exclusively in a small-volume intravenous piggyback (flexbag) labeled with prominent warning stickers: "FOR INTRAVENOUS USE ONLY — FATAL IF GIVEN BY OTHER ROUTES."

Alkylating Agents & Platinum Compounds

Alkylating agents and platinum analogs form covalent DNA cross-links, inhibiting DNA replication and transcription. These agents are cell cycle-nonspecific (CCNS).

Nitrogen Mustards & Oxazaphosphorines

• Cyclophosphamide & Ifosfamide: Undergo hepatic cytochrome P450 bioactivation to form mustard active species and toxic metabolite acrolein. Acrolein accumulates in the urinary bladder, inducing urothelial ulceration and severe hemorrhagic cystitis.
  • Prevention & Management: Concurrent administration of Mesna (2-mercaptoethanesulfonate), which binds acrolein in the bladder to form an inactive thioether. Aggressive IV hyperhydration (2–3 L/m²/day) and frequent voiding are mandatory. Ifosfamide always requires Mesna; high-dose cyclophosphamide (≥ 50 mg/kg or 1500 mg/m²) requires Mesna.
  • Ifosfamide Encephalopathy: Caused by metabolite chloroacetaldehyde; treated with IV Methylene Blue (50 mg Q4H).

Platinum Analogs

• Cisplatin: Highly emetogenic (HEC) platinum compound. Primary dose-limiting toxicity is nephrotoxicity (acute tubular necrosis, hypomagnesemia, hypokalemia) and ototoxicity (irreversible high-frequency hearing loss).
  • Prevention: Pre- and post-infusion hydration with 1–2 liters of 0.9% Normal Saline supplemented with 20 mEq/L KCl and 8 mEq/L MgSO₄. Mannitol diuresis is indicated for high doses (≥ 75 mg/m²).
• Carboplatin: Less nephrotoxic and emetogenic than cisplatin; dose-limiting toxicity is myelosuppression (specifically severe thrombocytopenia with a delayed nadir at 21 days).
• Oxaliplatin: First-line agent in colorectal cancer. Dose-limiting toxicity is neuropathy:
  • Acute Neurotoxicity: Cold-induced transient pharyngolaryngeal dysesthesia occurring during or within hours of infusion (triggered by cold fluids, cold air, touching cold objects). Patient education regarding avoiding cold exposure is critical.
  • Chronic Cumulative Neuropathy: Dose-dependent peripheral sensory neuropathy occurring at cumulative doses >780–850 mg/m².

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Antimetabolites & S-Phase Inhibitors

Antimetabolites structurally mimic endogenous nucleosides, inhibiting key metabolic enzymes during the S-phase of the cell cycle.

Fluoropyrimidines (5-FU & Capecitabine)

• Mechanisms: Inhibits thymidylate synthase (TS) and incorporates into RNA/DNA.
• Toxicities: Continuous infusion 5-FU causes stomatitis, mucositis, and diarrhea; bolus 5-FU causes myelosuppression. Oral prodrug capecitabine causes severe Hand-Foot Syndrome (palmar-plantar erythrodysesthesia). Both cause rare coronary vasospasm/angina.
• Antidote: Uridine Triacetate (Vistogard) is the FDA-approved oral antidote for 5-FU or capecitabine overdose or severe early-onset toxicities (e.g., in unrecognized DPYD deficiency). Must be administered within 96 hours of 5-FU completion.

Folic Acid Analogs (Methotrexate)

• Mechanism: Competitive inhibition of dihydrofolate reductase (DHFR), blocking tetrahydrofolate synthesis.
• High-Dose Methotrexate (HD-MTX ≥ 500 mg/m²): Causes severe acute kidney injury via intratubular drug precipitation.
  • Supportive Protocol: Maintain vigorous IV hydration and urinary alkalinization (pH ≥ 7.0 using NaHCO₃) to enhance methotrexate solubility.
  • Rescue Therapy: Leucovorin (folinic acid) bypasses DHFR inhibition, rescuing normal host tissues. Leucovorin dosing is titrated based on serial serum methotrexate levels.
  • Glucarpidase (Voraxaze): Recombinant carboxypeptidase enzyme indicated for toxic serum methotrexate levels (>1 µmol/L) in patients with delayed clearance due to renal impairment.

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Antitumor Antibiotics & Topoisomerase Inhibitors

Anthracyclines (Doxorubicin, Epirubicin, Idarubicin)

• Mechanisms: Intercalates DNA, inhibits Topoisomerase II, and generates free radicals.
• Cardiotoxicity: Causes cumulative dose-dependent irreversible cardiomyopathy and congestive heart failure.
  • Lifetime Dose Caps: Doxorubicin cumulative dose must not exceed 450 – 550 mg/m² (lower cap of 400 mg/m² if prior mediastinal radiation). Baseline LVEF evaluation via Echocardiogram or MUGA scan is mandatory.
  • Cardioprotectant: Dexrazoxane (Zinecard) is an iron-chelating agent indicated to reduce doxorubicin-induced cardiotoxicity in metastatic breast cancer patients who have received a cumulative doxorubicin dose of ≥ 300 mg/m² and require continued therapy.

Doxorubicin Exposure
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  ├─► Cumulative Dose < 300 mg/m² ──► Standard Infusion & LVEF Monitoring
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  ├─► Cumulative Dose >= 300 mg/m² ─► Consider Dexrazoxane Cardioprotection
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  └─► Cumulative Dose 450-550 mg/m² ─► Absolute Lifetime Dose Ceiling (Discontinue)

Pulmonary Toxic Antibiotics (Bleomycin)

• Bleomycin: Glycopeptide antibiotic causing DNA strand breaks. Lacks significant bone marrow suppression, but carries severe dose-dependent pulmonary toxicity (interstitial pneumonitis progressing to pulmonary fibrosis).
  • Lifetime Limit: Maximum lifetime cumulative dose of 400 units.
  • Surveillance: Baseline and periodic Pulmonary Function Tests (PFTs) assessing DLCO (diffusing capacity of the lung for carbon monoxide). A >15–20% drop in DLCO mandates drug discontinuation. High FiO2 during anesthesia triggers acute respiratory failure.

Topoisomerase I Inhibitors (Irinotecan)

• Irinotecan: Causes dose-limiting diarrhea with two distinct mechanisms:
  • Acute Cholinergic Diarrhea: Occurs during or within 24 hours of infusion, accompanied by diaphoresis, abdominal cramps, and salivation. Caused by acetylcholinesterase inhibition. Treated with IV or SC Atropine (0.25 to 1.0 mg).
  • Delayed Secretory Diarrhea: Occurs >24 hours post-infusion due to mucosal damage from active metabolite SN-38. Treated immediately with high-dose Loperamide (4 mg at onset, then 2 mg Q2H until diarrhea-free for 12 hours).

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Antimicrotubule Agents

Taxanes (Paclitaxel, Docetaxel, Cabazitaxel)

• Mechanism: Hyper-stabilize polymerized microtubules, preventing mitotic spindle disassembly and causing M-phase arrest.
• Paclitaxel: Formulated in Cremophor EL (polyoxyethylated castor oil), inducing severe hypersensitivity reactions (HSR). Mandates premedication with Dexamethasone, Diphenhydramine, and an H2 antagonist.
• Docetaxel: Causes severe fluid retention and pleural effusions; requires premedication with oral Dexamethasone (8 mg BID for 3 days starting the day before infusion).

Vinca Alkaloids (Vincristine, Vinblastine, Vinorelbine)

• Mechanism: Inhibit tubulin polymerization, preventing mitotic spindle formation.
• Vincristine: Minimal myelosuppression, but dose-limiting neurotoxicity (peripheral neuropathy, foot drop, paralytic ileus/severe constipation). Single doses capped at 2.0 mg to limit toxicity.