Management of Anticancer Drug Toxicity

Management of Anticancer Drug Toxicity

1. Why anticancer drugs are uniquely toxic — the selectivity problem

• Anticancer drugs are one of the most toxic classes in all of therapeutics; "few categories of medication have a narrower therapeutic index and greater potential for causing harmful effects" (G&G 14e Ch.69, p.1337).
• The fundamental reason: unlike bacteria, malignant cells are host cells with deranged growth regulation and only relatively minor biochemical differences from normal cells — so the selectivity of cytotoxic drugs is inherently limited, and dose-limiting host toxicity is the rule (KDT 8e Ch.64, pp.933–934).
• Most classical cytotoxics act preferentially on rapidly multiplying cells because their targets are nucleic acids and their precursors, and nucleic-acid synthesis peaks during cell division. The normal tissues with the highest growth fraction therefore bear the brunt of toxicity: bone marrow, epithelial linings (oral, GI mucosa), reticuloendothelial system, hair follicles and gonads (KDT 8e Ch.64, p.916; G&G 14e Ch.69, p.1337).
• Toxicity is largely dose-dependent and predictable for a given drug, though susceptibility differs between individual agents (KDT 8e Ch.64, pp.916–917).
• Cell-cycle context of toxicity (G&G 14e Ch.69, pp.1337–1338; KDT 8e Ch.64, pp.934–935):
  • Cell-cycle non-specific (CCNS) drugs (alkylating agents, nitrosoureas, cisplatin, dacarbazine, antitumour antibiotics, procarbazine) kill resting and dividing cells.
  • Cell-cycle specific (CCS) drugs kill only actively dividing cells (toxicity usually expressed in S or M phase) — antimetabolites (S), vinca alkaloids/taxanes (M), bleomycin/etoposide (G₂).
  • Implication for toxicity: CCS drugs given in short pulses allow non-cycling normal cells to recover between courses — pulsed dosing is itself a toxicity-sparing strategy.
• Cautionary principle (G&G 14e Ch.69, p.1342): "It is imperative to recognise toxicities early, to alter doses or discontinue the offending medication … and to provide vigorous supportive care." Toxicities affecting heart, lungs, nervous system or kidneys may be irreversible if recognised late, leading to permanent organ damage or death.