Management of Anticancer Drug Toxicity

Introduction — why anticancer drugs are uniquely toxic

• The narrowest therapeutic index in therapeutics — anticancer drugs are one of the most toxic classes in all of medicine — few categories have a narrower therapeutic index; dose-limiting host toxicity is the rule.
• The selectivity problem — malignant cells are host cells with deranged growth regulation and only minor biochemical differences from normal cells, so the selectivity of cytotoxics is inherently limited.
• High-growth-fraction tissues bear the brunt — classical cytotoxics act preferentially on rapidly multiplying cells (targets are nucleic acids/precursors), so the normal tissues with the highest growth fraction suffer most — bone marrow, oral & GI mucosa, reticuloendothelial system, hair follicles and gonads. Toxicity is largely dose-dependent and predictable for a given drug.
• Cell-cycle context — cell-cycle non-specific (CCNS) drugs (alkylators, nitrosoureas, cisplatin, antitumour antibiotics) kill resting and dividing cells; cell-cycle specific (CCS) drugs kill only dividing cells (antimetabolites in S, vinca/taxanes in M) — giving CCS drugs in short pulses lets non-cycling normal cells recover and is itself a toxicity-sparing strategy.
• Governing principle — recognise toxicity early, alter doses or discontinue the offending drug, and give vigorous supportive care — toxicities affecting the heart, lungs, nervous system or kidneys may be irreversible if recognised late.