Medical Oncology Pharmacology and Principles of Systemic Therapy
Pharmacokinetics and pharmacodynamics
Absorption, bioavailability, distribution, metabolism and elimination determine exposure; most antineoplastics follow first-order kinetics. Drug action is best understood through the log-kill hypothesis (a dose kills a fixed fraction, not a fixed number of cells), the Norton-Simon model of dose-dense scheduling, and Gompertzian growth. Dose intensity (mg/m2/week actually delivered) predicts outcome better than total dose given late.
Drug classes
Alkylators and platinum (DNA cross-links, cell-cycle nonspecific), antimetabolites such as methotrexate, 5-FU, gemcitabine and pemetrexed (S phase), topoisomerase inhibitors (etoposide, irinotecan, doxorubicin), tubulin agents (vinca alkaloids, taxanes), anthracyclines (free radical and topoisomerase II mediated), targeted agents and endocrine therapy.
Selected toxicities
Cisplatin: nephrotoxicity, ototoxicity, neuropathy, emesis. Doxorubicin: cumulative cardiomyopathy. Bleomycin: pulmonary fibrosis. Vincristine: neurotoxicity with little myelosuppression. Cyclophosphamide: haemorrhagic cystitis from acrolein, prevented with mesna. Methotrexate: mucositis, rescued with leucovorin.
Resistance and interactions
Resistance arises from efflux transporters (MDR1/P-glycoprotein), target amplification, bypass pathway activation and defective apoptosis. Most cytotoxics are hepatically metabolised and subject to CYP interactions, for example azoles raising vinca alkaloid toxicity.
Traps
Questions test the dose-limiting toxicity of each classic drug, the concept of nadir and recovery, and whether an agent is cell-cycle phase-specific.
Rule of thumb
The best dose is the highest dose that can be delivered repeatedly on time; a regimen delivering 90% of planned dose over 18 weeks has a relative dose intensity of 0.9.