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Chemotherapy uses cytotoxic agents that interfere with DNA replication or cell division, preferentially affecting cells with high proliferation (tumor cells, but also bone marrow, mucous membranes, hair follicles). Skipper's log-kill hypothesis states that a given dose always destroys the same fraction (not the same number) of cells: if a dose destroys 99%, it will destroy 10¹ of 10¹² cells and leave 10¹ viable. This means that chemotherapy must be administered in multiple cycles.

The Norton-Simon model extends that of Skipper for tumors with Gompertz kinetics: chemotherapy is more effective when the tumor is large (higher fraction in active proliferation) than when it is small. This justifies preoperative (neoadjuvant) chemotherapy in large tumors: it shrinks the tumor before surgery by maximizing the fraction of cells destroyed. The model also predicts that dose-dense chemotherapy is more effective than standard chemotherapy for certain tumors.

Bone marrow toxicity (neutropenia) is the most common limiting complication of chemotherapy. Friberg's model describes the dynamics of the ANC: the cytotoxic agent suppresses the production of marrow progenitors the ANC falls to the nadir (714 days post-cycle) and recovers in 2128 days. Nadir ANC < 500/L (febrile neutropenia) is the most common oncological emergency. G-CSF (colony factor) stimulates k_prod, shortening the nadir and recovery time.

Resistance to chemotherapy is inevitable if the tumor has enough cells: the Goldie-Coldman model calculates P_resistance = 1 - (1-_res)^N with N = 10 cells and _res = 10, resistant clones are virtually guaranteed to exist. Polychemotherapy (multiple drugs with different mechanisms) reduces the probability of simultaneous resistance to all drugs, justifying combination regimens (CHOP in lymphoma, FOLFOX in colorectal cancer).

The therapeutic index (TI = LD/ED) of cytotoxics is extremely narrow (TI 12): the effective dose is similar to the toxic dose. Monitoring C_max and AUC (drug level in blood) allows individual dosing to be optimized (adjusted by weight, body surface area, renal/hepatic function) and reduces pharmacokinetic variability, bringing each patient closer to the optimal therapeutic window.

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