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BASIC PRINCIPLES OF CANCER CHEMOTHERAPY

  • Knowledge of drug actions, clinical toxicities, pharmacokinetics, and interactions is essential for the safe and effective administration of chemotherapy.

  • Treatment should be based on clinical trials that define optimal doses, schedule, and drug combinations.

  • Choice of treatment should depend on the tumor stage and histology with consideration of individual patient tolerance.

  • Drug approval by regulatory authorities and availability differ by countries.

  • High-dose conditioning regimens used in hematopoietic cell transplantation (HCT) result in additional organ toxicities not seen at conventional doses.

  • Chemotherapy often targets the process of DNA replication. More recently, drugs have been introduced to target specific cellular processes, including receptor signaling, inhibition of oncoproteins, angiogenesis, and membrane cluster of differentiation antigens.

  • Dose modification may be needed for patients with renal or hepatic dysfunction depending on the major route of drug clearance (Table 38–1).

TABLE 38–1DOSE MODIFICATION IN PATIENTS WITH RENAL OR HEPATIC DYSFUNCTIONa

COMBINATION CHEMOTHERAPY

  • Combination chemotherapy uses several drugs simultaneously based on certain empiric principles:

    — Each drug selected has demonstrable antitumor activity against the neoplasm for which it is used.

    — Each drug should have a different mechanism of action.

    — The drugs should not have a common mechanism of resistance.

    — Drug dose-limiting toxicities should not overlap.

    — Specific combinations chosen should be based on preclinical and clinical protocol-based evidence of synergistic activity.

CELL KINETICS AND CANCER CHEMOTHERAPY

  • Cell cycle–specific agents, such as antimetabolites, kill cells as they traverse the DNA synthetic phase (S phase) of the cell cycle.

    — Prolonged drug exposure maximizes the number of cells exposed during the vulnerable period of the cell cycle.

  • Non–cell cycle-dependent agents do not require cells to be exposed during a specific phase of the cell cycle.

    — Total dose of drug is more important than duration of exposure.

DRUG RESISTANCE

  • The basis for drug resistance is spontaneous occurrence of resistant cancer cell mutants and selection of drug-resistant cells under pressure of chemotherapy (clonal selection).

  • Sequential studies of human tumors before treatment and at the time of drug resistance have defined resistance mechanisms such as target gene mutation, amplification, and activation of an alternative signaling pathway.

  • Use of multiple drugs not sharing resistance mechanisms should ...

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