Chapter 081. Principles of
Cancer Treatment
(Part 9)

Following demonstration of activity in animal models, conventional
chemotherapeutic agents are further evaluated to define an optimal schedule of
administration and arrive at a drug formulation designed for a given route and
schedule. Safety testing in two species on an analogous schedule of administration
defines the starting dose for a phase I trial in humans. This is established as a
fraction, usually one-sixth to one-tenth, of the dose just causing easily reversible
toxicity in the more sensitive animal species. Escalating doses of the drug are then
given during the human phase I trial until reversible toxicity is observed. Dose-
limiting toxicity (DLT) defines a dose that conveys greater toxicity than would be
acceptable in routine practice, allowing definition of a lower maximal tolerated
dose (MTD). The occurrence of toxicity is, if possible, correlated with plasma
drug concentrations. The MTD or a dose just lower than the MTD is usually the
dose suitable for phase II trials, where a fixed dose is administered to a relatively
homogeneous set of patients with a particular tumor type in an effort to define
whether the drug causes regression of tumors. An "active" agent conventionally
has PR rates of at least 20–25% with reversible non-life-threatening side effects,
and it may then be suitable for study in phase III trials to assess efficacy in
comparison to standard or no therapy.
Response, defined as tumor shrinkage, is but the most immediate indicator
of drug effect. To be clinically valuable, responses must translate into clinical
benefit. This is conventionally established by a beneficial effect on overall
survival, or at least an increased time to further progression of disease. Active
efforts are being made to quantitate effects of anticancer agents on quality of life.
Cancer drug clinical trials conventionally use a toxicity grading scale where grade
I toxicities do not require treatment, grade II often require symptomatic treatment
but are not life-threatening, grade III toxicities are potentially life-threatening if
untreated, grade IV toxicities are actually life-threatening, and grade V toxicities

transduction systems that promote a cell's demise after a certain level of insult is
achieved, or in response to specific cell-surface receptors that mediate cell death
signals. Modulation of apoptosis by manipulation of signal transduction pathways
has emerged as a basis for understanding the actions of drugs and designing new
strategies to improve their use.
A general view of how cancer treatments work is that the interaction of a
chemotherapeutic drug with its target induces a "cascade" of further signaling
steps. These signals ultimately lead to cell death by triggering an "execution
phase" where proteases, nucleases, and endogenous regulators of the cell death
pathway are activated (Fig. 81-3).
Figure 81-3