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 are those that result in the patient's death. Development of targeted agents should proceed quite differently. While Phase I–III trials are still conducted, molecular analysis of human tumors more precisely defines targets expressed in a patient's tumor and should allow patient selection to enrich all trial phases with patients potentially responsive to the agent by virtue of expressing the target in the tumor. Clinical trials may be designed that assess the behavior of the drug in relation to its target. Ideally, the plasma concentration that affects the drug target is known, so escalation to MTD may not be necessary. Rather, the correlation of host toxicity while achieving an "optimal biologic dose" becomes a more relevant endpoint for Phase I and early Phase II trials with targeted agents. Valuable cancer drug treatment strategies using conventional chemotherapy agents, targeted agents, hormonal treatments, or biologicals have one of two valuable outcomes. They can induce cancer cell death, resulting in tumor shrinkage with corresponding improvement in patient survival, or increase the time until the disease progresses. Another potential outcome is to induce cancer cell differentiation or dormancy with loss of tumor cell replicative potential and reacquisition of phenotypic properties resembling normal cells. Blocking tumor cell differentiation may be a key feature in the pathogenesis of certain leukemias. Cell death is a closely regulated process. Necrosis refers to cell death induced, for example, by physical damage with the hallmarks of cell swelling and membrane disruption. Apoptosis, or programmed cell death, refers to a highly ordered process whereby cells respond to defined stimuli by dying, and it recapitulates the necessary cell death observed during the ontogeny of the organism. Anoikis refers to the death of epithelial cells after removal from the normal milieu of substrate, particularly from cell-to-cell contact. Cancer chemotherapeutic agents can cause both necrosis and apoptosis. Apoptosis is characterized by chromatin condensation (giving rise to "apoptotic bodies"); cell shrinkage; and, in living animals, phagocytosis by surrounding stromal cells without evidence of inflammation. This process is regulated either by signal 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 . Chapter 081. Principles of Cancer Treatment (Part 9) Following demonstration of activity in animal models, conventional chemotherapeutic. 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. 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