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. Doselimiting...
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Chapter 081. Principles of Cancer Treatment (Part 9) Chapter 081. Principles of Cancer Treatment (Part 9) Following demonstration of activity in animal models, conventionalchemotherapeutic agents are further evaluated to define an optimal schedule ofadministration and arrive at a drug formulation designed for a given route andschedule. Safety testing in two species on an analogous schedule of administrationdefines the starting dose for a phase I trial in humans. This is established as afraction, usually one-sixth to one-tenth, of the dose just causing easily reversibletoxicity in the more sensitive animal species. Escalating doses of the drug are thengiven during the human phase I trial until reversible toxicity is observed. Dose-limiting toxicity (DLT) defines a dose that conveys greater toxicity than would beacceptable in routine practice, allowing definition of a lower maximal tolerateddose (MTD). The occurrence of toxicity is, if possible, correlated with plasmadrug concentrations. The MTD or a dose just lower than the MTD is usually thedose suitable for phase II trials, where a fixed dose is administered to a relativelyhomogeneous set of patients with a particular tumor type in an effort to definewhether the drug causes regression of tumors. An active agent conventionallyhas 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 incomparison to standard or no therapy. Response, defined as tumor shrinkage, is but the most immediate indicatorof drug effect. To be clinically valuable, responses must translate into clinicalbenefit. This is conventionally established by a beneficial effect on overallsurvival, or at least an increased time to further progression of disease. Activeefforts are being made to quantitate effects of anticancer agents on quality of life.Cancer drug clinical trials conventionally use a toxicity grading scale where gradeI toxicities do not require treatment, grade II often require symptomatic treatmentbut are not life-threatening, grade III toxicities are potentially life-threatening ifuntreated, grade IV toxicities are actually life-threatening, and grade V toxicitiesare those that result in the patients death. Development of targeted agents should proceed quite differently. WhilePhase I–III trials are still conducted, molecular analysis of human tumors moreprecisely defines targets expressed in a patients tumor and should allow patientselection to enrich all trial phases with patients potentially responsive to the agentby virtue of expressing the target in the tumor. Clinical trials may be designed thatassess the behavior of the drug in relation to its target. Ideally, the plasmaconcentration that affects the drug target is known, so escalation to MTD may notbe necessary. Rather, the correlation of host toxicity while achieving an optimalbiologic dose becomes a more relevant endpoint for Phase I and early Phase IItrials with targeted agents. Valuable cancer drug treatment strategies using conventional chemotherapyagents, targeted agents, hormonal treatments, or biologicals have one of twovaluable outcomes. They can induce cancer cell death, resulting in tumorshrinkage with corresponding improvement in patient survival, or increase thetime until the disease progresses. Another potential outcome is to induce cancercell differentiation or dormancy with loss of tumor cell replicative potential andreacquisition of phenotypic properties resembling normal cells. Blocking tumorcell differentiation may be a key feature in the pathogenesis of certain leukemias. Cell death is a closely regulated process. Necrosis refers to cell deathinduced, for example, by physical damage with the hallmarks of cell swelling andmembrane disruption. Apoptosis, or programmed cell death, refers to a highlyordered process whereby cells respond to defined stimuli by dying, and itrecapitulates the necessary cell death observed during the ontogeny of theorganism. Anoikis refers to the death of epithelial cells after removal from thenormal milieu of substrate, particularly from cell-to-cell contact. Cancerchemotherapeutic agents can cause both necrosis and apoptosis. Apoptosis ischaracterized by chromatin condensation (giving rise to apoptotic bodies); cellshrinkage; and, in living animals, phagocytosis by surrounding stromal cellswithout evidence of inflammation. This process is regulated either by signaltransduction systems that promote a cells demise after a certain level of insult isachieved, or in response to specific cell-surface receptors that mediate cell deathsignals. Modulation of apoptosis by manipulation of signal transduction pathwayshas emerged as ...