Challenges associated with evaluating the clinical utility of non-cytotoxic pharmaceutical agents in oncology.

For the last several decades the development of new cytotoxic agents for the treatment of malignant diseases has proceeded along a relatively standardized pathway. Following initial evaluation in preclinical in vitro and in vivo model systems, phase 1 human trials are conducted to define the pharmacokinetic, pharmacodynamic and safety profile of the new agent. If the toxicity of the investigative agent is found acceptable in the phase 1 testing, and there is even limited evidence of efficacy, phase 2 trials will be initiated in specific tumor types to determine the objective level of activity of the drug in that clinical setting. Also recorded during phase 2 testing will be the duration of responses in individuals achieving this clinical state, time to progression of all patients, and survival of the responding patients as well as the entire treated population. If the level of activity achieved in phase 2 testing is of sufficient magnitude to suggest the agent may have a role in the standard (non-investigative) management of a malignancy, phase 3 testing will be initiated directly comparing the new agent to an acceptable astandard of careo in that particular clinical setting. The randomized controlled clinical trial is the ultimate and gold standard test of the clinical utility of a new drug or drug combination in oncology. Several additional features characterize clinical testing of cytotoxic agents in cancer medicine. First, in the design of phase 1 trials it is generally assumed that the maximally tolerated dose is the dose level which should be tested in future clinical trials. Second, it is assumed that the agent should be administered as soon as toxicity from the previous treatment has resolved. Thus, the basic aim of treatment is to deliver drug with maintenance of maximal adose intensityo. For example, if a new cytotoxic agent can be delivered at its maximally tolerated dose every 3-weeks for 6 courses, this will be considered the preferred (aoptimalo) method of delivery, even though a number of alternative strategies might be proposed (e. g., administering a lower dose every 1 ± 2 weeks, or giving the maximally tolerated dose every 5 or 6 weeks for 10+ courses). Finally, it is assumed that most of the aacute side effectso of the new agent will be observed during phase 1 testing. It is recognized that many patients will progress rapidly during phase 1 trials and will be on treatment with the new agent for only one or two courses, making an assessment of more achronic toxicityo difficult. However, patients will generally receive more courses during phase 2 drug testing in which the potential negative effects of more prolonged treatment may become evident. Despite the success of this drug development strategy with cytotoxic chemotherapeutic agents, there are serious concerns with this approach for a number of new investigational agents being considered as potential therapeutic strategies in oncology. If an agent exerts its therapeutic effect by slowing tumor growth, or preventing tumor spread, actual regression of existing cancerous masses may not be observed. For example, it has been hypothesized that certain pharmaceutical agents may produce clinically relevant antineoplastic effects by inhibiting the ability of cancer cells to form new blood vessels (anti-angiogenesis agents) or by preventing the malignancy from establishing metastases (anti-metastatic agents). In the clinical trial setting such effects might be considered stable disease (i. e., no increase or decrease in existing tumor masses). Unfortunately, in the absence of actual tumor regression, it will be completely unknown if this astable disease stateo is the result of a biological effect of an The Journal Cancer Research and Clinical Oncology occasionally publishes Editorials and Guest editorials on current and controversial problems in experimental and clinical oncology. These papers reflect the personal opinions of the authors. Readers should send any comments directly to the authors