Angiogenesis modulation in cancer research: novel clinical approaches

For a tumour to grow beyond a certain size, it must develop a network of blood vessels to supply nutrients and oxygen and to remove waste products.Advances in the understanding of this process of tumour angiogenesis have led to the development of many drugs that target the different steps that are involved, more than 30 of which have entered clinical trials. However, so far, none has been approved, and there have been several prominent failures, which might be because clinical approaches that were established for traditional cytotoxic agents are inappropriate for angiogenic modulators.The usual clinical development of a cytotoxic agent is based on the following concepts: first, that the agent is associated with dose-dependent toxicity; second, that there is an upper limit for dose escalation, which is defined as the dose-limiting toxicity (DLT); third, that the maximum-tolerated dose (MTD) has a higher probability of shrinking tumours (defined as objective remission) and improving palliation of symptoms; and finally, that the agent or combination regimens that are associated with tumour shrinkage might prolong survival.By contrast, in early Phase I/II trials, angiogenic modulators have shown modest toxic effects and are mainly cytostatic, slowing or stopping the tumour growth and the development of metastases without producing an objective remission.It seems clear that the end points for dose-defining trials (Phase I) and efficacy trials (Phase II) should be reconsidered. We strongly recommend the extensive use of correlative studies in the early phases of drug development to establish surrogate biomarkers for use in efficacy trials. Novel Phase II trial designs should be considered to address issues such as the low probability of an objective measurable response with angiogenic modulators.Imaging studies could have a key role in assessing the efficacy of treatments. Various imaging modalities, such as magnetic resonance imaging, ultrasonography, positron emission tomography and computed tomography, can be selected for this purpose; the choice of imaging studies should be based on an accurate evaluation of the novel agents in preclinical models.Finally, careful selection of the clinical setting for the investigation (for example, tumour type and stage of disease) must be carried out before expensive, definitive Phase III clinical trials are initiated.