How do we define success or failure of a targeted therapy
Authors: Jaap Verweij
Journal: Cancer Research (2004)

The introduction of targeted therapy has faced us with the problem on how to assess activity and efficacy, and how to do this as early in the development as possible. Much of the problem is related to the fact that most of the agents in development yield growth inhibition and negligible tumor regression in animal models. Particularly the latter means that the old dogma of tumor response can not be used for assessment of anti-tumor activity. For this reason there has been a lot of focus on discovery and validation of so called surrogate markers. This development has up to now been hampered by the fact that there is no matrix of reference. All possible new markers will have to be validated by correlating their changes during treatment with the ultimate desired effect being improvement of time to tumor progression or survival. Since the latter only can be derived from randomized phase III studies, the development of surrogate markers seems to be a box of Pandora. A surrogate marker should be proven to reflect tumor tissue activity and as such the tissue selection is crucial. Particularly for solid tumors obtaining tumor biopsies is an invasive and potentially risky procedure. Repeated biopsies are extremely difficult to obtain. Unfortunately there is lack of knowledge on the level at which other tissues such as skin, hairfollicle, buccal smear, GI mucosa, can be used. Studies with Tyrosine Kinase inhibitors have used all of these but none of them where conclusive.  Recently the measurement of circulating cells has drawn a lot of attention. Circulating tumor cells could be a major source of information when trying to identify effects of agents inhibiting the membrane and intracellular signalling. The major current problem is to find easy techniques enabling to collect adequate numbers of circulating tumor cells without having to perform major invasive procedure. For agents affecting the vasculature or inhibiting angiogenesis the measurement of circulating endothelial precursors cells has been proposed. There are several types of such cells, including true progenitors that may reflect response to angiogenic treatment, or apoptotic and viable cells that may reflect the amount of direct effect on endothelium. Similar to the circulating tumor cells, circulating endothelial cell collection and assessment still faces a few technical problems that as yet do not render their use commonly applicable.  Imaging the effect of treatment by other means than assessing response is another area of research. Although interesting techniques have been developed as yet only PET scanning has shown a predictive value for ultimate response. Dynamic MRI may become another tool for this purpose. But similar to marker changes, changes in imaging will first have to be validated against survival and/or TTP before becoming universally applicable.  Nonetheless progress has been made. The recent introduction of various monoclonal antibodies has shown that certainly in the combination with active cytotoxic treatment intermittent trial designs can be helpful in the early determination of potential efficacy. Recent examples on erbitux and bevacizumab again confirm this. Trial designs driven by assessing progression rather than response, or trials using the randomized discontinuation method have already shown to be beneficial. The development of tools to determine success or failure will be discussed.