A New Method for the High-Precision Assessment of Tumor Changes in Response to Treatment

Imaging demonstrates that preclinical and human tumors are heterogeneous, i.e. a single tumor can exhibit multiple regions that behave differently during both normal development and also in response to treatment. The large variations observed in control group tumors can obscure detection of significant therapeutic effects due to the ambiguity in attributing causes of change. This can hinder development of effective therapies due to limitations in experimental design, rather than due to therapeutic failure. An improved method to model biological variation and heterogeneity in imaging signals is described. Specifically, Linear Poisson modelling (LPM) evaluates changes in apparent diffusion co-efficient (ADC) before and 72 hours after radiotherapy, in two xenograft models of colorectal cancer. The statistical significance of measured changes are compared to those attainable using a conventional t-test analysis on basic ADC distribution parameters. When LPMs were applied to treated tumors, the LPMs detected highly significant changes. The analyses were significant for all tumors, equating to a gain in power of 4 fold (i.e. equivelent to having a sample size 16 times larger), compared with the conventional approach. In contrast, highly significant changes are only detected at a cohort level using t-tests, restricting their potential use within personalised medicine and increasing the number of animals required during testing. Furthermore, LPM enabled the relative volumes of responding and non-responding tissue to be estimated for each xenograft model. Leave-one-out analysis of the treated xenografts provided quality control and identified potential outliers, raising confidence in LPM data at clinically relevant sample sizes.