New criteria for analyzing the statistical relationships between biological parameters and therapeutic responses of xenografted tumor models.

ABSTRACT

Analysis of preclinical studies using human tumors xenografted into rodents is commonly performed with Tumor Growth Index (TGI) and Tumor Growth Delay index (TGDi). To circumvent the limitations of these parameters, two new parameters, Time To Relapse (TTR) and Tumor Growth Speed (TGS), were developed using a mathematical modeling approach based on an exponential tumor growth. TTR is similar to progression free survival used in human clinical trials and TGS characterizes the pattern of tumor cell proliferation. Parameters were estimated for each rodent by the maximum likelihood method and statistical analyses were performed using ANOVA. These criteria can be used when tumor growths are assessed by repeated measures of their volume. As an example, we used data from a previously published study, which aimed to evaluate the relationship between histology, genetic parameters, and response to alkylating agents in a series of twelve gliomas. The group treated with temozolomide was reanalyzed using our criteria. This group presented a significantly longer TTR than the control group. TTR was also different according to tumor type oligodendrogliomas relapsed later than glioblastomas. The TGS was different according to the tumor type. Loss of heterozygosity (LOH) 1p ± 19q, LOH 10p ± 10q, telomerase activity, PTEN mutation, and EGFR amplification were related to temozolomide efficacy. Our criteria provide additional information to those given by TGI and TGDi. Due to statistical properties of TTR and TGS, some relations between the parameters such as tumor type or genetic alterations can be studied with TTR and TGS and not with TGI or TGDi.