The primary goal of this project is to evaluate the role of FDG PET and its ability to predict early treatment response and to correlate with bio-molecular markers of treatment resistance in advanced epithelial ovarian cancer (AOC). A vast majority of ovarian cancer patients present with advanced stages of the disease and are managed using tumor reductive surgery, followed by multi-agent platinum-based chemotherapy. In nearly one quarter of the cases, in order to achieve effective disease control, neoadjuvant chemotherapy is given prior to surgical debulking. In spite of aggressive treatment approaches, most women with AOC are likely to die with chemotherapy resistant disease and identifying these patients is key, since this may allow early treatment modifications, avoiding prolonged treatment with futile toxic chemotherapy regimens. This project will focus on two roles of F-18 Fluorodeoxyglucose (FDG) PET: (a) to evaluate early response of AOC to chemotherapy and (b) as an independent prognostic indicator. Our proposal is the first such study using serial FDG PET scans with quantitative approaches using kinetic analysis to accurately evaluate treatment response in patients with AOC undergoing neoadjuvant chemotherapy and correlating it with biomarkers of tumor aggressiveness and drug resistance (many of which may be targets for novel therapeutic agents) in evaluating treatment resistance and response.
The specific aims are: (1) Correlate the changes in FDG uptake from serial FDG scans with early treatment response and clinical endpoints;(2) Determine the association between FDG PET measure of glycolysis and biomarkers of chemoresistance and tumor burden (serum CA125 levels) using classification and regression tree (CART) analysis to measure the overall aggressive potential and provide a clinical decision support framework that could personalize therapy by directing eligible patients to novel targeted/combination therapies. Using serial FDG scans (FDG 2 &3) taken during the course of neoadjuvant chemotherapy, we will determine if patients who show a significant decrease in FDG uptake will have a better and longer lasting response to treatment. The last FDG scan (FDG PET #3) will help in evaluating non-responsive disease and help direct tissue sampling at the time of surgery. We will also investigate the role of quantitative measures such as the metabolic rate of FDG (Ki) vis-`-vis semi-quantitative specific uptake value (SUV) measure in the prognostic evaluation of AOC patients. We will correlate FDG uptake in tumors with molecular markers of chemoresistance in characterizing tumor aggressiveness and treatment response in these patients. The results from this pilot study will lead to a classification algorithm that combines FDG and biomarker data (using CART analysis) for identifying chemoresistant patients and would provide a measure of aggressiveness of ovarian cancer. Early identification of non-responders will help design studies that allow introduction of alternative treatment regimens. This will lay the foundation for future large-scale studies and more rational treatment selection to improve survival in patients with AOC.
This pilot study will set the stage for large scale trials by exploring the non-invasive role for FDG PET imaging along with biomarkers in evaluating aggressiveness and early treatment response in patients with advanced ovarian cancer. Identification of drug resistance and lack of response to chemotherapy will guide in selecting alternative treatment regimens and help avoid unnecessary toxicities in non-responders.
