The proposal seeks to develop the first meaningful objective radiographic parameter that correlates with the clinical symptoms of radiation pneumonitis (RP) as an imaging biomarker of RP. RP is the dose limiting toxicity in thoracic radiotherapy for lung cancer making local control (based on bronchoscopic biopsy) achievable in less than 20% of patients. RP is an inflammatory reaction within lung tissue in response to radiation injury. [18F]-2-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) imaging provides an assessment of pneumonitis, pulmonary inflammation appears as enhanced 18F-FDG uptake in response to inflammatory stimuli. We found with statistical modeling a linear relationship between the 18F-FDG PET uptake (normalized to unirradiated lung) and the radiation dose in normal lung after radiotherapy for esophagus cancer. This metabolic response was found only in lung tissue. We found this linear relation in each patient examined, however the slope varied from individual to individual over an order of magnitude. We refer to the regression slope of this relationship as the pulmonary metabolic radiation response (PMRR). We found a significant correlation between clinical symptoms and the PMRR measured by 18F-FDG PET imaging following thoracic radiotherapy. Using the PMRR as a surrogate imaging biomarker of toxicity we found a greater PMRR response among thoracic radiotherapy patients who received both induction and concurrent taxane chemotherapy. The development of the PMRR as a RP imaging biomarker requires a prospective study to demonstrate reproducibility and correlation with clinical symptoms. Our hypothesis is: The PMRR, first described by the principal investigator, provides an imaging biomarker of clinical and molecular pulmonary radiation toxicity. To develop this hypothesis we propose to conduct a phase II imaging trial to obtain 18F-FDG PET imaging post-radiotherapy in non-small cell lung cancer patients. To improve the clinical correlation compared with our prior retrospective studies we will: 1) query respiratory symptoms weekly using a standard respiratory questionnaire, and 2) utilize a consistent PET imaging post-radiotherapy delay and post- injection uptake period. We will assess the correlation of radiation induced inflammatory signaling, cytokine, and adhesion molecules with the metabolic response. Weekly measurement of these molecular biomarkers will allow their predictive power to be evaluated and provide for correlation with the PMRR and clinical symptoms. To make the PMRR calculation more robust and broadly available for multi-center use, the PMRR calculation methods and processing will be evaluated and standardized. Software to calculate the PMRR will be released on the Internet allowing other investigators to conduct studies using the PMRR as an imaging biomarker.
This study will further the development of a novel imaging biomarker, called the pulmonary metabolic radiation response (PMRR), developed by the principal investigator. The PMRR is the first meaningful objective radiographic parameter that correlates with the clinical symptoms of radiation pneumonitis, a major toxicity after radiation treatment for thoracic malignancies such as lung or esophagus cancer. We anticipate the PMRR, the focus of this study, may have a significant impact on the development of drug to reduce radiation treatment toxicity in cancer patients.
