Can Washout Rate be a Biomarker of Tumor Viability in Charged Particle Therapy? A Rat In-beam PET Study

Purpose/Objective(s)Positron emission tomography (PET) is a practical tool for range verification in charged particle therapy. We aimed to apply in-beam PET imaging for tracking the evolution of irradiated particles in living tissue. The quantitative biological washout rate of the positron emitters has a potential usefulness as a diagnostic index that provides a unique opportunity to probe the status of tumor viability, but the modeling for this has not been established. Therefore, we measured biological washout rates of tumor-bearing nude rat and performed kinetic analysis on dynamic PET data to explore the biological washout mechanism.Materials/MethodsC6 rat glioma cells were implanted into right shoulder subcutaneous regions of six nude rats. Tumors volume reached to about 3 cm3 on day 14 after implantation. Tumor tissue (right shoulder) and normal tissue (left shoulder) were irradiated by 11C radioactive ion beam. Time activity curves (TACs) of the irradiated field were acquired by our original PET prototype. The biological washout rate was quantified based on the two-washout model assuming medium decay rate (k2m) and slow decay rate (k2s). In this model, k2m is speculated as the component which spread out via interstitial fluid, and k2s is speculated as the trapping component by the stable molecules in the tissue. After irradiation and PET dynamic scan, pathological morphology of tumor tissue (Hematoxylin & Eosin staining) was observed under microscope.ResultsThe two-washout model fitted the experimental TACs well for five of six nude-rats irradiation studies. The observed k2m of tumor irradiation was 0.31+/-0.04 min-1, which was consistent with the normal tissue irradiation. While k2s of tumor irradiation was faster (0.017 +/-0.002 min-1) than that of normal tissue irradiation (0.006 +/-0.002 min-1). These results suggested that the component, which was trapped in normal tissue, diffused out more smoothly from tumor tissue due to vascular hyperpermeability which characterizes pathological tumor-angiogenesis. For one of six nude rats, only slow washout component (k2s = 0.014 +/-0.003 min-1) was observed in tumor irradiation study. Necrosis in tumor was observed in pathological tissue sample of this nude rat. It is also suggested that the decrease of washout rate was caused by the decrease of blood flow in the necrotic region.ConclusionWe measured the biological washout rate of irradiated 11C ion beam in tumor tissue and normal tissue. The physiological difference of tissue condition reflected the biological washout rates. This effect may be used as a clinical diagnostic index to monitor the dose response of the tumors in individual patients as well as the observation of the functional metabolism of tumor