The next significant advance in cancer therapy will occur with the paradigm shift from a population-based to a personalized patient-based dose prescription. In radiation therapy this paradigm shift will require, not only adjustment of the total dose prescribed, but also a shift from the current standard of uniform dose prescription to a non-uniform dose prescription, which will be tailored to the spatial distribution of biological properties in the tumor - the process most often termed "dose-painting". To ensure safe translation to human patients, we propose a thorough investigation on a canine spontaneous nasal tumor model. Four treatment groups will be considered: (1) Standard radiotherapy, (2) Uniform dose escalation, (3) Non- uniform dose escalation based on hypoxia and (4) Non-uniform dose escalation based on proliferative response. PET/CT imaging will be performed to guide treatment dose prescription and evaluate treatment response. FLT-PET will be used as a surrogate of cell proliferation, CuATSM-PET as a surrogate of tumor hypoxia and FDG-PET as a surrogate of tumor metabolism. Correlation to biological surrogates will be established by performing extensive IHC assessment on a tissue biopsy sample taken prior to the start of radiation therapy. The overall hypothesis is that non-uniform dose escalation based on biological imaging (dose painting) leads to more effective radiotherapy than uniform dose escalation delivering the same integral dose boost. This hypothesis will be tested within three specific aims:
Specific Aim 1 : To compare uniform dose escalation to standard therapy Specific Aim 2: To compare non-uniform dose escalation based on hypoxia (hypoxia-based dose painting) to uniform dose escalation Specific Aim 3: To compare non-uniform dose escalation based on proliferative response (proliferative response-based dose painting) to uniform dose escalation In addition, we will perform three auxiliary studies: Auxiliary Study 1: To correlate early proliferative response and pre-treatment hypoxia to treatment response Auxiliary Study 2: To correlate early proliferative response to reoxygenation. Auxiliary Study 3: To spatially correlate early proliferative response to the position o tumor recurrence.
Individualized radiotherapy, where radiation dose will be tailored to individual patient tumor biological characteristics, is the next logical step in radiotherapy development. This approach will revolutionize the way that radiotherapy is prescribed and planned, and will improve the therapeutic outcome in terms of local tumor control and side-effects to unaffected tissue.
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