Non-invasive, image-based, in-vivo assessment of tumor hypoxia to guide hypoxia-driven adaptive radiation therapy

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ABSTRACT Stereotactic radiosurgery is an effective treatment modality for brain metastases. In clinical practice, the radiation dose prescribed to a lesion balances risk of tumor recurrence and risk of radiation necrosis, with only minor crude adjustments in dose and fractionation based upon tumor diameter. In vitro studies have established the relevance of tumor hypoxia on tumor recurrence, tumor malignant behavior, and radiation necrosis which suggests that tumor hypoxia may be a valuable predictor of radiation response and a biomarker for adaptive or personalized radiation treatments. However, clinical adoption of tumor hypoxia as a biomarker has been limited due to the invasive nature and inaccessibility of hypoxia evaluation methods. Physiologically, tumor hypoxia results in neo-angiogenesis which elevates regional cerebral blood volume (CBV) and cerebral blood flow (CBF), but contra-intuitively causes decreased oxygen extraction due to elevated capillary transit times (CTT) which restricts diffusion. Magnetic resonance imaging (MRI)-based collective assessment of CBV, CBF, CTT and oxygen extraction fraction (OEF) may provide insight into tumor oxygenation status. MRI-based CBF, CBV and CTT evaluations can be accomplished by implementing well-established dynamic susceptibility contrast MRI. MRI-OEF evaluations are more challenging but work by us and others has demonstrated that this parameter can be quantified non-invasively in vivo using an asymmetric spin echo (ASE) MRI sequence. The overarching objective of this study is to validate an MRI protocol to assess brain tumor hypoxia non- invasively in vivo. Of the above proposed MRI-indicators of tumor hypoxia, we hypothesize that OEF is the parameter most likely to detect tumor hypoxia. To address our objective, we will pursue two aims: Aim (1) to obtain normative values and assess reproducibility and repeatability of MRI-based CBF, CBV, CTT and OEF in healthy participants undergoing both DSC and modified ASE MRI, and Aim (2) to validate regional ASE-MRI derived OEF as a marker for tumor hypoxia in patients with brain metastases. For the latter aim, participants will undergo both MRI and 18F-Fluoromisonidazole Positron Emission Tomography (18F-FMISO-PET) which is a known, sensitive indicator of tissue hypoxia. This work is impactful because validation of a scalable, non- invasive MRI indicator for tumor hypoxia will allow for clinical trials that evaluate the role of hypoxia on both tumor recurrence and radiation necrosis. In addition, the data gathered in this study will allow these trials to be responsibly motivated and designed. The long-term goal is to use these methodologies to elucidate a clinically useful biomarker which may allow for patient- and tumor-specific titrations in radiation treatment plan to optimize the therapeutic ratio in the setting of personalized cancer care.