Lung Functional Avoidance Radiotherapy Using Hyperpolarized Xenon MRI

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SUMMARY Customized 3D planning of radiation therapy for lung cancer delivers a lethal dose to the tumor region while avoiding important structures (spine) and organs (esophagus, heart, lungs) Since radiation dose to functioning lung is associated with acute radiation pneumonitis and chronic radiation fibrosis, researchers seek to shift dosage preferentially away from lung regions with highest function. Several lung functional imaging modalities have been investigated (ventilation- perfusion SPECT and PET, 4DCT, hyperpolarized 3He). These studies indicate that regional ventilation is not the optimal biomarker. What is needed is a high-resolution imaging modality, tolerable to patients who have difficulty holding their breath, that delineates regions of full lung function warranting preservation, and also identifies regions whose function is irrevocably gone. Hyperpolarized xenon-129 (HXe) MRI provides highly detailed maps of several lung functional characteristics. Its solubility in tissues and affinity for hemoglobin allow it to be used as a tracer for gas exchange kinetics, a so-called “regional DLCO”. Up until now, HXe imaging modalities required long breath holds, which are not well tolerated by lung-compromised patients. We developed an HXe assessment technique that probes several lung function characteristics, including gas exchange to/from red blood cells, with a natural tidal-breathing protocol. Our industrial team developed an automated xenon hyperpolarizer that delivers the required multi-liter volumes at polarizations that approach 50%, enabling this protocol to become routine. We propose a translational study applying HXe MRI to functional avoidance plan optimization to minimize fibrosis in lung cancer patients. To maximize statistical significance, we stratify the patient cohort selecting patients with significant heterogeneity: half with de novo lung cancer with GOLD stage 3+ emphysema comorbidity and half receiving RT for their second (primary) lung cancer. Maps will delineate three functional regions: full function with both ventilation and gas exchange to RBCs (extra importance for avoidance), regions where function is irrevocably absent (reduced avoidance), and other regions where function may be present or recoverable (normal avoidance). In year 1 we conduct an open-label trial to optimize the functional imaging protocols with upgraded hardware. With IRB and DSMB approval, our Phase 2 clinical trial will enroll 70 patients: half receiving standard-of-care treatment and half undergoing RT guided by HXe MRI. Six-month post-treatment assessments include changes in HXe MRI, for regional correlation with local dose. Primary endpoint will be change in DLCO, with secondary endpoints of breathing- related quality of life change from baseline, spirometry/DLCO relative to predicted, incidence/severity of pneumonitis, and change in HXe-MRI.