M. J. Dubec1,2, J. Price1, M. Berks1, J. Gaffney3, R. Little1, N. Sridharan4, N. Porta4, A. Datta1, D. McHugh1,5, S. Cheung1, M. B. van Herk1, J. Matthews6, A. Choudhury7, K. Harrington8,9, G. J. Parker10,11, D. L. Buckley2,12, A. McPartlin13, and J. P. OConnor1,14; 1Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom, 2Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, United Kingdom, 3Radiation Oncology, University Hospital Galway, Galway, Ireland, 4The Institute of Cancer Research, London, United Kingdom, 5Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, United Kingdom, 6Neuroscience and Experimental Psychology, University of Manchester, Manchester, United Kingdom, 7Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom, 8Royal Marsden NHS Foundation Trust, London, United Kingdom, 9Targeted Therapy Group, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom, 10Bioxydyn Ltd, Manchester, United Kingdom, 11Centre for Medical Image Computing, University College London, London, United Kingdom, 12Biomedical Imaging, University of Leeds, Leeds, United Kingdom, 13Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 14Radiotherapy and Imaging, Institute of Cancer Research, London, United Kingdom
Purpose/Objective(s): Hypoxia is common to most solid tumours and is associated with poor prognosis in head and neck (H&N) cancer by negatively affecting treatment efficacy. Oxygen-enhanced (OE)-MRI is a non-invasive method for mapping and quantifying the extent of regional hypoxia. We aimed to determine if OE-MRI derived hypoxic volume (HVMRI) could detect response to radiotherapy in patients with p16-positive oropharyngeal cancer. Materials/
Methods: This prospective study evaluated OE-MRI in patients with p16-positive oropharyngeal cancer undergoing standard-of-care (chemo)radiotherapy. Patients were recruited after ethics approval and written informed consent. Patients underwent OE-MRI scanning along with perfusion mapping prior to commencing treatment, followed by scans at week 2 and 4 (W2, W4) of therapy. A subset of patients had two pre-treatment scans to assess repeatability of HVMRI measured using within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Treatment response was measured at the cohort level using mixed effects modelling. We considered those individual lesions showing change greater than the RC limits of agreement (LOA) to exhibit true hypoxia modification. OE-MRI gas was delivered during a dynamic MR acquisition consisting of air and 100% O2 breathing phases, delivered at 15 L/min via a non-rebreathe mask. Dynamic contrast enhanced (DCE)-MRI was combined with OE-MRI to permit classification of lesion voxels as normoxic, hypoxic (based on a lack of OE-MRI-induced signal change between air and 100% O2 breathing phases (p < 0.05)) or non-perfused (based on lack of significant signal enhancement on DCE-MRI (p < 0.05)). Results: 20 patients were studied in a well-tolerated protocol. OE-MRI identified hypoxia in all primary and nodal lesions at baseline. HVMRI wCV was 24.6% and RC LOA were -45.7% to 84.1%. Cohort median HVMRI reduced from 11.3 cm3 to 6.9 cm3 (W2) (p < 0.001) to 5.9 cm3 (W4) (p < 0.001). Per-lesion analysis showed 54.6% of lesions showed significant hypoxia reduction at W2 which increased to 90% at W4 after comparing with RC LOA. All lesions considered as responsive at W2 remained so at W4. Lesion-specific hypoxia modification was discordant between primary tumours and nodes in 46.2% of patients with multiple lesions. Conclusion: HVMRI is a repeatable biomarker in patients with p16-positive oropharyngeal cancer and can detect change in the microenvironment within two weeks of (chemo)radiotherapy. Comparison of W2 and W4 imaging identifies the incidence, onset time and persistence of hypoxia modification in each individual lesion, with implications for scheduling of dose de-escalation strategies. Discordant biological responses between primary tumours and nodes were observed in nearly half of patients with multiple lesions, highlighting the importance of quantifying hypoxia in all available lesions.
