18F-FMISO PET/CT Visualization of Tumor Hypoxia in Patients With Chordoma of the Mobile and Sacrococcygeal Spine

Abstract

SummaryLocal recurrence (LR) rates in chordoma patients following surgery ± radiation therapy (RT) or definitive RT are high. Tumor hypoxia is associated with radioresistance and LR. In this prospective study, [ 18 F]-FMISO-PET/CT detected hypoxic tumor sub-volumes in 60% of patients with chordoma of the mobile and sacrococcygeal spine, the majority of which were sufficiently large to allow an RT boost. Further study of hypoxia-directed, dose-escalated RT, particularly in patients at high risk for LR, is warranted.Purpose/Objectives-Local recurrence (LR) rates in chordoma patients following surgery ± radiation therapy (RT) or definitive RT are high. Tumor hypoxia is associated with radioresistance and LR. [ 18 F] fluoromisonidazole positron emission tomography/computed tomography (FMISO-PET/CT) can visualize skull base chordoma hypoxic sub-volumes (HSV) and feasibility of hypoxia-directed RT dose-escalation has been demonstrated in head and neck cancer. This study investigates FMISO-PET/CT detection of targetable HSVs in chordoma of the mobile or sacrococcygeal spine.Methods and Materials-A prospective, pilot study of 20 patients with primary or locally recurrent chordoma of the mobile or sacrococcygeal spine treated with proton or combined proton/ photon RT ± surgery was completed. FMISO-PET/CT was performed prior to RT and after 19.8-34.2 GyRBE (relative biologic effectiveness). Gross tumor volumes (GTV) were delineated Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and HSVs defined including voxels with standardized uptake values ≥ 1.4 times the muscle mean. Clinical characteristics and treatments received were compared between patients with and without HSVs. Conclusions-FMISO-PET/CT detection of targetable HSVs within patients undergoing RT ± surgery for treatment of chordoma of the mobile and sacrococcygeal spine is feasible. The study's inability to attribute interval HSV changes to treatment, rapidly changing hypoxic physiology, or imaging inconsistencies is a limitation. Further study of double-baseline FMISO-PET/CT and hypoxia-directed RT dose-escalation, particularly in patients at high risk for LR, is warranted. NIH Public Access Results-FMISO-PET/CT

Radioresistant tumours: From identification to targeting

“…A single parameter such as an ( 18 F)fluoromisonidazole-PET mapping is probably insufficient to ascertain hypoxic resistance and to escalate the dose if one considers that tumours reoxygenate during fractionated radiotherapy [31], to the point that the same imaging arguments can be used to suggest therapeutic de-escalation when reoxygenation occurs [32]. A second obstacle to targeting hypoxia with radiotherapy is that there may be spatial variations in hypoxic subvolumes [33,34]. Therefore, a critical step could be to define a reliable and reproducible diagnosis of tumour radioresistance to be repeated over the course of radiotherapy if needed.…”

A journey of skull base chordoma

“…Some immunohistochemical markers, like increased expression of p53, CDK4, and high Ki-67 proliferation index have prognostic value (63)(64)(65)(66), but cannot explain the difference in outcome alone. Also, expression levels of brachyury, transforming growth factor alpha (TGF-a) and fibroblast growth factor-2 (FGF-2) are correlated with recurrence (67,68). However, the mechanisms behind these markers are still unknown.…”

“…The feasibility of FMISO-PET-CT guided radiotherapy with hypoxia-directed intensity modulated radiotherapy has been demonstrated in multiple tumours (63,65,66), including head and neck cancer (67). Cheney et al (68) showed that hypoxic areas could be identified with FMISO-PET-CT in 12 out of 20 chordoma of the mobile or sacrococcygeal spine. The benefits and risks of hypoxia-guided boost volumes in radiotherapy of chordoma still has to be investigated in the future.…”