Repeatability and sensitivity of T2* measurements in patients with head and neck squamous cell carcinoma at 3T.

Tissue oxygenation is an important parameter of the tumor microenvironment that influences both proliferation and angiogenesis.1, 2 The presence of hypoxic regions within tumors is considered an important cause of treatment failure affecting both radiotherapy and chemotherapy, and adversely affects the prognosis of head and neck squamous cell carcinoma (HNSCC).3, 4, 5 Noninvasive methods to rapidly quantify the spatial distribution and extent of hypoxia within an individual tumor are thus highly desirable in clinical practice to allow modification of treatment strategies in this poorer prognosis group. Magnetic resonance imaging (MRI) measurements of the transverse relaxation time ( T2*) have been proposed as imaging biomarkers of tissue oxygenation status in both preclinical and clinical settings.3, 4, 6, 7 Paramagnetic deoxyhemoglobin increases the apparent MRI transverse relaxation rate R2* (=1/ T2*) of water in blood and surrounding tissues, which provides the opportunity to image tissue oxygenation at high spatial resolution. The T2* of the vascular space is dependent on fractional blood oxygenation (Y), and can be described by a quadratic function of hematocrit levels (Hct) and magnetic field strength (B0).8, 9 Changes in R2* are used to study brain activity associated with modulated regional brain perfusion (the blood oxygen level dependent or BOLD effect).10 However, the strength of the correlation between tissue R2* and tissue oxygen partial pressure (pO2), measured using oxygen electrodes, and immunohistochemical detection of the hypoxia marker pimonidazole, has been reported to be only weak to moderate.11, 12, 13 Consequently, quantitative measurements of tissue oxygenation using BOLD have yet to be established.14 BOLD measurements can also be performed in combination with hyperoxic gas breathing, whereby the oxy/deoxygenated hemoglobin ratio is altered. The magnitude of changes in BOLD measurements within tumors, on breathing hyperoxic gas relative to air, have been shown to relate to the tumor hypoxic fraction as determined by pimonidazole labelling.15 An increase in T2* was found to correlate with inhalation of higher percentages of oxygen in preclinical studies, but the magnitude of signal changes was not proportional to the absolute measured tissue oxygenation.16 Preclinical and clinical studies in prostate, cervix, and head and neck cancers have consistently reported increases in tumor tissue T2* in response to hyperoxic gas challenge.17, 18, 19, 20 In contrast, studies in breast cancer have shown differing results, as tumors were found to exhibit T2* decreases following hyperoxic challenge but with relatively large magnitude variation in the magnitude of T2* changes.21 This discrepancy is thought to relate to differences in tumor biology across histologies.15, 21, 22 Such discordant results may be explained by T2*‐weighted signal dependence on physiological factors, including the hematocrit, blood volume (BV), vessel caliber,23, 24 and the intermittent tumor vessel blood flow.16, 25 Therefore, the relationship of baseline tumor tissue T2* to tumor hypoxia varies according to the nature of the tumor vasculature and its host hematological status. It therefore should not be surprising that tumor T2* and its response to various tumor challenges (treatment, hyperoxia) varies according to tumor type. In addition to the tumor vascular microenvironment, quantitation of T2* is also dependent on physiochemical and methodological parameters.14, 26, 27 Macroscopic magnetic field homogeneity resulting from the iterative shimming process affects the repeatability of T2* measurements. The measured T2* value within a voxel is a composite of spin relaxation rates within the intra‐ and extravascular tissue spaces, a consequence of the scanning spatial resolution. Spin relaxation in the extravascular space has a much weaker and variable dependency on blood oxygenation than that for the intravascular space within a tumor.10, 26 Hypoxia is a common and well‐recognized cause of radioresistance in HNSCC, and therefore MRI‐based measurements of oxygenation in this region are of significant interest.3, 4, 5 In this study we evaluated whether T2* measurements are sufficiently sensitive to detect clinically relevant oxygenation levels in HNSCC at 3T, acknowledging the influence of measurement repeatability, blood volume, and hematocrit.