Head and neck cancer patients are commonly treated with chemoradiotherapy as standard of care. Although it is generally believed that clinically effective radiation doses do not cause long term muscle tissue damage, few studies evaluated potential biological changes in irradiated muscle tissues longitudinally during the course of treatment. Here, we report preliminary findings of such changes as measured by Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) before, during, and after chemoradiotherapy treatment of a subset of human papilloma positive (HPV+) oropharyngeal cancer (OPC).

Data from nine HPV+OPC patients were included in this study. Each subject underwent three DCE-MRIs at the following time points: 1) within one week prior to, 2) at the mid-point of (3-4 weeks after treatment start), and 3) 6-8 weeks after the chemoradiotherapy treatment. MRI was acquired on 3.0 T Discovery 750 MRI scanner (GE Healthcare, Waukesha, WI) using a custom immobilization method ¹ with the patient on a flat insert table (GE Healthcare) with laterally placed 6-element flex coils centered on the base of the tongue. The DCE-MRI acquisition consisted of a 3D SPGR sequence with the following parameters: FA = 15°, TR/TE = 3.6/1 ms, spatial resolution 2 mm × 2 mm × 4 mm, temporal resolution = 5.5 s, number of frames = 56, pixel bandwidth = 326 Hz, and parallel imaging (ASSET) with an acceleration factor of 2. Prior to the DCE-MRI, the same SPGR sequence was run six times, each with a different flip angle: 2,5,10,15,20,25 ̊. This variable flip angle approach was used for mapping native tissue T1. A bolus injection of gadopentetate dimeglumine (Magnevist, Bayer Healthcare Pharmaceuticals) was administered (dose 0.1 mmol/kg at a rate of 3 mL/s) followed by a 20 ml saline flush, via a power injector (Spectris MR Injector, MedRad, Pittsburgh Pa) at a rate of 3 mL/s. A Medrad Solaris MR-compatible power injector was used for all contrast agent injections in order to standardize the contrast agent administration. The total duration of the DCE-MRI acquisition was ~8 min. The superior pharyngeal constrictor (SPC) and mylohyoid muscles were identified and segmented by an expert radiation oncologist on DCE-MRI images at all three time points using T2MRI images as reference.

Within these two muscle regions, pixel DCE-MRI time-courses were modeled individually using the Tofts model ² with K^trans (contrast agent transfer constant) and v_e (extravascular extracellular volume fraction) as the fitting parameters. A previously published ³ arterial input function (AIF) was used for all pharmacokinetic modeling. Parameter mean and standard deviation (SD) were calculated from the pixel parameter values.

Figure 1a shows a post-contrast head and neck DCE-MRI image of one subject. 1b-1d are the SPC and mylohyoid muscle K^trans maps pre-, mid- and post-treatment, respectively. 1e-1g show the corresponding v_e maps. The patterns of K^trans and v_e elevations are clearly visible throughout the course of treatment. Figure 2 summarizes the 9-subject averaged K^trans and v_e values for the SPC muscle at three time points. Although the error bars appear to be large, increases in both K^trans and v_e post-radiation are observed. The difference in the mean SPC v_e value between pre- and post-treatment is statistically significant (p=0.01; paired t-test). Figure 3 shows the Fig. 2 equivalent for mylohyoid muscle. In this muscle region the differences in mean K^trans between pre- and mid-treatment (p=0.003), pre- and post-treatment (p=0.004), as well as the difference in mean v_e between pre- and mid-treatment (p=0.003), are all statistically significant.Although the conventional wisdom is that radiation does not cause long-term adverse effects in healthy, well-perfused tissues like the SPC muscle, in this preliminary study we observed elevated muscle K^trans and v_e values post-radiation. K^trans elevation may indicate a more permeable microvasculature, while increase in v_e points to decreased cellularity. Both could be direct consequences of irradiation. All of the 9 HPV+OPC patients achieved complete clinical responses following completion of the chemoradiotherapy course. However, the long term radiation toxicity in healthy muscle tissue is unknown. Post-treatment follow-up of head and neck cancer patients using quantitative DCE-MRI may provide a useful noninvasive method to evaluate not only cancer recurrence, but also recovery or deterioration of the irradiated muscle tissue functionality. This may facilitate more individually tailored clinical management plans that can help improve a patient’s quality of life.