Our study demonstrates a significant increase in FDG uptake in the parotid glands of HNC patients following photon RT and chemotherapy treatments. Investigating the impact of these treatments on the parotid gland is critical, not only because of its role in saliva production but also due to the fact that cranial nerve VII (facial nerve) lies in close proximity to and innervates the gland. This nerve also innervates numerous muscles of facial expression, as well as the stylohyoid and posterior belly of the digastric muscles, which play a critical role in swallowing (Dulak & Naqvi, 2019). The glossopharyngeal nerve provides parasympathetic innervation to the parotid gland, as well as sensory innervation to the posterior one-third of the tongue and pharynx. Photon RT and/or chemotherapy-induced damage of the parotid gland can impact glossopharyngeal nerve function and indirectly lead to deleterious effects on adjacent structures in the head and neck region (García Santos et al., 2018). Thus, determining the FDG uptake in the parotid gland is of clinical importance in investigating potential previously underappreciated side effects of radiotherapy in HNC cancer patients.
In our study, we found that Avg SUVmean was significantly higher in the parotid gland following photon RT, but not in patients who underwent proton RT or combined proton/photon RT. Although Avg SUVmean was significantly increased in patients receiving photon RT, SUVmax values were not significantly different in pre-treatment versus post-treatment scans of patients receiving any form of RT. SUVmax is the maximum voxel value of SUV in the target structure/ROI. SUVmax is simple and observer independent; hence, SUVmax is the most commonly used parameter in clinical practice. However, SUVmax does not represent an entire structure’s metabolic burden because the value is from only one voxel. Furthermore, SUVmax is sensitive to image noise, and is therefore impacted by various patient characteristics and imaging parameters. On the other hand, Avg SUVmean accounts for all uptake within the ROIs and is more reflective of the total pathological changes in glucose metabolism, which suggests that Avg SUVmean is a more accurate value to use in this data collection. Since we suspect that radiation-induced parotid injury is a diffuse pathology that has the potential to elicit an inflammatory response across the entire gland, we used the Avg SUVmean, as it is likely to be a more accurate indicator of the extent of the global inflammation (Høilund-Carlsen et al., 2019; Borja et al., 2020b).
There are several artifacts encountered in PET/CT imaging including attenuation correction artifacts commonly associated with the use of CT. Attenuation correction algorithms work well for most applications in the majority of patients. However, these algorithms tend to overcorrect objects that have higher density but are not true bone pixels. Dental implants or fillings can cause such an attenuation correction artifact and can confound image interpretation and affect the quantification in the head and neck region. In the present study, of the 64 patients, 17 were not included in the study due to technical issues including the presence of artifacts related to metallic based restorations, orthodontic appliances, and other dental procedures, which are the main cause of beam hardening. This confirms the lack of beam hardening artifact effect on our measurements.
We assert that the increased FDG uptake observed in this study was a result of RT-induced inflammation in the parotid gland. Cellular uptake of FDG is a marker for inflammation, and these results confirm its utility in identifying parotid gland pathology following RT in HNC patients. In classic parotitis, this inflammation is most often the result of a localized infection or cellular damage, though the irritation can be caused by a myriad of factors, including pathogenic microbes derived from the oral cavity, metabolic imbalances, and autoimmune disorders (Patel et al., 2017). Initiation of inflammatory processes in the gland can lead to a decrease in salivary production, causing dehydration of the gland as well as a distortion of the parotid duct and metaplasia of the ductal epithelium (Chitre & Premchandra, 1997). Uptake of FDG may begin to increase subsequent to the preliminary irritation and continue to increase as the inflammatory response progresses (Chitre & Premchandra, 1997). Since RT has been shown to increase systemic inflammation, patients experience a significant risk in the perturbation of the parotid gland, since it is particularly susceptible to irritation (Brook, 1992; Schaue et al., 2015).
It is critical to acknowledge the limitations of our study. This was a retrospective analysis with a relatively small sample size of patients. Thus, future evaluation of the use of FDG-PET/CT as a surrogate measurement of inflammatory activity in the parotid gland after RT treatment should be directed toward prospective studies using large numbers of patients. Information regarding full tumor stage, type of radiation field, the exact dosage of radiotherapy administered to patients, and oral complications were not available for the current study, which limited the description of our patient cohort. A survey reported that 64% of at least 3 years survivors after RT suffered from moderate to severe xerostomia (Wijers et al., 2002). Thus, future studies must include detailed information regarding the occurrence of xerostomia in order to determine whether increased parotid-uptake of FDG can be used to predict the onset of this condition. The partial volume effect, which accounts for signal overlap from neighboring anatomical structures and potential movement of the patients during scan acquisition, may have altered the data used in these analyses. Therefore, the regions used as borders in determining the extent of the ROIs may have been ambiguous, depending on the quality of the scan. The influence of partial volume effect is due to the limited resolution of the technology used in obtaining these scans (Cysouw et al., 2016; Soret et al., 2007). This could account for the single outlier observed in the data, which might have introduced further uncertainty into the results (Fig. 2). In addition, because the patients who participated in the study received both chemotherapy and photon RT, it is not possible to differentiate between the inflammatory effects of each treatment individually. Finally, there were only two-time points assessed in this study, pre-treatment and 3 months post-treatment, which prevented the evaluation of FDG uptake throughout the entire post-treatment period.
The present study suggests that an increase beyond normal physiological glucose uptake in the parotid gland occurs as a manifestation of RT-induced inflammation. Given that inflammation is followed by cell damage and fibrosis of some of the glandular tissue (Wynn & Ramalingam, 2012), we predict that additional follow-up scans will demonstrate a decrease in the parotid gland uptake due to lack of normal gland activity and function. It would be helpful to direct future studies toward more longitudinal assessments of FDG uptake in the parotid gland to better track changes in signaling over time to determine the time frame of cell damage and fibrosis manifesting as a decline in parotid gland function compared to pre-treatment.
Protocols utilizing photon beams are currently the most common form of RT for HNC, while less than 1% of patients are treated with proton therapy (Mohan & Grosshans, 2017). When comparing proton to photon therapy, proton therapy reveals an added advantage of lower dose and smaller number of beams (Levin et al., 2005). In the present study, no significant differences were found between pre- and post-treatment parotid FDG uptake in patients treated with proton RT. This observation might be indicative of there being less radiation delivered to normal tissues in close proximity to actual tumors, thereby minimizing collateral toxicity and limiting the extent of side effects traditionally associated with photon-based RT (Mohan & Grosshans, 2017; Lin, 2012). Considering the small patient population receiving only proton therapy, the result must be interpreted with caution and should be confirmed in further studies.
The present study demonstrated significantly higher FDG uptake in the parotid glands of patients undergoing photon-based RT for treatment of HNC. This increase in glucose metabolism may be indicative of radiation-induced inflammation, which subsequently can progress result in decreased functionality of the parotid gland. Future studies should include a larger sample to allow comparison of the effect of photon RT for treatment of HNC to other modalities of RT in order to assess the differential impact on parotid gland function. Confirmation of the correlation between FDG uptake and saliva production might enable clinicians to choose alternative RT regimens and/or intervene at an earlier stage and prevent the sequela of xerostomia.