To reduce radiation damage to oral tissues during radiotherapy and prevent oral complications, oral radiotherapy appliance is an appropriate and feasible method(Chen et al. 2020). Patients wear this intraoral appliance during RT, which can protect the adjacent organs affected by radiation. There are two types of oral appliance: One type is a positioning stent that pushes adjacent normal tissues such as salivary glands, tongue, and part of the oral mucosa away from planning target. And it ensures that every radiation treatment is fixed in the same jaw position and reduces setup errors; The other type is a shielding stent, made of shielding material for directly blocking the radiation. And it is suitable for tumors on the facial surface such as unilateral buccal cancer or lip cancer.(Kaanders 1992) For NPC, positional stent is feasible(Chen et al. 2020).Previous study by Qin et al. about individual oral stents in NPC patients just paid attention to taste, oral mucous reaction, and tongue mucous reaction during RT.(Qin et al. 2007) Mall et al. have confirmed the role of oral stents in preventing dry mouth in patients with tongue cancer.(Mall et al. 2016)But until now, the relevant research is insufficient. Therefore, this study was designed to analyze the change of xerostomia and caries risk under the protection of the personalized PMMA oral stents before, during and after RT in NPC patients. In addition, Cariostat, as an initial attempt, was used to monitor the caries risk change in NPC patients in order to offer important references to avoid or decrease the occurrence of radiation caries.
Radiation results in significant decreases in unstimulated and stimulated salivary flow. In this study, RT results in an 73.9% maximum reduction in stimulated saliva and 41.7% maximum reduction in unstimulated saliva. This is because salivary glands are exquisitely sensitive to radiation, which has been confirmed by lots of studies. (Grundmann et al. 2009; Chen et al. 2020)Salivary glands are made up of highly differentiated cell and proliferate slowly (Hall 2018). Early effects of radiation are due to high levels of loss of acinar cells and glandular shrinkage, which attributed to the acute reduction in saliva flow. (Robar et al. 2007; Hoebers et al. 2008)Late effects may be affected by vascular damage, loss of parenchymal cells, and attrition of acinar cells followed by replacement with fibrotic tissue. (Radfar and Sirois 2003; Hall 2018) Radiation-induced xerostomia may last the lifetime.
Most studies used stimulated salivary as an evaluation indicator, while unstimulated salivary was rarely analyzed. This is due to the small amount of unstimulated salivary after RT, and the stimulated salivary could be adapted to reflect the reserve function of the salivary glands better. Although both of these indicators were included in this study, stimulated salivary is more commonly used in articles for comparison and discussion.
In terms of the recovery turning point, a sharp decline in unstimulated and stimulated saliva output was observed at mid-RT and 1 months after RT, followed by minimal recovery trend at 3 months after RT in stimulated saliva in our study. The turning point at 1 months and recovery trend at 3 months are ahead of most other studies. Sim et al. reported the minimum saliva flow rate started to show up at 3 months after RT. (Sim et al. 2018) Some other studies reported a recovery trend started from 6 months after RT in the IMRT group. (Kwong et al. 2004; Pow et al. 2006; Marucci et al. 2012)And even there seemed to show a slightly recovering sign until 12 months after RT in the research of Lan et al. and Kam et al. (Kam et al. 2007; Lan et al. 2020)
In terms of the percentage reduction of saliva flow, this study shows that at 1 months after RT, the mean stimulated saliva flow was reduced by 73.9% compared with baseline, but by 3 months after RT, the mean percentage reduction of stimulated saliva flow improved to 55.4%. The condition of the percentage change of saliva flow was more optimistic. Kwong et al. reported the mean stimulated whole salivary flow was reduced by 88.5% compared with baseline at 2 months post-RT. (Kwong et al. 2004) A randomized study of IMRT versus 2DRT for NPC was recently reported by Kam et al. and reported the ratio of post-RT/pre-RT whole salivary flow rate at 6 weeks and 6 months, were 0.32 and 0.30, respectively, in patients treated with IMRT. (Kam et al. 2007) A similar study carried out by Pow et al. also reported the post-RT/pre-RT whole salivary flow rate ratio were 0.14 and 0.19 at 2 months and 6 months, respectively. (Pow et al. 2006) The result of the recovery turning point and the percentage reduction of saliva flow have demonstrated an excellent protective ability of the personalized PMMA oral stents as well as related oral intervention in NPC patients with xerostomia.
For unstimulated salivary, as the result shows, there were differences between the change of unstimulated salivary flow and stimulated salivary flow after RT in this study. Unstimulated whole saliva, also known as the resting salivary, may be more directly related to daily perception of dry mouth.( Proctor 2016; Lan et al. 2020) In the healthy, the submandibular and minor salivary glands contributed about 65% and 10% of the resting salivary flow respectively and secreted saliva mainly with mucins. Mucins or seromucous secretions have a better lubricating effect on oral soft tissues than the serous parotid gland secretions. Thus, the lack of mucinous saliva would lead to inadequate lubrication of the soft tissues.(Chaudhury et al. 2015; Sim et al. 2018) Studies also showed that submandibular glands contribute approximately two-thirds of unstimulated saliva volume, whereas parotid glands contribute the majority of stimulated saliva volume(Ship et al. 1991; de Almeida et al. 2008). The variational rage of the unstimulated salivary flow rate over time is smaller than stimulated saliva flow rate, and RT results in an 73.9% maximum reduction in stimulated saliva and 41.7% maximum reduction in unstimulated saliva in this study. It could demonstrate the personalized PMMA oral stents had a better protective effect on the submandibular glands than the parotid glands. Combined with above information, it suggested that the personalized PMMA oral stents possessed good protective ability of salivary glands, especially the submandibular and minor salivary glands, and kept the unstimulated salivary flow rate at a relatively stable and acceptable level.
Besides saliva collection, xerostomia questionnaire was used to measure the impact of xerostomia in subjective aspect at the same time. The score of XeQoLS significantly increased during RT and ascended gradually to the highest at 1 months after RT and decreased at 3 months after RT, the trend of which was just contrary to those of saliva flow rate. And the correlation between whole saliva flow rate and xerostomia score were statistically significant. This opinion was consistent with several studies, (Pow et al. 2003; Parliament et al. 2004; Meirovitz et al. 2006)while some investigators reported the correlation between parotid flow rate and patient-rated xerostomia scores was weak. (Eisbruch 2001; Lin et al. 2003; Kam et al. 2007)The two standpoints were not actually in conflict, and it suggested that whole saliva flow rate, rather than parotid flow rate, could better reflect the patient-reported xerostomia. And other salivary glands such as submandibular, sublingual, and other minor salivary glands also played an important role in maintaining lubrication, preventing moisture loss, and alleviating subjective symptom of xerostomia in patients. But parotid flow was not used for this study in consideration that saliva was scarce after RT. Moreover, Meirovitz et al. demonstrated there was a mismatch between physician score and patient score, but a significant correlation between patient-reported xerostomia and total saliva output, and suggested that patient self-reported scores seem to be more reliable in predicting the outcome of head-and-neck cancer therapy compared with physician-based assessments. (Meirovitz et al. 2006)
In addition, in terms of XeQoLS, there were similar trends over time in the aspect of physical, psychological, social functions and discomfort issues, but the average scores of physical and psychological were obviously higher. And Lan et al. using the same xerostomia questionnaire as us, also demonstrated psychosocial and functional impacts were greatest in the early period and suggested possible strategies such as pre-treatment psychological preparation for the dry mouth and providing timely counselling and dealing strategies were essential. (Lan et al. 2020) Consistent with the change of salivary flow, the subjective symptoms of the patient's dry mouth also began to recover at 3 months after RT in this study. It indicated that the protection capacity of the personalized PMMA oral stents on xerostomia was also obvious from subjective aspect.
NPC and other head-and-neck cancer patients have different oral microbes from the normal. (Chen et al. 2017; Chattopadhyay et al. 2019) RT could cause further changes of microbes.(Gaetti-Jardim et al. 2018) As early as 2005, Meng et al. found that the amount of Streptococcus mutants was significantly elevated after RT by collecting plaque from NPC patients before and after RT.(Meng et al. 2005) Other studies by the high-throughput sequencing have shown a significant decrease in oral microbiome diversity after RT in patients with head and neck cancer. And it resulted in increasing trend in certain pathogenic species and decreasing trend in health-related species.(Gao et al. 2015; Almstahl et al. 2018; Mougeot et al. 2019) This study showed that RT would significantly increase caries risk in the short term. And there were no relative studies that I know of exploring the change of the caries risk in NPC patients so far. The Cariostat method, proved as a good predictor of caries risk, especially in young children, is based on color changes produced by acidogenic and aciduric oral bacteria present in a plaque sample. It is suitable for using beside the chair, for it is faster, easier and more effective than conventional identification techniques such as colony morphology, biochemical and immunological analyses.(Maningo Rodis et al. 2005) In this study, the average values of Cariostat scores showed a continuous upward trend and 8 of 12 patients showed a higher Cariostat score in 3 months after RT than before RT. The change of the caries risk might be attributed to the radiation effects on dental hard tissue and the composition of oral microbiota, decrease in salivary flow, neglect of oral hygiene, changes in eating habits, which would promote advanced dental caries. (Liang et al. 2016; Villa and Akintoye 2018; Fonseca et al. 2020) And even oral instruction and intervention such as oral hygiene instruction and personalized PMMA oral stents could not completely avoided the change of the caries risk in this study. However, it is undeniable that the oral stents may have a preventive effect on the formation of radiation caries in the long term, which requires longer follow-up.
Oral instruction and intervention such as oral hygiene instruction and personalized PMMA oral stents are important for the health of the NPC patients. The sample size of this study was small due to few patients were willing to persisting in follow-up. In our research we came across an even bleaker notion: most patients have limited knowledge about oral health maintenance and seldom seek oral care. Further, some studies have pointed out that the clinical management of xerostomia or other complications caused by radiotherapy requires multidisciplinary cooperation and long-term follow-up, in which stomatologists play an important role.(Sonis 2013; Villa and Akintoye 2018) But under the current circumstances, the integration of oral health management with the treatment of the tumor has been slow to develop due to limited professional oral care resources, neglect of the importance of oral protection and the incomplete prevention and treatment system of oral complications induced by radiotherapy. And oral complications not only increase the cost of dental treatment and management, but also have a considerable impact on patients’ quality of life. Therefore, it is very important for stomatologists and related clinical researchers to participate in the multidisciplinary treatment on NPC patients before, during and after radiotherapy to minimize any oral complications for a long time.