Clinical Study On Maxillofacial And Oral Massage In Reducing Radiotherapy-induced Oral Mucositis In Nasopharyngeal Carcinoma Patients And Construction Of Nomograms For Nasopharyngeal Carcinoma

Background and purposeNasopharyngeal carcinoma(NPC)occurs worldwide,but its distribution is not balanced.South China is an endemic area for NPC.NPC is sensitive to radiotherapy,and intensity-modulated radiotherapy(IMRT)is the standard radiotherapy technology,and concurrent chemoradiotherapy is the standard treatment for NPC.At present,the 5-year overall survival(OS)of NPC is about 80%,and the 5-year OS of stage I and II can reach 90%or higher.Acute oral mucositis is the most common toxicity in chemoradiotherapy for NPC.The oral mucositis caused by radiation with the symptoms of pain,dysphagia,xerostomia and erosion,ulcer in mouth,seriously affects the quality of life.Moreover,the radiation delivery has to be terminated without reaching the prescription dose,which has become the bottleneck of head and neck malignant tumors.Nowadays,there are many oral drugs and oral care solution for the prevention and treatment of acute radiotherapy-induced oral mucositis(RTOM),such as glucocorticoid,vitamins,antibiotics,mucosal protective agents,hematopoietic growth factors,Kangfuxin liquid,Chinese medicine,etc.The clinical outcomes are different,and there is no standard,specific treatment except for glucocorticoid.At present,basic oral care is the most commonly used to prevent and treat RTOM,but the effect is not satisfactory.An economically feasible and effective method to prevent RTOM urgently needs to be explored and developed.In the radiotherapy of NPC,salivary glands are usually covered in the radiation field.Ionizing radiation not only reduces the flow of saliva and mucus,but also reduces the content of glycoproteins in saliva,thus lowers the p H values in oral cavity.As the surface barrier of the oral mucosa,glycoprotein can prevent the adhesion of microorganisms to the oral mucosa.The decrease of p H easily leads to the proliferation of bacteria in acid environments.Therefore,the decrease of saliva flow,glycoprotein and p H values in oral cavity is the high risk of oral infection and promote the occurrence of RTOM.Studies have shown that oral massage can reduce the release of inflammatory cytokines and bacteria infection.On the other hand,oral massage can enhance the secretion of salivary glands,increase the secretion of anti-inflammatory factors,improve immune function,facilitate swallowing,and reduce oral infection.Therefore,we hypothesized maxillofacial and oral massage during the course of radiotherapy can stimulate the secretion of saliva and mucus in the oral cavity,increase the secretion of anti-inflammatory factors,thereby prevent and lessen the occurrence of RTOM.Therefore,we provide a special maxillofacial and oral massage according to the radiation field and the anatomical location of salivary glands,and setup a randomized control trial(RCT)in NPC patients undergoing IMRT.The purpose of the current study is to verify the efficacy and safety of maxillofacial and oral massage in preventing and treating RTOM.Furtherly,we explore the underlying mechanism of maxillofacial and oral massage by lipid metabolomics.At the same time,a prognostic nomograms was established by screening NPC in the SEER database to predict the prognosis of NPC.Methods1.To verify the efficacy and safety of maxillofacial and oral massage on RTOM in chemoradiotherapy for Nasopharyngeal Carcinoma(NPC):A randomized control trial.A randomized controlled clinical study was carried out on newly diagnosed patients with nasopharyngeal carcinoma in Xinqiao Hospital.With a 1:1 ratio of randomization,158 cases were enrolled from December 10,2018 to July 30,2020.the enrollments were randomly divided into treatment group and control group,Control group:from the beginning of radiotherapy,the patients were given routine oral care and functional exercises;treatment group:the patients were given maxillofacial and oral massage based on routine care the same as the control group.The primary endpoint is the incidence of RTOM of grade 3 and above.Secondary endpoints:the time and duration of RTOM,the severity of xerostomia,oral pain and dysphagia,and adverse events of massage.2.To study underlying mechanism of maxillofacial and oral massage by lipid metabolomics in protecting RTOM.A total of 10 eligible patients with NPC undergoing 3 days to 22 days radiotherapy were selected.The first time point of blood sample("0h")is right after the radiotherapy.Afterwards,the maxillofacial and oral massage was performed for one cycle.Then we wait for 12 hours and take a second blood sample("12h").We send blood samples to the laboratory to test the inflammation markers of"0h"and"12h".UPLC-MS/MS was used to analyze the lipid metabolites of"0h"and"12h".3.NPC patients were screened from the SEER database,and R software was used to establish nomograms to predict 5-year OS and 5-year CSS of NPC.Results1.Maxillofacial and oral massage reduced the severe RTOM in patients with NPC,delayed its occurrence time,shortened the duration of RTOM,reduced the pain,relieved dry mouth and reduced the incidence of dysphagia.Compared with the control group,the total incidence of RTOM in the treatment group was not significantly different,but the incidence of severe RTOM(grade 3 or higher)in the treatment group was significantly lower than that in the control group(26.3%vs.46.8%,P=0.008).The median latency period was 12 days in the treatment group,and 10 days in the control group(hazard ratio 0.5195.95%CI,0.3639-0.7418,P=0.0001).In subgroup analysis,the median latency period of severe RTOM was 28.5 days in the treatment group and 19 days in the control group(hazard ratio 0.5579,95%CI,0.3192–0.9750,P=0.002).The duration of RTOM and severe RTOM in the treatment group was shortened compared with that in the control group(RTOM:treatment:20.7±7.07 days,control:24.7±8.03days,t=3.286,P=0.001)(severe RTOM:treatment:8.05±3.95 days,control:13.08±5.88days,t=4.094,P=0.000).Patients in the treatment group had lower RTOM induced pain scores on the numerical rating scale(NRS)(X~2=10.943,P=0.001)and less sensation of xerostomia(X~2=12.285,P=0.003).The dysphagia of the treatment group was significantly lower than that of the control group(X~2=12.653,P=0.001).The incidence of grade 3 adverse reactions was 1.3%.2.Maxillofacial and oral massage stimulates the anti-inflammatory lipids which could be the underlying mechanism to reduce the severe RTOM during chemoradiotherapy.No significant changes were found in serum inflammatory marker(CRP,IL-6,TNF-a,and IL-8,P>0.05).The anti-inflammatory lipids(9S-HEPE and(±)15-HETE,P<0.05)had risen after massage.7 patients with GTVnx of 10 Gy or more(radiotherapy 5 times or more)before blood collection and 3 patients with 10 Gy or less were stratified.We found that several anti-inflammatory lipids(9S-HEPE,11-HEPE,5(6)-EET,(+-)15-HETE,15S-HETr E and LA,P<0.05)from patients who have completed a radiation dose of 10Gy or higher had risen after massage.3.Age,race,histology,primary tumor size,SEER stage,radiotherapy and chemotherapy were related to 5-year OS and CSS in NPC.All of these clinical features were included when constructing nomograms.The calibration plots showed that the predicted 5-year OS and CSS outcomes were in good agreement with the observed outcomes.Conclusion1.Maxillofacial and oral massage significantly lowered the severity of chemoradiotherapy-induced oral mucositis in patients with NPC,delayed the occurrence and shortened the duration of RTOM,relieved the pain,xerostomia and dysphagia.The incidence of grade 3 adverse reactions was 1.3%.2.Massage enhanced the anti-inflammatory lipids which could be the underlying mechanism to reduce the RTOM during chemoradiotherapy.3.Maxillofacial and oral massage is a high efficacy strategy to prevent and treat acute radiation RTOM with very low adverse events.It’s worth of future phase III RCT study.4.The treatment of NPC should not only pay attention to short-term efficacy and oral mucositis,but also pay attention to long-term survival prognosis.The predictive nomograms,which contain primary tumor size and SEER stage,can predict the 5-year OS and CSS rates of NPC patients and can be used as an auxiliary prediction tool for future clinical practice.