Development Of Radiation Oral Mucositis Animal Model,and Radiation Dosimetric And Clinical Intervention Study

Preclinical ResearchAnimal model of oral mucositis induced by radiation and preclinical study of rhIL-11 in treatment of mucositisPurpose:To establish animal model of radiation-induced oral mucositis(ROM),search for predictive factors of ROM and explore the efficacy of recombinant human interleukin 11(rhIL-11)in ROM of Syrian golden hamster.Methods:To construct animal model,48 Syrian golden hamsters at 7-9 weeks of age were irradiated with 40 Gy per fraction,once.To explore the efficacy of rhIL-11 in the treatment of ROM,all of the hamsters were randomly divided into two arms:rhIL-11 arm(n=24)and control arm(n=24).Buccal pouches were dissected at the corresponding time points.PCR was performed to test level of inflammatory factors(TGF ?,TNF-?,IL-1?).HE stain was used in the observation of mucosal repair and infiltration of inflammatory cells.Composition changes of oral microbes during ROM was detected by using high throughput sequencing.Results:The composition of oral microorganisms significantly changed during ROM,of which Bacteroides,Lactobacillus and Streptococcus significantly increased.Intervention of rhIL-11 can postpone the peak of ROM,accelerate restoration,facilitate repair and shorten the length of disease.Conclusion:There is an explicit correlation between oral microorganism and ROM process.RhIL-11 can facilitate repair of ROM and shorten the length of disease in Syrian golden hamster.Clinical TrialPart ? Dosimetry study of oral mucositis induced by radiation in patients with nasopharyngeal carcinoma1.Predictive factors of acute radiation-induced oral mucositis after intensity-modulated radio-chemotherapy in patients with locally advanced nasopharyngeal carcinomaPurpose:To explore the dosimetric and clinic predictors of acute radiation-induced oral mucositis(ROM)in locally advanced nasopharyngeal carcinoma(NPC)patients who treated with simultaneous intensity-modulated radiation therapy(IMRT)and chemotherapy.Methods:Ninety-two locally advanced nasopharyngeal carcinoma patients treated with chemo-radiotherapy were included in this study.Acute radiation-induced oral mucositis was evaluated according to the RTOG scoring systems.ROM?3 grade was defined as severe ROM.Dose volume histogram(DVH)of all patients were exported from RayStation version 3.0 treatment planning system.Clinic data combined with dosimetric parameters were statistically analyzed to figure out predictive factors.Results:The incidence of severe ROM in this group of patients was 20.7%(19/92).Weight loss and V30 were independent predictors for severe ROM(P=0.017 and 0.003,respectively).Weight loss? 5%was associated with an increase risk(about 4 times)to develop severe ROM.ROC analysis was performed to figured out optimal cut-off of V30.It is 73.155%with AUC of 0.753(sensitivity:0.842,specificity:0.671,P=0.001).Conclusion:Weight loss? 5%and V30>73%are predictive factors for severe ROM in locally advanced nasopharyngeal carcinoma patients receiving chem-radiotherapy.2.Predictive model of severe radiation-induced oral mucositis in nasopharyngeal carcinoma patients underwent chemo-radiotherapyPurpose:To establish predictive model of severe radiation-induced oral mucositis in nasopharyngeal carcinoma patients underwent chemo-radiotherapy.Methods and materials:A total of 270 newly diagnosed nasopharyngeal carcinoma patients receiving radical chemo-radiotherapy were included.Oral mucosa structure was contoured by using two methods:oral cavity contour(OCC)and mucosa surface contour(MSC)in radiation treatment plan.Univariate and multivariate analysis were performed to build the predictive model.Results:Multivariate analysis showed that body mass index(BMI)before radiation,radiation technique,retropharyngeal lymph node region irradiation and V55 were independent predictive factors for severe oral mucositis based on OCC.While BMI before radiation,retropharyngeal lymph node region irradiation and V55 are independent predictive factors for severe oral mucositis based on MSC.The AUC of OCC based model is 0.761(95%CI:0.701-0.821)with a sensitivity of 0.812 and specificity of 0.595.And AUC of MSC-based model is 0.766(95%CI:0.707-0.826)with a sensitivity of 0.700 and specificity of 0.716.Conclusion:Both OCC and MSC based predictive models can effectively discriminate severe oral mucositis in NPC patients during treatment.We recommend comprehensively consider dosimetric parameters and clinical factors for determining the likelihood of severe mucositis by using our models.Part ? The relationship between radiation-induced oral mucositis and nutrition status in patients with nasopharyngeal carcinoma1.Efficacy of nutrition support in locally advanced nasopharyngeal carcinoma patients receiving chemo-radiotherapyPurpose:To explore the efficacy of nutrition support in locally advanced nasopharyngeal carcinoma patients receiving chemo-radiotherapy and figure out related factors of malnutrition.Methods:A total of 117 locally advanced nasopharyngeal carcinoma(?-?B AJCC stage)patients received chemo-radiotherapy in The Affiliated Cancer Hospital of University of Chinese Academy of Sciences from December 2015 to March 2016 were included.Firstly,all patients were divided into nutrition support arm and control arm to evaluate the efficacy of nutrition support.Nutritional indicators were repeatedly measured before(T0),during(T1)and after(T2)radiotherapy to access the variation of nutrition status during radiotherapy and compare the differences of the two arms at the same point.Then,all patients were divided into malnutrition arm and normal arm according to weight loss exceeds 5%or not to figure out risk factors of malnutrition.Results:Nutrition indicators dramatically declined during chemo-radiotherapy(P<0.001).There were no significant differences in nutritional indexes between the two arms at the same point(P>0.05),However,nutrition support significantly shortens overall radiotherapy time(P=0.023).Logistic regression analysis showed that severe(? grade 3)radiation-induced oral mucositis and pre-albumin decrease>15%were risk factors for malnutrition(P=0.021 and 0.04,respectively).Conclusion:Nutrition support fails to significantly improve nutrition status in nasopharyngeal cancer patients received chemo-radiotherapy.Severe(?grade 3)radiation-induced oral mucositis and pre-albumin decrease>1 5%are risk factors for malnutrition.2.Effects of oral nutritional intervention on short-term nutritional status and treatment tolerance of patients with locally advanced nasopharyngeal carcinomaObjective:To explore the impact of oral nutritional supplements on the locally advanced nasopharyngeal carcinoma patients receiving chemo-radiotherapy.Methods and materials:A prospective,randomized and comparative study was performed in our hospital.Patients in the intervention group were given oral nutritional supplements from the beginning of radiotherapy,while the controls received usual diet care.We collected data of weights,hematological indexes and nutritional assessments before,during and after treatments.Results:In total,114 patients were recruited to this study from Oct 2016 to May 2018(58 cases in the intervention group and 56 in the control group).All patients experienced weight loss during radiotherapy.The declining trend in intervention groups is more obvious but with no statistical difference.Compared with the control group,the intervention group gets lower radiotherapy interruption(0 vs 7%,P=0.039)and higher completion of concurrent chemotherapy(90%vs 71%,P=0.013),as well as more stability of plasma protein level.But no differences were found between acute toxicities.During treatment,nutrition screening status also declined,more patients with NRS 2002? 3 scores in the control group(P<0.05),but no significant differences was found in PGSGA between two groups.Conclusion:The risk of weight loss and malnutrition gradually increased during the treatment Oral nutritional supplements can improve treatment tolerance and serum protein stability,but it has no obvious advantages in weight and short-term nutritional assessment.Part ? Recombinant human IL-11 in prevention and treatment of radiation-induced oral mucositis in patients with nasopharyngeal carcinoma:a phase 3,multicenter,randomized controlled trial.Purpose:To investigate the effect of recombinant human interleukin-11(rhIL-11)in prevention and treatment of radiation-induced oral mucositis(ROM)in nasopharyngeal carcinoma(NPC)patients,and observe the effectiveness of nutritional support on ROM.Methods:Ninety-seven patients with T1-4N1-3M0-1 NPC were enrolled.After 0-3 course of induction radiotherapy,patients in the two groups received chemo-radiotherapy.During radiotherapy,the experimental group received nebulizer inhalation using rhIL-11 plus normal saline,while the control group only used normal saline for nebulizer inhalation.ROM grade and nutritional indexes during treatment were weekly recorded:NRS 2002(nutritional risk screening tool,nutritional risk screening 2002),body weight,pre-albumin,retinol binding protein Results:from October 2018 to August 2019,97 cases were recruited in total,47 cases in rhIL-11 group and 45 cases in normal saline group.The incidence of 3 and 4 grade ROM was 27.2%and 31.5%(P=0.672)according to CTC AE 4.0,while according to RTOG criteria incidence of 3 and 4 grade ROM was 15.2%and 23.9%respectively(P=0.140).With the progress of radiotherapy,the nutritional indexes of the two groups significantly deteriorated.There was no statistical difference between the experimental group and the control group at all time points.Conclusion:RhIL-11 fail to reduce ROM of NPC patients.Appropriate nutritional support is conducive to the repair of oral mucosal injury.