Clinical And Experimental Studies On Treatment Of Patients With Nasopharyngeal Carcinoma By Late Course Accelerated Hyperfractionation Radiation Therapy

Nasopharyngeal carcinoma(NPC)is one of the most common malignant tumors in China, especially in Guangxi Autonomous Region.Owing to the particularity of anatomic position of nasopharynx and the characteristics of cells of nasopharyngeal carcinoma sensitive to radiation,the primary treatment of NPC remains radiotherapy at all times.The overall survival rates for 5-year was approximately 50%with conventional fractionated radiation therapy.However,there were 10%risk of pathological residue and 30%risk of locoregional recurrence after radiotherapy.One of the major factors of the failure in the disease is the accelerative multiplication of tumor cells in the radiotherapy.On the basis of the exploration of the prognostic factors of patients with NPC after treatment in our hospital,the research finds out the shortcomings of the conventional fractionated radiotherapy and studies the late course accelerated hyperfractionation(LCAHF)radiotherapy in NPC.At the same time,in order to realize the value of LCAHF in NPC,we also perform evidence-based researches on LCAHF radiotherapy in NPC based on the data of individual patient randomized controlled trial that have vended in the world wide magazine.Finally,this clinical result will be confirmed by experimental research.The main aim of this research is to provide the gist and clinical experience of LCAHF radiotherapy in NPC.Analysis of the Prognostic Factors of Nasopharyngeal Carcinoma Treated with RadiotherapyPurpose:To investigate the impact factor of prognosis of nasopharyngeal carcinoma(NPC) radiotherapy(RT),to improve and guide the NPC RT technique and multimodality schedules.Methods:From January 1996 to December 2001,840 cases of NPC received RT in our hospital,we analyzed the data retrospection.The data were analyzed statistically using SPSS 13.0 software,the Kaplan—Meier method was used to calculate the control rate of nasopharynx,the tumor-free survival rate and overall survival.Log-rank test is conducted for the difference significance.The Cox proportional hazards regression model was used to confirm the significance of prognostic factor.Results:â‘ The total control rates of nasopharynx for 3,5 and 10 years were 70.6%,56.7% and 36.6%,the tumor-free survival rates were 66.8%,51.8%and 32.0%,the overall survival rates were 73.8%,58.6%and 39.4%.â‘¡Univariate logistic regression analysis showed gender, age,clinical stage,T stage,N stage,skull base invasion,cranial nerve invasion,nasal cavity invasion,cervical node metastasis,unilateral/bilateral neck node metastasis,cervical node metastasis position,intracavity brachytherapy of nasopharynx,external beam radiotherapy method and chemotherapy were significantly associated with nasopharynx,the control rate, tumor-free survival,overall survival(P=0.000 or＜0.05).Irradiation dose of nasopharynx was significantly associated with nasopharynx control rate and overall survival(P＜0.05).The tumor-free survival of carotid sheath involvement group was lower than that of the group without carotid sheath involvement(P＜0.05),but was not significantly associated with control rate of nasopharynx and overall survival(P＞0.05);â‘¢Multivariate logistic regression analyses showed gender,age,clinical stage,T stage,unilateral/bilateral cervical node metastasis,intracavity brachytherapy of nasopharynx were independent impact factors of the control rate of nasopharynx,tumor-free survival and overall survival;â‘£The stratified analysis showed that T2 and T3 patients adjuvant high dose rate intracavity brachytherapy of nasopharynx increased the control rate of nasopharynx,tumor-free survival and overall survival(P＜0.01-0.05),except T1 and T4(P＞0.05);⑤The analysis of the two most used regimens(10-hydroxycamptothecin alone and 5-Fu/DDP)and radiotherapy/chemotherapy combined regimens showed that the 5-year overall survival of 10-hydroxycamptothecin induction chemotherapy combined with radiotherapy group was significantly lower than that of concurrent chemo-radiotherapy using 10-hydroxycamptothecin alone(P=0.048),the other groups had no significance of treatment result differences(P＞0.05).Conclusions:Advanced clinical stage(especially T stage),bilateral cervical node metastasis and male NPC patients had poor prognosis,adjuvant intracavity brachytherapy of nasopharynx improved the prognosis of T2 and T3 patients.To investigate a new RT technique and effective combined chemo-radiotherapy regimen is still an important problem. As a retrospective study,the results still need more trials to confirm. Long-term Effects Analysis of Nasopharyngeal Carcinoma Treated with Conventional Fractionation Radiotherapy and Late Course Accelerated Hyperfractionation RadiotherapyPurpose:To observe the long-term effects of nasopharyngeal carcinoma(NPC)treated with conventional fractionation(CF)radiotherapy and late course accelerated hyperfractionation (LCAHF)radiotherapy,and seek an appreciated NPC radiotherapy protocol.Methods:A total of 496 patients with NPC accrued in our retrospective analysis according to the previous criteria,CF group had 269 cases and LCAHF group had 227 cases.Two lateral parallel opposite large fields were used to treat the nasopharynx and upper neck first,with a fraction of 200cGy daily,5 days per week,after 36-40Gy,two lateral parallel opposite small fields were used to treat the primary tumor while spinal cord was excluded.In CF group,the total dose of nasopharynx was 68-76Gy with 2Gy daily.In LCAHF group,the radiation fraction of primary tumor was 1.5Gy twice daily,with a minimized six-hour interval in the late course,and total dose was 69-72Gy.Survival was assessed by Kaplan-Meier plots and log-rank analysis.Results:In LCAHF and CF group in 5 years,the primary site control,tumor-free survival and overall survival rate were 65.4%,61.5%,68.1%and 52.8%,49.4%,57.5%respectively.The difference between two groups were significant(P=0.006,0.006,0.031).In 5 years the primary site control,tumor-free survival and overall survival rate of LCAHF group were higher than those of CF group,but the local recurrence rate of primary site was lower than CF group(P＜0.05).Further analysis showed that LCAHF improved primary site control,tumor-free survival and overall survival rate of T2-T3 NPC(P＜0.05).There was no significant difference in radiation reaction and sequela between these two groups(P＞0.05).Conclusions:The results show that LCAHF is tolerable for NPC patients and improve the NPC local control,tumor-free survival,overall survival rate and reduce the local recurrence rate comparing to CF.But the recurrence rates of cervical lymph nodes and distant metastasis were similar between these two groups.Evidence-based Research on Nasopharyngeal Carcinoma Late Course Accelerated Hyperfraetionation Radiotherapy——a meta-analysis based on 1985—2005 literaturesPurpose To assess the efficacy and clinical value of nasopharyngeal carcinoma(NPC)late course accelerated hyperfractionation radiotherapy(LCHART).Methods We searched MEDLINE(1985.1- 2005.12),the Cochrane Library(1985.1-2005.12),and CBM disc(1985.1-2005.12).The authors screened and selected the randomized controlled trials(RCT)of NPC LCHART,and appraised their methodological quality and extracted data from the studies.Analyses were performed using Stata version 9.0. The Egger's test was used to evaluate publication bias of 1-,3-year overall survival and 1-,3-year control rates of nasopharynx,the heterogeneity was detected by the chi-squared test.Results After strict screening,4 randomized controlled trials involving 488 patients were included,with 241 patients in LCHART group,247 patients in conventional radiotherapy (CRT)group.Publication bias was significant(P=0.03)in the data of 1-year local control rate. Publication bias was not significant(P＞0.05)in the data of 1-,3-year overall survival and 3-year nasopharynx control rate.The homogeneities of 4 randomized trials were relatively good(P＞0.05).Statistical differences were found in 1-,3-year overall survival and 1-,3-year nasopharynx control rates comparisons between LCHART and CRT group,the OR(odds ratio) values and 95%confidence interval were 3.113(1.232-7.867),1.913(1.195-3.063)and 5.434 (1.560-18.935),4.308(2.210-8.396),respectively.Conclusions Based on the current evidence,CRT,NPC LCHART may increase 1-,3-year overall survival and 1-,3- year nasopharynx control rates.For the reasons of the limited case number and publication bias in 1-year nasopharyx control rate,the long-term results of large and multi-center RCTs are still need to confirm.Primary Study on the Molecular Mechanism of Accelerated Repopulation in Nasopharyngeal Carcinoma with IrradiationPurpose To investigate the status of accelerated repopulation in the CNE-2 cell lines during irradiation,search after the molecular mechanism of accelerated repopulation in nasopharyngeal carcinoma with irradiation,provide gist for LCAHF radiation therapy in NPC.Materials and methodsâ‘ MTT,cell division index and flow cytometry(FC)assay were performed to determine the CNE-2 cell lines proliferation dynamics during ⁶⁰Co-γ,2Gy 5-day-continuous fractionated irradiation.â‘¡Cell cycle and DNA damage repair genes related microarray were performed to select the differentially genes in different proliferation status of CNE-2 cell lines during ⁶⁰Co-γ,2Gy 5-day-continuous fractionated irradiation.â‘¢ Real-time quantitative PCR and western blotting were performed to detect the expression of differentially genes,in mRNA and protein level including our interesting differentially genes, such as CCNE1,CDC25A,CDKN1A,DDIT3,GADD45βand CDC25A protein.Resultsâ‘ Changes of CNE-2 cell lines proliferation dynamics were detected by MTT,cell division index and flow cytometry(FC)assay during ⁶⁰Co-γ2Gy 5-day-continuous fractionated irradiation.Accelerated repopulation of the CNE-2 cell lines occurred in the 3^rd day,and the decelerated repopulation occurred in the 5^thday.â‘¡A comprehensive, differentially gene expression profile was obtained for the accelerated repopulation nasopharyngeal carcinoma cell lines(CNE-2)during 2Gy 5-day-continuous fractionated radiotherapy.Totally,three cell cycle genes(CCNE1,CUE-5,CDKN1A)and six DNA damage repair genes(CDC25A,DDIT3,GADD45β,CDKN1A,BNIP3,FOXO3A,which were seldom reported to be related with accelerated repopulation before,were different expressed between the 3.(rd)day with the 5^thday during continuous irradiation.â‘¢We analyze several interesting differentially genes which were up or down at least 2 fold(CCNE1,CDC25A,CDKN1A,DDIT3,GADD45β,BNIP3)and its coded protein(CDC25A)with the real-time quantitative PCR and western blotting.The analysis revealed a similar expression pattern to microarray results.Conclusionsâ‘ The results showed that there was accelerated repopulation in the CNE-2 cell lines during the middle period of irradiation.â‘¡The application of Affymetrix Genechip microarray technique for analysis of gene expression profiles is a powerful strategy to identify novel accelerated repopulation-associated genes of nasopharyngeal carcinoma.Microarray profiles provide us with new insights into the accelerated repopulation process of nasopharyngeal carcinoma.Our results suggest that the accelerated repopulation process of nasopharyngeal carcinoma is a complicated and multifactorial process and may involve some genes of the following changes:activation of DNA damage repair and disturbance of cell cycle.â‘¢The genes may take part in the accelerated repopulation process which related with DNA damage repair and cell cycle,such as CCNE1,CDC25A,CDKN1A,DDIT3,GADD45β,BNIP3,CUL-5 etc.Further study of these accelerated repopulation genes may provide the insights into the molecular mechanism of the accelerated repopulation process of nasopharyngeal carcinoma.