Clinical Research Of Induction Chemotherapy Followed By Concurrent Chemoradiotherapy For Locally Advanced(T_3-4/N₊) Nasopharyngeal Carcinoma

Objective:According to the world health organization,40%of all nasopharyngeal cancers occur in China.Due to the hidden location of the disease,more than 70%of the patients were diagnosed as locally advancd stage,with a poorer treatment efficacy.At present,patients with early stage are treated with radiotherapy alone,and patients with advanced stage are treated with radiotherapy,chemotherapy and other comprehensive treatments.The treatment basis of these patients is concurrent chemoradiotherapy,but about 20%of them still have distant metastasis after treatment,which is the main reason for the failure of treatment.As early as 2008,the NCCN guidelines recommended concurrent chemoradiotherapy with adjuvant chemotherapy as the standard treatment for locally advanced nasopharyngeal cancer.2012,a domestic multicenter?clinical trial demonstrate the adjuvant chemotherapy failed to further improve the curative effect,and brings obvious adverse reaction such as vomiting,mucosal inflammation.How to improve the curative effect on the basis of concurrent chemoradiotherapy needs further studies.The results of a subsequent multicenter,three-drug randomized controlled trial of induction chemotherapy demonstrated for the first time that induction chemotherapy combined with concurrent chemoradiotherapy reduced 5-year distant metastasis by 7%and improved 5-year overall survival by 6%.The 2018 edition of the NCCN guidelines has raised the level of evidence for induction chemotherapy from level 3 evidence which lasting 8 years to level 2A evidence recommended for locally advanced patients?T1N1-3M0?T2-4N0-3M0?.Purpose:To investigate the short-term efficacy,long-term survival,acute and chronic adverse reactions and prognostic factors of 103 patients with locally advanced nasopharyngeal carcinoma with T_3-4 or N₊who were not initially diagnosed with distant metastasisafter treated with induction chemotherapy and concurrent chemoradiotherapy.Method:A retrospective analysis was performed on 103 newly treated patients with nasopharyngeal carcinoma without distant metastasis in the radiotherapy department of the union hospital affiliated to fujian medical university from January 2012 to May2016,,including 70 males?78%?and 30 females?32%?.The average age was 45 years old?15-66 years old?.T ₁?T ₂?T₃?T ₄ stage include 17?16.5%??22?21.4%??27?26.2%??37?35.9%?cases,respectively.and 6?5.8%??28?27.2%??50?48.5%?,and 19cases?18.4%?of N ₀,N ₁,N ₂,and N ₃,respectively.II???IV clinical stage include12?11.7%??43?41.7%??48??46.6%?cases,respectively.The mean volume of primary nasopharyngeal lesions was 43.58cm,and 83 patients?87.4%?were EB-VCA-IgA positive before treatment,among which 17 patients?39.5%?were higher after treatment than before treatment,26 patients were lower than before treatment?60.5%?,and 37patients were not re-examined after treatment.The mean value of hemoglobin before treatment was 136g/L?79-158g/L?,and the mean value of hemoglobin decreased by25g/L?1-67g/L?in 93 patients?90.3%?after treatment.Mean radiotherapy time was 46.3days,median radiotherapy time was 45 days?42-66 days?.All patients received platinum-based sequential intensity-modulated radiotherapy and synchronous platinum-type single drug chemotherapy.TP regimen?paclitaxel+cisplatin?was the main induction chemotherapy regimen,accounting for 79.6%?82/103?,and the synchronous chemotherapy regimen included nedaplatin and cisplatin.Radiotherapy was performed with IMRT.Acute adverse reactions were recorded during the treatment,nasopharyngeal and neck MRI was re-examined after the induction chemotherapy and 1month after the treatment,respectively,to evaluate the tumor remission,and survival and long-term complications were followed up after the treatment.Results:1)The short-term clinical effecacy:After induction chemotherapy,the total response rate was 79.6%,77.3%of nasopharyngeal primary lesions and cervical metastatic lymph nodes respectively,while the total response rate was 98.1%and 100%after the end of the treatment.2)Long-term survival:The median follow-up time was 51months,with a follow-up rate of 90.6%.3-year OS,FFS,LRRFS and DMFS were80.2%,75.1%,93.0%and 84.5%,respectively.5-year OS,FFS,LRRFS and DMFS were 69.8%,69.6%,88.8%and 84.5%,respectively.3)Long-term survival of different clinical stages:The 5-year OS of II,III and IV stage were 83.3%,74.7%and 68.5%,FFS were 91.7%,65.4%and 61.7%,LRRFS were 100%,94.4%and 79.0%,and DMFS were 90.0%,83.7%and 82.9%,respectively.4)The pattern of failure:There were 21cases of treatment failure,8 cases of local treatment failure?7.8%?,including 3 cases of nasopharyngeal primary recurrence?14.3%?,5 cases of regional lymph node recurrence?23.8%?.13 cases?61.9%?with distant metastatic failure were mostly bone metastases.5)Univariate analysis:Aged?50 years old is a factor influencing poor prognosis at 3 and5 years FFS?P=0.021,P=0.011?;T_3-4-4 is a bad prognostic factor of 3-year OS?P=0.015?,3-year FFS?P=0.006,P=0.002?and 3-year and 5-year LRRFS?P=0.024,P=0.039?.Clinical stage is a prognostic factor of 3-year OS?P=0.050?and 3-year FFS?P=0.048?.The higher,the worse.GTV volume that?40cm3is a bad prognostic factor of 5-year OS?P=0.024?,3-year FFS?P=0.028,P=0.011?and DMFS?P=0.007?.EB-VCA-IgA negative before treatment is an adverse prognostic factor of 5-year LRRFS?P=0.045?,and has a tendency to reduce 3-year LRRFS.The number of induction chemotherapy cycles 3 May be an adverse prognostic factor of 5-year LRRFS?P=0.066?,but the number of induction chemotherapy cycles increased,showing a trend of increasing DMFS?P=0.078?.6)Multivariate prognostic analysis:Age is an independent prognostic factor of 5-year FFS?P=0.027?.T staging is an independent prognostic factor of 5-year FFS?P=0.006?,3-year LRRFS?P=0.024?and 5-year LRRFS?P=0.04?.GTV volume is an independent prognostic factor of 5-year DMFS?P=0.01?.7)Adverse reactions:Major adverse reactions during treatment can be tolerated by patients after symptomatic support treatment.Long-term adverse reactions included dry mouth,hearing loss,limited mouth opening,and dysphagia,are mostly level1-2,and none of them had a serious impact on the patient's normal life.Conclusion:1)In the era of IMRT,sequential concurrent chemoradiotherapy with induction chemotherapy achieved good clinical results in the treatment of advanced nasopharyngeal carcinoma.The 5-year OS of stage II,III and IV were 83.3%,74.7%and 68.5%,FFS were 91.7%,65.4%and 61.7%,LRRFS were 100%,94.4%and 79.0%,and DMFS were 90.0%,83.7%and 82.9%,respectively.Acute toxicities were acceptable and no serious long-term complications were found.2)The main adverse prognostic factors of middle and advanced nasopharyngeal carcinoma were:Patients aged?50 years old,T_3-4,advanced clinical stage,and GTV volume?40 cm3.3)Increasing the number of induction chemotherapy cycles is expected to reduce the distant metastasis rate of advanced nasopharyngeal carcinoma.4)Patients with positive EB-VCA-IgA have higher LRRFS,and those with decreased EB-VCA-IgA test value after treatment seem to have better survival benefits,suggesting that changes in EB-VCA-IgA test value before and after treatment may be used to predict the prognosis of nasopharyngeal cancer.