Efficacy And Radiotherapy Resistance Mechanism Of Reduced Dose Cisplatin Combined With Radiotherapy In Nasopharyngeal Carcinoma

Background:The 3-year recurrence-free survival rate of induction chemotherapy combined with concurrent chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma is 85%.How to ensure the curative effect while reducing the side effects,and how to identify patients resistant to treatment early and carry out individualized treatment has become an important clinical problem to be solved urgently.Objective:To evaluate the efficacy and side effects of induction chemotherapy combined with concurrent chemoradiotherapy with reduced the cumulative dose of cisplatin in the treatment of locally advanced nasopharyngeal carcinoma,establish a prognostic model,explore the molecular mechanism of radiotherapy resistance to locally advanced nasopharyngeal carcinoma,and guide individualized therapy.Methods:A prospective phase Ⅱ single-arm clinical trial was conducted for the treatment of locally advanced nasopharyngeal carcinoma using induction chemotherapy combined with concurrent chemoradiotherapy with reduced cumulative dose of cisplatin.The primary endpoint was progression-free survival,and secondary endpoint included overall survival and side effects.For patients in this clinical trial,dynamic changes of clinical factors,blood and inflammatory markers were included to establish a prognostic model of progression-free survival.Single-cell transcriptome sequencing was used to explore the molecular mechanism of radiotherapy resistance in locally advanced nasopharyngeal carcinoma.Results:Three main results are listed below.(1)Single-arm phase Ⅱ trial of induction chemotherapy followed by concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma with reduced cumulative dose of cisplatinFrom January 2015 to September 2019,135 patients with newly diagnosed stageⅢ-ⅣA nasopharyngeal carcinoma were prospectively recruited and enrolled.PX induced chemotherapy combined with cisplatin concurrent chemoradiotherapy was used,and the cumulative dose of cisplatin was 440mg/m2.The 3-year progression-free survival and overall survival were 83.7%and 94.1%,respectively.The results of survival data were similar to those reported in NPC-0501 trial.A total of 76.3%patients had acute grade 3-4 adverse events.Only two patients(1.5%)had grade 3-4 late complications,numerically fewer than those reported in the NPC-0501 trial.(2)To establish a prognostic model of locally advanced nasopharyngeal carcinoma by dynamic changes of blood and inflammatory markers throughout the course of treatmentA total of 130 patients with locally advanced nasopharyngeal carcinoma who completed all radiotherapy plans in phse Ⅱ trial were selected to establish the model.Clinical factors,blood indicators and inflammatory markers were included,four factors related to PFS were incorporated into the prognostic model and a nomogram was established based on multivariate analysis combined with Akaike information criterion.The four factors were as follows:Log GTVn-preIC(HR,3.976;P=0.01),clinical stage(HR,2.792;P=0.034),the largest platelet-lymphocyte ratio(platelet-to-lymphocyte,PLR)during CCRT/PLR after induction chemotherapy(ΔmaxPLR,HR,0.819;P=0.024)and the minimum platelet count(PLT)during CCRT/PLT after induction chemotherapy(ΔminPLT,HR,5.914;P=0.139).The C index was 0.815,which is better than the C index 0.633 of the current 8th edition AJCC/UICC staging system.(3)Exploring the molecular mechanism of radiotherapy resistance in locally advanced nasopharyngeal carcinoma based on single cell transcriptome sequencingSingle cell transcriptome sequencing of tumor tissues from 3 locally advanced nasopharyngeal carcinoma patients treated with induction chemotherapy followed by concurrent chemoradiotherapy was analyzed(follow-up showed that 2 patients were sensitive to radiotherapy and 1 patient was resistant to radiotherapy).Tumor microenvironment(TME)enriched more myeloid cells and cancer-associated fibroblasts in patients with radiotherapy resistance,Inflammatory fibroblasts can recruit myeloid cell subpopulations(including tumor-associated macrophages,dendritic cells,and myeloid-derived suppressor cells)and regulatory T cells(Tregs)to TME through CXCL12-CXCR4.Myeloid cell subpopulations can further recruit Tregs to TME by CXCL16-CXCR6 ± SELPLG-SELL,thus forming immunosuppressive TME.Conclusions:The efficacy of induction chemotherapy followed by concurrent chemoradiotherapy with reduced cumulative dose of cisplatin in the treatment of locally advanced nasopharyngeal carcinoma was no worse than that of similar study NPC-0501 with higher cumulative dose of cisplatin,and the tolerance was good.The C index 0.815 of the PFS model with four factors of prognosis including Log GTVn_preIC,clinical stage,ΔmaxPLR and ΔminPLT can effectively distinguish between different locally advanced nasopharyngeal carcinoma prognosis.Immunosuppressive TME formed by the interaction of cancer-associated fibroblasts,myeloid cells and Tregs may be one of the mechanisms of locally advanced nasopharyngeal carcinoma radiotherapy resistance.