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The role of surgery compared with reirradiation in the primary treatment of patients with resectable, locally recurrent nasopharyngeal carcinoma (NPC) who have previously received radiotherapy is a matter of debate. In this trial, we compared the efficacy and safety outcomes of salvage endoscopic surgery versus intensity-modulated radiotherapy (IMRT) in patients with resectable locally recurrent NPC. This multicentre, open-label, randomised, controlled, phase 3 trial was done in three hospitals in southern China. We included patients aged 18–70 years with a Karnofsky Performance Status score of at least 70 who were histopathologically diagnosed with undifferentiated or differentiated, non-keratinising, locally recurrent NPC with tumours confined to the nasopharyngeal cavity, the post-naris or nasal septum, the superficial parapharyngeal space, or the base wall of the sphenoid sinus. Eligible patients were randomly assigned (1:1) to receive either endoscopic nasopharyngectomy (ENPG group) or IMRT (IMRT group). Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre. Treatment group assignment was not masked. The primary endpoint was overall survival, compared between the groups at 3 years. Efficacy analyses were done by intention to treat. Safety analysis was done in patients who received treatment according to the treatment they actually received. This trial was prospectively registered at the Chinese Clinical Trial Registry, ChiCTR-TRC-11001573, and is currently in follow-up. Between Sept 30, 2011, and Jan 16, 2017, 200 eligible patients were randomly assigned to receive either ENPG (n=100) or IMRT (n=100). At a median follow-up of 56·0 months (IQR 42·0–69·0), 74 patients had died (29 [29%] of 100 patients in the ENPG group and 45 [45%] of 100 patients in the IMRT group). The 3-year overall survival was 85·8% (95% CI 78·9–92·7) in the ENPG group and 68·0% (58·6–77·4) in the IMRT group (hazard ratio 0·47, 95% CI 0·29–0·76; p=0·0015). The most common grade 3 or worse radiation-related late adverse event was pharyngeal mucositis (in five [5%] of 99 patients who underwent ENPG and 26 [26%] of 101 patients who underwent IMRT). Five [5%] of the 99 patients who underwent ENPG and 20 [20%] of the 101 patients who underwent IMRT died due to late toxic effects specific to radiotherapy; attribution to previous radiotherapy or trial radiotherapy is unclear due to the long-term nature of radiation-related toxicity. Endoscopic surgery significantly improved overall survival compared with IMRT in patients with resectable locally recurrent NPC. These results suggest that ENPG could be considered as the standard treatment option for this patient population, although long-term follow-up is needed to further determine the efficacy and toxicity of this strategy. Sun Yat-sen University Clinical Research 5010 Program

Patients with locoregionally advanced nasopharyngeal carcinoma with a high pretreatment plasma concentration of Epstein–Barr virus (EBV) DNA remain at high risk for recurrence after concurrent chemoradiotherapy. This study aimed to compare the efficacy and safety of neoadjuvant–adjuvant treatment with the PD-1 inhibitor toripalimab and concurrent chemoradiotherapy versus placebo and concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. This randomised, single-centre, double-blind, placebo-controlled, phase 2 trial was conducted at Sun Yat-sen University Cancer Centre in Guangzhou, China. Adult patients (aged 18–65 years) with newly diagnosed high-risk stage III–IVa locoregionally advanced nasopharyngeal carcinoma, with a pretreatment plasma EBV DNA concentration of at least 1500 copies per mL and an Eastern Cooperative Oncology Group performance score of 0–1, were eligible. Patients were randomly assigned (2:1) using an interactive web response system (block size of six), stratified by TNM stage (III vs IVa), to neoadjuvant toripalimab (240 mg intravenously) or placebo once every 2 weeks for two cycles, followed by concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 during intensity-modulated radiotherapy and adjuvant toripalimab (240 mg intravenously) or placebo once every 3 weeks for up to eight cycles. The primary endpoint was 2-year progression-free survival in the intention-to-treat population. This study was registered with ClinicalTrials.gov, NCT03925090, and is closed to enrolment; follow-up is ongoing. Between Dec 6, 2019, and Dec 9, 2021, 150 patients were enrolled and randomly assigned to the toripalimab group (n=100) or placebo group (n=50). 115 (77%) patients were male and 35 (23%) were female. As of data cutoff (May 31, 2024), median follow-up for progression-free survival was 37·8 months (IQR 34·2–46·5) for the intention-to-treat population analyses. 2-year progression-free survival was higher in the toripalimab group (92·0% [95% CI 86·7–97·3]) than in the placebo group (74·0% [61·8–86·2]; stratified hazard ratio 0·40 [95% CI 0·18–0·89]; log-rank p=0·019). The most common grade 3 or worse acute adverse events (occurring within 1 year of randomisation) were leukopenia (40 [40%] of 99 patients in the toripalimab group vs 22 [44%] of 50 patients in the placebo group), mucositis (28 [28%] vs ten [20%]), neutropenia (17 [17%] vs nine [18%]), anaemia (16 [16%] vs five [10%]), and weight loss (12 [12%] vs six [12%]). The most common grade 3 or worse late adverse events (occurring >1 year after randomisation) was auditory or hearing loss (eight [8%] vs four [8%]). Immune-mediated adverse events of grade 3 or worse occurred in ten (10%) patients only in the toripalimab group. One (2%) of 50 patients in the placebo group died due to septic shock caused by bacteraemia considered not treatment related. There were no treatment-related deaths in the toripalimab group. Our findings suggested that a so-called sandwich approach involving toripalimab (in the neoadjuvant and adjuvant phases) combined with concurrent chemoradiotherapy could be a highly promising therapy for the treatment of locoregionally advanced nasopharyngeal carcinoma. Phase 3 non-inferiority trials are warranted comparing neoadjuvant and adjuvant toripalimab versus cisplatin plus gemcitabine neoadjuvant chemotherapy combined with concurrent chemoradiotherapy. National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, Science and Technology Program of Guangzhou, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Postdoctoral Innovative Talent Support Program, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, and Fundamental Research Funds for the Central Universities. For the Chinese translation of the abstract see Supplementary Materials section.

Gemcitabine-cisplatin (GP) chemotherapy is the standard first-line systemic treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In this international, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT03581786), 289 patients with RM-NPC and no previous chemotherapy for recurrent or metastatic disease were randomized (1/1) to receive either toripalimab, a monoclonal antibody against human programmed death-1 (PD-1), or placebo in combination with GP every 3 weeks for up to six cycles, followed by monotherapy with toripalimab or placebo. The primary endpoint was progression-free survival (PFS) as assessed by a blinded independent review committee according to RECIST v.1.1. At the prespecified interim PFS analysis, a significant improvement in PFS was detected in the toripalimab arm compared to the placebo arm: median PFS of 11.7 versus 8.0 months, hazard ratio (HR) = 0.52 (95% confidence interval (CI): 0.36–0.74), P  = 0.0003. An improvement in PFS was observed across key subgroups, including PD-L1 expression. As of 18 February 2021, a 40% reduction in risk of death was observed in the toripalimab arm compared to the placebo arm (HR = 0.603 (95% CI: 0.364–0.997)). The incidence of grade ≥3 adverse events (AEs) (89.0 versus 89.5%), AEs leading to discontinuation of toripalimab/placebo (7.5 versus 4.9%) and fatal AEs (2.7 versus 2.8%) was similar between the two arms; however, immune-related AEs (irAEs) (39.7 versus 18.9%) and grade ≥3 irAEs (7.5 versus 0.7%) were more frequent in the toripalimab arm. In conclusion, the addition of toripalimab to GP chemotherapy as a first-line treatment for patients with RM-NPC provided superior PFS compared to GP alone, and with a manageable safety profile. Interim analysis from the randomized phase 3 JUPITER-02 trial shows that the addition of anti-PD-1 toripalimab to standard gemcitabine/cisplatin as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma has manageable toxicity and improves progression-free survival, suggesting a potential new treatment standard in this setting.

Vascular endothelial growth factor (VEGF) is overexpressed in nasopharyngeal carcinoma and suppresses the anti-tumour immune response. Previous studies have shown that adding anti-VEGF treatment to PD-1 inhibition treatment strategies improves tumour response. We aimed to compare the efficacy of pembrolizumab, a PD-1 inhibitor, with or without bevacizumab, a VEGF inhibitor, in nasopharyngeal carcinoma. In this randomised, open-label, phase 2 trial done at two hospitals (National University Cancer Institute and Tan Tock Seng Hospital) in Singapore, patients with platinum-resistant recurrent or metastatic nasophayngeal carcinoma were eligible if they were aged 21 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Patients were assigned (1:1; using random permuted blocks with varying sizes of 4 and 6) to receive either intravenous pembrolizumab (200 mg) every 21 days or a combination of pembrolizumab with intravenous bevacizumab (7·5 mg/kg) administered 1 week prior to each dose, until radiographic disease progression, unacceptable toxicity, completion of 32 cycles, or withdrawal of consent. The study was open label, therefore no masking of treatment assignment was implemented. The primary endpoint was objective response rate, assessed using RECIST (version 1.1) by independent radiologists and analysed in the intention-to-treat population (ie, all randomly assigned patients). This trial is registered with ClinicalTrials.gov, NCT03813394, and enrolment has closed. Between May 13, 2019, and Dec 6, 2023, we assessed 60 individuals for eligibility, 12 were excluded, and 48 were randomly allocated to pembrolizumab alone (n=24) or a combination of bevacizumab and pembrolizumab (n=24). The median age was 56 years (IQR 48–65), and 40 (83%) of 48 patients were male and eight (17%) were female. The median follow-up was 28·3 months (IQR 15·1–55·9). The objective response rate was significantly higher in the bevacizumab and pembrolizumab group (58·3% [95% CI 36·6–77·9] than in the pembrolizumab group (12·5% [2·7–32·4]; unadjusted RR 4·67 [95% CI 1·54–14·18]; p=0·0010). Grade 3 treatment-related adverse events occurred in two (8%) of 24 patients in the pembrolizumab group and in seven (29%) of 24 patients in the bevacizumab and pembrolizumab group; the most common severe or grade 3–4 treatment-related adverse events were thrombosis or bleeding (four [17%] of 24 patients in the bevacizumab and pembrolizumab group vs none of 24 patients in the pembrolizumab group), and others were transaminitis (none vs 1 [4%]), colitis (1 [4%] vs none]), cytopenias (none vs 1 [4%]), dermatological toxicities (1 [4%] vs none]), hypertension (1 [4%] vs none]), and proteinuria (1 [4%] vs none]). There were no grade 4 treatment-related adverse events or treatment-related deaths in either group. Pembrolizumab in combination with bevacizumab was more efficacious than pembrolizumab monotherapy, with manageable toxicities in platinum-resistant nasopharyngeal carcinoma. If validated in a phase 3 trial, the combination therapy could be a new standard of care in this population of patients. National Medical Research Council of Singapore, National Research Foundation Singapore, Singapore Ministry of Education under its Research Centres of Excellence initiatives, and Merck Sharp & Dohme.

Background In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. Methods All patients, including retrospective training ( n  = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n  = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. Results Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25–0.74, p  = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups ( p  = 0.063), with a significant treatment interaction ( p interaction  <  0.001). This trend was also found in the validation cohort with high ( n  = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06–0.51, p  <  0.001) and low ICTOS ( n  = 175, p  = 0.31), with a significant treatment interaction ( p interaction  = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors. Conclusion An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment. Trial registration ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.

Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18–60 years with previously untreated, non-keratinising stage III–IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68–70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62–68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30–32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9–81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7–80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69–1·39; log-rank p=0·92), with a difference of 0·5% (95% CI −7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (−6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3–4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. For the Chinese translation of the abstract see Supplementary Materials section.

Radiotherapy-induced oral mucositis (RTOM) is a common side effect of radiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) receiving concurrent chemoradiotherapy (CCRT). In this phase 3 trial, we aim to evaluate the efficacy and safety of Ulinastatin (UTI) for the prevention and treatment of RTOM in LA-NPC patients (NCT03387774). The primary endpoint is the incidence of grade ≥3 acute RTOM during radiotherapy. Secondary endpoints include cumulative incidence of RTOM, recovery rate, the onset time and duration of grade ≥3 RTOM, oral pain (severe), safety and survival outcomes. 179 eligible patients are randomly assigned to UTI Group ( n  = 89) or Control group ( n  = 90). All UTI group patients complete UTI treatment as planned, and both groups complete scheduled CCRT. The incidence of grade 3 RTOM is significantly lower in UTI group compared with control group (25.8% vs 41.1%, P  = 0.030). The trial meet its prespecified primary endpoint. No Ulinastatin related adverse events are observed during treatment. The 3-year overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) in UTI group and control group are similar between two groups. In this work, Ulinastatin can effectively reduce the severity of RTOM and oral pain without increasing toxicity and compromising survivals. Radiotherapy-induced oral mucositis is a common side effect in nasopharyngeal carcinoma treatment. Here, the authors present a phase 3 randomized clinical trial assessing the safety and efficacy of ulinastatin to prevent the incidence and severity of this condition.

Background Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have demonstrated significant survival benefits in treating recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). While baseline peripheral blood lymphocyte subsets have been identified as prognostic biomarkers in various cancers treated with ICIs, their relevance in R/M-NPC has not been extensively studied. Methods This post hoc analysis used data from 153 R/M-NPC patients treated with PD-L1 inhibitor monotherapy in the phase 2 trial KL167-2-05-CTP. The lymphocyte subsets, including total T cells, CD4/CD8 ratio, helper T cells, suppressor cytotoxic T cells, NK cells, and B cells, were tested by flow cytometry. These subsets were grouped using optimal cutoff values identified by the Maximally Selected Log-rank Statistic. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan–Meier and Cox regression analysis, and logistic regression analysis evaluated the associations with objective response rate (ORR) and disease control rate (DCR). Results Patients with lower NK cell percentages showed significantly longer OS (26.3 vs. 12.1 months, p  < 0.001) and PFS (5.5 vs. 3.7 months, p  < 0.001) compared to those with higher NK cell percentages. No significant differences in OS or PFS were observed for other lymphocyte subsets. High NK cell percentages were identified as risk factors for shorter OS (HR, 2.49) and PFS (HR, 1.62). There were no significant differences in ORR and DCR between high and low lymphocyte subsets. Conclusion Lower baseline NK cell percentages are associated with improved OS and PFS in R/M-NPC patients undergoing PD-L1 inhibitor therapy.

Introduction The effect of diffusion-weighted magnetic resonance imaging (DWI)-guided dose-painting intensity-modulated radiation therapy (DP-IMRT) on locally advanced recurrent nasopharyngeal carcinoma (NPC) remains unclear. This study aimed to compare the outcomes and toxicities of DWI-guided DP-IMRT in patients with locally recurrent NPC. Methods In this prospective trial, 150 patients with locally advanced recurrent NPC were randomly assigned (1:1) to receive reirradiation with DWI-guided DP-IMRT (DWI group, n  = 75) or conventional MRI-based IMRT (MRI group, n  = 75). In the DWI group, DWI-guided gross tumor volume received escalation to 65.4 Gy/30 fx in 2.18 Gy per fraction, while in the MRI group, the planning target volume was irradiated at 60 Gy/30fx in 2.0 Gy per fraction. The trial was registered at Chictr.org.cn (ChiCTR2100052340) on October 24, 2021. Survival rates were compared, and multivariate analyses were conducted. Results The median follow-up duration was 16 months. Compared with the MRI group, patients in the DWI group had better 18-month progression-free survival (PFS) 75.1% vs. 53.6%; P  = 0.006), local recurrence-free survival (LRFS) (83.4% vs. 61.8%; P  = 0.010), and locoregional recurrence-free survival (73.1% vs. 64.9%; P  = 0.025). Grade 3–4 toxicities between the two groups showed no significant difference. Multivariate analysis revealed that DWI-guided DP-IMRT was an independent prognostic factor for PFS and LRFS. Conclusion Compared with conventional MRI-based IMRT, DWI-guided DP-IMRT improved PFS in patients with recurrent NPC without increasing acute and late toxic effects.

AbstractObjectiveTo compare the effects of four cycles of docetaxel with cisplatin as a neoadjuvant chemotherapy followed by concurrent chemoradiotherapy with concurrent chemoradiotherapy alone by assessing reductions in distant metastasis and improvements in survival in patients with stage N2-3nasopharyngeal carcinoma.DesignPhase 3, multicentre, randomised controlled trial.SettingSix sites in China from 23 February 2016 to 18 February 2019.Participants186 participants aged ≤70 years with a diagnosis of untreated stage T1-4N2-3M0 nasopharyngeal carcinoma.InterventionParticipants were prospectively enrolled and randomly allocated to either the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group (four cycles of neoadjuvant chemotherapy (docetaxel 75 mg/m2 on day 1 and cisplatin 37.5 mg/m2 on days 2-3, every 3 weeks) followed by concurrent chemoradiotherapy (intensity modulated radiotherapy plus weekly cisplatin 40 mg/m2) or the concurrent chemoradiotherapy only group, in a 1:1 ratio.Main outcome measuresFive year distant metastasis-free survival and overall survival were analysed using the intention-to-treat approach.Results93 participants were assigned to each of the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups. After a median follow-up time of 76.9 (interquartile range 65.4-85.9) months, the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group had superior five year distant metastasis-free survival (91.3% (95% confidence interval (CI) 85.4% to 97.2%) versus 78.2% (69.8% to 86.6%); hazard ratio 0.41 (95% CI 0.19 to 0.87); P=0.02) and five year overall survival (90.3% (84.2% to 96.4%) versus 82.6% (75.0% to 90.2%); hazard ratio 0.38 (0.18 to 0.82); P=0.01). Grade 3/4 acute toxicities were observed in 60 (65%) and 46 (51%) patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively (P=0.05). The higher acute toxicity observed in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group was primarily due to grade 3/4 neutropenia (43 (47%) v 10 (11%); P<0.001). No significant difference in any late toxicity was observed between the two groups, and participants in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group tended to have a better quality of life five years after enrolment.ConclusionsFour cycles of docetaxel plus cisplatin neoadjuvant chemotherapy with concurrent chemoradiotherapy can effectively reduce distant metastasis and improve survival for patients with stage N2-3 nasopharyngeal carcinoma with manageable toxicities.Trial registrationClinicalTrials.gov NCT02512315.