Four cycles of docetaxel plus cisplatin as neoadjuvant chemotherapy followed by concurrent chemoradiotherapy in stage N2-3 nasopharyngeal carcinoma: phase 3 multicentre randomised controlled trial ==================================================================================================================================================================================================== * Wei-Hao Xie * Wei-Wei Xiao * Hui Chang * Ming-Jun Xu * Yong-Hong Hu * Tong-Chong Zhou * Qiong Zhong * Chun-Yan Chen * Li-Xia Lu * Qiao-Xuan Wang * Yu-Jia Zhu * Jing Yang * Xing-Yuan Shi * Hua-Long Kang * Jia-Wang Wei * Rong Huang * Hai-Hua Peng * Yan Yuan * Shi-Hai Wu * Xin-Hua Jiang * Ya-Jie Liu * Bi-Xiu Wen * Yuan-Hong Gao ## Abstract **Objective** To 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. **Design** Phase 3, multicentre, randomised controlled trial. **Setting** Six sites in China from 23 February 2016 to 18 February 2019. **Participants** 186 participants aged ≤70 years with a diagnosis of untreated stage T1-4N2-3M0 nasopharyngeal carcinoma. **Intervention** Participants 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 measures** Five year distant metastasis-free survival and overall survival were analysed using the intention-to-treat approach. **Results** 93 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. **Conclusions** Four 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 registration** ClinicalTrials.gov [NCT02512315](https://www.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02512315&atom=%2Fbmj%2F389%2Fbmj-2024-081557.atom). ## Introduction Nasopharyngeal carcinoma is an epithelial carcinoma with a low and uneven global incidence. Worldwide, more than 120 000 patients had a new diagnosis of nasopharyngeal carcinoma in 2022, accounting for approximately 0.6% of all cancers.1 Most patients were distributed in South East Asia, especially southern China.2 For locoregionally advanced nasopharyngeal carcinoma, advances in radiation techniques, such as intensity modulated radiation therapy, and the application of concurrent chemotherapy have greatly improved disease control compared with traditional radiotherapy alone. Nevertheless, distant metastasis remains the main cause of treatment failure.3 To the best of our knowledge, the risk of distant metastasis is highly correlated with tumour burden. Approximately 27.2-37.6% of patients with nasopharyngeal carcinoma have stage N2-3.45 Compared with stage N0-1, stage N2-3 nasopharyngeal carcinoma indicates bilateral or more inferior cervical involvement, which increases the risk of direct tumour dissemination, lymphatic metastasis, and haematogenous metastasis. We have proposed that the high risk of distant metastasis for stage N2-3 nasopharyngeal carcinoma may be because of pre-existing undetectable micrometastases in distant organs and that it should be considered as a disseminated disease and managed with intense systemic chemotherapy.67 To develop an effective neoadjuvant chemotherapy regimen for locoregionally advanced nasopharyngeal carcinoma, Hui and colleagues did a phase 2 trial comparing two cycles of docetaxel plus cisplatin neoadjuvant chemotherapy plus cisplatin based concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in 2009 and showed a favourable impact on overall survival.8 Jin and colleagues compared the chemotherapy regimens of 822 patients in 2012 and concluded that docetaxel plus cisplatin, cisplatin plus 5-fluorouracil, and gemcitabine plus cisplatin were effective and tolerated regimens for metastatic nasopharyngeal carcinoma.9 Since 2015, randomised controlled trials of neoadjuvant chemotherapy followed by concurrent chemoradiotherapy on locoregionally advanced nasopharyngeal carcinoma have been conducted.1011121314 Neoadjuvant chemotherapy plus concurrent chemoradiotherapy was shown to be effective for locoregionally advanced nasopharyngeal carcinoma, with three cycles of either docetaxel, cisplatin, and fluorouracil or gemcitabine plus cisplatin being the most recommended by the National Comprehensive Cancer Network guidelines. However, before the results of the aforementioned randomised controlled trials were published, a consensus on neoadjuvant chemotherapy regimens was lacking. For stage N2-3 nasopharyngeal carcinoma specifically, we previously analysed 924 cases to show that four cycles of neoadjuvant chemotherapy plus concurrent chemoradiotherapy led to improved distant metastasis-free survival, overall survival, locoregional relapse-free survival, and disease-free survival compared with concurrent chemoradiotherapy alone or two cycles of neoadjuvant chemotherapy plus concurrent chemoradiotherapy.15 The docetaxel plus cisplatin regimen is an active regimen in recurrent or metastatic head-and-neck cancers with the potential to control distant metastasis.16171819 Furthermore, administration involves an intravenous drip for three days, which is considered a clinically convenient regimen. According to our previous results and studies from other institutions, we believe that the docetaxel plus cisplatin regimen could be an effective and safe option for stage N2-3 nasopharyngeal carcinoma. To further verify our hypothesis, we did a phase 3 multicentre randomised controlled trial. The trial compared the efficacy of four cycles of docetaxel plus cisplatin neoadjuvant chemotherapy followed by concurrent chemoradiotherapy with concurrent chemoradiotherapy alone, by assessing their abilities to lower the risk of metastasis and improve the survival of patients with stage T1-4N2-3M0 nasopharyngeal carcinoma. ## Methods ### Trial design and participants A phase 3, multicentre, open label, randomised controlled trial was conducted by the Sun Yat-sen University Cancer Centre (SYSUCC) and included five tertiary hospitals in China (supplementary table A). Patients aged ≤70 years with a pathological diagnosis of untreated stage T1-4N2-3M0 nasopharyngeal carcinoma (Union for International Cancer Control and American Joint Committee on Cancer, 7th edition) were considered eligible. Exclusion criteria included a Karnofsky’s performance score ≤70; distant metastasis before treatment; severe dysfunction of the heart, lung, liver, kidney, or haematopoietic system; severe neurological, mental, or endocrine diseases; history of other malignant tumours; history of radiotherapy, chemotherapy, or biological target therapy; participation in pharmaceutical clinical trials within the previous three months; pregnancy or lactation; and unadvisable enrolments judged by investigators. Pre-treatment examination comprised a detailed medical history, physical examination, fibreoptic nasopharyngoscopy with biopsy, enhanced magnetic resonance imaging of the nasopharynx and neck, enhanced thoracoabdominal computed tomography for N2 patients, positron emission tomography-computed tomography for N2 patients with suspicious distant metastasis and all N3 patients, whole body bone scan, and plasma DNA load of Epstein-Barr virus. We obtained written informed consent from all patients before enrolment. A detailed description of the trial is provided in the supplementary protocol. ### Randomisation Randomisation was done at the SYSUCC. Eligible patients were first stratified by N stages (N2 and N3) and then randomly assigned to the control (concurrent chemoradiotherapy alone) or study (neoadjuvant chemotherapy plus concurrent chemoradiotherapy) group in a 1:1 ratio in each stratification. Random numbers were generated using a computed random number code and sealed in opaque envelopes marked with two colours to distinguish stage N2 (white) and N3 (brown) stratifications. Each number corresponded to the unique information of the group to which each patient was assigned. ### Blinding We did not apply blinding to participants or care providers after randomisation because which intervention was assigned was obvious on the basis of whether neoadjuvant chemotherapy was or was not administered. However, we applied blinding during the outcome assessment. Outcomes with no objective indicators were presented to the trial committee anonymously and were decided only after consensus was achieved among committee members; otherwise, an independent third party was invited to determine the final conclusion. ### Interventions In the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, patients received up to four cycles of neoadjuvant chemotherapy followed by concurrent chemoradiotherapy. The first two cycles of neoadjuvant chemotherapy were followed by a short term efficacy evaluation based on the Respond Evaluation Criteria in Solid Tumours (RECIST, version 1.1). The largest measurable and involved cervical lymph node was evaluated using magnetic resonance imaging, but evaluation of the primary tumour from the nasopharynx was not mandatory at this point. Subsequently, for patients who achieved a partial response or a complete response, two more cycles of neoadjuvant chemotherapy were administered, followed by concurrent chemoradiotherapy; for patients with sustained stable disease, the process of neoadjuvant chemotherapy was terminated and concurrent chemoradiotherapy was started immediately; patients who showed progressive disease, with or without distant metastasis, were withdrawn from the study and received an adjusted treatment modality such as change of neoadjuvant chemotherapy regimen followed by concurrent chemoradiotherapy. In the concurrent chemoradiotherapy only group, patients received concurrent chemoradiotherapy alone without neoadjuvant chemotherapy. The intention-to-treat population comprised patients who were randomised, regardless of subsequent treatment. The per protocol population comprised patients with a partial or complete response who finished concurrent chemoradiotherapy after three or four cycles of neoadjuvant chemotherapy, patients with stable disease who finished concurrent chemoradiotherapy after two cycles of neoadjuvant chemotherapy in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, and patients who finished concurrent chemoradiotherapy in the concurrent chemoradiotherapy only group. The intensity modulated radiation therapy technique was applied to all radiotherapy plans. Nasopharyngeal gross tumour and the involved retropharyngeal lymph nodes, involved cervical lymph nodes, high risk clinical target volumes, and low risk clinical target volumes were targeted with prescription doses of 66-72, 60-66, 60, and 50-54 Gy in 30-33 fractions, respectively. The intensity modulated radiation therapy guidelines were administered under the comprehensive guidance of the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) and the experience of nasopharyngeal carcinoma radiotherapy practice from the SYSUCC (supplementary protocol).32021 The neoadjuvant chemotherapy regimen included docetaxel (75 mg/m2 on day 1) and cisplatin (37.5 mg/m2 on days 2-3). Both drugs were administered intravenously, and this was repeated every three weeks for a maximum of four cycles. The concurrent chemotherapy regimen was a weekly dose of cisplatin (40 mg/m2 on day 1) administered intravenously. Prophylactic antiemetic was applied in cases of severe emesis induced by cisplatin, but the prophylactic application of granulocyte colony stimulating factor was not permitted. We used the Common Terminology Criteria for Adverse Events (version 4.0) to evaluate the degree of toxicity. For patients with grade 3/4 toxicities, symptomatic treatment was administered and chemotherapy paused until related toxicities recovered to grade 1 or subsided. We did blood tests and physical examinations at least once a week to assess recovery from toxicity. Chemotherapy was administered at a full dose for both treatment groups from the beginning. Dose reduction primarily occurred under the following circumstances: haematopoietic toxicity of grade 4, leading to a 20% and 40% dose reduction for the first and second occurrences and termination of neoadjuvant chemotherapy for the third occurrence; hepatotoxicity or nephrotoxicity of grade 2, leading to a 20% and 40% dose reduction for the first and second occurrence and termination of neoadjuvant chemotherapy for the third occurrence; gastrointestinal toxicity of grade 3 for the second occurrence or grade 4 for the first occurrence would lead to a 20% dose reduction; neurotoxicity or cardiotoxicity of grade 2 would lead to a 20% dose reduction for the first occurrence and termination of neoadjuvant chemotherapy for the second occurrence. Any hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, or allergic reaction of grade 3/4 would lead to termination of neoadjuvant chemotherapy. Severe adverse events were defined as follows: treatment related toxicity that causes a treatment delay for more than two weeks; chemotherapy or radiotherapy that results in the necessity of a third time dose reduction; and life threatening toxicities including, but not limited to, severe renal function damage with a glomerular filtration rate of <40 mL/min or grade 3/4 neurotoxicity related to cisplatin and grade 3/4 allergic reaction related to cisplatin and docetaxel. All patients were to be followed-up until death or for at least five years after enrolment. Post-treatment assessments included fibreoptic nasopharyngoscopy, enhanced magnetic resonance imaging of the nasopharynx and neck, enhanced thoracoabdominal computed tomography, and plasma Epstein-Barr virus DNA load, which should be done every three months for the first three years, every six months in the fourth and fifth years, and annually after the fifth year. Locoregional relapse or distant metastasis should be supported by pathological evidence or at least two imaging examinations. The site and date of any relapse or metastasis should be recorded. If a patient dies, the cause and date of death are recorded. Patients are considered lost during the follow-up if their survival status cannot be confirmed for more than six months. ### Outcomes The primary endpoints were five year distant metastasis-free survival and overall survival, which were centrally assessed. The secondary endpoints were five year locoregional relapse-free survival and disease-free survival. We calculated the time-to-event intervals from the date of enrolment to the date of the corresponding event, which was distant metastasis for distant metastasis-free survival, death for overall survival, locoregional relapse for locoregional relapse-free survival, and locoregional or distant failure or death for disease-free survival. For safety reasons, we compared the incidence of any grade ≥3 acute toxicity during neoadjuvant chemotherapy, concurrent chemoradiotherapy, and the entire procedure between the two groups. We assessed late toxicities from five years after enrolment and compared them between the two groups. We assessed quality of life from five years after enrolment by using the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). ### Sample size and statistical methods We used Power Analysis and Sample Size 11 software to analyse sample size, with a power of 80% and a two sided significance level of 0.05. On the basis of our previous results from 924 patients with stage N2-3 nasopharyngeal carcinoma and different neoadjuvant chemotherapy cycles, we anticipated an estimated increase in five year distant metastasis-free survival from 68.8% to 84.8% and in five year overall survival from 74.0% to 89.2% in patients receiving four cycles of neoadjuvant chemotherapy compared with the control group.15 The analysis indicated that a minimum sample size of at least 84 qualified patients was needed for each grouup.14 Considering a maximum dropout rate of 14%, we needed a minimum of 96 patients for each group. As the approximate ratio of stage N2 and N3 was 3:1, this study intended to enrol 144 patients with stage N2 disease and 48 with stage N3 disease in the case study series. We used SPSS Statistics software (version 22.0), and R (version 4.1.3) to analyse data collected in this trial. We analysed efficacy data according to the intention-to-treat approach. In addition, we did a safety analysis, which comprised patients who had undergone at least one cycle of chemotherapy or one fraction of radiotherapy in the corresponding phases. We described time-to-event data by using Kaplan-Meier curves and compared them with the log-rank test. For other data, we compared ordered categories, unordered categories, and continuous variables by using Wilcoxon rank-sum, χ2, and Student’s t tests, respectively. We calculated hazard ratios and 95% confidence intervals by using an unadjusted Cox proportional hazards model. Full details of the trial protocol can be found in the supplementary protocol. ### Patient and public involvement As patient and public involvement was not a routine practice in the areas where this trial was conducted, no patients were involved in the design or implementation of this trial, and nor did they participate in the subsequent data analysis, interpretation, or writing of the manuscript. However, all patients were aware of the trial objectives and protocols during recruitment. ## Results ### Participants We enrolled 192 patients with stage T1-4N2-3M0 nasopharyngeal carcinoma from 23 February 2016 to 18 February 2019. After exclusion of six patients who withdrew consent before randomisation, 186 patients were randomly assigned to the neoadjuvant chemotherapy plus concurrent chemoradiotherapy (n=93) and concurrent chemoradiotherapy only (n=93) groups (fig 1). Table 1 shows the baseline demographic and clinical characteristics of the two groups. Until the most recent follow-up on 1 March 2024, the median follow-up duration was 76.9 (interquartile range 65.4-85.9) months. In the intention-to-treat population, of the 186 patients, only one (0.5%) was lost during follow-up after 16.7 months. The other 185 patients were followed up until death or over five years. The last enrolled patient had a follow-up duration of 61.3 months. ![Fig 1](https://www.bmj.com/https://www.bmj.com/content/bmj/389/bmj-2024-081557/F1.medium.jpg) [Fig 1](https://www.bmj.com/content/389/bmj-2024-081557/F1) Fig 1 Flowchart of trial design. CCRT=concurrent chemoradiotherapy; NACT=neoadjuvant chemotherapy View this table: [Table 1](https://www.bmj.com/content/389/bmj-2024-081557/T1) Table 1 Baseline characteristics. Values are numbers (percentages) unless stated otherwise In the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, one patient withdrew consent after randomisation and received concurrent chemoradiotherapy at a non-participating hospital. A total of 92 patients started neoadjuvant chemotherapy. Seventy seven (84%) patients completed all four cycles, and five (5%), eight (9%), and two (2%) patients completed three, two, and one cycles, respectively (table 2). Two patients withdrew from the cohort after the first cycle, because of one grade 4 febrile neutropenia and non-neoadjuvant chemotherapy related acute cardiac condition. After two cycles of neoadjuvant chemotherapy, 82 (91%), five (6%), and three (3%) patients were confirmed by magnetic resonance imaging to have partial or complete response, stable disease, and progressive disease of the cervical lymph nodes, respectively. Among the eight patients who received only two cycles of neoadjuvant chemotherapy, three patients with progressive disease were withdrawn from the cohort and one patient with stable disease also chose to withdraw consent and requested two more cycles of neoadjuvant chemotherapy followed by concurrent chemoradiotherapy; the other four patients followed the protocol to cancel the subsequent two cycles of neoadjuvant chemotherapy and start concurrent chemoradiotherapy directly. Eighty six patients received concurrent chemoradiotherapy following neoadjuvant chemotherapy, two of whom discontinued treatment after 13 and 17 radiotherapy fractions; both discontinuations were due to refusal caused by acute toxicities. Thus, of the 93 patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, 84 completed the protocol defined treatments. View this table: [Table 2](https://www.bmj.com/content/389/bmj-2024-081557/T2) Table 2 Compliance with and response to treatment of enrolled patients. Values are numbers (percentages) unless stated otherwise During treatment preparation for the concurrent chemoradiotherapy only group, three patients withdrew from the study and requested neoadjuvant chemotherapy plus concurrent chemoradiotherapy. Consequently, 90 patients started concurrent chemoradiotherapy, one of whom discontinued treatment owing to refusal caused by acute toxicities after 12 radiotherapy fractions; two finished weekly concurrent chemotherapy but terminated treatment before the final three and one radiotherapy fractions, for personal reasons. Thus, of the 93 patients in the concurrent chemoradiotherapy only group, 87 completed the protocol defined treatment. Detailed information on withdrawal of patients from the cohort at each phase is provided in supplementary table B. In the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, the median radiation doses were 70.1 (interquartile range 69.8-71.9) Gy and 70.4 (69.9-71.9) Gy, respectively (P=0.38), and the median fractionated doses were 2.19 (2.18-2.20) Gy and 2.18 (2.18-2.20) Gy, respectively (P=0.84) (table 2). A dose of ≥70 Gy was administered to 60 (70%) and 68 (76%) patients, respectively. Intravenous cisplatin (40 mg/m2) was administered as a concurrent chemotherapy regimen weekly for a maximum of seven cycles. During concurrent chemoradiotherapy, 14 (16%) versus two (2%) patients received an accumulated cisplatin dose of <100 mg/m2 in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively; the median accumulated cisplatin dose was lower in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group (160 (interquartile range 125-160) mg/m2) than in the concurrent chemoradiotherapy only group (240 (200-240) mg/m2) (P<0.001). ### Efficacy In the intention-to-treat population (table 3; fig 2), failure events (including distant metastases, locoregional relapses, and deaths) occurred in 19 (20%) and 36 (39%) patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively, among which nine (10%) and 20 (22%) distant metastases, 10 (11%) and 22 (24%) locoregional relapses, and nine (10%) and 22 (24%) deaths occurred. The failure patterns and cause of death for each patient are listed in supplementary table C. The five year distant metastasis-free survival (91.3% (95% confidence interval (CI) 85.4% to 97.2%) and 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%) and 82.6% (75.0% to 90.2%); hazard ratio 0.38 (0.18 to 0.82); P=0.01) were significantly higher in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group than in the concurrent chemoradiotherapy only group. We also observed superior five year locoregional relapse-free survival (91.1% (95% CI 85.2% to 97.0%) and 76.7% (67.9% to 85.5%); hazard ratio 0.41 (95% CI 0.19 to 0.90); P=0.02) and five year disease-free survival (81.7% (73.9% to 89.5%) and 63.4% (53.6% to 73.2%); hazard ratio 0.46 (0.26 to 0.80); P=0.005) in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group compared with the concurrent chemoradiotherapy only group. In the per protocol population, the distant metastasis-free survival, overall survival, locoregional relapse-free survival, and disease-free survival at five years were also superior in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group compared with the concurrent chemoradiotherapy only group, with more evident improvements and greater significance (supplementary table D and figure A). View this table: [Table 3](https://www.bmj.com/content/389/bmj-2024-081557/T3) Table 3 Survival in intention-to-treat population. Values are percentages (95% confidence intervals) unless stated otherwise ![Fig 2](https://www.bmj.com/https://www.bmj.com/content/bmj/389/bmj-2024-081557/F2.medium.jpg) [Fig 2](https://www.bmj.com/content/389/bmj-2024-081557/F2) Fig 2 Kaplan-Meier survival curves in intention-to-treat (ITT) population. CCRT=concurrent chemoradiotherapy; CI=confidence interval; NACT=neoadjuvant chemotherapy One (1%) and two (2%) patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group had distant metastasis and locoregional relapses, respectively from five years after treatment, as did one (1%) patient with locoregional relapse in the concurrent chemoradiotherapy only group. The latest event of treatment failure occurred after 78.1 and 69.9 months in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively. The concurrent chemoradiotherapy group tended to have higher risks and earlier occurrences of failure events than did the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group. The small number of treatment failures after five years also indicated the necessity for regular annual follow-ups. ### Toxicities and quality of life We analysed the acute toxicities associated with neoadjuvant chemotherapy and concurrent chemoradiotherapy and present them in table 4 and supplementary tables E-G. We observed 60 (65%) and 46 (51%) grade 3/4 toxicities in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively. The neoadjuvant chemotherapy plus concurrent chemoradiotherapy group showed no significant increase in overall grade 3/4 toxicities compared with the concurrent chemoradiotherapy only group (P=0.05). Furthermore, toxicities in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group were not associated with serious adverse events or mortality throughout the procedure. The incidence of grade 3/4 toxicity during neoadjuvant chemotherapy was 38%, which included 27 (29%) grade 3/4 leukopenia, 34 (37%) grade 3/4 neutropenia, and eight (9%) grade 3 gastrointestinal toxicities. Grade 3/4 toxicities of leukopenia/neutropenia caused by neoadjuvant chemotherapy and were the main reason for higher treatment risks in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group than in the concurrent chemoradiotherapy only group. However, the accumulated dose of neoadjuvant chemotherapy did not increase the risk of grade 3/4 toxicity during concurrent chemoradiotherapy because the incidences were 44 (51%) and 46 (51%) in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively (P=1.00). View this table: [Table 4](https://www.bmj.com/content/389/bmj-2024-081557/T4) Table 4 Toxicities in safety analysis population. Values are numbers (percentages) unless stated otherwise Regarding late toxicities, after excluding 31 participants who died and one participant who was lost to follow-up, we assessed symptoms in the remaining 150 participants in the safety analysis population. Three (4%) and six (9%) patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively, developed grade 3 late toxicities; the incidences were comparable (P=0.19). All seven patients with grade 3 hearing impairments reported the need to listen with the aid of an audiphone. One (1%) patient in the concurrent chemoradiotherapy group reported complete loss of olfactory sensation while other senses were still functional. A total of 72 (48%) participants reported damage to teeth and claimed to have altered their diets owing to dental dysfunction, including one patient in the concurrent chemoradiotherapy group who experienced significant loss of functional teeth. Conditions included losses of teeth, dental caries, and tooth disintegration. However, among these patients, some used their remaining healthy teeth, some had tooth implant surgery, and some installed artificial teeth to aid in chewing and maintain an altered but nutritionally balanced diet. EORTC QLQ-C30 data were collected from 80 and 68 surviving patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradiotherapy only groups, respectively. The overall completion rates were >95%, with three patients in each group being non-compliant. The two groups showed comparable distribution in scales among the responses to question (supplementary table H); however, participants in the concurrent chemoradiotherapy only group tended to have a non-significant increase in physical or mental discomfort and lower mean scores when rating their health status and quality of life. Only five (6%) in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group and six (9%) participants in the concurrent chemoradiotherapy only group rated their health status and quality of life as below 4 points, indicating that most survivors in both groups lived moderate or satisfactory lives. ### Post hoc analysis Owing to the different prognosis between stages N2 and N3 nasopharyngeal carcinoma, we did stratified analysis by N stage to assess the performance of four cycles of docetaxel plus cisplatin neoadjuvant chemotherapy separately. Baseline characteristics were balanced between the two groups in each stratification. The Kaplan-Meier curves in both stratifications showed relatively stable hazard ratios between two groups among the four survival outcomes. The stage N2 stratification showed a significant increase in five year survival and lower hazard ratios in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, whereas the stage N3 stratification showed only a trend of superiority (supplementary tables I-L and figures B and C). We determined the independent prognostic factors for survival by using a Cox proportional hazards model and present them in supplementary figure D. ## Discussion This was a phase 3 randomised controlled trial involving patients with stage N2-3 nasopharyngeal carcinoma who were consequently at a high risk of distant metastasis. Both five year overall survival and five year distant metastasis-free survival, the two primary endpoints, were superior in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group compared with the concurrent chemoradiotherapy only group. Furthermore, the long term results have confirmed the two hypotheses of this study. Firstly, docetaxel plus cisplatin can be part of an effective neoadjuvant chemotherapy regimen for nasopharyngeal carcinoma, evidenced by the 7.7% (90.3% *v* 82.6%; P=0.01) improvement in five year overall survival. Secondly, the risk of distant metastasis in stage N2-3 nasopharyngeal carcinoma was primarily caused by the preliminary micrometastasis and could be controlled by increasing neoadjuvant chemotherapy cycles, evidenced by the 13.1% (91.3% *v* 78.2%; P=0.02) improvement in five year distant metastasis-free survival. ### Meaning of findings Docetaxel and cisplatin exert anti-tumour activities through different mechanisms.2223 The combination of these two drugs as a neoadvuvant chemotherpy regimen has been studied in nasopharyngeal carcinoma. Hui and colleagues’ phase 2 study compared two cycles of a docetaxel plus cisplatin neoadjuvant chemotherapy regimen with concurrent chemoradiotherapy and concurrent chemoradiotherapy alone in stage III-IVB nasopharyngeal carcinoma. The results provided basic evidence that docetaxel plus cisplatin was an effective neoadjuvant chemotherapy.8 Notably, ours was the first phase 3 randomised controlled trial to use docetaxel plus cisplatin in a neoadjuvant chemotherapy regimen for the treatment of nasopharyngeal carcinoma. This study has a similar design and could be considered a successive study. However, our study differed as it was based on a larger sample size and the survival results were of greater significance. Consequently, this work has increased the available evidence indicating that a docetaxel plus cisplatin based regimen could be used to treat locoregionally advanced nasopharyngeal carcinoma. Owing to the progression of immune checkpoint blockade and target therapies against nasopharyngeal carcinoma, the survival of patients with recurrent and metastatic nasopharyngeal carcinoma has generally been prolonged.2425 Despite the fact that this study observed more failure events in the concurrent chemoradiotherapy group than the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, the docetaxel plus cisplatin regimen still achieved a significant improvement in five year overall survival. The toxicities induced by the additional cycle of neoadjuvant chemotherapy were determined to be acceptable and manageable during the treatment procedure. Both groups accepted radiotherapy for locoregional tumour eradication. Late toxicities in this trial were primarily induced by radiation to the normal structures around the nasopharynx and neck, and they were mild and comparable between the two groups. The small proportion of grade 3 late toxicities were also properly managed without having a great effect on daily life. On the basis of the survival outcomes and results from the EORTC QLQ-C30, we assume that the biggest impact factor for quality of life was whether a patient had treatment failures. Therefore, applying chemotherapy of sufficient intensity to lower the risk of treatment failure in patients with stage N2-3 nasopharyngeal carcinoma is critical. ### Comparison with other studies In comparison with two other large randomised controlled trials from our institution, by Sun and colleagues and Zhang and colleagues, this study included patients with stage N2-3 nasopharyngeal carcinoma to tackle their poorer prognosis. However, the docetaxel plus cisplatin regimen seemed to be non-inferior to the docetaxel, cisplatin, and fluorouracil and the gemcitabine plus cisplatin regimens.2627 The preliminary results of another randomised controlled trial by Wang and colleagues comparing docetaxel plus cisplatin and docetaxel, cisplatin, and fluorouracil as neoadjuvant chemotherapy regimens also indicated similar conclusions.12 Therefore, we believe that the docetaxel plus cisplatin regimen could be an effective and convenient alternative to current neoadjuvant chemotherapy regimens. In addition, we believe that the curative effect of the docetaxel plus cisplatin regimen was not the only factor that contributed to the survival advantages in this study. Differing from previous studies applying two to three cycles, this is also the first randomised controlled trial to apply four cycles of neoadjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma. We suggest that the high tumour cell burden in metastatic cervical lymph nodes circulated easily and implanted as seeds in distant organs.28 The improved distant metastasis-free survival contributed by the increased cycles of neoadjuvant chemotherapy proved the existence of such micrometastases and the effectiveness of this treatment modality. The high intensity of neoadjuvant chemotherapy affected dose escalation of concurrent chemotherapy, as only 21% of patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group received more than 200 mg/m2 of concurrent cisplatin. Surprisingly, locoregional control was not compromised. Instead, the high intensity of neoadjuvant chemotherapy reduced the size of the primary tumour, improved the tumour microenvironment, and provided compensation for concurrent chemotherapy, which eventually led to significant improvement in five year locoregional relapse-free survival for the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group. The reduced risks of distant metastasis as well as the improved control of locoregional sites leads to a better prognosis with four cycles of docetaxel plus cisplatin neoadjuvant chemotherapy. Regarding safety, four cycles of the docetaxel plus cisplatin regimen did not induce higher toxicity than three cycles of the docetaxel, cisplatin, and fluororacil or gemcitabine plus cisplatin regimens (supplementary table M). Myelosuppression, primarily neutropenia, was the most common toxic effect of docetaxel. The intensity of four cycles of neoadjuvant chemotherapy containing docetaxel induced a high proportion of grade 3/4 leukopenia (50%) and neutropenia (47%). Gastrointestinal toxicities, including nausea and vomiting, occur in almost all patients receiving chemotherapy containing cisplatin. However, with the proper management of prophylactic antiemetics, grade 3/4 gastrointestinal toxicities were observed in only 14% of the patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group. Overall grade 3/4 toxicities were observed in 65% of patients in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, and this incidence rate was 8% and 11% lower than in the studies by Sun and colleagues (73%) and Zhang and colleagues (76%). All grade 3/4 toxicities were adequately managed without interference with the subsequent treatment, although one (1%) and five (5%) patients discontinued neoadjuvant chemotherapy after the first and third cycles owing to subjective intolerance of toxicity. No neoadjuvant chemotherapy induced death was observed in this study. ### Limitations and prospects This study had three main limitations. Firstly, stage N2-3 nasopharyngeal carcinoma has high risks for distant metastasis, but our theory about the pre-existing micrometastasis in distant organs is based on clinical experience only. Although such risks were demonstrated by the improved distant metastasis-free survival in the neoadjuvant chemotherapy plus concurrent chemoradiotherapy group, examinations to identify tumour cells in circulation, such as cell-free DNA testing and minimal residual disease detection, are needed to provide direct evidence. Secondly, plasma Epstein-Barr virus DNA load is an important prognostic biomarker for stage N2-3 nasopharyngeal carcinoma.29 Although it was regularly examined in all patients during preliminary assessments and follow-up, we did not include it as an inclusion criterion or grouping factor in this multicentre study considering the assays for quantification differed between laboratories. Thirdly, this trial was conducted in the epidemic areas in China; whether this treatment modality is applicable in other areas needs further validation. Research to develop new treatment methods for locoregionally advanced nasopharyngeal carcinoma is continuously advancing. The most recent results of [NCT03700476](https://www.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03700476&atom=%2Fbmj%2F389%2Fbmj-2024-081557.atom) opened a new era of immune checkpoint blockade therapies.30 The addition of sintilimab to the three cycles of neoadjuvant chemotherapy plus concurrent chemoradiotherapy was shown to further reduce the risks of locoregional relapse and distant metastasis in patients with more advanced T and N stage nasopharyngeal carcinoma. However, we note that the effects of sintilimab have not been transformed to prolonged survival yet, and its safety for humans is not fully understood, with 60% incidence of immune related toxicities and 1% incidence of immune related mortality. Further elucidation of immunotherapy is crucial. In the meantime, an urgent need remains to decrease the risk of distant metastasis and improve survival for patients with locoregionally advanced nasopharyngeal carcinoma. Therefore, considering the immune related toxicities and the satisfactory efficacy achieved by chemotherapy with a sufficient intensity, we believe that this study has great clinical significance (supplementary table N). On one hand, it confirms the effectiveness of the traditional neoadjuvant-concurrent chemoradiotherapy in a subgroup of patients with poor prognosis (stage N2-3) among those with locoregionally advanced nasopharyngeal carcinoma. Besides three cycles of gemcitabine plus cisplatin or docetaxel, cisplatin, and fluorouracil, four cycles of docetaxel plus cisplatin neoadjuvant chemotherapy could be another alternative that is effective, safe, and economical. On the other hand, it provides evidence that most patients with nasopharyngeal carcinoma do not need immunotherapy as first line treatment, which provokes peer investigators to put emphasis on targeting the beneficiary populations more precisely. ### Conclusions For patients with stage N2-3 nasopharyngeal carcinoma, four cycles of docetaxel plus cisplatin neoadjuvant chemotherapy before concurrent chemoradiotherapy could lower the risk of distant metastasis and locoregional relapse, consequently improving overall survival and disease-free survival with manageable toxicities. The results of this study could provide an alternative neoadjuvant chemotherapy regimen to the currently available docetaxel, cisplatin, and fluororacil and gemcitabine plus cisplatin regimens and improve clinical treatment models to facilitate individualised treatment of nasopharyngeal carcinoma. ## What is already known on this topic * The treatment modality of neoadjuvant chemotherapy plus concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma had uncertain efficacy * A phase 2 study provided basic evidence that docetaxel plus cisplatin was an effective neoadjuvant chemotherapy regimen for nasopharyngeal carcinoma * Stage N2-3 nasopharyngeal carcinoma is typified by a high risk of distant metastasis and should be managed with intense systemic chemotherapy ## What this study adds * The docetaxel plus cisplatin neoadjuvant chemotherapy regimen is effective, safe, and economical for the treatment of locoregionally advanced nasopharyngeal carcinoma * Four cycles of neoadjuvant chemotherapy reduce the risks of distant metastasis and prolong survival for patients with stage N2-3 nasopharyngeal carcinoma ## Ethics statements ### Ethical approval This trial was approved by the ethics committee of the Sun Yat-sen University Cancer Centre and each participating centre (ID: 5010-2015-03). All patients gave written informed consent before enrolment. ## Data availability statement Data can be requested from the corresponding author. The raw database will be deposited on the Research Data Deposit public platform ([www.researchdata.org.cn](http://www.researchdata.org.cn)). De-identified participant data will be made available following approval by the corresponding author and Sun Yat-sen University Cancer Centre. A detailed research protocol will be required to evaluate the reasonability of the data request. The corresponding author and Sun Yat-sen University Cancer Centre reserve the right to decide whether to share the data on the basis of the materials provided by researchers. ## Acknowledgments This is an investigator initiated study. Sun Yat-Sen University was involved in trial management and auditing. We thank the patients who participated in this study as well as their families. We thank the medical, nursing, and research staff at each of the study centres. We are grateful to Yu-Pei Chen, Yuan Zhang, and Wen-Fei Li (Department of Radiation Oncology, Sun Yat-Sen University Cancer Centre) for reviewing the manuscript. We are grateful to Qing Liu (Department of Tumour Prevention, Sun Yat-Sen University Cancer Centre) for his help with statistics and Xiao-Xing Hu (Department of Radiation Oncology, Sun Yat-Sen University Cancer Centre) for assistance with data management and logistical support. We thank the staff of the National Clinical Study Centre for Anticancer Drugs, Sun Yat-Sen University Cancer Centre, for monitoring the trial. ## Footnotes * Contributors: WHX, WWX, HC, MJX, YHH, TCZ, QZ, and CYC are joint first authors. YHG obtained funding. YHG and WWX were responsible for the conception and design of the trial, supervising the project, doing quality assessments, and reviewing and approving the manuscript. WHX, HC, MJX, YHH, TCZ, QZ, and CYC contributed to the design of the clinical trial and the writing of the protocol, the recruitment and treatment of patients, data and trial management, data analysis and interpretation, and final approval of the manuscript. WHX drafted the manuscript. YHG and WHX assessed and verified all the data in the study. LXL, QXW, YJZ, JY, XYS, HLK, JWW, RH, HHP, YY, SHW, YJL, and BXW participated in the recruitment and treatment of patients, data and trial management, and manuscript preparation. WHX and HC were responsible for statistical analysis and interpretation as well as data review. XHJ was responsible for the staging during preliminary diagnosis and the guidance of contouring during the planning of radiotherapy. All authors have read and approved the final manuscript. YHG is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. * Funding: This work was supported by grants from the Science and Technology Planning Project of Guangdong Province, China (grant number 2017A020215157). The funder had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. * Competing interests: All authors have completed the ICMJE uniform disclosure form at [https://www.icmje.org/coi\_disclosure.pdf](https://www.icmje.org/coi_disclosure.pdf) and declare: support from the Science and Technology Planning Project of Guangdong Province, China for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. * Transparency: The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. * Dissemination to participants and related patient and public communities: To disseminating the findings, WeChat official accounts of all participating hospitals will be used to brief about the study. 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