Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial.
BACKGROUND
The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial.


METHODS
We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III-IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18-59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2on day 1), intravenous cisplatin (60 mg/m2on day 1), and continuous intravenous fluorouracil (600 mg/m2per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959.


RESULTS
Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38-49), 3-year failure-free survival was 80% (95% CI 75-85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66-78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48-0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]).


CONCLUSIONS
Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities.


BACKGROUND
Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Ying
Y
Sun
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Wen-Fei
WF
Li
Department of Radiation Oncology, Cancer Centre, West China Hospital, Sichuan University, Chengdu, China.
Nian-Yong
NY
Chen
Department of Radiation Oncology, The First People's Hospital of Foshan, Foshan, China.
Ning
N
Zhang
Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Guo-Qing
GQ
Hu
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Fang-Yun
FY
Xie
Department of Radiation Oncology, Peking University School of Oncology, Beijing, China.
Yan
Y
Sun
Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
Xiao-Zhong
XZ
Chen
Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, China.
Jin-Gao
JG
Li
Department of Radiation Oncology, Cancer Hospital of Guangxi Medical University, Nanning, China.
Xiao-Dong
XD
Zhu
Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Chao-Su
CS
Hu
Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
Xiang-Ying
XY
Xu
Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
Yuan-Yuan
YY
Chen
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Wei-Han
WH
Hu
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Ling
L
Guo
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Hao-Yuan
HY
Mo
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Lei
L
Chen
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Yan-Ping
YP
Mao
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Rui
R
Sun
Department of Radiation Oncology, Cancer Centre, West China Hospital, Sichuan University, Chengdu, China.
Ping
P
Ai
Department of Radiation Oncology, The First People's Hospital of Foshan, Foshan, China.
Shao-Bo
SB
Liang
Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Guo-Xian
GX
Long
Department of Radiation Oncology, Peking University School of Oncology, Beijing, China.
Bao-Min
BM
Zheng
Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
Xing-Lai
XL
Feng
Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, China.
Xiao-Chang
XC
Gong
Department of Radiation Oncology, Cancer Hospital of Guangxi Medical University, Nanning, China.
Ling
L
Li
Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Chun-Ying
CY
Shen
Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
Jian-Yu
JY
Xu
Clinical Trials Centre, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Ying
Y
Guo
Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
Yu-Ming
YM
Chen
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Fan
F
Zhang
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Li
L
Lin
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Ling-Long
LL
Tang
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China.
Meng-Zhong
MZ
Liu
Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, China. Electronic address: majun2@mail.sysu.edu.cn.
Jun
J
Ma
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002277:Carcinoma; D059248:Chemoradiotherapy / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D060828:Induction Chemotherapy / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000401:mortality / Q000628:therapy*; D043823:Taxoids / Q000008:administration & dosage
D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil