title: Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis.
abstract: BACKGROUND
  A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy.
  
  
  METHODS
  We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis.
  
  
  RESULTS
  We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84).
  
  
  CONCLUSIONS
  Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed.
  
  
  BACKGROUND
  French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.
authors.affiliation: Gustave-Roussy, Villejuif, France; Centre for Research in Epidemiology and Population Health, INSERM U1018, Paris-Saclay University, Villejuif, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Blanchard
authors.affiliation: Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: Anne
authors.initials: A
authors.lastname: Lee
authors.affiliation: Gustave-Roussy, Villejuif, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Marguet
authors.affiliation: Gustave-Roussy, Villejuif, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Leclercq
authors.affiliation: Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.
authors.forename: Wai Tong
authors.initials: WT
authors.lastname: Ng
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Partner State Key Laboratory of Oncology in South China, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Huang
authors.affiliation: Gustave-Roussy, Villejuif, France; Centre for Research in Epidemiology and Population Health, INSERM U1018, Paris-Saclay University, Villejuif, France.
authors.forename: Ellen
authors.initials: E
authors.lastname: Benhamou
authors.affiliation: Fudan University Shanghai Cancer Center, Shanghai, PR China.
authors.forename: Guopei
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Hong Kong Sanatorium & Hospital, Hong Kong, China.
authors.forename: Daniel T T
authors.initials: DT
authors.lastname: Chua
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, PR China.
authors.forename: Hai-Qiang
authors.initials: HQ
authors.lastname: Mai
authors.affiliation: Queen Mary Hospital, Hong Kong, China.
authors.forename: Dora L W
authors.initials: DL
authors.lastname: Kwong
authors.affiliation: National Cancer Centre, Singapore, Singapore.
authors.forename: Shie Lee
authors.initials: SL
authors.lastname: Cheah
authors.affiliation: SWOG Statistical Center, Seattle, WA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Moon
authors.affiliation: Tuen Mun Hospital, Hong Kong, China.
authors.forename: Yuk
authors.initials: Y
authors.lastname: Tung
authors.affiliation: Shin Kong Wu Ho-Su, Memorial Hospital, Tapei, Taiwan.
authors.forename: Kwan-Hwa
authors.initials: KH
authors.lastname: Chi
authors.affiliation: Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Partner State Key Laboratory of Oncology in South China, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Edwin Pun
authors.initials: EP
authors.lastname: Hui
authors.affiliation: Sun Yat-sen University Cancer Center, Guangzhou, PR China.
authors.forename: Tai-Xiang
authors.initials: TX
authors.lastname: Lu
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.affiliation: Gustave-Roussy, Villejuif, France; Centre for Research in Epidemiology and Population Health, INSERM U1018, Paris-Saclay University, Villejuif, France. Electronic address: jean-pierre.pignon@gustaveroussy.fr.
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Pignon
mesh_terms: D002277:Carcinoma; D017024:Chemotherapy, Adjuvant; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000453:epidemiology* / Q000473:pathology / Q000532:radiotherapy*; D016896:Treatment Outcome