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The primary site of head and neck squamous cell carcinoma predicts survival benefits of EGFR inhibitors: A systematic review and meta-analysis

Published:February 12, 2021DOI:https://doi.org/10.1016/j.radonc.2021.02.001

      Highlights

      • Anti-EGFRs confer overall survival benefit in oral cavity-oropharyngeal carcinoma.
      • Anti-EGFRs confer no overall survival benefit in hypopharyngeal-laryngeal carcinoma.
      • The primary site of head and neck cancers may predict anti-EGFR survival benefit.

      Abstract

      Background and purpose

      To assess the survival benefits associated with epidermal growth factor receptor (EGFR) inhibitors in head and neck squamous cell carcinoma (HNSCC) according to the primary site.

      Materials and methods

      A systematic review and meta-analysis were conducted for randomized phase III trials comparing treatment with or without EGFR inhibitors in locoregionally advanced, recurrent, or metastatic HNSCC. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively. Data were pooled using a random-effects model.

      Results

      Seven trials with a total of 3391 patients were included. The addition of EGFR inhibitors improved OS in patients with oral cavity-oropharyngeal carcinoma (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.67–0.87, P < 0.001) but not in patients with hypopharyngeal-laryngeal carcinoma (HR 0.94, 95% CI 0.82–1.08, P = 0.398). A significant interaction was found in favor of oral cavity-oropharyngeal carcinoma (P = 0.029). The addition of EGFR inhibitors increased PFS in both patients with oral cavity-oropharyngeal carcinoma (HR 0.67, 95% CI 0.52–0.85, P = 0.001) and patients with hypopharyngeal-laryngeal carcinoma (HR 0.81, 95% CI 0.69–0.94, P = 0.005). A trend towards significant interaction was found in favor of oral cavity-oropharyngeal carcinoma (P = 0.161). Comparable results were observed in the pre-specified subgroup analyses. Meta-regression analyses suggested that the primary site appeared to be a predictor of survival benefits in HNSCC patients who received treatment with EGFR inhibitors over those who did not.

      Conclusion

      Our meta-analysis suggests that the survival benefits of EGFR inhibitors might depend on primary sites in HNSCC. Further studies are needed to confirm this finding.

      Abbreviations:

      CI (confidence interval), CNKI (China National Knowledge Infrastructure), EGFR (epidermal growth factor receptor), FDA (Food and Drug Administration), HNSCC (head and neck squamous cell carcinoma), HPV (human papillomavirus), HR (hazard ratios), OS (overall survival), PFS (progression-free survival), TKI (tyrosine kinase inhibitor)

      Keywords

      In clinical studies, medical oncologists generally group squamous cell carcinomas that originate in the oral cavity, oropharynx, hypopharynx, and larynx as the same disease, head and neck squamous cell carcinoma (HNSCC). The epidermal growth factor receptor (EGFR) is overexpressed in the overwhelming majority of HNSCC, and its overexpression is associated with poor prognosis [
      • Chung C.H.
      • Ely K.
      • McGavran L.
      • Varella-Garcia M.
      • Parker J.
      • Parker N.
      • et al.
      Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas.
      ]. Cetuximab, an antibody against EGFR, has been approved in combination with chemotherapy as the first-line treatment for recurrent or metastatic HNSCC [

      National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Head and Neck Cancers. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. [Accessed 10 May 2020].

      ]. The approval was based on the phase III EXTREME trial, in which the addition of cetuximab significantly prolonged the overall survival (OS) [
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      ]. However, subgroup analyses suggested that the survival benefits were limited to HNSCC with primary site on the oral cavity [
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      ]. Cetuximab was also shown to improve OS in locoregionally advanced disease when combined with radiotherapy in another phase III trial [
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • Cohen R.B.
      • Jones C.U.
      • Sur R.K.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      ]. In this trial, oral cavity primaries were not included, and patients with oropharyngeal carcinoma appeared to benefit most from the addition of cetuximab [
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • Cohen R.B.
      • Jones C.U.
      • Sur R.K.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      ]. To date, no studies have been adequately powered or designed to detect the differences in the treatment outcomes associated with cetuximab among primary sites in HNSCC.
      We hypothesized that the OS benefits of EGFR inhibitors were limited to patients with oral cavity or oropharyngeal carcinoma of HNSCC. It would be interesting to study survival differences among all the primary sites, but a statistically sound investigation would have been unlikely due to availability of limited data from published literature. Here, we conducted a systematic review and meta-analysis of phase III randomized controlled trials in patients with locoregionally advanced, recurrent, or metastatic HNSCC who were treated with or without EGFR inhibitors. We aimed to assess the differences in the improvement of survival between patients with oral cavity-oropharyngeal carcinoma and those with hypopharyngeal-laryngeal carcinoma.

      Materials and methods

      We conducted this systematic review and meta-analysis by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      ]. Disagreements in the process of this meta-analysis were resolved by discussion among the authors, with reference to a third reviewer, if necessary.

      Selection criteria

      We searched the following bibliographic databases: PubMed, ClinicalTrials.gov, EMBASE, Web of Science, and Chinese databases (China National Knowledge Infrastructure [CNKI], Database for Chinese Technical Periodicals, and Wan Fang) for articles published before May 1, 2020. The main search terms were “(EGFR OR HER1 OR ErbB1 OR epidermal growth factor receptor OR cetuximab OR panitumumab OR zalutumumab OR nimotuzumab OR duligotuzumab OR afatinib OR dacomitinib OR tyrosine kinase inhibitor OR TKI OR gefitinib OR erlotinib) AND (head and neck OR oral cavity OR oropharynx OR hypopharynx OR larynx) AND (carcinoma OR cancer) AND trial.” A full search strategy is presented in the Supplementary Materials and Methods. To ensure complete coverage, we manually searched the reference lists of the retrieved review articles and primary studies.
      Inclusion criteria were: (1) phase III, randomized controlled trials; (2) locoregionally advanced, recurrent, or metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; (3) the anti-EGFR agents used, either antibodies or tyrosine kinase inhibitors (TKIs), selectively targeted at EGFR rather than other members of the human EGFR family; (4) the study compared chemotherapy, radiotherapy, chemoradiotherapy, or best supportive care among treatment regimens with and without an EGFR inhibitor; and (5) the study provided the hazard ratios (HRs) with 95% confidence intervals (CIs) for OS according to primary sites, or reported information to calculate these. There were no language restrictions, and the most recently updated results were included if more than one publication was reported for a trial.
      The exclusion criteria were: (1) studies with surgery as the curative treatment; (2) trials focusing on human papillomavirus (HPV)-positive HNSCC, because some evidence suggest that HPV-positive disease might not benefit from anti-EGFR treatment [
      • Vermorken J.B.
      • Stöhlmacher-Williams J.
      • Davidenko I.
      • Licitra L.
      • Winquist E.
      • Villanueva C.
      • et al.
      Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
      ,
      • Machiels J.P.
      • Haddad R.I.
      • Fayette J.
      • Licitra L.F.
      • Tahara M.
      • Vermorken J.B.
      • et al.
      Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
      ,
      • Su Y.
      • Cui J.
      • Xu D.
      • Wang M.
      • Xu T.
      • Tian H.
      • et al.
      p16(INK4a) status and survival benefit of EGFR inhibitors in head and neck squamous cell cancer: a systematic review and meta-analysis.
      ]; (3) trials in abstract forms; and (4) non-specific anti-EGFR inhibitors, such as afatinib [
      • Machiels J.P.
      • Haddad R.I.
      • Fayette J.
      • Licitra L.F.
      • Tahara M.
      • Vermorken J.B.
      • et al.
      Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
      ] and lapatinib [
      • Harrington K.
      • Temam S.
      • Mehanna H.
      • D'Cruz A.
      • Jain M.
      • D'Onofrio I.
      • et al.
      Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study.
      ]. Patients enrolled in the specific EGFR inhibitor trials differed from those included in non-specific EGFR inhibitor trials. Specific EGFR inhibitor trials enrolled patients who had never received anti-EGFR therapy or patients who had undergone anti-EGFR therapy as part of an initial curative multimodality therapy completed more than 6 months prior to trial entry [
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      ,
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • Cohen R.B.
      • Jones C.U.
      • Sur R.K.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      ,
      • Vermorken J.B.
      • Stöhlmacher-Williams J.
      • Davidenko I.
      • Licitra L.
      • Winquist E.
      • Villanueva C.
      • et al.
      Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
      ,
      • Argiris A.
      • Ghebremichael M.
      • Gilbert J.
      • Lee J.-W.
      • Sachidanandam K.
      • Kolesar J.M.
      • et al.
      Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial.
      ,
      • Ang K.K.
      • Zhang Q.
      • Rosenthal D.I.
      • Nguyen-Tan P.F.
      • Sherman E.J.
      • Weber R.S.
      • et al.
      Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522.
      ,
      • Patil V.M.
      • Noronha V.
      • Joshi A.
      • Agarwal J.
      • Ghosh‐Laskar S.
      • Budrukkar A.
      • et al.
      A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer.
      ,
      • Machiels J.-P.
      • Subramanian S.
      • Ruzsa A.
      • Repassy G.
      • Lifirenko I.
      • Flygare A.
      • et al.
      Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial.
      ]. In contrast, non-specific EGFR inhibitors were designed to improve efficacy and overcome resistance to specific anti-EGFR inhibitors [
      • Solca F.
      • Dahl G.
      • Zoephel A.
      • Bader G.
      • Sanderson M.
      • Klein C.
      • et al.
      Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker.
      ]. Non-specific EGFR inhibitor trials enrolled patients who had already been exposed to an EGFR targeted antibody [
      • Machiels J.P.
      • Haddad R.I.
      • Fayette J.
      • Licitra L.F.
      • Tahara M.
      • Vermorken J.B.
      • et al.
      Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
      ,
      • Guo Y.
      • Ahn M.J.
      • Chan A.
      • Wang C.H.
      • Kang J.H.
      • Kim S.B.
      • et al.
      Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial.
      ]. In the phase III LUX-Head & Neck 1 and 3 trials [
      • Machiels J.P.
      • Haddad R.I.
      • Fayette J.
      • Licitra L.F.
      • Tahara M.
      • Vermorken J.B.
      • et al.
      Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
      ,
      • Guo Y.
      • Ahn M.J.
      • Chan A.
      • Wang C.H.
      • Kang J.H.
      • Kim S.B.
      • et al.
      Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial.
      ], progression-free survival (PFS) benefit was unique to patients not previously treated with EGFR targeted antibodies. Therefore, the inclusion of patients previously treated with EGFR inhibitors may affect the validity and robustness of the conclusions drawn from the present meta-analysis.

      Data extraction and risk of bias assessments

      The following data were independently extracted by two authors from each trial: study design, inclusion and exclusion criteria, patient characteristics, number of patients, histology, TNM stage, performance status, treatment protocol, follow-up, EGFR inhibitors, clinical endpoints, HRs and their 95% CIs for OS and PFS. For randomization integrity, we assessed the patterns of treatment allocation and balance in baseline characteristics between patient groups. In case of missing data, we contacted the corresponding author via e-mail to request the provision of the missing information.
      For this meta-analysis of subgroup data from trials, the risk of bias of each eligible study was assessed independently by two authors following the guidelines in the Cochrane Risk of Bias Tool for Non-Randomized Studies of Interventions [

      Sterne J, Higgins J, Reeves B. A Cochrane risk of bias assessment tool: for non-randomized studies of interventions (ACROBAT-NRSI). Version 1.0.0. https://www.riskofbias.info. [Accessed 15 October 2019].

      ].

      Statistical analysis

      Our prespecified hypothesis was that the OS benefits of EGFR inhibitors would be limited to HNSCC with oral cavity and oropharynx primary sites. Therefore, we assessed differences in the improvement of survival between anti-EGFR beneficiary (oral cavity-oropharyngeal) carcinoma and anti-EGFR non-beneficiary (hypopharyngeal-laryngeal) carcinoma. This hypothesis was inferred from the results of subgroup analyses of two phase III trials, EXTREME [
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      ] and IMCL-9815 [
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • Cohen R.B.
      • Jones C.U.
      • Sur R.K.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      ], based on which cetuximab was approved for use in patients with HNSCC. The feasibility of this classification was also verified by a pilot study prior to the present meta-analysis. The pilot study included meta-analyses and meta-regression analyses by each primary cancer site (Fig. S1 and Table S1). An improved OS was observed in patients with oral cavity carcinoma (HR 0.64, P = 0.004) and patients with oropharyngeal carcinoma (HR 0.81, P = 0.005) who underwent treatment with EGFR inhibitors when compared to that in the control groups. In contrast, no OS benefit was observed in hypopharyngeal carcinoma (HR 0.89, P = 0.372) or laryngeal carcinoma (HR 1.01, P = 0.938). Meta-regression analyses showed no difference in OS benefits between oral cavity carcinoma and oropharyngeal carcinoma (P = 0.095) and a significant OS difference in favor of oral cavity carcinoma when compared to that in hypopharyngeal carcinoma (P = 0.049) or laryngeal carcinoma (P = 0.003). Therefore, it is feasible to combine oral cavity carcinoma with oropharyngeal carcinoma as anti-EGFR beneficiary carcinoma and hypopharyngeal carcinoma with laryngeal carcinoma as anti-EGFR non-beneficiary carcinoma for a meta-analysis.
      All analyses were pre-specified in the protocol unless otherwise indicated. The primary and secondary endpoints were OS and PFS, respectively. Owing to the clinical heterogeneity among the trials identified a priori, the random-effects model was used to pool data [

      Higgins J, Thomas J, (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 6.1. https://training.cochrane.org/handbook/current. [Accessed 20 October 2019].

      ]. HRs and their 95% CIs were calculated to assess the survival advantage of treatment with or without EGFR inhibitors. The Cochrane Q test and I2 statistic were used to assess heterogeneity among trials [
      • Higgins J.P.T.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      ]. The test of interaction proposed by Altman et al. [
      • Altman D.G.
      • Bland J.M.
      Interaction revisited: the difference between two estimates.
      ] was used to compare treatment effects between patients with oral cavity-oropharyngeal carcinoma and those with hypopharyngeal-laryngeal carcinoma.
      To assess the relationship between study level covariates, and the effect size of treatment with and without EGFR inhibitors, we performed the random-effects model meta-regression analysis in the overall population [
      • Borenstein M.
      • Hedges L.V.
      • Higgins J.P.T.
      • Rothstein H.R.
      Introduction to meta-analysis. CHAPTER 20 meta-regression.
      ]. The covariates included primary site (oral cavity and oropharynx vs. hypopharynx and larynx), anti-EGFR agent (antibody vs. tyrosine kinase inhibitor), treatment line (first-line vs. subsequent-line), disease pattern (locoregionally advanced vs. recurrent and metastatic), agents approved by the Food and Drug Administration (FDA; cetuximab vs. non-cetuximab), and FDA-approval of regimens (approved vs. non-approved). In addition, subgroup analyses were conducted to evaluate whether the differences in survival benefits between primary sites (oral cavity-oropharynx vs. hypopharynx-larynx) were dependent on these covariates. To conduct a subgroup analysis, at least two trials were required. We conducted sensitivity analyses by excluding one trial at a time to explore whether the results were strongly influenced by a specific trial. Potential publication bias was graphically presented by funnel plots, and the asymmetry was assessed with linear regression tests.
      All statistical analyses were performed using R version 3.5.2 (www.r-project.org). Statistical significance was defined as a 2-sided P-value of 0.05.

      Results

      A total of 7 phase III randomized controlled trials [
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      ,
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • Cohen R.B.
      • Jones C.U.
      • Sur R.K.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      ,
      • Vermorken J.B.
      • Stöhlmacher-Williams J.
      • Davidenko I.
      • Licitra L.
      • Winquist E.
      • Villanueva C.
      • et al.
      Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
      ,
      • Argiris A.
      • Ghebremichael M.
      • Gilbert J.
      • Lee J.-W.
      • Sachidanandam K.
      • Kolesar J.M.
      • et al.
      Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial.
      ,
      • Ang K.K.
      • Zhang Q.
      • Rosenthal D.I.
      • Nguyen-Tan P.F.
      • Sherman E.J.
      • Weber R.S.
      • et al.
      Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522.
      ,
      • Patil V.M.
      • Noronha V.
      • Joshi A.
      • Agarwal J.
      • Ghosh‐Laskar S.
      • Budrukkar A.
      • et al.
      A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer.
      ,
      • Machiels J.-P.
      • Subramanian S.
      • Ruzsa A.
      • Repassy G.
      • Lifirenko I.
      • Flygare A.
      • et al.
      Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial.
      ] were included in this meta-analysis (Fig. 1). We did not identify an eligible trial in the Chinese databases. Two phase III trials (Burtness et al., 2005 [
      • Burtness B.
      • Goldwasser M.A.
      • Flood W.
      • Mattar B.
      • Forastiere A.A.
      Eastern cooperative oncology G. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.
      ] and IMEX [
      • Stewart J.S.
      • Cohen E.E.
      • Licitra L.
      • Van Herpen C.M.
      • Khorprasert C.
      • Soulieres D.
      • et al.
      Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected].
      ]) were excluded because the OS by primary sites were not reported.
      Figure thumbnail gr1
      Fig. 1Flow diagram of trial selection. Abbreviations: HPV, human papillomavirus; OS, Overall survival. Note: We did not identify an eligible randomized controlled trial in the Chinese databases.
      The study characteristics are listed in Table 1. The experimental and control groups in all the trials were reported to be well balanced with respect to the patient baseline characteristics, including the primary site. Three trials [
      • Vermorken J.B.
      • Stöhlmacher-Williams J.
      • Davidenko I.
      • Licitra L.
      • Winquist E.
      • Villanueva C.
      • et al.
      Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
      ,
      • Ang K.K.
      • Zhang Q.
      • Rosenthal D.I.
      • Nguyen-Tan P.F.
      • Sherman E.J.
      • Weber R.S.
      • et al.
      Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522.
      ,
      • Patil V.M.
      • Noronha V.
      • Joshi A.
      • Agarwal J.
      • Ghosh‐Laskar S.
      • Budrukkar A.
      • et al.
      A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer.
      ], where the primary site was a planned stratification factor, were graded to have a low risk of bias; while the others [
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      ,
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • Cohen R.B.
      • Jones C.U.
      • Sur R.K.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      ,
      • Argiris A.
      • Ghebremichael M.
      • Gilbert J.
      • Lee J.-W.
      • Sachidanandam K.
      • Kolesar J.M.
      • et al.
      Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial.
      ,
      • Machiels J.-P.
      • Subramanian S.
      • Ruzsa A.
      • Repassy G.
      • Lifirenko I.
      • Flygare A.
      • et al.
      Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial.
      ] were graded to have a moderate risk of bias.
      Table 1Characteristics of eligible trials in the meta-analysis.
      Trial, publication yearSample size
      A total of 84 patients with carcinomas not originating from the oral cavity, oropharynx, hypotharynx, or larynx were excluded from this meta-analysis (32 in EXTREME, 47 in ECOG-E1302, and 5 in Hx-EGFr-202).
      Eligible criterionTreatmentInclusion periodPrimary endpoint
      SPECTRUM, 2013
      • Vermorken J.B.
      • Stöhlmacher-Williams J.
      • Davidenko I.
      • Licitra L.
      • Winquist E.
      • Villanueva C.
      • et al.
      Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
      657First-line therapy for R/M HNSCCCisplatin and fluorouracil with or without panitumumab2007–2009OS
      EXTREME, 2008
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      410
      A total of 84 patients with carcinomas not originating from the oral cavity, oropharynx, hypotharynx, or larynx were excluded from this meta-analysis (32 in EXTREME, 47 in ECOG-E1302, and 5 in Hx-EGFr-202).
      First-line therapy for R/M HNSCCCisplatin or Carboplatin plus 5-Fluorouracil with or without cetuximab2004–2005OS
      ECOG-E1302, 2013
      • Argiris A.
      • Ghebremichael M.
      • Gilbert J.
      • Lee J.-W.
      • Sachidanandam K.
      • Kolesar J.M.
      • et al.
      Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial.
      192
      A total of 84 patients with carcinomas not originating from the oral cavity, oropharynx, hypotharynx, or larynx were excluded from this meta-analysis (32 in EXTREME, 47 in ECOG-E1302, and 5 in Hx-EGFr-202).
      First- or subsequent-line therapy for R/M HNSCCDocetaxel with or without gefitinib2004–2008OS
      RTOG 0522, 2014
      • Ang K.K.
      • Zhang Q.
      • Rosenthal D.I.
      • Nguyen-Tan P.F.
      • Sherman E.J.
      • Weber R.S.
      • et al.
      Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522.
      891Previously untreated III to IVa,b HNSCCRadiotherapy plus cisplatin with or without cetuximab2005–2009PFS
      CTRI/2014/09/004980
      The primary carcinomas were classified into oropharyngeal and non-oropharyngeal carcinomas, and the latter included oral cavity carcinoma (n = 3, 1%) and hypopharyngeal-laryngeal carcinoma (n = 264, 99%).
      , 2019
      • Patil V.M.
      • Noronha V.
      • Joshi A.
      • Agarwal J.
      • Ghosh‐Laskar S.
      • Budrukkar A.
      • et al.
      A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer.
      536Previously untreated III to IVa,b HNSCCRadiotherapy plus cisplatin with or without nimotuzumab2012–2018PFS
      IMCL-9815, 2009
      • Bonner J.A.
      • Harari P.M.
      • Giralt J.
      • Cohen R.B.
      • Jones C.U.
      • Sur R.K.
      • et al.
      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      424Previously untreated III to IVa,b HNSCCRadiotherapy with or without cetuximab1999–2002Duration of locoregional control
      Hx-EGFr-202, 2011
      • Machiels J.-P.
      • Subramanian S.
      • Ruzsa A.
      • Repassy G.
      • Lifirenko I.
      • Flygare A.
      • et al.
      Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial.
      281
      A total of 84 patients with carcinomas not originating from the oral cavity, oropharynx, hypotharynx, or larynx were excluded from this meta-analysis (32 in EXTREME, 47 in ECOG-E1302, and 5 in Hx-EGFr-202).
      R/M HNSCC after failure of platinum-based chemotherapyBest supportive care with zalutumumab versus best supportive care with optional methotrexate2006–2009OS
      Abbreviations: HNSCC, head and neck squamous cell carcinoma; PFS, progression-free survival; R/M, recurrent or metastatic; OS, overall survival.
      a A total of 84 patients with carcinomas not originating from the oral cavity, oropharynx, hypotharynx, or larynx were excluded from this meta-analysis (32 in EXTREME, 47 in ECOG-E1302, and 5 in Hx-EGFr-202).
      b The primary carcinomas were classified into oropharyngeal and non-oropharyngeal carcinomas, and the latter included oral cavity carcinoma (n = 3, 1%) and hypopharyngeal-laryngeal carcinoma (n = 264, 99%).
      A total of 7 trials with 3391 patients were eligible for the meta-analysis of OS. Patients with oral cavity-oropharyngeal carcinoma who underwent treatment with EGFR inhibitors had an improved OS (HR 0.77, 95% CI 0.67–0.87, P < 0.001) compared to the control group (Fig. 2). In contrast, patients with hypopharyngeal-laryngeal carcinoma did not exhibit OS benefits through the addition of EGFR inhibitors (HR 0.94, 95% CI 0.82–1.08, P = 0.398). The interaction between the treatment effects on OS and the primary site was statistically significant (P = 0.029). Heterogeneity was barely observed across trials. Five trials [
      • Vermorken J.B.
      • Mesia R.
      • Rivera F.
      • Remenar E.
      • Kawecki A.
      • Rottey S.
      • et al.
      Platinum-based chemotherapy plus cetuximab in head and neck cancer.
      ,
      • Vermorken J.B.
      • Stöhlmacher-Williams J.
      • Davidenko I.
      • Licitra L.
      • Winquist E.
      • Villanueva C.
      • et al.
      Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
      ,

      Sterne J, Higgins J, Reeves B. A Cochrane risk of bias assessment tool: for non-randomized studies of interventions (ACROBAT-NRSI). Version 1.0.0. https://www.riskofbias.info. [Accessed 15 October 2019].

      ,

      Higgins J, Thomas J, (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 6.1. https://training.cochrane.org/handbook/current. [Accessed 20 October 2019].

      ,
      • Higgins J.P.T.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      ] with a total of 2775 patients were included in PFS analysis. The addition of EGFR inhibitors increased PFS in both patients with oral cavity-oropharyngeal carcinoma (HR 0.67, 95% CI 0.52–0.85, P = 0.001) and hypopharyngeal-laryngeal carcinoma (HR 0.81, 95% CI 0.69–0.94, P = 0.005). A trend towards a significant interaction was found in favor of oral cavity–oropharyngeal carcinoma (P = 0.161), and heterogeneity was observed across trials of oral cavity-oropharyngeal carcinoma.
      Figure thumbnail gr2
      Fig. 2Forest plot of survival benefits associated with anti-EGFR versus non-anti-EGFR treatments according to primary sites. Abbreviations: CI, confidence interval; EGFR, epidermal growth factor receptor; HP, hypopharynx; HR, hazard ratio; LY, larynx; OC, oral cavity; OP, oropharynx. aTwo trials (IMCL-9815 and ECOG-E1302) did not report progression-free survival (PFS) according to the primary site. bNon-oropharynx group is the combination of patients with oral cavity carcinoma (n = 3, 1%) and hypopharyngeal-laryngeal carcinoma (n = 264, 99%).
      The patients in all trials were combined for the meta-regression analysis. Among the covariates investigated, the primary site was the only significant predictor of OS benefits of anti-EGFR treatment compared to control group (univariate HR 1.23, 95% CI 1.02–1.48, P = 0.027; multivariate HR 1.23, 95% CI 1.03–1.48, P = 0.025; Table 2). Although no significant predictor was identified in the analysis of PFS, the primary site showed a trend towards significance.
      Table 2Meta-regression model for predictors of survival benefit in HNSCC after anti-EGFR versus non-anti-EGFR treatments.
      VersusOverall survivalProgression-free survival
      Univariate analysisMultivariate analysisUnivariate analysisMultivariate analysis
      HR (95% CI)P effectHR (95% CI)P effectHR (95% CI)P effectHR (95% CI)P effect
      HL vs. OO1.23 (1.02–1.48)0.0271.23 (1.03–1.48)0.0251.19 (0.97–1.47)0.0951.19 (0.96–1.48)0.120
      Antibody vs. TKI
      TKI was used as an anti-EGFR agent in one trial (ECOG-E1302), where the subgroup data of PFS was not reported.
      1.10 (0.80–1.50)0.5581.19 (0.79–1.81)0.390N.A.N.A.N.A.N.A.
      Subsequent- vs. first-line
      The ECOG-E1302 trial was a combination of first-line (26%) and subsequent-line (74%) treatment, and was classified into the subsequent-line group.
      1.00 (0.80–1.26)0.9900.88 (0.63–1.23)0.4760.90 (0.66–1.23)0.5110.89 (0.63–1.27)0.532
      Recurrent and metastatic vs. locoregionally advanced1.01 (0.83–1.21)0.9531.06 (0.85–1.33)0.5950.92 (0.73–1.15)0.4521.04 (0.74–1.44)0.838
      Non-cetuximab vs. cetuximab1.05 (0.87–1.26)0.6150.86 (0.62–1.21)0.4010.98 (0.78–1.22)0.8480.88 (0.60–1.29)0.515
      Non-approved vs. approved
      Food and Drug Administration approved: IMCL-9815 and EXTREME.
      1.15 (0.94–1.39)0.1761.30 (0.93–1.82)0.1201.10 (0.87–1.37)0.4521.25 (0.77–2.04)0.367
      Abbreviation: CI, confidence interval; EGFR, epidermal growth factor receptor; HNSCC, head and neck squamous cell carcinoma; HR, hazard ratio; HL, hypopharyngeal-laryngeal carcinoma; N.A., not applicable; OO, oral cavity-oropharyngeal carcinoma; TKI, tyrosine kinase inhibitor.
      a TKI was used as an anti-EGFR agent in one trial (ECOG-E1302), where the subgroup data of PFS was not reported.
      b The ECOG-E1302 trial was a combination of first-line (26%) and subsequent-line (74%) treatment, and was classified into the subsequent-line group.
      c Food and Drug Administration approved: IMCL-9815 and EXTREME.
      Table 3 shows subgroup analyses. A significant difference in OS, or a trend towards a significant difference, was observed in most subgroups. Some heterogeneity was observed across studies on oral cavity-oropharyngeal carcinoma. Similarly, the subgroup analyses of PFS generated roughly comparable results with the main meta-analysis of PFS (Table S2). Sensitivity analyses (Table S3) yielded results that were consistent with the main analysis. Fig. 3 shows the funnel plots, which suggest absence of publication bias.
      Table 3Differences in overall survival benefits between primary sites after anti-EGFR versus non-anti-EGFR treatments according to patient groups.
      GroupsTrials (n)Oral cavity-oropharynx carcinomaHypopharynx-larynx carcinomaP interaction
      Patients (n)HR (95%CI)P effectI2 (%)Patients (n)HR (95%CI)P effectI2 (%)
      Anti-EGFR agent
      Because there is only one trial that used tyrosine kinase inhibitors (TKIs) as an anti-EGFR agent (ECOG-E1302), the subgroup analysis of trials on TKIs was not conducted (at least two trials were needed for a subgroup analysis).
       Antibody619270.76 (0.65–0.88)<0.00125.012720.93 (0.80–1.07)0.3000.00.058
      Treatment line
      The ECOG-E1302 trial was a combination of first-line (26%) and subsequent-line (74%) treatment, and was excluded from either the first- or subsequent-line treatment subgroup.
       First-line517600.76 (0.64–0.90)0.00240.011580.94 (0.80–1.09)0.3810.00.069
      Disease pattern
       Locoregionally advanced311500.79 (0.62–1.01)0.06435.07010.89 (0.72–1.10)0.2880.00.478
       Recurrent and metastatic49080.75 (0.64–0.88)<0.0018.06320.98 (0.82–1.18)0.8370.00.029
      Agents approved by FDA
       Cetuximab311150.69 (0.50–0.94)0.01963.06100.97 (0.79–1.19)0.7880.00.075
       Non-cetuximab49430.81 (0.70–0.95)0.0090.07230.92 (0.76–1.11)0.3670.00.308
      FDA-approval of regimens
      Food and Drug Administration approved: IMCL-9815 and EXTREME.
       Approved24900.62 (0.43–0.89)0.01062.03440.95 (0.75–1.21)0.6850.00.054
       Non-approved515680.83 (0.72–0.96)0.0100.09890.94 (0.79–1.11)0.4550.00.275
      Abbreviation: CI, confidence interval; EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; HR, hazard ratio.
      a Because there is only one trial that used tyrosine kinase inhibitors (TKIs) as an anti-EGFR agent (ECOG-E1302), the subgroup analysis of trials on TKIs was not conducted (at least two trials were needed for a subgroup analysis).
      b The ECOG-E1302 trial was a combination of first-line (26%) and subsequent-line (74%) treatment, and was excluded from either the first- or subsequent-line treatment subgroup.
      c Food and Drug Administration approved: IMCL-9815 and EXTREME.
      Figure thumbnail gr3
      Fig. 3Funnel plots of publication bias. Note: Each comparison in a trial was considered as a separate study.

      Discussion

      Our meta-analysis assessed the impact of the primary site of locoregionally advanced, recurrent, or metastatic HNSCC on the OS benefit of EGFR inhibitors. The results showed that the addition of EGFR inhibitors improved the OS of patients with oral cavity-oropharyngeal carcinoma, but not that of patients with hypopharyngeal-laryngeal carcinoma. Controlling for all possible confounders made little difference to this finding.
      This finding contradicts the standard of care for the use of EGFR inhibitors in HNSCC, which is independent of the primary site. The credibility of our meta-analysis was assessed based on the guidance by Sun et al. [
      • Sun X.
      • Ioannidis J.P.
      • Agoritsas T.
      • Alba A.C.
      • Guyatt G.
      How to use a subgroup analysis: users' guide to the medical literature.
      ]. First, the main meta-analysis showed a significant difference in OS benefits between the primary sites after EGFR inhibitor treatment. The meta-regression analysis also suggested that the primary site is an effect modifier. Second, the subgroup analyses of OS demonstrated roughly consistent results with the main analysis. As for oral cavity-oropharyngeal carcinoma, the effect of EGFR inhibitors might depend on the agents (e.g., cetuximab or gefitinib) and treatment regimens (e.g., the addition of EGFR inhibitors to chemotherapy or radiotherapy). As a result, subgroup analyses yielded effects of varying quantities depending on the patient group. This implies that the addition of EGFR inhibitors is significantly associated with OS benefits (i.e., true positive), and that the change in inhibitors or treatment regimens has an influence on the effect. Third, a trend towards a significant interaction was found in favor of oral cavity-oropharyngeal carcinoma in the meta-analysis of PFS. Finally, consistent results were observed in the independent studies. In the SEER-medicare-based analysis of 2135 patients (median age: 73 years old) with squamous cell carcinoma of the oropharynx, hypopharynx, larynx, and nasopharynx, definitive radiotherapy with concurrent cetuximab was compared to chemoradiotherapy to evaluate OS. The benefits of radiotherapy with concurrent cetuximab on OS versus radiotherapy alone were shown in patients with oropharyngeal carcinoma but not in those with hypopharyngeal or laryngeal carcinoma [
      • Zandberg D.P.
      • Cullen K.
      • Bentzen S.M.
      • Goloubeva O.G.
      Definitive radiation with concurrent cetuximab vs. radiation with or without concurrent cytotoxic chemotherapy in older patients with squamous cell carcinoma of the head and neck: analysis of the SEER-medicare linked database.
      ]. In a prospective observational study of chemotherapy with or without cetuximab in recurrent or metastatic HNSCC, patients with oral cavity and oropharynx carcinomas had a significantly better response than patients with hypopharynx and larynx carcinomas [
      • Tiwari S.
      • Goel V.
      • John M.C.
      • Patnaik N.
      • Doval D.C.
      Efficacy and toxicity of cetuximab with chemotherapy in recurrent and metastatic head and neck cancer: a prospective observational study.
      ]. Taken together, it is unlikely that the difference between the primary sites occurs by chance, so the finding is highly credible.
      This study had several limitations. First, the objective response rate was not investigated due to the lack of data. Second, due to the lack of OS data according to primary tumor site, we had to exclude two phase III trials involving a total of 603 patients [
      • Burtness B.
      • Goldwasser M.A.
      • Flood W.
      • Mattar B.
      • Forastiere A.A.
      Eastern cooperative oncology G. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.
      ,
      • Stewart J.S.
      • Cohen E.E.
      • Licitra L.
      • Van Herpen C.M.
      • Khorprasert C.
      • Soulieres D.
      • et al.
      Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected].
      ]. Compared to the sample size of our meta-analysis (7 trials with 3391 patients), the exclusion of these two trials should not have a significant impact on the real effect size. Third, the test of interaction analysis has limited power to detect interactions [
      • Altman D.G.
      • Bland J.M.
      Interaction revisited: the difference between two estimates.
      ], especially on the PFS analyses, which have a much smaller sample size. These results on PFS should be considered cautiously. Fourth, there was substantial diversity in the included studies in terms of the treatment regimens and agents. This clinical heterogeneity could be considered a potential problem in interpreting the results of the present meta-analysis. Indeed, greater variability between studies was equivalent to adding “noise” to the analysis, making it unlikely to convert a null result into a positive finding [
      • Dong L.
      • Cui J.
      • Tang F.
      • Cong X.
      • Han F.
      Ataxia telangiectasia-mutated gene polymorphisms and acute normal tissue injuries in cancer patients after radiation therapy: a systematic review and meta-analysis.
      ,
      • De Laurentiis M.
      • Arpino G.
      • Massarelli E.
      • Ruggiero A.
      • Carlomagno C.
      • Ciardiello F.
      • et al.
      A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer.
      ]. In contrast, it is more likely that a positive correlation between primary tumor site and OS benefit would be masked or weakened by this “noise”. However, as suggested by the subgroup, meta-regression, and sensitivity analyses, the correlation is fairly stable, thereby suggesting that it may be a general feature of HNSCC in response to anti-EGFR treatment across different clinical situations. Finally, this meta-analysis was based on summarized data rather than individual patient data. However, results from summarized data are often consistent with individual patient data [

      Huncharek M, Kupelnick B. In regards to Baujat et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients (Int J Radiat Oncol Biol Phys 2006;64:47-56). Int J Radiat Oncol Biol Phys. 2006;65(3):958; author reply -9. https://doi.org/10.1016/j.ijrobp.2006.02.057.

      ,
      • Steinberg K.K.
      • Smith S.J.
      • Stroup D.F.
      • Olkin I.
      • Lee N.C.
      • Williamson G.D.
      • et al.
      Comparison of effect estimates from a meta-analysis of summary data from published studies and from a meta-analysis using individual patient data for ovarian cancer studies.
      ].

      Conclusion

      To our knowledge, this is the first study that examined the impact of HNSCC primary sites on the survival benefits of anti-EGFR treatment. Our meta-analysis supports the association between primary sites and OS benefits from anti-EGFR based treatments in patients with HNSCC. This is a hypothesis-generating study, and confirmation with prospective studies is required.

      Funding

      This work was supported by Natural Science Foundation of Science and Technology Agency of Jilin Province (Bethune special foundation) [grant number 20200201603JC ], the General Program of National Natural Science Foundation of China [grant number 81673090 ], and the growth foundation of the General Program of National Natural Science Foundation of China [grant number 2020-CXM-08 ]. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

      Declarations of interest

      None.

      CRediT authorship contribution statement

      Deheng Nie: Methodology, Software, Writing - review & editing. Xin Wang: Data curation, Investigation, Resources, Supervision, Validation, Writing - original draft. Meiting Sun: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Supervision, Validation, Writing - original draft, Writing - review & editing. Zhenbang Feng: Data curation, Methodology, Software. Fengli Pei: Conceptualization, Methodology, Visualization, Writing - original draft. Wenhui Liu: Data curation, Methodology, Software, Visualization. Zonghan Wang: Data curation, Methodology, Visualization, Writing - original draft. Fujun Han: Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing - review & editing.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Chung C.H.
        • Ely K.
        • McGavran L.
        • Varella-Garcia M.
        • Parker J.
        • Parker N.
        • et al.
        Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas.
        J Clin Oncol. 2006; 24: 4170-4176https://doi.org/10.1200/JCO.2006.07.2587
      1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Head and Neck Cancers. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. [Accessed 10 May 2020].

        • Vermorken J.B.
        • Mesia R.
        • Rivera F.
        • Remenar E.
        • Kawecki A.
        • Rottey S.
        • et al.
        Platinum-based chemotherapy plus cetuximab in head and neck cancer.
        N Engl J Med. 2008; 359: 1116-1127https://doi.org/10.1056/NEJMoa0802656
        • Bonner J.A.
        • Harari P.M.
        • Giralt J.
        • Cohen R.B.
        • Jones C.U.
        • Sur R.K.
        • et al.
        Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
        Lancet Oncol. 2010; 11: 21-28https://doi.org/10.1016/S1470-2045(09)70311-0
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • Mulrow C.
        • Gøtzsche P.C.
        • Ioannidis J.P.A.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        PLoS Med. 2009; 6: e1000100https://doi.org/10.1371/journal.pmed.1000100
        • Vermorken J.B.
        • Stöhlmacher-Williams J.
        • Davidenko I.
        • Licitra L.
        • Winquist E.
        • Villanueva C.
        • et al.
        Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial.
        Lancet Oncol. 2013; 14: 697-710https://doi.org/10.1016/S1470-2045(13)70181-5
        • Machiels J.P.
        • Haddad R.I.
        • Fayette J.
        • Licitra L.F.
        • Tahara M.
        • Vermorken J.B.
        • et al.
        Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
        Lancet Oncol. 2015; 16: 583-594https://doi.org/10.1016/S1470-2045(15)70124-5
        • Su Y.
        • Cui J.
        • Xu D.
        • Wang M.
        • Xu T.
        • Tian H.
        • et al.
        p16(INK4a) status and survival benefit of EGFR inhibitors in head and neck squamous cell cancer: a systematic review and meta-analysis.
        Crit Rev Oncol Hematol. 2018; 124: 11-20https://doi.org/10.1016/j.critrevonc.2018.02.006
        • Harrington K.
        • Temam S.
        • Mehanna H.
        • D'Cruz A.
        • Jain M.
        • D'Onofrio I.
        • et al.
        Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study.
        J Clin Oncol. 2015; 33: 4202-4209https://doi.org/10.1200/JCO.2015.61.4370
        • Argiris A.
        • Ghebremichael M.
        • Gilbert J.
        • Lee J.-W.
        • Sachidanandam K.
        • Kolesar J.M.
        • et al.
        Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial.
        J Clin Oncol. 2013; 31: 1405-1414https://doi.org/10.1200/JCO.2012.45.4272
        • Ang K.K.
        • Zhang Q.
        • Rosenthal D.I.
        • Nguyen-Tan P.F.
        • Sherman E.J.
        • Weber R.S.
        • et al.
        Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522.
        J Clin Oncol. 2014; 32: 2940-2950https://doi.org/10.1200/JCO.2013.53.5633
        • Patil V.M.
        • Noronha V.
        • Joshi A.
        • Agarwal J.
        • Ghosh‐Laskar S.
        • Budrukkar A.
        • et al.
        A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer.
        Cancer. 2019; 125: 3184-3197https://doi.org/10.1002/cncr.v125.1810.1002/cncr.32179
        • Machiels J.-P.
        • Subramanian S.
        • Ruzsa A.
        • Repassy G.
        • Lifirenko I.
        • Flygare A.
        • et al.
        Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial.
        Lancet Oncol. 2011; 12: 333-343https://doi.org/10.1016/S1470-2045(11)70034-1
        • Solca F.
        • Dahl G.
        • Zoephel A.
        • Bader G.
        • Sanderson M.
        • Klein C.
        • et al.
        Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker.
        J Pharmacol Exp Ther. 2012; 343: 342-350https://doi.org/10.1124/jpet.112.197756
        • Guo Y.
        • Ahn M.J.
        • Chan A.
        • Wang C.H.
        • Kang J.H.
        • Kim S.B.
        • et al.
        Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial.
        Ann Oncol. 2019; 30: 1831-1839https://doi.org/10.1093/annonc/mdz388
      2. Sterne J, Higgins J, Reeves B. A Cochrane risk of bias assessment tool: for non-randomized studies of interventions (ACROBAT-NRSI). Version 1.0.0. https://www.riskofbias.info. [Accessed 15 October 2019].

      3. Higgins J, Thomas J, (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 6.1. https://training.cochrane.org/handbook/current. [Accessed 20 October 2019].

        • Higgins J.P.T.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558https://doi.org/10.1002/(ISSN)1097-025810.1002/sim.v21:1110.1002/sim.1186
        • Altman D.G.
        • Bland J.M.
        Interaction revisited: the difference between two estimates.
        BMJ. 2003; 326: 219https://doi.org/10.1136/bmj.326.7382.219
        • Borenstein M.
        • Hedges L.V.
        • Higgins J.P.T.
        • Rothstein H.R.
        Introduction to meta-analysis. CHAPTER 20 meta-regression.
        John Wiley & Sons, Ltd., 2009
        • Burtness B.
        • Goldwasser M.A.
        • Flood W.
        • Mattar B.
        • Forastiere A.A.
        Eastern cooperative oncology G. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.
        J Clin Oncol. 2005; 23: 8646-8654https://doi.org/10.1200/JCO.2005.02.4646
        • Stewart J.S.
        • Cohen E.E.
        • Licitra L.
        • Van Herpen C.M.
        • Khorprasert C.
        • Soulieres D.
        • et al.
        Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected].
        J Clin Oncol. 2009; 27: 1864-1871https://doi.org/10.1200/JCO.2008.17.0530
        • Sun X.
        • Ioannidis J.P.
        • Agoritsas T.
        • Alba A.C.
        • Guyatt G.
        How to use a subgroup analysis: users' guide to the medical literature.
        JAMA. 2014; 311: 405-411https://doi.org/10.1001/jama.2013.285063
        • Zandberg D.P.
        • Cullen K.
        • Bentzen S.M.
        • Goloubeva O.G.
        Definitive radiation with concurrent cetuximab vs. radiation with or without concurrent cytotoxic chemotherapy in older patients with squamous cell carcinoma of the head and neck: analysis of the SEER-medicare linked database.
        Oral Oncol. 2018; 86: 132-140https://doi.org/10.1016/j.oraloncology.2018.09.023
        • Tiwari S.
        • Goel V.
        • John M.C.
        • Patnaik N.
        • Doval D.C.
        Efficacy and toxicity of cetuximab with chemotherapy in recurrent and metastatic head and neck cancer: a prospective observational study.
        Indian J Cancer. 2016; 53: 487-492https://doi.org/10.4103/ijc.IJC_7_17
        • Dong L.
        • Cui J.
        • Tang F.
        • Cong X.
        • Han F.
        Ataxia telangiectasia-mutated gene polymorphisms and acute normal tissue injuries in cancer patients after radiation therapy: a systematic review and meta-analysis.
        Int J Radiat Oncol Biol Phys. 2015; 91: 1090-1098https://doi.org/10.1016/j.ijrobp.2014.12.041
        • De Laurentiis M.
        • Arpino G.
        • Massarelli E.
        • Ruggiero A.
        • Carlomagno C.
        • Ciardiello F.
        • et al.
        A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer.
        Clin Cancer Res. 2005; 11: 4741-4748https://doi.org/10.1158/1078-0432.CCR-04-2569
      4. Huncharek M, Kupelnick B. In regards to Baujat et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients (Int J Radiat Oncol Biol Phys 2006;64:47-56). Int J Radiat Oncol Biol Phys. 2006;65(3):958; author reply -9. https://doi.org/10.1016/j.ijrobp.2006.02.057.

        • Steinberg K.K.
        • Smith S.J.
        • Stroup D.F.
        • Olkin I.
        • Lee N.C.
        • Williamson G.D.
        • et al.
        Comparison of effect estimates from a meta-analysis of summary data from published studies and from a meta-analysis using individual patient data for ovarian cancer studies.
        Am J Epidemiol. 1997; 145: 917-925https://doi.org/10.1093/oxfordjournals.aje.a009051