Anti‐epidermal growth factor receptor (anti‐EGFR) agents as adjuncts to conventional treatment for head and neck squamous cell carcinomas

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine the efficacy and safety of the addition of anti‐EGFR therapy to conventional treatments in patients with locoregionally advanced, recurrent or metastatic mucosal head and neck squamous cell carcinoma.

Background

Description of the condition

Head and neck cancer encompasses malignant tumours of the upper aerodigestive tract including the pharynx, larynx, oral cavity, nasal cavity, paranasal sinuses and salivary glands. Approximately 550,000 new cases are diagnosed each year throughout the world (Jemal 2011), the majority of which are mucosal squamous cell carcinoma (NCCN 2014). Tobacco and alcohol abuse are two important risk factors associated with oral, pharyngeal and laryngeal cancer (Blot 1988; Decker 1982; Sankaranarayanan 1998). Viral infection also plays a role, with associations between the human papilloma virus (HPV) and oropharyngeal cancer (Gillison 2000).

An individual patient's prognosis is determined by the type and extent of their cancer, established during staging. Head and neck cancer staging takes into consideration anatomic subsite, tumour size, cervical lymph node involvement and the presence of distant metastasis (AJCC 2010). Up to 40% of patients have early stage I and II cancer when they first present (NCCN 2014).

Conventional treatment options for mucosal head and neck squamous cell carcinomas include surgery, radiation and chemotherapy. The majority of early stage I and II patients can be treated with single modality therapy using either surgery or radiation alone, and survival rates are similar for both types of treatment (Gregoire 2010; Higgins 2009; NCCN 2014). In contrast, when advanced stage III and IV cancer is treated with the aim of curing the patient, this requires multimodality therapy to include surgery with adjuvant radiotherapy or organ preservation chemoradiation. Adjuvant chemotherapy has proven beneficial for some patients with advanced disease (Forastiere 2003). Ultimately, head and neck cancer treatment is individualised to the patient and based not only on the stage of the cancer and the likely prognosis associated with that stage, but also the patient's comorbidities and wishes. Sometimes treatment is palliative and not intended to try and elicit a cure.

Description of the intervention

Anti‐epidermal growth factor receptor (EGFR) agents are used as adjuncts to chemotherapy, radiotherapy or chemoradiotherapy in the treatment of patients with mucosal head and neck squamous cell carcinomas. Mucosal head and neck squamous cell carcinomas that demonstrate over‐expression of EGFR have been associated with poorer survival outcomes (Ang 2002; Chung 2006; Dassonville 1993). Activation of EGFR may promote angiogenesis and increase motility and adhesion of cancer cells, leading to increased tumour growth and metastasis. Anti‐EGFR agents, such as monoclonal antibodies that bind to EGFR or small molecules that inhibit the tyrosine kinase activity of EGFR, may be effective therapeutic agents in the treatment of mucosal head and neck squamous cell carcinoma.

Factors that might affect or predict the effectiveness of treatment may include p16‐positive/negative status for cetuximab and panitumumab (Ang 2014; Vermorken 2013), EGFR expression levels and the appearance of rashes for cetuximab (Burtness 2005), although this has been recently challenged (Ang 2014), and age and c‐Met genotype for gefitinib (Argiris 2013).

Common side effects of anti‐EGFR therapy include:

• acneiform skin rash (Bonner 2006; Peréz‐Soler 2005; Robert 2001);

• fatigue (Ang 2014); and

• diarrhoea (Argiris 2013; Vermorken 2013).

Side effects may be dependent on the anti‐EGFR agent. For example, treatment‐related deaths occurred in 4% of patients treated with panitumumab compared to control (2%) (Vermorken 2013), whereas treatment‐related deaths with cetuximab have been less well documented (Vermorken 2008), potentially suggesting different safety profiles depending on the choice of anti‐EGFR agent. This warrants further investigation.

How the intervention might work

Anti‐EGFR agents broadly consist of the small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mABs), which induce tumour cell death via slightly different mechanisms of action. TKIs inhibit EGFR‐activated signal transduction cascades such as the MAPK, PI3K‐Akt, PLC‐γ and STAT pathways by targeting the intracellular tyrosine kinase, whereas mABs bind to the extracellular ligand‐binding domain of the EGFR and inhibit EGFR activation. Furthermore, the therapeutic effects of mABs may also be attributed to induction of immunologic antitumour mechanisms, such as antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent (cell‐mediated) cytotoxicities (CDC) (Vermorken 2010).

It is not currently clear whether clinical efficacy is affected by the choice of anti‐EGFR agent. However, cetuximab is currently the only anti‐EGFR agent approved for the treatment of head and neck squamous cell carcinoma (Hansen 2013). In the trial by Bonner 2010, cetuximab demonstrated superiority in combination with radiotherapy over radiotherapy alone in patients with locoregionally advanced disease (overall survival: 49.0 versus 29.3 months; hazard ratio 0.73, P = 0.018). For cetuximab, differences in progression‐free survival may be evident between treatment and control group, with the median duration of progression‐free survival being 5.6 versus 3.3 months in patients with recurrent or metastatic disease (Vermorken 2008).

Why it is important to do this review

The survival benefit and safety profile of anti‐EGFR agents as an adjunct to conventional treatment for head and neck squamous cell carcinoma is unclear. Cetuximab was approved by the US Food and Drug Administration (FDA) in 2006 for the treatment of squamous cell carcinoma of the head and neck following positive results from the randomised trial conducted by Bonner and colleagues (Bonner 2006), which demonstrated that cetuximab plus radiation was superior to radiation alone in terms of locoregional control and five‐year overall survival in patients with locally advanced mucosal head and neck carcinomas (Bonner 2010). The EXTREME study also demonstrated a survival benefit of adding cetuximab to cisplatin/carboplatin and fluorouracil in patients with recurrent or metastatic mucosal head and neck squamous cell carcinomas (Vermorken 2008). However, more recent trials have questioned the role of adjunctive cetuximab. The RTOG 0522 trial involving patients with grade III/IV mucosal head and neck squamous cell carcinoma found that cetuximab plus cisplatin‐radiation led to more frequent interruptions to radiotherapy and grade 3/4 mucositis, rash, fatigue, anorexia and hypokalaemia, and no benefit was seen in terms of three‐year progression‐free survival or overall survival (Ang 2014). The SCOPE1 trial found that patients who received cetuximab in addition to chemoradiotherapy had shorter overall survival and more non‐haematological grade 3/4 toxicities (Crosby 2013).

Hence, it is important to conduct this review to clarify the effectiveness and safety of EGFR‐targeted therapies as adjuncts to conventional treatments for squamous cell carcinoma of the head and neck.

Objectives

To determine the efficacy and safety of the addition of anti‐EGFR therapy to conventional treatments in patients with locoregionally advanced, recurrent or metastatic mucosal head and neck squamous cell carcinoma.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials. We will not include non‐standard study designs such as quasi‐randomised or cluster‐randomised trials. We do require full journal publication, with the exception of unpublished online data. We will consider extended or conference abstracts if there are sufficient data to analyse.

Types of participants

Patients with locally advanced, metastatic or recurrent mucosal squamous cell carcinoma of head and neck region, aged 18 years and over, of any gender and in any setting. Locoregionally advanced disease is defined as primary tumours or metastases confined to the head and neck region, excluding distant metastases to regions outside of the head and neck. Metastatic disease is defined as distant metastases to regions outside of the head and neck.

We will not include studies using an anti‐EGFR agent to treat conditions resulting from causes other than mucosal squamous cell carcinoma.

Types of interventions

Intervention

Anti‐EGFR agent as an adjunct to conventional treatment.

Comparison

Conventional treatment alone.

Conventional treatments can include surgery, radiation therapy or chemotherapy as single or combined modalities.

The main comparison pairs are as follows:

Locoregionally advanced squamous cell carcinoma

• Radiation therapy + anti‐EGFR versus radiation therapy

• Radiation therapy + anti‐EGFR versus chemoradiotherapy

• Chemoradiotherapy + anti‐EGFR versus radiation therapy

• Chemoradiotherapy + anti‐EGFR versus chemoradiotherapy

Metastatic squamous cell carcinoma

• Chemotherapy + anti‐EGFR versus chemotherapy

Types of outcome measures

We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies.

Primary outcomes

• Overall survival: time from randomisation to death from any cause.

• Locoregional control: defined as the time from randomisation until progression or recurrence of locoregional disease or until death from any cause.

• Disease‐free survival: defined as days from randomisation to disease recurrence or death from any cause.

• Progression‐free survival: time elapsed to disease progression or death from any cause.

Secondary outcomes

• Quality of life, measured using a scale that has been validated through reporting of norms in a peer‐reviewed publication.

• Adverse events, classified according to Common Terminology Criteria for Adverse Events (CTCAE) version 2.0, 3.0 and 4.0 (CTCAE 2010). We will extract and group grades of toxicity as follows:

  • Blood and lymphatic system disorders: anaemia, neutropenia, febrile neutropenia, thrombocytopenia, leucopenia, haemorrhage.

  • Cardiac disorders: bradycardia, atrial fibrillation.

  • Ear and labyrinth disorders: hearing loss, tinnitus, vertigo.

  • Skin and subcutaneous tissue disorders: nail disorders, alopecia, stomatitis, mucositis, allergy, rashes.

  • Gastrointestinal disorders: diarrhoea, anorexia, nausea, vomiting, liver, proctitis.

  • Neurological disorders: peripheral and central.

• Direct and indirect costs to patients and health services.

• Patient satisfaction.

Search methods for identification of studies

The Cochrane ENT Information Specialist will conduct systematic searches for randomised controlled trials and controlled clinical trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.

Electronic searches

Published, unpublished and ongoing studies will be identified by searching the following databases from their inception:

• Cochrane Register of Studies ENT Trials Register (search to date);

• Cochrane Central Register of Studies Online (CRSO) (search to date);

• Ovid MEDLINE (1946 to date):

  • Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations);

  • PubMed (as a top‐up to searches in Ovid MEDLINE);

• Ovid EMBASE (1974 to date);

• EBSCO CINAHL (1982 to date);

• Ovid CAB abstracts (1910 to date);

• LILACS (search to date);

• KoreaMed (search to date);

• IndMed (search to date);

• PakMediNet (search to date);

• Web of Knowledge, Web of Science (1945 to date);

• CNKI (searched via Google Scholar to date);

• ClinicalTrials.gov (www.clinicaltrials.gov) (search via the Cochrane Register of Studies to date);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (search to date);

• ISRCTN (www.isrctn.com) (search to date);

• Google Scholar (search to date);

• Google (search to date).

The subject strategies for databases will be modelled on the search strategies designed for CRSO and Ovid MEDLINE (Appendix 1). Where appropriate, these will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)).

Searching other resources

We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. In addition, the Information Specialist will search PubMed, TRIPdatabase, theCochrane Library and Google to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. We will search for conference abstracts using the Cochrane ENT Trials Register and EMBASE.

Unpublished and grey literature

We will search the following for ongoing trials:

• metaRegister (http://www.controlled‐trials.com/rct);

• Physicians Data Query (http://www.nci.nih.gov);

• http://www.clinicaltrials.gov; and

• http://www.cancer.gov/clinicaltrials.

We will search conference proceedings and abstracts through:

• ZETOC (http://zetoc.mimas.ac.uk);

• WorldCat Dissertations.

If ongoing trials that have not been published are identified through these searches, we will contact the principal investigators to request the relevant data.

We will handsearch the citation lists of included studies, key textbooks and previous systematic reviews to identify further reports of trials. We will also handsearch the reports of conferences in the following sources:

• British Journal of Cancer;

• British Cancer Research Meeting;

• Annual Meeting of European Society of Medical Oncology (ESMO);

• Annual Meeting of the American Society of Clinical Oncology (ASCO).

Data collection and analysis

Selection of studies

We will download all titles and abstracts retrieved by electronic searching to a reference management database (e.g. Mendeley) and remove duplicates. Two review authors (RMG, NLS) will examine the remaining references independently. We will exclude those studies that clearly do not meet the inclusion criteria and obtain copies of the full text of potentially relevant references. Two review authors (RMG, NLS) will independently assess the eligibility of retrieved papers and resolve disagreements through discussion or, if necessary, by referral to a third review author (YYS or BCG). We will document the reasons for exclusion.

Data extraction and management

Two review authors (RMG, NLS) will independently extract study characteristics and outcome data from included studies onto a pre‐piloted data collection form. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by appeal to a third review author (BCG). One review author (RMG or NLS) will transfer data into the Cochrane Review Manager software (RevMan) (RevMan 2014). A second review author (YYS) will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports.

For included studies, we will extract the following data:

• Author, year of publication and journal citation (including language).

• Country.

• Setting.

• Inclusion and exclusion criteria.

• Study design, methodology.

• Study population.

  • Total number enrolled.

  • Patient characteristics.

  • Age.

  • Co‐morbidities.

  • Other baseline characteristics e.g. stage, grade, histotype, HPV status.

• Intervention details.

  • Choice, dose intensity and frequency of chemotherapy agent, if applicable.

  • Details of radiotherapy and debulking surgery, if applicable.

  • Details of anti‐EGFR agent.

• Risk of bias in study (see below).

• Duration of follow‐up.

• Outcomes: for each outcome, we will extract the outcome definition and unit of measurement (if relevant). For adjusted estimates, we will record the variables adjusted for in analyses.

• Results: we will extract the number of participants allocated to each intervention group, the total number analysed for each outcome and the missing participants.

• Notes: funding for the study and notable conflicts of interest of study authors.

We will extract results as follows:

• For time‐to‐event data (survival and disease progression), we will extract the log of the hazard ratio (log(HR)) and its standard error from the study reports. If these are not reported, we will attempt to estimate the log(HR) and its standard error using the methods of Parmar 1998.

• For dichotomous outcomes (e.g. adverse events or deaths), if it is not possible to use a hazard ratio we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a risk or odds ratio.

• For continuous outcomes (e.g. quality of life measures), we will extract the final value and standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow‐up, in order to estimate the mean difference between treatment arms and its standard error.

• For ordinal outcomes (e.g. quality of life measures), as per the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Section 7.7.4), we will either dichotomise the scale for analysis (for shorter scales) or treat the ordinal scale as a continuous outcome (for longer scales where the data appear to be approximately normally distributed or if the analysis that the investigators performed suggests parametric tests were appropriate). We will not pre‐specify the method of data extraction, but we will extract data in all forms in which they are reported (Handbook 2011), as it will not be clear which is the most common method used for analysing data until all studies have been reviewed. We may undertake more than one form of analysis if applicable. If dichotomisation is performed, we may investigate the choice of the cut‐off point in a sensitivity analysis.

If reported, we will extract both unadjusted and adjusted statistics, as well as data relevant to an intention‐to‐treat and per‐protocol analysis. We will note the time points at which outcomes were collected and reported.

Assessment of risk of bias in included studies

We will assess and report on the methodological risk of bias of the included studies using the Cochrane 'Risk of bias' tool, which assesses the explicit reporting of the following individual elements for RCTs (Appendix 2; Handbook 2011):

• Selection bias: random sequence generation and allocation concealment.

• Performance bias: blinding of participants and personnel (patients and treatment providers).

• Detection bias: blinding of outcome assessment.

• Attrition bias: incomplete outcome data.

• Reporting bias: selective reporting of outcomes.

• Other potential sources of bias.

Two review authors (RMG, NLS) will apply the 'Risk of bias' tool independently and resolve differences by discussion or by appeal to a third review author (BCG). We will judge each item as being at high, low or unclear risk of bias as set out in the criteria provided in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We will provide a quote from the study report and/or a statement as justification for the judgement for each item in the 'Risk of bias' table. We will summarise results in both a 'Risk of bias' graph and a 'Risk of bias' summary. When interpreting treatment effects and meta‐analyses, we will take into account the risk of bias for the studies that contribute to that outcome. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

Measures of treatment effect

We will use the following measures of the effect of treatment:

• For time‐to‐event data, we will use the hazard ratio, if possible.

• For dichotomous outcomes, we will use the odds ratio (OR) or risk ratio (RR), if possible.

• For continuous outcomes, we will use the mean difference, if possible.

We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense. We will narratively describe skewed data reported as medians and interquartile ranges. Where multiple arms are reported in a single study, we will include only the relevant arms. If two comparisons are combined in the same meta‐analysis, we will halve the control group to avoid double‐counting.

Unit of analysis issues

If any studies have multiple treatment groups, we will divide the 'shared' comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons.

Dealing with missing data

We will attempt to contact study authors to obtain missing data (participant, outcome or summary data). We will report on the levels of loss to follow‐up and assess this as a potential source of bias.

For missing outcome or summary data, including for the primary outcome, we will impute missing data and report any assumptions in the review if appropriate, using the recommended guidelines detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We will investigate, through sensitivity analyses, the effects of any imputed data on the pooled effect estimates.

Assessment of heterogeneity

Where studies are considered similar enough (in terms of participants, settings, intervention and outcome measures) to allow pooling of data using meta‐analysis, we will assess the degree of heterogeneity by visual inspection of forest plots, by estimation of the percentage of heterogeneity (I² statistic) between studies that cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Chi² test) (Deeks 2001) and, if possible, by subgroup analyses. We will regard heterogeneity as substantial if the I² value is greater than 30% or there is a low P value (< 0.10) in the Chi² test for heterogeneity.

If there is evidence of substantial clinical, methodological or statistical heterogeneity across included studies we will not report pooled results from meta‐analysis but will instead use a narrative approach to data synthesis. In this event we will investigate and report the possible clinical or methodological reasons for this.

Assessment of reporting biases

We will examine funnel plots corresponding to meta‐analysis of the primary outcome to assess the potential for small study effects such as publication bias if more than 10 studies are identified. We will assess funnel plot asymmetry visually and, if asymmetry is suggested by this visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

If sufficient and clinically similar studies (in terms of participants, settings, intervention, comparison and outcome measures) are available to ensure meaningful conclusions, and if statistical heterogeneity is low (I² < 30%), we will pool the results in meta‐analyses using the fixed‐effect model in RevMan 5 (RevMan 2014). If there is variability in the participants, settings and interventions in the included studies, or if statistical heterogeneity is substantial (I² > 30%), we will use the random‐effects model with inverse variance for meta‐analysis (DerSimonian 1986).

• For time‐to‐event data, we will pool hazard ratios using the generic inverse variance facility in RevMan (RevMan 2014).

• For any dichotomous outcomes, we will calculate the odds or risk ratio (OR/RR) as appropriate for each study and then pool these. We may analyse data based on the number of events and the number of people assessed in the intervention and comparison groups, and use these to calculate the OR or RR and 95% confidence interval (CI).

• For continuous outcomes, will pool the mean differences (MD) between the treatment arms at the end of follow‐up, if all studies measure the outcome on the same scale; otherwise we will pool standardised mean differences (SMD). We will analyse data based on the mean, standard deviation (SD) and number of people assessed for both the intervention and comparison groups to calculate mean difference (MD) between treatment arms with a 95% CI. If the MD is reported without individual group data, we will use this to report the study results. If more than one study measures the same outcome using different tools, we will calculate the standardised mean difference (SMD) and 95% CI using the inverse variance method in RevMan (RevMan 2014).

If any studies have multiple treatment groups, we will divide the 'shared' comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons.

If we are unable to pool the data statistically using meta‐analysis we will conduct a narrative synthesis of results. We will present the major outcomes and results, organised by intervention categories according to the major types and/or aims of the identified interventions. Depending on the assembled research, we may also explore the possibility of organising the data by population. Within the data categories we will explore the main comparisons of the review.

Subgroup analysis and investigation of heterogeneity

If possible, we will perform subgroup analyses for the following factors:

• type of anti‐EGFR agent administered: grouped as tyrosine kinase inhibitors versus monoclonal antibodies;

• type of conventional treatment: grouped as single versus multi modalities;

• stage of disease: grouped as localised versus metastatic or recurrent.

Sensitivity analysis

We will perform sensitivity analyses by excluding studies with unclear or high risk of bias, and imputed data.

GRADE and 'Summary of findings' table

We will use the GRADEprofiler (GRADEpro) software to assist with the preparation of a 'Summary of findings' table (GRADEpro 2014). 'Summary of findings' tables present the review's main findings in a table format and provide key information about the best estimate of the magnitude of the effect, in relative terms, and the absolute differences for each relevant comparison of alternative management strategies, the number of participants and studies addressing each important outcome and the rating of the overall confidence in the effect estimates for the comparisons in a outcome‐specific manner. The outcomes we will include in the 'Summary of findings' table are, as defined above:

• overall survival;

• progression‐free survival;

• adverse events;

• quality of life.

We acknowledge that it may not be possible to address all important outcomes within the constraints of results reported in randomised controlled trials only.

Quality of evidence

We will assess the quality of evidence as 'high', 'moderate', 'low' or 'very low' using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach (Schünemann 2004), which evaluates studies on five domains: study limitations (risk of bias), consistency, imprecision, indirectness and publication bias. Two review authors (RMG, NLS) will independently rate the quality for each outcome. We will resolve disagreements by appeal to a third (YYS) or fourth review author (BCG) if necessary.

Ensuring relevance to decisions in health care

We will disseminate the results of the review, once published, to major organisations and working groups with an interest in clinical oncology, especially in the field of head and neck malignancies, and those with the ability to influence healthcare policy making, e.g. the American Society for Clinical Oncology (ASCO), American Association for Cancer Research (AACR), National Comprehensive Cancer Network (NCCN), Cancer Research UK, National Cancer Institute (NCI) and World Health Organization (WHO) Cancer Control Programme. We will also push for a Wiley press release as well as coverage on Cochrane social media platforms and relevant PLoS blogs. We will also update the relevant Wikipedia pages.

Appendices

Appendix 1. CRSO and MEDLINE search strategies

CRSO

Ovid MEDLINE

#1 MESH DESCRIPTOR Head and Neck Neoplasms EXPLODE ALL TREES 3292 #2 MESH DESCRIPTOR Larynx EXPLODE ALL TREES 500 #3 MESH DESCRIPTOR pharynx EXPLODE ALL TREES 968 #4 MESH DESCRIPTOR Mouth EXPLODE ALL TREES 7432 #5 MESH DESCRIPTOR Palate EXPLODE ALL TREES 267 #6 #2 OR #3 OR #4 OR #5 8739 #7 MESH DESCRIPTOR Neoplasms EXPLODE ALL TREES 42321 #8 #6 AND #7 426 #9 (((mouth or gingival or lip* or palat* or tongue or Laryn* or pharyn* or hypopharyn* or oropharyn* or tonsil* or otorhinolaryngologic or oral or nasopharyn* or nose) near (cancer* or carcinoma* or neoplas* or tumor* or tumour* or malignan* or SCC))):TI,AB,KY 3686 #10 (head next neck near (cancer* or carcinoma* or neoplas* or tumor* or tumour* or malignan* or SCC)):TI,AB,KY 96 #11 (HNSCC or SCCHN or OP‐SCC or OPSCC or LASCCHN):TI,AB,KY 391 #12 #1 OR #8 OR #9 OR #10 OR #11 6321 #13 MESH DESCRIPTOR Receptor, Epidermal Growth Factor EXPLODE ALL TREES WITH QUALIFIERS AI 118 #14 MESH DESCRIPTOR Antibodies, Monoclonal EXPLODE ALL TREES 4021 #15 MESH DESCRIPTOR Protein Kinase Inhibitors EXPLODE ALL TREES 444 #16 MESH DESCRIPTOR Quinazolines EXPLODE ALL TREES 1684 #17 MESH DESCRIPTOR Morpholines EXPLODE ALL TREES 1727 #18 (Afatinib or cetuximab or matsuzumab or nimotuzab or zalutumumab or panitumumab or gefitinib or erlotinib or lapatinib or canertinib or nimotuzumab):TI,AB,KY 1723 #19 (Alemtuzumab or Bevacizumab or Gemtuzumab or Ipilimumab or Ofatumumab or Panitumumab or Pembrolizumab or Rituximab or Trastuzumab):TI,AB,KW 3500 #20 (Iressa or Erbitux or BIBW2992 or Gilotrif or BIBW‐2992 or Quinazolines or ABX‐EGF or (monoclonal near antibod*) or Vectibix or Tarceva or CP 358774 or CP 358,774 or OSI‐774 or Tykerb or GW 282974X or GW282974X or GW572016 or ?GW 572016? or CI1033 or CI 1033 or Morpholines or Pmab or TKI* or dacomitinib or PF 00299804? or PF00299804):TI,AB,KY 5677 #21 MESH DESCRIPTOR Receptor, Epidermal Growth Factor EXPLODE ALL TREES 275 #22 (EGFR or "epidermal growth factor*" or EGF or erbB* or photo‐oncogene * or (tyrosine near kinase) or TGF‐alpha* or Transforming‐Growth Factor alpha or Urogastrone* or HER or HER1 or HER2 or EGF‐R or HER3):TI,AB,KY 5588 #23 #21 OR #22 5588 #24 MESH DESCRIPTOR Antineoplastic Combined Chemotherapy Protocols EXPLODE ALL TREES 10199 #25 MESH DESCRIPTOR Antineoplastic Agents EXPLODE ALL TREES 33726 #26 (Antineoplastic or anti or antibod* or target* or inhibit*):TI,AB,KY 156924 #27 #24 OR #25 OR #26 169023 #28 #23 AND #27 2705 #29 #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #28 14505 #30 #12 AND #29 339

1. "Head and Neck Neoplasms"/ 2. mouth neoplasms/ or gingival neoplasms/ or lip neoplasms/ or palatal neoplasms/ or tongue neoplasms/ or exp otorhinolaryngologic neoplasms/ 3. exp larynx/ or exp pharynx/ 4. exp Mouth/ or exp Palate/ 5. 3 or 4 6. exp Neoplasms/ 7. 5 and 6 8. ((gingival or lip* or palat* or tongue or Laryn* or pharyn* or hypopharyn* or oropharyn* or tonsil* or otorhinolaryngologic or nasopharyn*) adj6 (cancer* or carcinoma* or neoplas* or tumor* or tumour* or malignan* or SCC)).ab,ti. 9. (head adj3 neck adj6 (cancer* or carcinoma* or neoplas* or tumor* or tumour* or malignan* or SCC)).ab,ti. 10. (HNSCC or SCCHN or OP‐SCC or OPSCC or LASCCHN).ab,ti. 11. 1 or 7 or 8 or 9 or 10 12. exp Receptor, Epidermal Growth Factor/ai [Antagonists & Inhibitors] 13. exp Antibodies, Monoclonal/ 14. exp Protein Kinase Inhibitors/ 15. exp Quinazolines/ 16. exp Morpholines/ 17. (Afatinib or cetuximab or matsuzumab or nimotuzab or zalutumumab or panitumumab or gefitinib or erlotinib or lapatinib or canertinib or nimotuzumab).tw. 18. (Alemtuzumab or Bevacizumab or Gemtuzumab or Ipilimumab or Ofatumumab or Panitumumab or Pembrolizumab or Rituximab or Trastuzumab).ab,ti. 19. exp Receptor, Epidermal Growth Factor/ 20. (EGFR or "epidermal growth factor*" or EGF or erbB* or "photo‐oncogene*" or tyrosine near kinase or TGF‐alpha* or "Transforming‐Growth Factor alpha" or Urogastrone* or HER or HER1 or HER2 or EGF‐R or HER3).tw. 21. 19 or 20 22. exp Antineoplastic Agents/ 23. exp Antineoplastic Combined Chemotherapy Protocols/ 24. (Antineoplastic or anti or antibod* or target* or inhibit*).ab,ti. 25. 22 or 23 or 24 26. 21 and 25 27. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 26 28. 11 and 27

Appendix 2. Assessment of risk of bias (further steps)

We will use the following criteria to assess risk of bias:

• Random sequence generation

• • Low risk of bias, e.g. participants assigned to treatments on basis of a computer‐generated random sequence or a table of random numbers.

  • High risk of bias, e.g. participants assigned to treatments on basis of date of birth, clinic ID number or surname, or no attempt to randomise participants.

  • Unclear risk of bias, e.g. not reported, information not available.

• Allocation concealment

• • Low risk of bias, e.g. where the allocation sequence could not be foretold.

  • High risk of bias, e.g. allocation sequence could be foretold by patients, investigators or treatment providers.

  • Unclear risk of bias, e.g. not reported.

• Blinding of participants and personnel (NB blinding of patients and treatment providers is usually possible only for pharmacological interventions)

• • Low risk of bias, if participants and personnel were adequately blinded.

  • High risk of bias, if participants were not blinded to the intervention that the participant received.

  • Unclear risk of bias, if this was not reported or unclear.

• Blinding of outcomes assessors

• • Low risk of bias, if outcome assessors were adequately blinded.

  • High risk of bias, if outcome assessors were not blinded to the intervention that the participant received.

  • Unclear risk of bias, if this was not reported or unclear.

• Incomplete outcome data: we will record the proportion of participants whose outcomes were not reported at the end of the study. We will code a satisfactory level of loss to follow‐up for each outcome as follows:

• • Low risk of bias, if fewer than 20% of patients were lost to follow‐up and reasons for loss to follow‐up were similar in both treatment arms.

  • High risk of bias, if more than 20% of patients were lost to follow‐up or reasons for loss to follow‐up differed between treatment arms.

  • Unclear risk of bias, if loss to follow‐up was not reported.

• Selective reporting of outcomes

• • Low risk of bias, e.g. reports all outcomes specified in the protocol.

  • High risk of bias, e.g. it is suspected that outcomes have been selectively reported.

  • Unclear risk of bias, e.g. it is unclear whether outcomes have been selectively reported.

• Other bias

• • Low risk of bias, if no other source of bias is suspected and the study appears to be methodologically sound.

  • High risk of bias, if it is suspect that the study was prone to an additional bias.

  • Unclear risk of bias, if it is uncertain whether an additional bias may have been present.

Contributions of authors

Drafting the protocol: Robby Goh, Nicholas Syn.

Developing and running the search strategy: Cochrane ENT Information Specialist (Samantha Faulkner).

Obtaining copies of studies: Yu Yang Soon, Lingzhi Wang.

Selecting which studies to include: Robby Goh, Nicholas Syn, Lingzhi Wang, Yu Yang Soon, Boon‐Cher Goh.

Extracting data from studies: Robby Goh, Nicholas Syn.

Entering data into RevMan: Robby Goh, Nicholas Syn.

Carrying out the analysis: Robby Goh, Nicholas Syn, Yu Yang Soon.

Interpreting the analysis: Robby Goh, Nicholas Syn, Lingzhi Wang, Yu Yang Soon, Boon‐Cher Goh.

Drafting the final review: Robby Goh, Nicholas Syn, Lingzhi Wang, Yu Yang Soon, Boon‐Cher Goh.

Updating the review: Robby Goh, Nicholas Syn, Lingzhi Wang, Yu Yang Soon, Boon‐Cher Goh.

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research, UK.

  Infrastructure funding for Cochrane ENT

Declarations of interest

Robby M Goh: declares no conflicts of interest.

Nicholas Li‐Xun Syn: declares no conflicts of interest

Lingzhi Wang: declares no conflicts of interest..

Yu Yang Soon: declares no conflicts of interest.

Boon Cher Goh: declares no conflicts of interest.

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