Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

Primary objectives

  • To determine whether molecularly targeted therapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity or oropharyngeal cancers result in increased overall survival, disease free survival, progression free survival, locoregional control and reduced recurrence.

  • To determine whether immunotherapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity or oropharyngeal cancers result in increased overall survival, disease free survival, progression free survival, locoregional control and reduced recurrence.

Secondary objectives

  • To determine whether molecularly targeted therapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity oropharyngeal cancers are associated with increased quality of life, harm, costs and patient satisfaction.

  • To determine whether immunotherapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity or oropharyngeal cancers are associated with increased quality of life, harm, costs and patient satisfaction.

Background

Description of the condition

Oral cancers are the sixth most common cancer worldwide, accounting for an estimated 4% of all cancers, with an estimated 274,000 new cases of oral cavity and 130,000 new cases of oropharyngeal cancer worldwide in 2002 (Parkin 2005; Warnakulasuriya 2009). The incidence and mortality from oral cancers varies geographically;the highest age standardised rates of oral cancers are reported in parts of Europe (France, Hungary), Botswana and South Central Asia (Sri Lanka, Pakistan, Banglasdesh and India) (Parkin 2005). There is overwhelming evidence that tobacco use, alcohol consumption and betel quid chewing are the main risk factors in the aetiology of intraoral cancer (La Vecchia 1997; Macfarlane 1995). There is also strong evidence that low socio-economic status is associated with a higher incidence and poorer survival of oral cancers (Faggiano 1997). There is a higher incidence of oral cancers in men (Freedman 2007) that is generally attributed to a greater exposure to the known risk factors and vast majority of cases occur in men over 50 (Warnakulasuriya 2009) and among low socio-economic groups (Conway 2008). However, the ratio of males to females diagnosed with oral cancers has declined from approximately 5:1 in the 1960s to less than 2:1 in 2002 (Parkin 2005). Another recent trend is the increasing incidence of oral cavity and oropharyngeal cancers in younger adults in the European Union and the United States (Warnakulasuriya 2009).

The epidemiological data concerning 'oral cancer' obscures the fact that 'oral cancer' includes both oral cavity and oropharyngeal cancers which have clinically different aetiology, are generally diagnosed at different stages and managed in different ways. Patients with oral cavity cancers generally present with early stage disease and the primary treatment is surgery or radiotherapy or both. However, oropharyngeal cancers are likely to be advanced at the time of diagnosis and primary treatment is more likely to be radiation therapy or chemoradiation. It is now recognised that oral infection with human papilloma virus (HPV) is strongly associated with the development of oropharyngeal cancer. HPV infection is found in 40% to 60% of patients (D'Souza 2007), and HPV is thought to be associated with the increased incidence of oropharyngeal cancer (Hammarstedt 2006). The link between oncogenic HPV and oropharyngeal cancer is strong and has been documented in numerous studies, fulfilling the epidemiological criteria for disease causality, especially in the development of oropharyngeal cancer in non-smokers (Sturgis 2007). The proportion of patients with oropharyngeal cancer who are HPV positive has increased dramatically over recent years (Attner 2010; Ryerson 2008) but it is interesting to note that this group of patients have significantly improved rates of both overall survival and disease free survival (Fakhry 2006; Fakhry 2008; Licitra 2006). In comparison, the level of evidence and the degree of association between oral cavity cancer and HPV is much weaker (Herrero 2003).

The most common cancer of the oral cavity and oropharynx is the squamous cell carcinoma that arises from the lining of the oral cavity; over 95% of all oral cavity cancers are squamous cell carcinomas. Despite significant technical advances in the treatment of oral cancer, it still has a significant mortality with 128,000 deaths recorded, representing nearly half of the incident cases (48%) (Parkin 2001).
Survival following a diagnosis of oral cavity or oropharyngeal cancer remains poor with 5-year survival around 50% overall, with only limited improvement in the past 3 decades (Warnakulasuriya 2009).

Description of the intervention

With increasing understanding of the molecular changes associated with carcinogenesis of head and neck cancer, new targeted therapies are being developed to overcome those molecular changes. These changes may be associated with autonomous proliferation, dysregulation of growth inhibitory signals, evasion of apoptosis, development of immortalization, tumour-induced angiogenesis, and tissue invasion and metastasis.  Targeted therapies against any of these changes may represent therapeutic opportunities. When compared with conventional cytotoxic chemotherapies which are relatively unselective, acting against both cancer cells and normal cells, targeted therapies are more selective against cancer cells and therefore have the potential to minimize toxicities while maximizing therapeutic outcomes. For example, epidermal growth factor receptors (EGFR) are found to be over-expressed in 80% to 90% of head and neck cancers (Grandis 1993), and EGFR over-expression is associated with reduced survival (Ang 2002; Demiral 2004; Maurizi 1996), therefore making EGFR a rational target for the treatment of head and neck cancer.

Monoclonal antibodies have been developed which target EGFR, but there are a range of other targets including vascular endothelial growth factor (VEGF), and a group of proteins known as tyrosine kinases. As well as tyrosine kinase inhibitors which have multiple targets, research has identified a wide range of specific targets.

In addition, it is thought that cancer may develop in an individual following a break down or sub-optimal functioning of the immune system. Immunotherapy (also known as biological therapy, biotherapy, or biological response modifier therapy) may function to repair, stimulate or enhance the function of the immune system in destroying the cancer cells (CRUK 2012). Local immunotherapy delivers treatment directly into the tumour and systemic immunotherapy targets the whole body and may be useful for stopping metastasis or the recurrence of primary tumours in more advanced cancer. Non-specific immunotherapy is designed to boost the capability of the immune system cells, such as T-cells, NK-cells, and macrophages to fight against any foreign cells (CTCA 2012).

Oncolytic adenoviruses have been developed which replicate preferentially in tumours (Crompton 2007; Yu 2007), resulting in the destruction of tumour cells. An example is oncolytic herpes simplex virus such as HF10 (Fujimoto 2006) also being developed to target head and neck cancer cases. The efficacy of the delivery methods of these oncolytic adenoviruses (e.g. intratumoural approach versus intravenous delivery) is also under evaluation (Deng 2011). Antibody directed pro-drug therapy (ADEPT) can be used to attach an enzyme to the cancer cells which converts a pro-drug to an active anti-cancer agent at the site of the tumour (CRUK 2012).

There is a great deal of pre-clinical research in the area of targeted biological therapies for cancer, which is being conducted in laboratories all over the world.

How the intervention might work

The observation that epidermal growth factor is over-expressed in malignant head and neck squamous cell carcinomas, and that high levels of epidermal growth factor receptor (EGFR) are correlated with poor prognosis and poor response to radiotherapy has led to EGFR being recognised as an important therapeutic target in cancer (Bernardes 2010).

Monoclonal antibodies against EGFR, such as Cetuximab, Panitumub and Zalutumumab, have been developed for head and neck cancers (Kundu 2012). They work by binding to the extra-cellular domain of EGFR and prevent demonization, internalization and autophosphorylation. EGFR tyrosine kinase inhibitors, such as Gefitinib and Erlotinib, work by binding to the intracellular tyrosine kinase domain of EGFR to prevent intracellular signal transduction. EGFR inhibitors have also been shown to enhance tumour radiosensitivity (Hamakawa 2008). This provides biologic rationale to examine the effectiveness of combining EGFR therapy with radiotherapy.

Other target therapies include vascular endothelial growth factor receptor inhibitors (such Bevacizumab and Vandetanib) which inhibit the formation of new blood vessels that supply the tumour. There is a large group of small molecular multiple kinase inhibitors, some of which inhibit multiple targets (such as Sorafenib, Sunitinib, Lapatinib) and others which have a range of specific targets. Specific targets include PARP (Poly (ADP-ribose) polymerase) inhibitors (such as Iniparib and Olaparib), proteasome inhibitors (such as Bortezomib), histone acetylation inhibitors (such as Vorinostat and Romidepsin), mTOR (mammalian Target of Rapamycin) inhibitors (Everolimus and Temsirolimus), COX (cyclo-oxygenase) inhibitors (Celecoxib), CDK (cyclin dependant kinase) inhibitors (Seliciclib and Flavopiridol) and a heat shock protein inhibitor (Tanespimycin).

Immunotoxins (toxins bound to antibodies or growth factors) and antisense strategies (where drugs are designed to bind to the mRNA of a target protein, inhibiting the production of that protein) are further areas of research for effective cancer treatments (ATL 2012; Kundu 2012).

It has also been observed that specific genetic mutations, some of which are inherited and some occur during the lifetime, are associated with the subsequent development of specific cancers. Mutations can produce oncogenes which result in rapid cell division or, alternatively 'switch-off' tumour suppressor genes, which would normally repair DNA mistakes and slow down cell division (Deng 2011). Gene therapies are designed to 'correct' the mutations, and have been used in early trials but are far from being optimised for clinical use (Xi 2003).

Some non-specific immunotherapy treatments such as interferon and colony stimulating factors are already used in conjunction with other modalities such as radiation and chemotherapy to combat cancer.

Why it is important to do this review

This review is the fourth in a series of Cochrane reviews looking at different treatment modalities for oral cavity and oropharyngeal cancers: surgical treatment (Bessell 2011), chemotherapy (Furness 2011) and radiotherapy (Glenny 2010). There is a great deal of current research into new therapies for cancer and many of these make the headlines in the news. However, there is a significant time lag between laboratory discoveries and the introduction of new treatments into clinical care. This review will evaluate the randomised controlled trials of targeted and immunological therapies for patients with oral cavity or oropharyngeal cancer.

Objectives

Primary objectives

  • To determine whether molecularly targeted therapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity or oropharyngeal cancers result in increased overall survival, disease free survival, progression free survival, locoregional control and reduced recurrence.

  • To determine whether immunotherapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity or oropharyngeal cancers result in increased overall survival, disease free survival, progression free survival, locoregional control and reduced recurrence.

Secondary objectives

  • To determine whether molecularly targeted therapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity oropharyngeal cancers are associated with increased quality of life, harm, costs and patient satisfaction.

  • To determine whether immunotherapies, in addition to surgery and/or chemotherapy and/or radiotherapy for oral cavity or oropharyngeal cancers are associated with increased quality of life, harm, costs and patient satisfaction.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials comparing standard therapy (chemotherapy and/or radiotherapy and/or surgery) plus either targeted therapy or immunotherapy with either standard therapy alone, or a different type of targeted therapy or immunotherapy will be included in the review provided there is a minimum follow-up of at least 6 months.

It is anticipated that there will be no studies comparing targeted therapy or immunotherapy alone with placebo, or standard therapy plus targeted therapy with standard therapy plus immunotherapy (although if there are such studies they will be included, provided there is at least 6 months of follow-up).

Types of participants

Patients with cancer of either the oral cavity or the oropharynx as defined by the International Classification of Diseases for Oncology (ICD-O) codes as C01-C02, C03, C04, C05-C06 (oral cavity cancers) or cancer of the oropharynx (ICD-O: C09, C10) will be included. Trials where participants have cancers of hypopharynx (ICD-O: C13), nasopharynx (ICD-O: C11), larynx (ICD-O: C32) and lip (ICD-O: C00), or metastatic disease will be excluded (WHO 1992) (Additional Table 1).

Table 1. Summary of inclusion and exclusion criteria
Inclusion criteriaExclusion criteria
Patients with primary cancer of the oral cavity (ICD-O: C01-06) or oropharynx (ICD-O: C09-10 - includes tonsil).
Patients with primary cancer of the head & neck where > 50% of cases had oral/oropharynx cancer. If separate oral/oropharynx data are available they will be used to the exclusion of the combined head & neck cancer data.
Lip (ICD-O: C00) cancers.
Squamous cell carcinoma (SCC).Parotid gland (ICD-O: C07), unspecified major salivary gland (ICD-O: C08)
and thyroid gland (ICD-O: C73.9) cancers.
Nasopharynx (ICD-O: C11), hypopharynx (ICD-O: C13), larynx (ICD-O: C32), pyriform sinus (ICD-O: C12.9), accessory sinuses (ICD-O: C31), nasal cavity and middle ear (ICD-O: C30) cancers.
In combined head & neck trials, these cancers will be included if they comprise < 50% of the total cancer diagnoses of participants.
Histological variants of SCC.Recurrent cancer i.e. not treatment of the primary cancer. Sarcomas, lymphomas and odontogenic tumours.

Trials where participants are described as having head and neck cancer will be included providing either data are available separately for those participants who have cancer of the oral cavity or oropharynx, or at least 50% of participants in the trial have oral cavity or oropharyngeal cancers. Primary squamous cell carcinomas, histological variants of squamous cell carcinomas (adenosquamous, verrucous, basaloid, papillary etc) and carcinoma in situ will be included. Epithelial malignancies of the salivary glands, odontogenic tumours, all sarcomas and lymphomas will be excluded as these have a different aetiology and are managed differently.

Types of interventions

Targeted therapy or immunotherapy of the primary tumour must be one of the primary interventions. Any mode of administration of targeted therapy or immunotherapy will be considered.
The treatments received and compared must be the primary treatment for the tumour and patients should not have received any prior intervention other than diagnostic biopsy.

Types of outcome measures

Primary outcome measures
  • Overall survival/total mortality (disease related mortality will also be studied if possible).

  • Locoregional control.

  • Disease free survival.

  • Progression free survival or time to recurrence.

Secondary outcome measures
  • Quality of life.

  • Harms associated with treatment.

  • Direct and indirect costs to patients and health services.

  • Patient satisfaction.

Search methods for identification of studies

For the identification of studies included or considered for this review, detailed search strategies will be developed for each database searched. These will be based on the search strategy developed for MEDLINE but revised appropriately for each database to take account of differences in controlled vocabulary and syntax rules.

The search strategy will combine the subject search with the Cochrane Highly Sensitive Search Strategy for identifying reports of randomised controlled trials (2008 revision) (as published in box 6.4.c in the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0, updated March 2011) (Higgins 2011).

We will search the following electronic databases:

  • Cochrane Oral Health Group's Trials Register (to present)

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue)

  • MEDLINE (1946 to present) (Appendix 1)

  • EMBASE (1980 to present).

Articles of any language will be considered. The reference lists of relevant articles will be searched and authors contacted in order to identify unpublished or ongoing trials.

Data collection and analysis

Selection of studies

The titles and abstracts (when available) of all reports identified through the electronic searches will be scanned independently by two review authors for eligibility for the oral cancer reviews. For studies appearing to meet the inclusion criteria, or for which there are insufficient data in the title and abstract to make a clear decision, the full report will be obtained. The full reports obtained from all the electronic and other methods of searching will be assessed independently by two review authors to establish whether the studies met the inclusion criteria or not. Disagreements will be resolved by discussion. Where resolution is not possible, a third review author will be consulted.

Studies rejected at this or subsequent stages will be recorded in the Characteristics of excluded studies table, and reasons for exclusion recorded.

Data extraction and management

Head and neck cancer trials with only combined data (i.e. no outcome data available by primary tumour site) where greater than 50% of participants presented with oral cavity or oropharyngeal cancer will be included in this review. However, where separate 'pure' oral/oropharyngeal cancer data are available for a trial, these 'pure' data will be extracted and analysed and the combined head and neck data ignored. Where possible oral and oropharyngeal cancer data will be analysed separately.

Data will be extracted by at least two review authors independently and will be entered into a spreadsheet. Any disagreement will be discussed and a third review author consulted where necessary. When necessary authors will be contacted for clarification or missing information.

For each trial the following data will be recorded.

  • Year of publication, country of origin, number of centres, source of study funding, recruitment period.

  • Details of the participants including demographic characteristics and criteria for inclusion and exclusion, proportion with oral cavity and oropharyngeal cancer, numbers randomised to each treatment group.

  • Details of the type of intervention, timing, dose, mode of administration and duration.

  • Details of other concomitant treatments.

  • Details of the outcomes reported, including method of assessment, and time(s) assessed.

  • Sample size calculations.

Assessment of risk of bias in included studies

For the studies included in this review assessment of risk of bias will be conducted by at least two review authors using the Cochrane risk of bias assessment tool (Higgins 2011). We will assess six domains for each included study: sequence generation, allocation concealment, blinding (of patient, and outcome assessor), completeness of outcome data, risk of selective outcome reporting and risk of other potential sources of bias.

For this systematic review we will assess risk of bias according to the following.

  • Sequence generation: use of a random number table, use of a computerised system, central randomisation by statistical co-ordinating centre, randomisation by an independent service using minimisation technique, permuted block allocation or Zelan technique will be assessed as low risk of bias. If the paper merely states randomised or randomly allocated with no further information this domain will be assessed as being unclear.

  • Allocation concealment: centralised allocation including access by telephone call or fax, or pharmacy-controlled randomisation, sequentially numbered, sealed, opaque envelopes will be assessed as low risk of bias. If allocation concealment is not mentioned this will be assessed as unclear.

  • Blinding: in many studies it may not be possible to blind patients and their carers to the allocated intervention. Outcome assessor blinding is usually possible. If studies are described as double blind we will assume that patients and outcome assessors are blinded. If blinding is not mentioned we will assume that no blinding occurred and assess the study at high risk of bias for subjective outcomes. For the outcome of total mortality it is unlikely that absence of blinding will introduce a bias.

  • Outcome data: outcome data will be considered complete if all patients randomised are included in the analysis of the outcome(s). However, in trials of treatment for cancer this is rarely the case. Trials where less than 10% of those randomised are excluded from the analysis, where reasons for exclusions are described for each group, and where both numbers and reasons were similar in each group, will be assessed as being at low risk of bias due to incomplete outcome assessment. Where post-randomisation exclusions are greater than 10%, or reasons are not given for exclusions from each group, or where rates and reasons are different for each group, the risk of bias due to (in)complete outcome data will be assessed as unclear or high.

  • Selective outcome reporting: a trial will be assessed as being at low risk of bias due to selective outcome reporting, if the outcomes described in the methods section are systematically reported in the results section. Where reported outcomes do not include those outcomes specified or expected in trials of treatments for oral cancer, or where additional analyses are reported this domain will be assessed as unclear.

  • Other bias: imbalance in potentially important prognostic factors between the treatment groups at baseline, or the use of a co-intervention in only one group (for example nasogastric feeding) are examples of potential sources of bias noted.

After taking into account the additional information provided by the authors of the trials, studies will be grouped into the following categories.

  1. Low risk of bias in all domains (plausible bias unlikely to seriously alter the results).

  2. Unclear risk of bias if one or more of the domains are assessed as unclear.

  3. High risk of bias (plausible bias that weakens confidence in the results) if one or more domains are assessed at high risk of bias.

A summary risk of bias figure will be presented.

Measures of treatment effect

The primary outcome is total mortality expressed as a hazard ratio (it is acknowledged that it is preferable to talk in terms of overall survival, however, statistically the estimate of effect is the hazard ratio of death). If hazard ratios are not quoted in studies, we will calculate the log hazard ratio and the standard error (SE) from the available summary statistics or Kaplan-Meier curves, according to the methods proposed by Parmar et al (Parmar 1998), or these data will be requested from authors.

For dichotomous outcomes, the estimates of effect of an intervention will be expressed as risk ratios together with 95% confidence intervals. Dichotomous data will only be used for primary outcomes where hazard ratios are unavailable or cannot be calculated.

Dealing with missing data

Where data are not available from the trial report, we will contact authors of included trials in an attempt to obtain these data, or to clarify areas where data or trial design and conduct are unclear.

Assessment of heterogeneity

Meta-analyses will be conducted only if there are studies of similar comparisons reporting the same outcome measures. The significance of any discrepancies in the estimates of the treatment effects from the different trials will be assessed by means of Cochran's test for heterogeneity and the I2 statistic, and any heterogeneity investigated.

Assessment of reporting biases

Reporting biases arise when the reporting of research findings is influenced by the nature and direction of the findings of the research. We will attempt to minimise potential reporting biases including publication bias, multiple (duplicate) publication bias and language bias in this review, by conducting a sensitive search of multiple sources with no restriction on language. We will also search for ongoing trials and unpublished trials.

If there are more than ten studies in any one outcome we plan to construct a funnel plot and investigate any asymmetry detected.

Data synthesis

Risk ratios will be combined for dichotomous data, and hazard ratios for survival data, using a fixed-effect model, unless there are more than four trials to be combined, when a random-effects model will be used. Hazard ratio data will be entered into the meta-analysis using the inverse variance method.

Subgroup analysis and investigation of heterogeneity

Due to the different natural history and treatment regimens for oral cavity and oropharyngeal cancers we plan to analyse these cancer types separately, if there are sufficient data.

Sensitivity analysis

A sensitivity analysis to examine the effects of risk of bias is planned.

Presentation of main results

A summary of findings table will be developed for the primary outcomes of this review using GRADEPro software. The quality of the body of evidence will be assessed with reference to the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, the risk of publication bias, the magnitude of the effect and whether or not there is evidence of a dose response. The quality of the body of evidence for each of the primary outcomes will be categorised as high, moderate, low or very low.

Acknowledgements

Our thanks to Anne Littlewood, Trials Search Co-ordinator of the Cochrane Oral Health Group, who developed the search strategy in consultation with the authors of the protocol.

Appendices

Appendix 1. MEDLINE (OVID) search strategy

1.         "Head and Neck Neoplasms"/                       
2.         "Mouth Neoplasms"/                          
3.         "Gingival Neoplasms"/                                   
4.         "Palatal Neoplasms"/                         
5.         "Tongue Neoplasms"/                                    
6.         ((cancer$ or tumour$ or tumor$ or neoplas$ or malignan$ or carcinoma$ or metatasta$) adj5 (oral$ or intra-oral$ or intraoral$ or "intra oral$" or gingiva$ or oropharyn$ or mouth$ or tongue$ or cheek$ or gum$ or palatal$ or palate$ or "head and neck")).ti,ab.                                   
7.         or/1-6                          
8.         exp Gene therapy/                             
9.         exp Immunotherapy/                         
10.       Molecular targeted therapy/                           
11.       ((gene$ or target$ or DNA) adj6 therap$).ti,ab.                                 
12.       (immunotherap$ or "immuno therap").ti,ab.                          
13.       Antibodies, Monoclonal/                                 
14.       (cetuximab or Erbitux or C-225 or C225 or "immunoglobulin G1").ti,ab.                              
15.       (panitumumab or ABX-EGF$ or Amgen or Vectibix).ti,ab.                           
16.       (zalutumumab or 2F8 or HuMax-EGFr).ti,ab.                                   
17.       "anti-human epidermal growth factor receptor".ti,ab.                                    
18.       ("EGFR inhibitor$" or "epidermal growth factor inhibitor$").ti,ab.                              
19.       Quinazolines/                     
20.       ("tyrosine kinase inhibitor$" or "protein kinase inhibitor$").ti,ab.                                
21.       (erlotinib or CP358774 or CP-358774 or OSI-774 or Tarceva or Gefitnib or Iressa or ZD1839 or ZD-1839 or Gefitero or Gefonib or Geftib or Geftilon or Geftinat).ti,ab.  
22.       ("vascular endothelial growth factor$" adj2 inhibitor$).ti,ab.                          
23.       Vascular Endothelial Growth Factors/ai [Antagonists & Inhibitors]                           
24.       (Bevacizumab or Avastin or Genetech or Altuzan or R435 or R-435 or rhuMAb-VEGF or Vandetanib or Zactima or ZD6474 or ZD-6474 or Caprelsa).ti,ab.              
25.       Protein kinase inhibitors/                                
26.       ("molecular multiple kinase inhibitor$" or Sorafenib or BAY439006 or BAY-439006 or BAY5459085 or BAY545-9085 or Nexavar or Sunitinib or SU11248 or SU-11248 or Sutent or Lapatinib or GW572016 or GW282944X or Tykerb or Tyverb).ti,ab.       
27.       (trastuzumab or herceptin or lonafarnib or serasar or perifosine or afatinib).ti,ab.   
28.       Cyclooxygenase 2 Inhibitors/                                    
29.       (("COX 2" or COX-2 or "cyclooxygenase 2") adj2 inhibitor$).ti,ab.                          
30.       (celecoxib or SC58635 or SC-58635 or celebrex or selekoksib or YM-177 or Algybrex or celemax or cloxib or coxel or coxtenk or niflem or radicacine or tisorek or orsenal or solexa or celebra or aclarex or celact or celcib or celcox or celecap or celedol or celetop or celib or cobix or colcibra or coxib or eloxib or icel or orthocel or ultracele or artilog or zycel or aubrex or celcoxx or flogoxib or ranselex or reumoxib or cexb).ti,ab.
31.       Cyclin dependent kinase inhibitor proteins/                           
32.       ((CDK or "cyclin dependent kinase") adj2 inhibitor$).ti,ab.                           
33.       (Seliciclib or Roscovitine or CYC202 or CYC-202 or Flavopiridol or HMR1275 or HMR-1275 or L868275 or L868-275 or Avodenib).ti,ab.                         
34.       "Poly(ADP-ribose) Polymerases"/ai                          
35.       ("poly ADP-ribose polymerase" adj2 inhibitor$).ti,ab.                                    
36.       (PARP adj2 inhibitor$).ti,ab.                          
37.       (Iniparib or 4-ido-3-nitrobenzamide or BSI201 or BSI-201 or Olaparib or AZD2281 or AZD-2281).ti,ab.                            
38.       ((mTOR or "mammalian target of rapamycin") adj inhibitor$).ti,ab.                         
39.       (Everolimus or RAD001 or RAD-001 or Certican or SDZRAZ or "immunosuppressive agent$" or afinitor or votubia or sertican or zortress or temsirolimus or CCI779 or CCI-779 or Torisel).ti,ab.                               
40.       "proteasome inhibitor$".ti,ab.                         
41.       (bortezomib or PS341 or PS-341 or velcade or LDP341 or LDP-341 or bortenat or mibor).ti,ab.                           
42.       Histone Deacetylase Inhibitors/                                 
43.       ("histone acetylation inhibitor$" or "histone deacetylase inhibitor$").ti,ab.                 
44.       (Vorinostat or 18F-SAHA or M344 or M-344 or "suberanilohydroxamic acid" or "suberoylanilide hydroxamic acid" or zolinza or romidepsin or astella or FK228 or FK-228 or FR901228 or FR-901228 or isodax or depsipeptide).ti,ab.                             
45.       ("heat shock protein inhibitor$" or tanespimycin or IP1493 or IP-1493 or IPI504 or IPI-504 or retaspimycin or NSC330507 or NSC-330507).ti,ab.                           
46.       Immunotoxins/                                   
47.       (immunotoxin$ or affinotoxin$ or "antibody toxin conjugate$" or "antibody toxin hybrid$" or "chimeric toxin$" or "cytotoxin antibody conjugate$" or "monoclonal antibody toxin conjugate$" or "targeted toxin$" or "toxin carrier" or "toxin conjugate$" or "toxin antibody conjugate$" or "toxin antibody hybrid$").ti,ab.                               
48.       ((antisense adj strateg$) or (anti-sense adj strateg$) or ("anti sense" adj strateg$)).ti,ab.                            
49.       ("ONYX 015" or "HF 10").ti,ab.                                  
50.       Oncolytic virotherapy/                                   
51.       ((oncolytic adj5 adenovirus$) or "oncolytic virus$").ti,ab.                             
52.       Cancer vaccines/                               
53.       BCG vaccine/                                    
54.       (vaccine$ adj2 (cancer or neoplasm or tumour or tumor)).ti,ab.                              
55.       (vaccine$ adj2 (BCG or "Bacillus Calmette Guerin" or Calmette$)).ti,ab.                
56.       or/8-55                                    
57.       7 and 56

The above subject search will be linked with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials (RCTs) in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter 6.4.11.1 and detailed in box 6.4.c of the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 (updated March 2011) (Higgins 2011).

1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1-8
10. exp animals/ not humans.sh.
11. 9 not 10

Contributions of authors

The background was developed by Kelvin Chan (KC) and Susan Furness (SF).

The methods section was developed by KC, SF, Anne-Marie Glenny (AMG) and Helen Worthington (HW).

Declarations of interest

None known.

Sources of support

Internal sources

  • School of Dentistry, The University of Manchester, UK.

  • Cochrane Oral Health Group, UK.

  • The University of Dundee, UK.

  • The University of Glasgow, UK.

  • MAHSC, UK.

    The Cochrane Oral Health Group is supported by the Manchester Academic Health Sciences Centre (MAHSC) and the NIHR Manchester Biomedical Research Centre.

External sources

  • National Institutes of Health, National Institute of Dental and Craniofacial Research, USA.

  • Central Manchester & Manchester Children's University Hospitals NHS Trust, UK.

  • Cochrane Oral Health Group Global Alliance, UK.

    All reviews in the Cochrane Oral Health Group are supported by Global Alliance member organisations (British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; National Center for Dental Hygiene Research & Practice, USA and New York University College of Dentistry, USA) providing funding for the editorial process (http://ohg.cochrane.org).

  • National Institute for Health Research (NIHR), UK.

    All reviews in the Cochrane Oral Health Group are supported by NIHR Systematic Reviews Programme infrastructure funding.

Ancillary