title: Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy.
abstract: BACKGROUND
  Oral cancers are the sixth most common cancer worldwide, yet the prognosis following a diagnosis of oral cavity or oropharyngeal cancers remains poor, with approximately 50% survival at five years. Despite a sharp increase in research into molecularly targeted therapies and a rapid expansion in the number of clinical trials assessing new targeted therapies, their value for treating oral cancers is unclear. Therefore, it is important to summarise the evidence to determine the efficacy and toxicity of targeted therapies and immunotherapies for the treatment of these cancers.
  
  
  OBJECTIVE
  To assess the effects of molecularly targeted therapies and immunotherapies, in addition to standard therapies, for the treatment of oral cavity or oropharyngeal cancers.
  
  
  METHODS
  We searched the following electronic databases: Cochrane Oral Health Group Trials Register (to 3 February 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2015, Issue 1), MEDLINE via Ovid (1946 to 3 February 2015) and EMBASE via Ovid (1980 to 3 February 2015). We searched the US National Institutes of Health Trials Register (clinicaltrials.gov), the World Health Organization Clinical Trials Registry Platform, the American Society of Clinical Oncology conference abstracts and the Radiation Therapy Oncology Group clinical trials protocols for ongoing trials. We placed no restrictions on the language or date of publication.
  
  
  METHODS
  We included randomised controlled trials where more than 50% of participants had primary tumours of the oral cavity or oropharynx, and which compared targeted therapy or immunotherapy, plus standard therapy, with standard therapy alone.
  
  
  METHODS
  Two review authors independently screened the results of the electronic searches, extracted data and assessed the risk of bias of the included studies. We attempted to contact study authors for missing data or clarification where necessary. We combined sufficiently similar studies in meta-analyses using random-effects models when there were at least four studies and fixed-effect models when fewer than four studies. We obtained or calculated a hazard ratio (HR) and 95% confidence interval (CI) for the primary outcomes where possible. For dichotomous outcomes, we reported risk ratios (RR) and 95% CIs.
  
  
  RESULTS
  Twelve trials (2488 participants) satisfied the inclusion criteria. In the included trials, 12% of participants (298 participants) had tumours of the oral cavity and 59% (1468 participants) had oropharyngeal tumours. The remaining 29% had tumours of the larynx or hypopharynx and less than 1% had tumours at other sites.No included trial was at low risk of bias; seven had an unclear risk of bias, and five had a high risk of bias. We grouped trials by intervention type into three main comparisons: standard therapy plus epidermal growth factor receptor monoclonal antibody (EGFR mAb) therapy (follow-up period 24 to 70 months); standard therapy plus tyrosine kinase inhibitors (TKIs) (follow-up period 40 to 60 months) and standard therapy plus immunotherapy (follow-up period 24 to 70 months), all versus standard therapy alone.Moderate quality evidence showed that EGFR mAb therapy may result in 18% fewer deaths when added to standard therapy (HR of mortality 0.82; 95% CI 0.69 to 0.97; 1421 participants, three studies, 67% oropharyngeal tumours, 2% oral cavity tumours).There was also moderate quality evidence that EGFR mAb may result in 32% fewer locoregional failures when added to radiotherapy (RT) (HR 0.68; 95% CI 0.52 to 0.89; 424 participants, one study, 60% oropharyngeal tumours).A subgroup analysis separating studies by type of standard therapy (radiotherapy (RT) or chemoradiotherapy (CRT)) showed some evidence that adding EGFR mAb therapy to RT may result in a 30% reduction in the number of people whose disease progresses (HR 0.70; 95% CI 0.54 to 0.91; 424 participants, one study, 60% oropharyngeal tumours, unclear risk of bias). For the subgroup comparing EGFR mAb plus CRT with CRT alone there was insufficient evidence to determine whether adding EGFR mAb therapy to CRT impacts on progression-free survival (HR 1.08; 95% CI 0.89 to 1.32; 891 participants, one study, 70% oropharyngeal tumours, high risk of bias). The high subgroup heterogeneity meant that we were unable to pool these subgroups.There was evidence that adding cetuximab to standard therapy may result in increased skin toxicity and rash (RR 6.56; 95% CI 5.35 to 8.03; 1311 participants, two studies), but insufficient evidence to determine any difference in skin toxicity and rash in the case of nimotuzumab (RR 1.06; 95% CI 0.85 to 1.31; 92 participants, one study).There was insufficient evidence to determine whether TKIs added to standard therapy impacts on overall survival (HR 0.99; 95% CI 0.62 to 1.57; 271 participants, two studies; very low quality evidence), locoregional control (HR 0.89; 95% CI 0.53 to 1.49; 271 participants, two studies; very low quality evidence), disease-free survival (HR 1.51; 95% CI 0.61 to 3.71; 60 participants, one study; very low quality evidence) or progression-free survival (HR 0.80; 95% CI 0.51 to 1.28; 271 participants, two studies; very low quality evidence). We did find evidence of an increase in skin rash (erlotinib: RR 6.57; 95% CI 3.60 to 12.00; 191 participants, one study; lapatinib: RR 2.02; 95% CI 1.23 to 3.32; 67 participants, one study) and gastrointestinal complaints (lapatinib: RR 15.53; 95% CI 2.18 to 110.55; 67 participants, one study).We found very low quality evidence from one small trial that adding recombinant interleukin (rIL-2) to surgery may increase overall survival (HR 0.52; 95% CI 0.31 to 0.87; 201 participants, 62% oral cavity tumours, 38% oropharyngeal tumours) and there was insufficient evidence to determine whether rIL-2 impacts on adverse effects.
  
  
  CONCLUSIONS
  We found some evidence that adding EGFR mAb to standard therapy may increase overall survival, progression-free survival and locoregional control, while resulting in an increase in skin toxicity for some mAb (cetuximab).There is insufficient evidence to determine whether adding TKIs to standard therapies changes any of our primary outcomes.Very low quality evidence from a single study suggests that rIL-2 combined with surgery may increase overall survival compared with surgery alone.
authors.affiliation: Sunnybrook Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada, M4N3M5.
authors.forename: Kelvin K W
authors.initials: KK
authors.lastname: Chan
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Glenny
authors.forename: Jo C
authors.initials: JC
authors.lastname: Weldon
authors.forename: Susan
authors.initials: S
authors.lastname: Furness
authors.forename: Helen V
authors.initials: HV
authors.lastname: Worthington
authors.forename: Helen
authors.initials: H
authors.lastname: Wakeford
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000628:therapy*; D000068818:Cetuximab / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D000077143:Docetaxel; D066246:ErbB Receptors; D000077156:Gefitinib; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D000077341:Lapatinib; D058990:Molecular Targeted Therapy / Q000009:adverse effects / Q000379:methods*; D009062:Mouth Neoplasms / Q000401:mortality / Q000628:therapy*; D009959:Oropharyngeal Neoplasms / Q000401:mortality / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D043823:Taxoids / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D043823:Taxoids; D000077341:Lapatinib; D000077143:Docetaxel; C501466:nimotuzumab; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000068818:Cetuximab; D002945:Cisplatin; D000077156:Gefitinib