Worldwide oral cancer is the 6^th commonest cancer and 5-year survival rates following diagnosis remain around 50% globally (63% in the USA) but have only shown limited improvements since the 1970s. There has been a marked increase in research into molecularly targeted therapies and these may have benefits for treating oral cancers although their value is unclear.

The aim of this Cochrane review was 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

Searches were conducted in the Cochrane Oral Health Group’s Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) Medline, Embase, US National Institutes of Health Trials Register, World Health Organization (WHO) Clinical Trials Registry Platform, American Society of Clinical Oncology conference abstracts and Radiation Therapy Oncology Group (RTOG) clinical trials protocols databases. Randomised controlled trials (RCTs) 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 were considered.

Two reviewers independently screened the studies, extracted data and assessed risk of bias using the Cochrane risk of bias tool. The primary outcome was total mortality expressed as a hazard ratio (HR)

Results

• 12 trails involving a total of 2488 patients were included.
• 12% (298 patients) had oral cavity tumours, 59% (1468 patients) oropharyngeal tumours, 29% tumours of the larynx or hypopharynx.
• 5 trials were considered to be at high risk of bias and 7 at unclear risk.
• 3 main comparisons against standard therapy alone were made:-
  • 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).
  • standard therapy plus immunotherapy (follow-up period 24 to 70 months).
• 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)
• 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

The authors concluded:

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.

Comments

This is the 4^th in a series of Cochrane reviews looking at different treatments for oral cancer, surgery (Bessell et al, 2011), radiotherapy (Glenny et al, 2010) and chemotherapy (Furness et al ,2011). It has been conducted following the usual Cochrane protocols. Ten out of the 12 included trials were multicenter studies with 4 studies involving more than one country. While all of the studies reported overall survival HR for mortality could only be calculated for 6 studies and only 2 reported on disease free survival and only one study comprehensively assessed quality of life.

Surgery and radiotherapy or a combination and the usual treatment for early stage oral cancer with chemoradiotherapy and sequential therapies rather than surgery for advanced cases. This review suggests that monoclonal antibodies (mAb) against the epidermal growth factor receptor (EGFR) in combination with standard treatment may improve outcomes. However, as the authors note the evidence for these therapies is still sparse and none of the included studies many of which were conducted by pharmaceutical companies, was at low risk of bias so further high quality studies are needed.

Links

Primary paper

Chan KKW, Glenny AM, Weldon JC, Furness S, Worthington HV, Wakeford H. Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy. Cochrane Database of Systematic Reviews 2015, Issue 12. Art. No.: CD010341. DOI: 10.1002/14651858.CD010341.pub2.

Other references

Cochrane Oral Health Group Blog – EGFR mAb shows promising results for the treatment of oral cancer

Glenny AM, Furness S, Worthington HV, Conway DI, Oliver R, Clarkson JE, Macluskey M, Pavitt S, Chan KKW, Brocklehurst P, The CSROC Expert Panel. Interventions for the treatment of oral cavity and oropharyngeal cancer: radiotherapy. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD006387. DOI: 10.1002/14651858.CD006387.pub2.

Bessell A, Glenny AM, Furness S, Clarkson JE, Oliver R, Conway DI, Macluskey M, Pavitt S, Sloan P, Worthington HV. Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD006205. DOI: 10.1002/14651858.CD006205.pub3.

Furness S, Glenny AM, Worthington HV, Pavitt S, Oliver R, Clarkson JE, Macluskey M, Chan KKW, Conway DI. Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy. Cochrane Database of Systematic Reviews 2011, Issue 4. Art. No.: CD006386. DOI: 10.1002/14651858.CD006386.pub3.