Worldwide oral cancers are the 16th most common cancer representing 2% of all cancers. Their incidence and mortality vary geographically with the highest rates being seen in south central Asia. Tobacco use, alcohol consumption and betel quid chewing are the main risk factors with a higher incidence in men being attributed to greater exposure to these risk factors. Squamous cell carcinoma is the most common cancer of the oral cavity accounting for about 95% of cancers with primary treatment involving surgery or radiotherapy. Oropharyngeal cancers have a different aetiology and are strongly associated with human papilloma virus (HPV) and primary treatment is generally with radiation therapy or chemoradiation. Surgical approaches for oral cancer can be disfiguring and both surgery and radiotherapy have significant functional side effects. New chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for oral cancer patients.
The main aim of this Cochrane review update was to determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal cancer, results in improved overall survival when incorporated as induction therapy given prior to locoregional treatment (i.e. surgery and/or radiotherapy), concurrent with radiotherapy or in the adjuvant (i.e. after locoregional treatment) setting.
Methods
Searches were conducted in the Cochrane Oral Health’s Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, the US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform with no restrictions on the language or date of publication. Randomised controlled trials (RCTs) where more than 50% of patients had primary tumours of the oral cavity or oropharynx that compared chemotherapy treatment, with locoregional treatment (radiotherapy or surgery) +/- concurrent chemotherapy, or an alternative chemotherapy regimen, or chemotherapy given at different times relative to locoregional treatment (either induction, concurrent or adjuvant chemotherapy), with a minimum follow-up of six months were considered. The primary outcome was overall survival (time to death from any cause). Secondary outcomes were disease-free survival (time to disease recurrence or death from any cause) and locoregional control (response to primary treatment).
Results
- 100 studies involving 18,813 patients were included.
- None of the included studies was at low risk of bias.
Induction chemotherapy (contemporary regimens)
- There is insufficient evidence to clearly demonstrate a survival benefit from induction chemotherapy with platinum plus 5-fluorouracil prior to: –
- radiotherapy (hazard ratio (HR) for death 0.85, (95%CI: 0.70 to 1.04), [7427 patients, 5 studies; moderate-certainty evidence]
- surgery (HR for death 1.06 (95%CI: 0.71 to 1.60), [198 patients, 1 study; low-certainty evidence].
- concurrent chemoradiation (CRT) with cisplatin (HR for death 0.71 (95%CI: 0.37 to 1.35), [389 patients, 2 studies; low-certainty evidence].
- There is insufficient evidence to support the use of an induction chemotherapy regimen with cisplatin plus 5-fluorouracil plus docetaxel prior to CRT with cisplatin (HR for death 1.08 (95%CI:0.80 to 1.44), [760 patients, 3 studies; low-certainty evidence].
Adjuvant chemotherapy (AC)
- There is insufficient evidence to support the use of AC over observation only following surgery (HR for death 0.95 (95%CI: 0.73 to 1.22), [353 patients, 5 studies; moderate-certainty evidence].
- In studies that compared post-surgical adjuvant CRT, as compared to post-surgical RT, adjuvant CRT showed a survival benefit (HR 0.84 (95%CI: 0.72 to 0.98), [ 1097 patients, 4 studies; moderate-certainty evidence].
- Primary treatment with CRT, as compared to radiotherapy alone, was associated with a reduction in the risk of death (HR for death 0.74, (95%CI: 0.67 to 0.83), [2852 patients, 24 studies; moderate-certainty evidence].
Conclusions
The authors concluded: –
The results of this review demonstrate that chemotherapy in the curative-intent treatment of oral cavity and oropharyngeal cancers only seems to be of benefit when used in specific circumstances together with locoregional treatment. The evidence does not show a clear survival benefit from the use of induction chemotherapy prior to radiotherapy, surgery or CRT. Adjuvant CRT reduces the risk of death by 16%, as compared to radiotherapy alone. Concurrent chemoradiation as compared to radiation alone is associated with a greater than 20% improvement in overall survival; however, additional research is required to inform how the specific chemotherapy regimen may influence this benefit.
Comments
This Cochrane review updates a 2011 review of this topic and is one of a series of Cochrane reviews on the treatment of oral cavity and oropharyngeal cancers covering chemotherapy, surgery, radiotherapy, and targeted therapy and immunotherapy (Dental Elf – 14th Jan 2019, Dental Elf – 5th Dec 2015). Of the 100 studies included 36 evaluated chemotherapy before surgery or radiotherapy and 11 evaluated chemotherapy after surgery or radiotherapy. Chemotherapy with radiotherapy was evaluated in 30 studies with 23 studies assessing different chemotherapy drugs given before, during or after surgery or radiotherapy. The reviews note that none of the included studies were at low risk of bias with blinding of patients, carers and outcome assessors being uncommon. While it is recognised that blinding is difficult the authors encourage the use of blinded outcome assessment in future studies. No clear evidence that chemotherapy given before surgery or radiotherapy or after surgery was found. However, treatment with radiotherapy and chemotherapy together after surgery compared to radiotherapy alone may increase survival. But there was not enough evidence to judge which chemotherapy drug is best to use. Consequently there is a need for further high quality research into the use of chemotherapy with surgery or radiotherapy.
Links
Primary Paper
Parmar A, Macluskey M, Mc Goldrick N, Conway DI, Glenny A-M, Clarkson JE, Worthington HV, Chan KKW. Interventions for the treatment of oral cavity and oropharyngeal cancer: chemotherapy. Cochrane Database of Systematic Reviews 2021, Issue 12. Art. No.: CD006386.
DOI: 10.1002/14651858.CD006386.pub4. PMID: 34929047
Other references
Cochrane Oral Health Blog – Chemotherapy for mouth and throat cancer
Dental Elf – 14th Jan 2019
Mouth and throat cancer: evidence for best surgical approaches uncertain
Dental Elf – 5th Dec 2015
Oral cancer- monoclonal antibodies combined with standard treatment may improve outcomes
Picture Credits
“Royal Liverpool Hospital Chemotherapy Unit” by robbelaw is licensed under CC BY-SA 2.0
