What is the problem?
Oral cavity (mouth) and oropharynx (throat) cancers that are detected early are treated primarily with surgery or radiotherapy. These treatments are effective in curing the cancer and improving survival. However, with surgery and radiotherapy alone there remains a chance that the cancer will recur, which can shorten survival for patients. The addition of chemotherapy to surgery or radiotherapy may help improve survival.
Why is this topic important?
Chemotherapy treatments are drugs that work by killing rapidly dividing cells such as cancer cells. There are other rapidly dividing cells in our body, such as those on our skin or in our gut. Chemotherapy can affect these healthy cells as well, which is why these treatments can have unpleasant side effects.
In the treatment of cancer, chemotherapy can be given before surgery or radiotherapy, during radiotherapy or after treatment with surgery or radiotherapy. There are also different types of chemotherapy that can be given either as pills or through the veins (intravenously). These differences in the ways of giving chemotherapy and types of chemotherapy are likely to have different effects on survival. At this time, we do not know which way is best.
This review updates one previously published in 2011.
What did we want to find out?
We wanted to know if chemotherapy given with either surgery or radiotherapy improved survival. We also wanted to know if chemotherapy given with surgery or radiotherapy improved the likelihood of shrinking the cancer and if these treatments reduced the risk of the cancer coming back (recurrence).
What did we do?
We searched several electronic databases for studies that evaluated the addition of chemotherapy before, during or after either radiotherapy or surgery in adult (age > 18 years) patients with cancers of the oral cavity or oropharynx.
We categorised studies into four groups and combined results within each category. We assessed the reliability of the evidence we found.
What studies did we find?
We found 100 studies that assessed the use of chemotherapy with surgery or radiotherapy. In total, over 18,000 patients from all over the world were included. Thirty-six studies evaluated the use of chemotherapy before surgery or radiotherapy; 11 studies evaluated the use of chemotherapy after surgery or radiotherapy; 30 studies evaluated the use of chemotherapy together with radiotherapy; and 23 studies assessed different chemotherapy drugs given before, during or after surgery or radiotherapy.
What were the main results?
We found no clear evidence that chemotherapy given before surgery or radiotherapy improved survival. Similarly, chemotherapy given after surgery did not seem to lead to an improvement in survival.
We found treatment with radiotherapy and chemotherapy together after surgery, as compared to radiotherapy alone following surgery, may increase the likelihood of survival. Also, in patients who are not eligible for surgery, it may improve survival if chemotherapy is added to radiotherapy, as compared to radiotherapy treatment alone. There was not enough evidence to judge which chemotherapy drug is best to use.
How reliable are the results?
There were differences among the included studies in the type and number of participants they included, as well as the type of chemotherapy drug administered. These differences may impact the results. As such, we cannot be certain about these results and future research could change our conclusions.
What does this mean?
These results support the addition of chemotherapy together with radiotherapy in patients who have undergone surgery for cancers of the oral cavity or oropharynx. In patients who are not eligible for surgery, our results support the use of chemotherapy with radiotherapy as compared to radiotherapy alone.
We conclude that there is insufficient evidence to support the use of chemotherapy outside of these situations. We believe this highlights the need for further study into the use of chemotherapy together with surgery or radiotherapy.
How up-to-date is this review?
This review has been updated to September 2021.
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.
Oral cavity and oropharyngeal cancers are the most common cancers arising in the head and neck. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects. The development of 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 this group of patients. This review updates one last published in 2011.
To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal squamous cell carcinoma results in improved overall survival, improved disease-free survival and/or improved locoregional control, when incorporated as either induction therapy given prior to locoregional treatment (i.e. radiotherapy or surgery), concurrent with radiotherapy or in the adjuvant (i.e. after locoregional treatment with radiotherapy or surgery) setting.
An information specialist searched 4 bibliographic databases up to 15 September 2021 and used additional search methods to identify published, unpublished and ongoing studies.
We included randomised controlled trials (RCTs) where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and that evaluated the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration.
For this update, we assessed the new included trials for their risk of bias and at least two authors extracted data from them. Our 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).
We contacted trial authors for additional information or clarification when necessary.
We included 100 studies with 18,813 participants. None of the included trials were at low risk of bias.
For induction chemotherapy, we reported the results for contemporary regimens that will be of interest to clinicians and people being treated for oral cavity and oropharyngeal cancers. Overall, 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% confidence interval (CI) 0.70 to 1.04, P = 0.11; 7427 participants, 5 studies; moderate-certainty evidence), prior to surgery (HR for death 1.06, 95% CI 0.71 to 1.60, P = 0.77; 198 participants, 1 study; low-certainty evidence) or prior to concurrent chemoradiation (CRT) with cisplatin (HR for death 0.71, 95% CI 0.37 to 1.35, P = 0.30; 389 participants, 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, P = 0.63; 760 participants, 3 studies; low-certainty evidence).
There is insufficient evidence to support the use of adjuvant chemotherapy over observation only following surgery (HR for death 0.95, 95% CI 0.73 to 1.22, P = 0.67; 353 participants, 5 studies; moderate-certainty evidence). Among 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, P = 0.03; 1097 participants, 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, P < 0.00001; 2852 participants, 24 studies; moderate-certainty evidence).