Dental extractions prior to radiotherapy to the jaws for reducing post‐radiotherapy dental complications
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objectives
We will address the following questions:
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Does pre‐radiotherapy extraction of carious molar teeth result in reduced risk of complications compared to conservative treatment of these teeth (restoration of these teeth and leaving them in situ)?
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Does pre‐radiotherapy extraction of healthy teeth result in reduced risk of complications compared to conservative treatment of these teeth (leaving them in situ)?
Secondary objectives
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What are the nature and rates of complications that occur with leaving teeth in situ during radiotherapy?
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Which teeth should be extracted?
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How long should the post‐extraction healing period be prior to commencement of radiotherapy to the head and neck?
Background
Oral cancer has an incidence of approximately 400,000 new cases each year globally (Mouth Cancer Foundation 2010) and is on the increase (15% from the mid 1960s until the latest National Cancer Institute's survey (2004) (NICDR 2004)). Although it has a mortality rate of just over 50% there is still a 5‐year survival of 60% (NICDR 2004). Rehabilitation and quality of life for those who have undergone successful oncology treatment is an important consideration. These patients want post‐treatment appearance and function to be as close as possible to that prior to the oncology treatment.
Radiotherapy causes damage to the deoxyribonucleic acid (DNA) of rapidly dividing cells so that the usual mechanisms of DNA repair fail and death of cells occur. Unfortunately as well as cancer cells, normal cells that proliferate rapidly will also be affected by therapeutic radiation (Cancer Research UK 2010). Radiotherapy may have both immediate and delayed adverse effects including mucositis, erythema, trismus, fibrosis and reduced quality and quantity of saliva.
Description of the condition
Radiotherapy as a part of head and neck oncology treatment potentially causes hypocellularity, hypovascularity and hypoxia in the tissues irradiated. Salivary gland damage can lead to a reduction in saliva and may affect the salivary buffering capacity and the remineralising capacity. There is less saliva available to wash away food debris from tooth surfaces and the saliva may be of poor quality, making it less able to neutralise acids. This coupled with the thin mucosa may result in mucositis and can be very painful for the patient. Patients may use frequent washes of sweet drinks to manage the discomfort in their mouths. In addition, the patient may be reluctant to brush or use fluoride mouthwashes or toothpaste as their oral mucosa is painful. All of the above means that the patient is more susceptible to caries and progression of periodontal disease. If these patients require extraction of teeth, there is the risk of developing osteoradionecrosis of the bone, which can be very difficult to control. Restoration of teeth may be very difficult if trismus is also present.
Description of the intervention
It is frequently recommended that patients with head and neck cancers undergo a dental examination and complete any required treatment prior to the start of radiotherapy. As part of this pre‐radiotherapy dental assessment it may be necessary or advisable to extract diseased teeth. There is debate as to whether potentially problematic teeth or those that may be impossible/difficult to treat if trismus should occur, should be extracted prior to radiotherapy?
The type of interventions to which the patients could be allocated are: pre‐radiotherapy extraction of all carious molars, pre‐radiotherapy extraction of all third molars, pre‐radiotherapy extraction of all second and third molars or pre‐radiotherapy extraction of all first, second and third molars that fall within the primary beam of radiation, in comparison with conservative treatment (prevention: improving oral hygiene, the use of fluoride and diet advice and repair/restoration of carious teeth) or post‐radiotherapy extraction of carious teeth. It would be useful to know whether extraction of posterior teeth falling within the primary beam would lead to fewer complications post‐radiotherapy compared with either leaving these teeth in situ or extraction of these teeth during radiotherapy.
How the intervention might work
The negative outcomes of radiotherapy to the head and neck include possible development of taste loss, mucositis, reduced salivary gland function, radiation caries, scarring leading to trismus, and osteoradionecrosis (possibly as a result of odontogenic infections or extractions) following radiotherapy (Andrews 2001; Dijkstra 2004; Kielbassa 2006; Oh 2004; Scott 2008; Toljanic 1984; Vissink 2003). All of these can have an impact on the patients' quality of life (Duke 2005; Epstein 2001; ,Morton 2003; Scott 2008). The potential negative effects of extractions prior to radiotherapy are related to healing following extraction as this may lead to a delay in commencing radiotherapy. One study suggests that an interval of 14 days still poses a minor risk of development of osteoradionecrosis and that the risk was reduced to zero if there was an interval of 21 days or more between extraction and radiation therapy (Vissink 2003).
Extraction of posterior teeth falling within the primary beam of radiation may make it easier for patients to maintain the remaining teeth and result in an overall reduction in carious or infected teeth needing post‐radiotherapy extraction. It may also mean easier and more comfortable dental treatment in future for these patients, especially if trismus occurs. There may also be a possible reduction in the number of cases of osteoradionecrosis post‐radiotherapy.
Why it is important to do this review
It is very difficult to predict patient reactions to radiotherapy, both in terms of overall benefits and also the rate of adverse effects. Some patients develop radiation caries and some do not. As treatments for head and neck cancer improve, resulting in prolonged survival, more patients are going to be living with post‐radiotherapy and (conformal radiation therapy) xerostomia, and possible trismus. Long term quality of life for this group is likely to become increasingly scrutinised and assessed.
There appears to be little agreement within the profession as to which one of these options is better than the others. This systematic review of randomised trials will summarise the available evidence relating to pre‐radiotherapy dental extractions.
Objectives
Primary objectives
We will address the following questions:
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Does pre‐radiotherapy extraction of carious molar teeth result in reduced risk of complications compared to conservative treatment of these teeth (restoration of these teeth and leaving them in situ)?
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Does pre‐radiotherapy extraction of healthy teeth result in reduced risk of complications compared to conservative treatment of these teeth (leaving them in situ)?
Secondary objectives
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What are the nature and rates of complications that occur with leaving teeth in situ during radiotherapy?
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Which teeth should be extracted?
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How long should the post‐extraction healing period be prior to commencement of radiotherapy to the head and neck?
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, excluding split‐mouth and cross‐over trials.
It is suggested that all randomised controlled comparisons of pre‐radiotherapy extractions with leaving the teeth in situ during radiotherapy should be included; however it is unlikely that oncology patients will be randomly allocated to leaving teeth in situ, extraction prior to radiotherapy, during radiotherapy, post‐radiotherapy. It is more likely that patients may be allocated to extraction compared with restoration of carious teeth/management of periodontal disease prior to radiotherapy and extraction of carious/periodontally involved teeth compared with preventative/conservative treatment followed by extraction of problematic teeth as and when there is a clinical indication to do so during or post‐radiotherapy. It is anticipated that there will be no studies comparing pre‐radiotherapy extractions with post‐radiotherapy extractions.
Types of participants
All those patients who have been diagnosed with head and neck cancer and are planned to undergo any type of radiotherapy (including external beam radiotherapy, intensity modulated radiation therapy, image guided radiation therapy, brachytherapy, conformal radiation therapy and any other type of radiotherapy to the head and neck):
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Any age, sex, socio‐economic status
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Any type of head and neck cancer, oral hygiene status, tobacco status (smoking and smokeless), alcohol status
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One or more courses of radiotherapy
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Any dose of radiation
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Radiation to any part of the jaws
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Unilateral or bilateral radiation
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With or without dental maintenance pre‐ and post‐radiotherapy.
Types of interventions
Studies which compare complications related to pre‐radiotherapy extractions with that of either leaving the teeth in situ during radiotherapy or post‐radiotherapy extractions will be included. Trials will also be included where the following are investigated:
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Extraction of teeth prior to radiotherapy
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Extraction of teeth during radiotherapy
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Extraction of teeth post‐radiotherapy
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Preventative/conservative treatment ‐ leaving teeth in situ pre‐radiotherapy, during radiotherapy and post‐radiotherapy with oral hygiene instructions, fluoride use and dietary advice, restoration of caries and management of periodontal disease.
Types of outcome measures
Dichotomous data on whether there is a delay in radiation treatment due to dental extractions, caries, fractured teeth, periapical infection, periodontal disease, trismus preventing further restorative dental treatment and osteoradionecrosis occurring or not following radiotherapy will be recorded. Continuous data on measuring the patients' overall survival and quality of life will be recorded.
Primary outcomes
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The development of post‐radiotherapy dental complications (e.g. caries, fractured teeth, periapical infection, periodontal disease, osteoradionecrosis).
Secondary outcomes
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Patients' quality of life
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Delay in start of radiation treatment
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Trismus preventing further restorative treatment
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Overall survival.
Search methods for identification of studies
To ensure all available studies are identified, a range of databases will be searched electronically. Handsearching of individual journals will be carried out as part of the Cochrane Collaboration's handsearching programme.
Electronic searches
The following electronic databases will be searched:
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The Cochrane Oral Health Group's Trials Register (to date)
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The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue)
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MEDLINE via OVID (1950 to present)
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EMBASE via OVID (1980 to present)
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CANCERLIT via PubMed (1950 to present)
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The Cumulative Index of Nursing and Allied Health Literature (CINAHL) via EBSCO (1980 to present).
The proposed search strategy for MEDLINE via OVID is included in Appendix 1. Similar search strategies will be developed for the other databases. The results of the searches will then be classified by hand in relevance to the inclusion criteria.
Articles in all languages will be considered and only excluded if it is not possible to translate them to the English language by members of The Cochrane Collaboration. All the first authors of trial reports will be contacted in an attempt to identify any unpublished studies and clarify information about the published trials (including missing data, method of randomisation, blinding and withdrawals).
Searching other resources
Any studies being carried out at the moment may be identified by contacting various head and neck oncology units around the world.
Data collection and analysis
Primarily the titles and then secondarily the abstracts of all the search results will be considered independently by three review authors. The full report will be obtained in cases where the studies appear to meet the inclusion criteria and in those with insufficient data in the title and abstract to make a clear decision. These full reports will then be studied independently by three review authors to establish whether the trials meet the inclusion criteria or not. Disagreements will be resolved by discussion and where resolution is not possible, a fourth review author will be consulted. The key inclusion and exclusion criteria are listed in Additional Table 1.
| Inclusion criteria | Exclusion criteria |
| Randomised controlled trials | Any trials which are not randomised controlled trials |
| Include patients who have suffered from head and neck cancer and have had either radiotherapy alone or radiotherapy in conjunction with surgery and/or chemotherapy | Patients who have not had radiotherapy |
| Sample should be randomly selected to have either extraction of teeth in the primary beam of radiation or leave these teeth in situ or compare with extraction post‐radiotherapy |
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| Diagnosis and tumour staging should be noted Radiation field and dose should be noted Oral health care pre‐radiotherapy, during radiotherapy and post‐radiotherapy should be noted Timing of extractions in relation to radiotherapy should be noted |
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| Site of extractions should be noted (molars, premolars, canines, incisors) |
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| Number of extractions should be noted and method of extraction should be described (antibiotic cover, surgical extraction, if post‐radiotherapy ‐ with or without hyperbaric oxygen) |
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| Patient demographics should be noted (age, gender, tobacco status, alcohol status/general and dental health) |
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| Follow‐up time should be clearly stated (with or without dental maintenance) |
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| Any interventions post‐radiotherapy should be noted |
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All studies meeting the inclusion criteria will then undergo a risk of bias assessment and data extraction using a specially designed data extraction form. Studies rejected at this or subsequent stages will be recorded in the 'excluded studies' table, with reasons for exclusion recorded.
Selection of studies
Randomised controlled comparisons will be included. These should compare extraction of teeth in the beam of primary radiation with leaving the teeth in situ or compare pre‐radiotherapy extractions with post‐radiotherapy extractions.
Data extraction and management
Once a decision is made on the studies to be included, data from these studies will be extracted independently by the authors. The following data will be entered on a customised data collection form:
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Trial design/location/number of centres
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Funding
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Recruitment period
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Year of publication
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Details of treatment and control intervention(s) and duration of treatment
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Numbers randomised to each group and numbers evaluated in each
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Trial inclusion criteria and patient characteristics (age/gender/socio‐economic group/tobacco status/alcohol status/general health/previous dental health)
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Site of primary tumour, tumour staging and radiation dose
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Number and anatomical site of teeth extracted (molars/premolars/incisors etc)
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Time period from each episode of extraction of teeth to first dose of radiotherapy
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Number of years of follow‐up
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Details of withdrawals by study group
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Primary and secondary outcomes and times these were measured
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Duration of follow‐up
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Sample size calculation.
Assessment of risk of bias in included studies
The risk of bias of eligible trials will be assessed according to the following criteria:
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Method of generation of random sequence
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Method of concealed allocation of treatment
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Blinding of participants/caregivers (where feasible)
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Blinding of outcome assessors
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Extent of drop outs/exclusions (trials using an intention‐to‐treat analysis will be noted)
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Selective reporting.
A description of the quality items will be tabulated for each included trial, along with a judgement of low, high or unclear risk of bias. Criteria for risk of bias judgements regarding allocation concealment are given below as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.0.2 (Higgins 2009). Low risk of bias being described as adequate concealment of the allocation (e.g. sequentially numbered, sealed, opaque envelopes or centralised or pharmacy‐controlled randomisation), unclear risk of bias being described as uncertainty about whether the allocation was adequately concealed (e.g. where the method of concealment is not described or not described in sufficient detail to allow a definite judgement) and high risk of bias being described as inadequate allocation concealment (e.g. open random number lists or quasi‐randomisation such as alternate days, date of birth, or case record number). A summary assessment of the risk of bias for the primary outcome (across domains) across studies will be undertaken (Higgins 2009).
Within a study, a summary assessment of low risk of bias will be given when there is a low risk of bias for all key domains, unclear risk of bias when there is an unclear risk of bias for one or more key domains, and high risk of bias when there is a high risk of bias for one or more key domains. Across studies, a summary assessment will be rated as low risk of bias when most information is from studies at low risk of bias, unclear risk of bias when most information is from studies at low or unclear risk of bias, and high risk of bias when the proportion of information is from studies at high risk of bias sufficient to affect the interpretation of the results.
Measures of treatment effect
The outcomes will be measured in terms of: risk ratios for dichotomous data such as rate of post‐radiotherapy complications related to dental extractions or infection rate and survival; outcomes for continuous data, such as quality of life scores will be presented in terms of mean differences and standard deviations.
Dealing with missing data
Where data from the trials are unclear, the authors will be contacted to clarify these details. If information supplied by the authors indicates that the trial does not meet the inclusion criteria for this review, the trial will be excluded. For drop outs of participants an intention‐to‐treat analysis will be carried out. Where there is missing statistics original data will be requested from the authors of the study and attempts will be made to carry out the missing statistical analysis on the raw data.
Assessment of heterogeneity
Clinical heterogeneity will be assessed by examining the participants, interventions and outcome measures included in the trials. Statistical heterogeneity will be assessed by inspection of a graphical display of the estimated treatment effects from the trials along with their 95% confidence intervals. 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 quantified by the I2 statistic.
Assessment of reporting biases
Where patient symptoms are recalled by the patient, reporting bias will be assessed.
A funnel plot will be drawn if sufficient trials are identified. Asymmetry of the funnel plot may indicate publication bias and other biases related to sample size, though it may also represent a true relationship between trial size and effect size. A formal investigation of the degree of asymmetry will undertaken using the method proposed by Egger 1997 if data allow.
Data synthesis
For dichotomous outcomes, the estimates of effect of an intervention will be expressed as risk ratios together with 95% confidence intervals.
For continuous outcomes, mean differences and standard deviations will be used to summarise the data. The statistical unit will be the patient.
Meta‐analyses will be undertaken only on studies of similar comparisons reporting the same outcome measures. The Cochrane Statistical Methods Group guidelines will be followed, calculating risk ratios along with 95% confidence intervals and they will be combined using a random‐effects model where more than three trials are combined. The number needed to treat (NNT) will be calculated as appropriate.
Subgroup analysis and investigation of heterogeneity
The Cochran's test for heterogeneity will be used providing there are sufficient trials included in the review.
Sensitivity analysis
Provided that there are sufficient trials included in the review, sensitivity analysis will be undertaken for aspects of study quality and for potential sources of heterogeneity specified a priori as follows: excluding/including unpublished studies, excluding/including studies of low quality and excluding/including one or more large studies to assess how much they dominate the results. The association of radiotherapy with estimated effects will be examined by performing random‐effects meta‐regression analysis in STATA version 7.0 (STATA Corporation, USA), using the program Metareg. Further potential sources of heterogeneity will be investigated as determined from the study reports, although these will clearly be identified as 'post‐hoc' analyses and the results treated with caution.
| Inclusion criteria | Exclusion criteria |
| Randomised controlled trials | Any trials which are not randomised controlled trials |
| Include patients who have suffered from head and neck cancer and have had either radiotherapy alone or radiotherapy in conjunction with surgery and/or chemotherapy | Patients who have not had radiotherapy |
| Sample should be randomly selected to have either extraction of teeth in the primary beam of radiation or leave these teeth in situ or compare with extraction post‐radiotherapy |
|
| Diagnosis and tumour staging should be noted Radiation field and dose should be noted Oral health care pre‐radiotherapy, during radiotherapy and post‐radiotherapy should be noted Timing of extractions in relation to radiotherapy should be noted |
|
| Site of extractions should be noted (molars, premolars, canines, incisors) |
|
| Number of extractions should be noted and method of extraction should be described (antibiotic cover, surgical extraction, if post‐radiotherapy ‐ with or without hyperbaric oxygen) |
|
| Patient demographics should be noted (age, gender, tobacco status, alcohol status/general and dental health) |
|
| Follow‐up time should be clearly stated (with or without dental maintenance) |
|
| Any interventions post‐radiotherapy should be noted |
|
