De‐intensified adjuvant (chemo)radiotherapy versus standard adjuvant chemoradiotherapy post transoral minimally invasive surgery for resectable HPV‐positive oropharyngeal carcinoma
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of de‐intensified adjuvant (chemo)radiotherapy in comparison to standard adjuvant (chemo)radiotherapy in patients treated with minimally invasive transoral surgery (transoral robotic surgery or transoral laser microsurgery) for resectable HPV‐positive oropharyngeal squamous cell carcinoma.
Background
Description of the condition
More than 400,000 cases of oropharyngeal squamous cell carcinoma (OPSCC) are diagnosed each year worldwide (Chaturvedi 2013). It has been estimated that there would be approximately 48,000 new cases of oral and pharyngeal cancer in the United States in 2016 (Siegel 2016). Worldwide the incidence of OPSCC ranges from 7 to 17 cases per 100,000 persons (Chaturvedi 2013), and in developed countries it is steadily rising, particularly in young males (Chaturvedi 2011).
Human papillomavirus (HPV) is a major carcinogen, with an estimated 4.8% of total worldwide cancers in 2008 linked to the virus (de Martel 2012). HPV now meets the epidemiological criteria for OPSCC causality, especially in non‐smokers (Gillison 2015; Sudhoff 2011). Meta‐analysis of the world literature has demonstrated that the proportion of HPV‐associated oropharyngeal cancer has increased from 40.5% in studies recruiting before the year 2000 to 72.2% in studies reporting after 2005 (Mehanna 2013), although this is known to vary by individual population (Schache 2016). In contrast to this apparent overall trend, recent published work has shown that in the UK over the period 2002 to 2011, whilst the overall incidence of OPSCC doubled, the proportion that were HPV‐positive stayed the same, demonstrating an increase in non‐HPV associated OPSCC (Schache 2016). In the UK population, therefore, the increase cannot be attributed to HPV alone.
It is worth noting that HPV‐positive OPSCC patients have significantly improved rates of both overall and disease‐free survival compared to HPV‐negative tumour groups. HPV‐positive OPSCC is associated with a 58% reduction in the risk of death compared to HPV‐negative disease (Ang 2010; Fakhry 2008). Indeed the presence or absence of HPV with regard to the tumour may have a greater impact on five‐year survival than T stage or nodal status alone (Haughey 2011).
Risk factors for oral HPV infection include a history of orogenital sexual practice, a large number of sexual partners and first intercourse at an early age. The same factors also reflect changes in modern society and combine to increase the cumulative effect of HPV infection in OPSCC (Chung 2009). HPV‐negative OPSCC tends to affect an older age group and is normally associated with smoking and alcohol. HPV‐positive OPSCC behaves differently, often presenting with a small primary in the oropharynx combined with a metastatic cystic deposit in the neck, thereby entailing a higher stage at presentation for the majority of patients (Ang 2010; Dwivedi 2013; Evans 2010).
Description of the intervention
Over the last 20 years the management of oropharyngeal cancer has changed dramatically. In 2002, Parsons et al published a review of 51 studies of patients with OPSCC who were treated with surgery with or without radiotherapy or primary radiotherapy without neck dissection (Parsons 2002). The cumulative five‐year survival was 47% for patients undergoing primary surgical resection with or without neck dissection, and 43% for those undergoing primary radiotherapy with or without neck dissection. However, the severe complication rate was 23% in the primary surgical group and only 6% in the primary radiotherapy group. This led to the conclusion that non‐operative therapy was superior to operative therapy for OPSCC of all stages. More recently a large meta‐analysis comparing primary radiotherapy with chemoradiotherapy in 16,192 head and neck squamous cell carcinoma (HNSCC) patients provided updated results. The study concluded an absolute survival benefit of 8.1% after five years in OPSCC patients treated with concurrent chemoradiotherapy (Blanchard 2011).
Acute and late toxicities associated with chemoradiotherapy are, however, a significant burden for oropharyngeal cancer patients, with rates of acute and late grade 3 or higher toxicity at approximately 80% and 25% to 60% respectively (Kelly 2016). Recognised toxicities include: gastric tube dependence, pain, scarring, fibrosis, dysphagia, xerostomia, dental decay, osteoradionecrosis, hypothyroidism, carotid stenosis and stroke (Lee 2011). A relationship between the radiation dose to the constrictor muscles and long‐term swallowing difficulties has been well established: patients in whom more than 78% of their cricopharyngeus inlet receives over 60 Gy have a 50% risk of developing a stricture (Chen 2010). The addition of chemotherapy to radiotherapy worsens toxicity as demonstrated by the Intergroup trial, which found rates of grade 3 or higher toxicity of 89.5% in the chemoradiotherapy cohort compared to 52% in the radiotherapy alone cohort (Adelstein 2003). Furthermore, late toxicities may be under‐recognised as the 10‐year results of RTOG 91‐11 found increased non‐cancer mortality in the concurrent chemoradiotherapy arm (30.8%) compared to the induction chemotherapy arm (20.8%) or radiotherapy alone arm (16.9%) (Forastiere 2013). The incidence of dysphagia and feeding tube dependence post chemoradiotherapy cannot be entirely attributed to the treatment as there is evidence that part of the effect is due to disuse atrophy and resultant adverse remodelling of aerodigestive tract muscles (Hutcheson 2013).
Both open surgery and radiotherapy/concurrent chemoradiotherapy have drawbacks in terms of cost, overall survival and patient quality of life (Haigentz 2009; Machtay 2008). The benefit of a novel treatment regimen with lower toxicity is therefore readily apparent, especially given the younger patient cohort who will have to live with treatment sequelae for longer.
As the biological differences in viral/non‐viral associated OPSCC are further elaborated (Masterson 2015; Pyeon 2007; Slebos 2006), radical change in most therapeutic interventions has taken place. In radiotherapy, intensity modulation and computerised planning have been introduced in addition to external beam therapy. In surgery, the focus has shifted to the use of minimally invasive procedures such as transoral laser microsurgery or transoral robotic surgery, which demonstrate reduced immediate postoperative toxicity, reduced length of hospital stay and faster functional recovery compared with open surgery (Holsinger 2015). Furthermore, these techniques have the potential to improve organ preservation and function, and ameliorate the economic burden of treatment. Additionally, with regard to control of lymphatic spread, neck dissections have become more selective (resulting in the removal of fewer normal structures and therefore lower morbidity) (Adelstein 2012).
We have reviewed the evidence from studies comparing transoral minimally invasive surgery with (chemo)radiotherapy in the related Cochrane Review: 'Minimally invasive surgery versus radiotherapy/chemoradiotherapy for small‐volume primary oropharyngeal carcinoma' (Howard 2016).
De‐intensified treatment strategies
The use of endoscopic head and neck surgery for the primary site provides two principal areas of benefit. Firstly, it results in less morbidity for the patient compared to traditional open surgery. Secondly, in the context of HPV‐related OPSCC, it raises the potential option of 'de‐intensification therapy' with a concomitant reduction in radiation‐related morbidity (Masterson 2014; Masterson 2014a; Moore 2009). So far this has been borne out by observational studies that suggest that transoral minimally invasive surgery may have an advantage by improving patient quality of life and functional outcome, and reducing the need for adjuvant concurrent chemoradiotherapy (Leonhardt 2012; Moore 2013).
De‐intensified treatment strategies fall into two groups. For primary concurrent chemoradiotherapy the options are to replace cisplatin with the epidermal growth factor receptor (EGFR) inhibitor cetuximab or to reduce the dose of radiation. These strategies have been covered by the Cochrane Review 'De‐escalation treatment protocols for human papillomavirus‐associated oropharyngeal squamous cell carcinoma' (Masterson 2014a). For primary surgery the options include:
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administration of a lower dose of adjuvant radiotherapy; or
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omission of chemotherapy from the adjuvant treatment regimen (radiotherapy alone).
It is these strategies that will be covered by this review.
The most appropriate option is decided based upon histopathological examination of the surgical specimen. This allows risk stratification of the individual patient, although it is worth noting that this stratification relies on traditional histopathological risk factors, which may not apply in HPV‐positive disease (Huang 2012; Masterson 2014).
Patients are usually stratified into three cohorts:
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Low risk: pathological findings associated with a low risk of locoregional relapse, which usually has no adjuvant treatment.
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Medium risk: locoregional disease (or early disease with adverse histological features), which is usually treated with adjuvant radiotherapy.
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High risk: presence of positive (< 1 mm) margins, extracapsular nodal spread or advanced disease, which is usually treated with adjuvant chemoradiotherapy.
How the intervention might work
Toxicities (both acute and late) as a result of chemotherapy and radiotherapy to the head and neck are well recognised. Provided that survival outcomes can be maintained, de‐intensification of adjuvant therapy provides the opportunity for a reduction in these toxicities and an improved quality of life for patients. This is increasingly important, especially in light of the younger age of some patients who will have to live with the consequences of treatment for many years.
Why it is important to do this review
The oropharynx plays an essential role in swallowing, speech and protecting the airway as it is situated at the bifurcation of the respiratory and digestive tract. The toxicities from standard‐dose chemotherapy and radiotherapy are well recognised and treatment modalities are therefore heavily influenced by the aim of reducing the risk of functional disability where possible. In the context of an expanding cohort of younger patients the potential effects of de‐intensification of adjuvant (chemo)radiotherapy facilitated by a minimally invasive approach should be systematically reviewed.
Objectives
To assess the effects of de‐intensified adjuvant (chemo)radiotherapy in comparison to standard adjuvant (chemo)radiotherapy in patients treated with minimally invasive transoral surgery (transoral robotic surgery or transoral laser microsurgery) for resectable HPV‐positive oropharyngeal squamous cell carcinoma.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials. We will exclude quasi‐randomised and cluster‐randomised trials.
Types of participants
We will include patients with HPV‐positive oropharyngeal carcinoma (subsites C09 and C10 as defined by the World Health Organization classification). Cancers included will be T1‐4a with or without nodal disease with no evidence of distant metastatic spread. All patients will have had minimally invasive transoral surgery.
We will exclude carcinoma of the oral cavity (C01‐06), nasopharynx (C11), hypopharynx (C13) and larynx (C32) (WHO 2000).
We will exclude patients receiving open surgery.
Types of interventions
Intervention
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De‐intensified adjuvant (chemo)radiotherapy.
De‐intensified radiotherapy, total dose 50 Gy given in 25 fractions.
De‐intensified chemoradiotherapy (= standard dose radiotherapy with omission of concurrent chemotherapy): radiotherapy alone, total dose 60 Gy given in 30 fractions.
Control
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Standard adjuvant (chemo)radiotherapy.
Radiotherapy, total dose 60 Gy given in 30 fractions.
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Chemotherapy: platinum‐based agent (usually cisplatin) administered concurrently with radiotherapy either weekly or three‐weekly.
The comparisons will be:
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Low‐dose adjuvant radiotherapy versus standard‐dose adjuvant radiotherapy.
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Standard‐dose adjuvant radiotherapy alone versus adjuvant chemoradiotherapy.
Types of outcome measures
We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies. Primary outcomes focus on survival whilst the secondary outcomes focus on quality of life indices that may be affected by de‐intensification of treatment.
Primary outcomes
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Overall survival/total mortality (disease‐related mortality will also be studied if possible).
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Disease‐free survival.
We plan to measure these outcomes at one, two, three and five years.
Secondary outcomes
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Swallowing ability, as measured by:
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the proportion of people with a gastrostomy tube (at one year);
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the MD Anderson Dysphagia Inventory (MDADI);
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modified barium swallow ratings.
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return to normal diet, measured with the Performance Status Scale for Head and Neck cancer (PSS‐HN) normalcy of diet scale.
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Voice, measured with the Voice Handicap Index (VHI).
With the exception of the proportion of people with a gastrostomy tube we plan to measure these outcomes at one, six, 12 and 24 months.
Despite the increasing focus on quality of life the optimal patient‐reported outcome instrument that should be used to measure the impact of cancer therapy for the HPV‐associated OPSCC patient population is not clearly defined. Moreover, we feel that it is important to distinguish between patient‐reported outcomes and quality of life measures that may be more subjective. Finally, there is a danger that subtle differences in particular areas (e.g. dysphagia) may be lost within more global scoring systems, adding further complexity to the comparison (dilution effect).
Search methods for identification of studies
The Cochrane ENT Information Specialist will conduct systematic searches for randomised controlled trials and controlled clinical trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.
Electronic searches
Published, unpublished and ongoing studies will be identified by searching the following databases from their inception:
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the Cochrane ENT Trials Register (search to date);
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the Cochrane Central Register of Studies Online (search to date);
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Ovid MEDLINE(R) Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to present);
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Ovid EMBASE (1974 to present);
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LILACS, lilacs.bvsalud.org (search to date);
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KoreaMed (search via Google Scholar to date);
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Web of Knowledge, Web of Science (1945 to present);
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ClinicalTrials.gov (search via the Cochrane Register of Studies to date);
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), www.who.int/ictrp (search to date).
The subject strategies for databases are the same as those detailed in Howard 2016 and they will be updated from the date of the last search for that review. The search strategy designed for CENTRAL is available in Appendix 1. Where appropriate, this will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)).
Searching other resources
We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. In addition, the Information Specialist will search Ovid MEDLINE to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials, and run non‐systematic searches of Google Scholar to retrieve grey literature and other sources of potential trials.
Data collection and analysis
Selection of studies
Three authors (JH, RD and LM) will ensure that each abstract is independently screened twice by different authors. We will independently assess full texts against the inclusion criteria. Any conflicts will be resolved through discussion with a senior author.
Data extraction and management
Three authors (JH, RD and LM) will ensure that data are extracted independently twice by different authors using a specifically designed data extraction form. We will pilot the data extraction form on several studies and adjust it as necessary prior to use. Any disagreements will be resolved through consultation with a senior author. Where required we will contact study authors for clarification or missing information.
For each study we will record the following:
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Year of publication, country of origin and source of study funding.
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Details of the participants, including demographic characteristics and criteria for inclusion and exclusion.
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Details of the type of intervention, timing and duration (including type of surgery).
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Details of survival outcomes reported, with time intervals.
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Details of treatment‐related morbidity, categorised as acute (less than 90 days after treatment) or late (more than 90 days) and classified according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03).
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Details of all other outcomes reported, including method of assessment and time intervals.
Assessment of risk of bias in included studies
JH and LM will undertake assessment of the risk of bias of the included trials independently, with the following taken into consideration, as guided by theCochrane Handbook for Systematic Reviews of Interventions (Handbook 2011):
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sequence generation;
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allocation concealment;
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blinding;
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incomplete outcome data;
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selective outcome reporting; and
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other sources of bias.
We will use the Cochrane 'Risk of bias' tool in RevMan 5.3 (RevMan 2014), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry: 'low', 'high' or 'unclear' risk of bias.
Measures of treatment effect
We will express continuous outcomes as a mean endpoint (or change from baseline) for each group with standard deviation and number of people. For continuous outcomes measured using different (but compatible) scales we will express treatment effects as a standardised mean difference (SMD).
We will express dichotomous outcomes as a risk ratio (RR) with the number of people with the outcome and number of participants.
We will express time‐to‐event outcomes as a hazard ratio (HR) with standard deviation (SD).
We will preferentially report ordinal data as continuous, however if studies only report data dichotomously then we will express as dichotomous.
Analysis will be on an intention‐to‐treat basis. Where useful we will calculate the number needed to treat to benefit/harm (NNTB/NNTH) to aid clinical interpretation of the findings.
Unit of analysis issues
We plan to use data only from individually randomised controlled trials to avoid unit of analysis issues. We are excluding cluster‐randomised trials.
Dealing with missing data
Where standard deviations or hazard ratios are not reported we plan to impute these from other reported data.
We plan to contact study authors:
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where a study protocol suggests that an outcome of interest has been measured but is not reported;
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if not all data required for meta‐analysis are reported;
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if standard deviation data or hazard ratios are not available or estimable from other reported data (using the methods detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011)).
Assessment of heterogeneity
We intend to assess clinical heterogeneity by examining the types of participants, interventions and outcomes in each study. We will conduct formal assessment using the Chi² test (with a significance level of α = 0.1 in view of the low power of this test) and the I² statistic (with 75% or more indicating a considerable level of inconsistency), both available in RevMan 5.3 (RevMan 2014). If meta‐analysis is performed we plan to further assess heterogeneity by inspecting the overlap of confidence intervals for the results of individual studies within a forest plot.
Assessment of reporting biases
We plan to assess reporting bias as within‐study (outcome reporting) bias and between‐study (publication) bias.
Outcome reporting bias
Bias can occur if outcomes are not adequately reported to allow further analysis. We plan to assess outcome reporting bias by comparing the reported outcomes against the outcomes listed in the trial protocol or methods section. Where the protocol, methods or results indicate that an outcome has been measured but the results are not presented sufficiently we plan to contact the study authors. If no further information can be found we will judge this a 'high' risk of bias. If insufficient information is found to allow adequate judgement we will judge this an 'unclear' risk of bias.
Publication bias
If sufficient trials are available we plan to create funnel plots for the outcomes overall survival and dysphagia (MDADI scores). If asymmetry is found we plan to investigate this further according to the methodology in the Cochrane Handbook of Systematic Reviews of Interventions (Handbook 2011).
Data synthesis
We plan to extract data from the included studies and enter the data into RevMan 5.3 for statistical analysis. In the event of incomplete data, we intend to contact the study authors to obtain further information and to seek statistical advice where necessary.
Our analysis of survival and disease recurrence will depend on the data available. We aim to analyse the proportion surviving at one, two, three and five years as either:
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proportion surviving; or
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hazard ratios, for comparison in meta‐analysis if appropriate.
We will express the proportion of people with a gastrostomy tube as a RR. The remaining secondary outcomes will be restricted to assessment of validated assessment tools (where appropriate). If the data provided are in the form of means and standard deviations, we intend to display the effects on outcomes as a mean with standard deviation. If there is disparity in terms of scales we will express the data as a SMD with 95% confidence interval (CI). If hazard ratios are not quoted in studies, we plan to calculate them from available summary statistics such as observed events, expected events, variance, confidence intervals, P values or survival curves (Parmar 1998). If required we will analyse the survival curves using the online tool: https://automeris.io/WebPlotDigitizer/.
We will attempt a meta‐analysis if studies are available with similar comparisons and reporting the same outcome measures. If appropriate, we intend to calculate pooled estimates using a random‐effects model (Handbook 2011), as there is likely to be significant statistical or clinical heterogeneity (an I² value > 50%, as specified in the Cochrane Handbook for Systematic Reviews of Interventions).
Subgroup analysis and investigation of heterogeneity
We have no planned subgroup analyses.
We plan to assess heterogeneity using the methods advised in the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).
Sensitivity analysis
If meta‐analysis is performed we plan to use sensitivity analysis. If we include studies with high risk of bias (e.g. poor follow‐up rate) we plan to re‐calculate outcomes including these studies individually to see what influence this has on our presumed treatment effect.
Where thresholds have been set for inclusion or analysis we plan to re‐analyse the data using values either side of the set threshold to assess whether our decisions have influenced the outcomes.
GRADE and 'Summary of findings' table
Three authors (JH, RD, LM) will ensure that each study is independently assessed twice by different authors using the GRADE approach to rate the overall quality of evidence. The quality of evidence reflects the extent to which we are confident that an estimate of effect is correct and we will apply this in the interpretation of results. There are four possible ratings: high, moderate, low and very low. A rating of high quality of evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low quality implies that any estimate of effect obtained is very uncertain.
The GRADE approach rates evidence from RCTs that do not have serious limitations as high quality. However, several factors can lead to the downgrading of the evidence to moderate, low or very low. The degree of downgrading is determined by the seriousness of these factors:
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study limitations (risk of bias);
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inconsistency;
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indirectness of evidence;
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imprecision; and
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publication bias.
We will include 'Summary of findings' tables, constructed according to the recommendations described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). The comparisons will be:
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low‐dose adjuvant radiotherapy versus standard‐dose adjuvant radiotherapy;
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standard‐dose adjuvant radiotherapy alone versus adjuvant chemoradiotherapy.
We will include the following outcomes in the 'Summary of findings' tables:
Primary outcomes
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Overall survival.
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Disease‐free survival.
Secondary outcomes
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Swallowing ability, as measured by:
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the proportion of people with a gastrostomy tube (at one year);
-
the MD Anderson Dysphagia Inventory (MDADI);
-
modified barium swallow ratings.
-
Return to normal diet, measured with the Performance Status Scale for Head and Neck cancer (PSS‐HN) normalcy of diet scale.
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Voice, measured with the Voice Handicap Index (VHI).
