Aims and objectives
Our aim is to determine whether a definitive RCT is feasible in head and neck cancer
patients with minimal swallowing problems undergoing CRT comparing oral feeding plus
prophylactic gastrostomy tube feeding versus oral feeding plus as-needed nasogastric
tube feeding (TUBE study). The TUBE study feasibility phase is a necessary prelude
to a full trial of these complex interventions, to assess (i) whether an adequate
proportion of eligible patients can be recruited into the study and (ii) whether an
adequate proportion of patients comply with the trial protocol including outcome measure
completion, according to both quantitative and qualitative data.
The objectives are:
A. To explore barriers and facilitators to trial implementation and to use this information
to improve recruitment and retention
1. Willingness of participants to be randomised, to accept and persist with allocated
treatment and comply with assessments.
2. Willingness of clinicians (including clinical oncologists, surgeons, nutritionists,
speech and language therapists) to recruit patients.
3. Qualitative assessment of patient and carer perspectives on trial participation,
barriers to randomisation among non-participants, acceptability of assessment tools
and experience of the tube feeding, conduct and compliance of the trial protocol and
reasons (and characteristics) of patients dropping out.
B. To carry out preliminary estimation of key parameters to inform definitive study
design and study processes
1. Confirm primary outcome measure and associated power/sample size for definitive
trial: dysphagia related quality of life as measured by MD Anderson Dysphagia Inventory
(MDADI) HNSCC-specific self report scale (variation and differences in change from
baseline at 6 months).
2. Trial our subsidiary QoL outcomes (the European Organization for Research and Treatment
of Cancer questionnaires EORTC QLQ-C30, EORTC QLQ – HN35), short form 36 (SF-36)
a multi-purpose, short-form health survey and data collection tools for use of health
and personal social services and patient costs.
3. Monitor nutritional parameters: body mass index, weekly weight changes (during
treatment) and quantity of enteral nutrition consumed.
4. Derivation of an algorithm for when NG tube should be placed in the oral intake
arm that is acceptable to patients and nutritionists.
C. Provide health economics metrics
1. Assess economic value of information based upon a modelling exercise informed by
the feasibility study and the existing systematic reviews.
2. Provide preliminary estimate of the costs, effects and relative cost-effectiveness
of the alternative methods of nutritional support based upon the modelling exercise.
Design
A mixed methods multicentre study to establish the feasibility of a RCT of feeding
methods in patients with stages III and IV head and neck cancer receiving CRT with
curative intent. The work will be conducted over 24 months.
The components are:
1. A multicentre randomised controlled pilot feasibility trial comparing oral feeding
plus pre-treatment gastrostomy versus oral feeding plus as required nasogastric tube
feeding in patients with HNSCC. Patients will be randomised on a 1:1 basis and stratified
by IMRT and by the treating centre.
2. A qualitative process evaluation to inform the trial design by investigating patient,
carer and staff experiences of trial participation.
3. A modelling exercise to synthesise available evidence and provide preliminary estimates
of cost-effectiveness and value of information from future research.
Setting
The setting was five tertiary NHS centres for HNSCC. For our definitive trial, additional
centres will be recruited via our links with the National Cancer Research Network,
Comprehensive Clinical Research Network and from respondents to our national survey
16].
Ethical considerations
Ethical approval was sought and granted by the Newcastle and North Tyneside 2 Committee,
NHS Health Research Authority, reference 14/NE/0045.
Target population
The target population will be patients with stage III and IV HNSCC who receive primary
CRT with curative intent.
Inclusion criteria:
(1) Grade 1 pre-treatment dysphagia, as defined by Common Terminology Criteria for
Adverse Events v4.0 (defined as asymptomatic/symptomatic/able to eat regular diet).
(2) Consent to be randomised.
Exclusion criteria:
Patients who (1) decline to participate, (2) are unable to give informed consent,
(3) cannot receive a gastrostomy for medical reasons, (4) do not receive treatment
with curative intent and (5) patients with malnutrition requiring immediate initiation
of enteral feeding.
Clinical experience suggests that patients with primary sites in the oropharynx, larynx,
nasopharynx and unknown primaries are those who will fulfil the inclusion criteria
(~35 to 40 % of all HNSCC patients).
Interventions
Pre-CRT gastrostomy arm: endoscopic or radiologic gastrostomy will be placed before
commencement of CRT. Given the pragmatic nature of this study and equivalent success
rates with either technique, the choice of method of insertion will be left to local
protocols of the treating centre. Patients will continue with oral feeding and commence
use liquid nutrition through the G tube when they are unable to maintain an adequate
oral intake to meet their nutritional requirements (75 % of requirements based on
a dietetic assessment of 24-h recall by patients).
No pre-CRT gastrostomy arm: this group will continue with oral feeding or have a nasogastric
tube if required during treatment. The decision to place a nasogastric tube will be
based on clinical assessment, patient request and published guidelines 6], patient request for gastrostomy tube may also lead to gastrostomy placement. Based
on published prospective data, we anticipate that 10 % will convert from NG tube
to G tube during the study.
Outcomes measures
The primary outcome of feasibility will comprise of the following entities:
1. Willingness of patients to be randomised (assessed via review of patient screening
logs) defined as:
i. The number of patients consenting to be randomised as a proportion of all patients
approached about the trial, with reasons for non-consent
ii. Qualitative assessment of barriers and facilitators to recruitment
2. Willingness of clinicians to randomise patients—assessed via qualitative interviews
3. Assessment of retention and drop-out rates, defined as:
i. The number of patients who start randomised treatment as a proportion of the number
randomised, with reasons for early drop outs
ii. The number of patients who complete randomised treatment as a proportion of the
number randomised, with reasons for drop outs (including death)
iii. Completeness of MD Anderson Dysphagia Inventory (MDADI) assessment within 6 months
iv. Qualitative assessment of barriers and facilitators to data collection and participant
retention
Secondary outcome measures are:
The following scores/ measures will be requested at baseline (before treatment) and
at 3 and 6 months after treatment (5 and 8 months from randomisation):
A. The MDADI is a self-administered questionnaire designed specifically for evaluating
the impact of dysphagia on the quality of life of patients with head and neck cancers
30]. This will be our primary outcome measure in the full trial.
B. Quality-of-life outcomes
We will use two questionnaires to assess quality of life outcomes. The European Organization
for Research and Treatment of Cancer questionnaire EORTC QLQ-C30 (version 3.0) is
a cancer-specific instrument, has a multidimensional structure, appropriate for self-administration
and is applicable across a range of cultural settings 31]. The EORTC QLQ – HN35 is the head and neck module for EORTC QLQ-C30 (version 3.0)
and is intended for use in conjunction with the QLQ-C30 in patients with head and
neck cancer 32].
C. Short form 36
The SF-36 is a multi-purpose, short-form health survey with 36 questions. It yields
an eight-scale profile of functional health and well-being scores as well as psychometrically
based physical and mental health summary measures and a preference-based health utility
index that will be used to derive quality-adjusted life-years for a cost-utility analysis
conducted as part of a subsequent full trial.
D. Use of health and personal social services and costs to patients and their families/carers
For the definitive economic evaluation costs to patients and their families/carers,
the NHS and personal social services will be elicited. Within the feasibility study,
we will develop the tools necessary to elicit these costs. Specifically, we will develop
case report forms and questionnaires to capture use of services and patient/family/carer
costs. The content of these forms will be developed in consultation with the study
team, our existing item bank of questions, web based resources e.g. www.dirum.org and experience from other RCTs of nutritional interventions e.g. the recent SIGNET
trial 33]. The tool developed will be administered at 3 and 6 months after treatment.
E. Nutritional parameters
We will measure the body mass index before treatment, at 3 months and at 6 months
following treatment. We will also measure weekly weight changes during treatment and
the quantity of enteral nutrition consumed.
F. Oral health monitoring
We will perform oral health assessment before commencing treatment and the end of
6 months for all dentate patients. A full dental chart with panaromic radiographs
will be performed at pre-treatment and at 6 months. Periodontal and oral hygiene assessment
and plaque scores will also form part of this assessment and be documented.
Statistical considerations
Target recruitment is 60 patients (30 per arm of the study) 34]. As a feasibility study, we will provide an assessment of recruitment and compliance
rates to inform future trial design. Statistical analyses are according to a confidence
interval rather than a hypothesis testing approach. Analyses will be descriptive reporting
rates as proportions with confidence intervals and graphical analyses of longitudinal
data. Recruitment is dependent on the number of patients approached but should be
no lower than 50 %. The upper limit of the 95 % confidence interval for the proportion
of patients recruited should exceed 50 %. If 120 patients were approached and 50 %
were recruited (60 patients randomised), the 95 % confidence interval for the recruitment
rate would have width ±9 %. This would provide a good level of accuracy to assess
the acceptability of the recruitment rate.
Progression criteria to phase III trial
The decision to move to a phase III trial will be based on:
1. Adequate timely recruitment with a 50 % recruitment rate.
2. Completeness of outcome measurement (MDADI at 6 months): excluding those individuals
who die during the study period. This outcome data successfully collected should be
greater than or equal to 80 %, as this will be the primary outcome for the planned
phase III trial.
3. Economic criteria of EVOI to suggest further research likely to be worthwhile.
Qualitative process evaluation
The integrated qualitative process evaluation will explore barriers and facilitators
to trial implementation. Through regular feedback of emerging findings to the trial
team it will inform the day-to-day running of the pilot trial and optimise recruitment
and retention. It will also identify aspects of trial processes which could be improved
for the definitive trial.
A. Normalisation process theory
Our analysis of facilitators and barriers to trial participation will be informed
by normalisation process theory 35]. Normalisation process theory considers factors that affect implementation in relation
to four key areas; how people make sense of a new practice (in this case—the trial)
(coherence); the willingness of people to sign-up and commit to the new practice (cognitive
participation); their ability to take on the work required of the practice (collective
action); and activity undertaken to monitor and review the practice (reflexive monitoring).
This theory is increasingly being used in studies of the implementation of interventions
in health care (www.normalizationprocess.org). In the current study, we will consider how well trial processes are introduced
and incorporated at each site for both patient and professional groups.
B. Methods and sampling
Numbers have been included to give an indication of the amount of data to be collected.
We have given particular thought, for example, to whether there might be significant
subgroups of patients or professionals, which would require an additional layer of
data collection and analysis. However, in keeping with the principles of rigorous
qualitative research, the actual sample size will be informed by the point of data
saturation; we will be responsive to the study context and anticipate that in some
cases, fewer interviews or observations will be conducted, and in others, additional
data will be collected in response to our emerging analysis or study events. We aim
to achieve a balance between spread of data (to avoid missing key events or issues)
and depth (a manageable data set that allows for in-depth analysis); having the flexibility
to identify and focus in on those issues which our analysis suggests is key to successful
study implementation.
Data collection will focus on three inter-related phases over the duration of the
trial
Following appropriate consent, we will include interviews with health professionals
(?=?15–24); patients (?=?32–36); observation of recruitment discussions (?=?9–18); and observations of multidisciplinary team meetings (?=?6–15); details below.
Pre-implementation of TUBE pilot trial
In order to understand the context, professionals’ views and expectations and to map
patient pathways, we will visit each study site. We will conduct formal interviews
with key individuals (?=?2–3 per site) involved in treatment planning for HNSCC (e.g. nurses; speech therapists;
ENT surgeons).
Patient recruitment phase
We will focus on patients’ and professionals’ experiences of recruitment. Patients
will be recruited from multidisciplinary clinics, with trial information being provided
by research nurses. We will conduct qualitative interviews with patients who have
consented to take part in the trial (?=?5 in the G-tube group; ?=?5 in oral feeding group) and where possible, those that decline to take part either
at recruitment or who withdraw at the point of randomisation (?=?10). We will focus on their experiences and understandings of trial processes (e.g.
the information they were given; the recruitment encounter; their ideas and/or concerns
about randomisation and consent) and the intervention (willingness to undergo either
feeding option; ideas and/or concerns about impact on health and acceptability).
Ideally, we would interview patients within 2 weeks of recruitment discussions. Patients
will be offered a choice of location and method (telephone; face-to-face) of interview.
We know that individuals often discuss clinical decisions with other people 36] so patients who wish to involve a family member in their interview will be able to
do so.
We will also conduct further interviews with professionals involved in some aspect
of patient recruitment (?=?3–5 per site) and, where possible, observe multidisciplinary team meetings to understand
the process of identification of eligible patients (?=?1–3 per site). Again, where possible, study recruitment discussions (either at
treatment planning clinic or subsequent discussion with clinical nurse specialist)
will, with consent, be observed (?=?3–6 per site). An initial visit to each site will take place shortly after (1–2 months)
the site commences patient recruitment. The timing of subsequent visits to a site
will be driven by factors such as variation in recruitment rates between sites or
changes in key personnel.
Patient follow-up phase
We will also investigate patients’ (and carers’) experiences of the tube feeding and
trial participation through qualitative interviews (?=?12–16) at approximately 8 months after recruitment, in order to explore the acceptability
of assessment tools and their experiences of the intervention. Where possible, the
follow-up interviews will include second interviews with patients and family members
(or friends) interviewed at the recruitment phase; additional participants will be
recruited based on emergent criteria (e.g. length of time of oral and/or supplementary
feeding).
C. Qualitative data management and analysis
Interviews and recruitment discussions will, with consent, be audio-recorded, transcribed
verbatim and edited to ensure anonymity of respondent. Data will be managed using
NVivo software. The analysis will be theoretically-informed by normalisation process
theory and will be conducted according to the standard procedures of rigorous qualitative
analysis 37] including open and focused coding, constant comparison, memoing 38], deviant case analysis 39] and mapping 40]. We will undertake independent coding and cross checking and a proportion of data
will be analysed collectively in ‘data clinics’ where the research team share and
exchange interpretations of key issues emerging from the data.
D. Relationship between process evaluation and pilot trial
Findings will be regularly fed back to the study team and appropriate changes made
to study processes during the lifetime of the study. For example, if the pre-pilot
work identifies a problem with the coherence of the trial to one group of professionals,
then additional awareness raising/education sessions or materials will be developed.
Economic modelling
The economic model will estimate the costs, effects and relative cost-effectiveness
of the alternative methods of nutritional support. Data collection takes place during
the study and all analyses will be conducted by health economists at the end of the
study period. It will take the perspective of the UK NHS and personal social services
(PSS). In the base case, all costs and effects will be discounted at 3.5 % 41]. In addition, as described below, the model will also estimate the expected value
of information and expected value of sampling information to help inform the future
definitive study.
The methods to paramaterise the model are described below. To allow for uncertainty
to be characterised around these data—costs, effects and cost-effectiveness—and to
enable the value of information analysis to be conducted a probabilistic sensitivity
analysis will be performed using Monte Carlo simulation. All uncertainty surrounding
estimates of input parameters will be informed by appropriate distributions. Modelling
will conform to recommendations for best practice including those developed for economic
evaluation models 42].
A. Structure of the economic model
Treatment pathways for patients undergoing chemoradiation for HNSCC will be developed.
The treatment pathway will start with the choice of nutritional support. These pathways
will be based upon the material prepared for the feasibility study and advice from
the key stakeholders involved in the study. Following recommendations for best practice,
these care pathways will be used to develop a mathematical model covering the period
of initial intervention and the costs and consequences of any subsequent outcomes
including further interventions.
B. Derivation of cost data
Information on the precise description of the resources required for each intervention
will be based upon data derived from the feasibility study. From participants recruited
to the trial, we will estimate costs for each method of nutritional support. Given
the small study size, these data will be imprecise and this imprecision will form
a key input into the analysis. Further cost data will be required on subsequent management;
these data will be identified with the help of members of the study group and a search
of the economic literature. Unit costs will be taken from appropriate routine sources
e.g. NHS reference costs, British National Formulary for drugs.
C. Derivation of utilities
For the cost-utility analysis, effects/benefits will be estimated in quality-adjusted
life-years. For each health state, a health state utility will be defined. The data
will be derived from the pilot trial and a focused search to identify utility data,
including a search on the CEA Registry (https://research.tufts-nemc.org/cear/default.aspx). The estimates used within the model will be based upon the best available data,
ideally derived using SF-6D (as the SF-36 will be used within the feasibility study
and can be used to derive SF-6D scores). Nevertheless, such data may not be readily
identifiable and data from other sources along with judgements as to how that measure
compares to SF-6D scores will be used.
D. Epidemiological and relative effectiveness data
The main source of evidence to inform the probabilities required for the model will
be the existing systematic reviews and other literature summarised in the ‘Background’
section of this application. From these sources, information on the likelihood of
key events described in the economic model will be sought. Additional focused searches
will be conducted as necessary to identify the best available evidence relevant to
the UK NHS for such probabilities.
E. Estimation of relative efficiency
The results of the economic model will be presented as a cost-utility analysis (CUA).
In the CUA, mean costs, mean quality-adjusted life-years, incremental costs and quality-adjusted
life-years will be presented.
F. Uncertainty
It is possible that sufficient data to populate the model will not be identified.
In such a case, threshold values will be explored where data is missing by varying
estimates through a range thought plausible (based on advice of the stakeholders involved
in the study). Within a probabilistic analysis, a plausible distribution will be assigned
to this range (which may include a uniform distribution to indicate that we do not
know what value a parameter might take within a specified range).
Deterministic sensitivity analyses will be carried out to test for the effect of assumptions
and variability 43] such as the impact of changes in discount rates. The probabilistic sensitivity analysis
will also be undertaken for both the base case analysis and, where sensible, all deterministic
sensitivity analyses allowing presentation of results in a series of cost-effectiveness
acceptability curves (CEAC). Estimates of costs and quality-adjusted life-years will
be calculated as the expectation over the joint distribution of the parameters. Relevant
distributions will be informed by the systematic reviews and meta-analyses, other
literature or expert opinion according to best practice 44].
G. Value of information analysis: Identification of future research needs
We anticipate that the economic model will only provide preliminary data on the relative
effectiveness and cost-effectiveness of the different methods of nutritional support.
The main purpose of the model will be to help inform decisions about the direction
of future research. Within the economic component of this study this will be explored
using variants of value of information analysis 45]–48].
We will initially estimate the expected value of perfect information and expected
value of removing uncertainty surrounding specific parameters or groups of parameters
to identify where further research should focus on identifying more precise and reliable
estimates of specific pieces of information e.g. relative effectiveness, costs, utilities
(the expected value of partial perfect information). Expected value of perfect information
and expected value of partial perfect information can be interpreted as the value
of eliminating a wrong decision and it places an upper value on conducting further
research overall (expected value of perfect information) or a specific area of information
(expected value of partial perfect information). Expected value of perfect information
and expected value of partial perfect information at an individual level can be estimated
directly from the model but will need to be combined with information on the number
of people who could benefit from the gastrostomy tube feeding over the expected lifetime
of the project. As these two factors are uncertain sensitivity analysis will be used
to explore alternative assumptions. If relatively small values are obtained for expected
value of perfect information and expected value of partial perfect information (although
we note that this is a judgement), then this suggests that no further research is
necessary or no further research is required to obtain ‘better’ estimates for specific
groups of parameters.
A judgement will be formed based upon the findings the expected value of perfect information
analysis as to whether a move to the analytically complex, expected value of sampling
information, will be made. Expected value of sampling information provides further
information on the value of removing some of the existing uncertainty and also explicitly
takes into account the cost of generating that future research to estimate the expected
net benefit of sampling. Specifically, in this study, we will explore the use of this
approach to identify, from an economic perspective, the optimal trial design. Such
methods have only very rarely been used to determine the size of randomised controlled
trials and therefore following the recommendations of forthcoming guidance the findings
of this analysis will be used along with other information to determine the sample
size for the trial 49].