Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03397823 |
| Other study ID # |
Radiotherapy caries |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 15, 2017 |
| Est. completion date |
October 30, 2019 |
Study information
| Verified date |
December 2018 |
| Source |
King's College London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Overcoming limitations of previous studies, the following research project will assess the
most significant acute and long-term complications of RT that affect HNC patients: oral
mucositis, dry mouth feeling, taste alteration and carious lesion incidence, all of which
negatively affect cancer treatment outcomes and the quality of life of cancer survivors. This
project was developed with an aim to study any possible correlations / links between the oral
sequelae of RT and the negative clinical outcomes listed, in order to help the development of
clinical management protocols for HNC patients to mitigate the effect on care and patient
comfort and its delivery in healthcare systems.
The project comprises of a longitudinal cohort study of HNC patients correlating biodata of
biochemical salivary parameters, clinical outcomes and oral health status over a period up to
12 months post-RT, focusing on baseline pre-IMRT (T0), 6 months post-IMRT (T1) and up to 12
months post-IMRT treatments (T2). The ultimate goal is to identify possible predictive
markers in the saliva at T0 to assist with evaluation of oral mucositis severity in
individual HNC patients prior to start of treatment so that treatment can be adapted for such
high-risk patients individually, to either prevent or minimise the severity of this
consequence of RT.
Description:
1. Introduction
Head and neck cancer is the sixth most common cancer in the world representing 4-5% of
all malignancies . Head and neck cancer (includes oral, nasal cavity, salivary glands,
paranasal sinus, pharynx, and larynx) is one of the top 10 most diagnosed cancers in the
UK . According to Cancer Research UK, there were 7591 newly diagnosed with oral cancer
in 2013 in the country, representing the 14th most common cancer in the UK.
Radiotherapy (RT) is the first choice treatment for the majority head and neck cancer
patients, which is a localized treatment to control the tumour . More than 50% of head
and neck cancer patients receive RT delivered in fractions of 2 Grays (Gy) daily during
5 days per week until the end of their therapy dosage (mean cumulative dose 55-77 Gy).
RT stimulates cellular changes that destroy the tumor cells, but may affect dramatically
the healthy oral tissues altering the homeostasis of this complex environment. RT is the
cause of a wide range of adverse oral tissue reactions such as permanent damage of the
major and minor salivary glands (hyposalivation, xerostomia), modification of connective
and vascular tissues and a reduction the healing capacity especially in mucosal and
mineralised tissues (mucositis, caries lesion, osteoradionecrosis). In order to try to
diminish the adverse side effects of the RT three-dimensional (3D) computed tomography
(CT) planned radiotherapy known as intensity-modulated radiotherapy (IMRT) has been
developed .
There are acute (mucositis) and late-onset adverse effects/sequelae that RT induces in
healthy oral tissues . Radiation-induced dental caries is the most common late effect,
but its origin and nature is not clear. RT related caries have a rapid onset as a result
of a combination of factors such as shift in oral microbial community composition
favouring acidophilic bacteria, hypo-salivation, poor oral hygiene and dietary
alterations . The patients often have little/no pain, even in the most severe cases.
Histological features show that the onset and development of caries is similar to non
RT-related ones but the sites affected are different. Indeed RT-related caries is more
frequent on the cervico-labial surface/ incisal edge of canines and incisors while non
RT-related ones are more frequent in the interproximal/ occlusal areas of the posterior
teeth (molar and premolars).
Also, caries associated with RT has a rapid circumferential progression which may lead
to tooth fracture. It is characterized by a localized lesion to the incisal or occlusal
surfaces which diffuse and progress in relation to irregular and generalized erosion of
the incisal edge of the tooth. In addition, mechanical changes (increased elastic
modulus and stiffness) within the tooth structure increase the wear of the incisal and
occlusal areas and could lead to complete fracture of the tooth.
Tooth destruction is one of the most severe consequences of RT and it may produce
complete edentulousness in 3 - 5 years. The dental management of RT patients is
challenging. It is necessary to gather a multidisciplinary team (restorative dentists,
periodontology, endodontic, dental hygienist, radiation oncologists, medical
oncologists, and oral surgeons) to maintain oral health and improve quality of life
(QoL). Almost 50% of cancer survivors reported depression, worry or tension related to
oral dryness symptoms. Hence, RT sequelae detrimentally affect the quality of life of
head and neck cancer patients.
Overall, it is necessary the quantitative analysis of chemical matrix components,
proteins and microbial changes that occur in patients' teeth/oral cavity, who have
undergone RT, in order to determine the aetiology and pathophysiology of the two
prevalent side effects (caries/mucositis) to correlate with preventive measurement and
appropriate treatment care for this population. Finally, it is necessary to perform a
complete oral assessment using a validated index in order to create a baseline record
before the treatment and a validated measured to compare after the RT and with healthy
individuals.
2. Aim The aim of this project is to perform a well-controlled and integrated longitudinal
study of HNC patients correlating biodata of biochemical parameters, clinical parameters
and oral health status, to overcoming the limitations of previous studies, that examined
the different side effects of radiotherapy of HNC patients (reduced number,
retrospective, observational, short term follow up, lack of detailed clinical
assessment, focused into treatment of side effects).
The first objective of this study will be to perform quantitative analysis of oral/
dental status of HNC patients pre and post IMRT and analyse the possible associations
between the clinical outcomes.
Followed by assessing salivary gland function of HNC patients pre and post IMRT by
analysing protein concentration and secretion rate and investigate the possible
associations between these proteins and clinical outcomes.
Next objective is to determine the possible association between selected proteins
concentration and secretion rate and oral mucositis outcomes after IMRT, and therefore,
the final objective is to evaluate whether protein concentration or secretion rate of
saliva is a reliable predictor of mucositis presence and severity.
Null Hypothesis There will be no correlation between salivary biochemical composition
and oral side effects of radiotherapy in the HNC patients before and after radiotherapy
3. Materials and Methods. Ethics application to Health Research Authority (IRAS Project
ID:199100). All the samples of the study would be obtained from the Special Care dental
Unit at KCL Dental Institute, Guy's Hospital and from the Dental Clinic at KCL Dental
Institute.
The samples will include saliva, biofilm, mucosal swabs, carious dentine and/or teeth. The
samples collection will add approximately 10 to 20 min to the conventional treatment time.
All the samples will be collected at 3-time points before and after IMRT from the head and
neck cancer up to 12 months follow up.
Patients over the age of 18 in order to analyse permanent dentition and the age range for
cancer patients are over 18 years old, both gender,at any stage of disease, except where
distant metastases.
Subjects withouth Head and neck cancer age and gender matched. Following these inclusion
criteria the next patients are excluded younger than 18 (non-permanent dentition), unable to
give the consent patients who have been administered antibiotics in the previous 3 months
because the oral microbiota could be altered , patients with systemic disease (such as
Sjogren syndrome), subjects with non-controlled systemic diseases, that can affect the
salivary flow and host defence mechanism.
Sample size Calculation Statement Statistical advice was obtained prior to start this study
in order to determine the sample size required by a suitable power calculation. The power
calculation was based on comparing the mean protein levels in head and neck cancer patients
before and after IMRT. A study with 80% power at 5% level of significance (Chaudhury et al.,
2015) will be able to detect the true difference in all parameters before and after cancer
treatment with an effect size of 0.5 (high according to Cohen 1988) using two tailed test
would require a total sample of 35 patients
Proposed statistical analysis:
Descriptive statistics will be used to summarize the sample characteristics and other
clinical factors.
All analysis will be carried out using STATA 15.1 (College Station, Texas USA,
www.stata.com), GraphPad Prism 8 software (La Jolla California USA, www.graphpad.com) and
Microsoft Excel 2018, after checking for normality. Normality of the data will be tested for
all the parametric analyses using histogram and box plots. Results expresses as a mean ± SEM
relative to the variables and 'n' represents the number of subjects, p <0.05 value was
considered statistically significant.
Sample Collection
The following samples will be collected:
- unstimulated whole mouth saliva (UWMS), saline solution rinse
- plaque biofilm
- mucosal swabs collecting residual saliva from the inner cheek
- excavated carious dentine tissue and/or extracted carious teeth. Sample collection will
add 15 min to the conventional treatment time. Samples will be collected during the day,
routinely between the hours 1:30pm to 3:30pm in the dental clinic in an attempt to avoid
diurnal variations.
Unstimulated Whole Mouth Saliva Sample Collection (UWMS)
UWMS samples will be obtained by passive drooling into a pre -weighed 50 mL sterile conical
polypropylene tube (Falcon; BD Biosciences, San Jose, CA, USA) for 10 minutes. All
participants will avoid food and drink for at least 60 min prior to sample collection. The
samples wll be kept on ice at 4°C, After collection, the tubes will be re-weighed and the net
saliva volume calculated. Saliva samples will be labelled and stored in - 80 °C freezers for
further analysis. Saliva flow rate will be calculated.
Clinical Oral Assessment Dry Mouth and Taste Report answering a question from a validated
questionaire by Fox et al (Fox et al., 1987) and a question extracted from the Late Effects
of Normal Tissue/Somatic Objective Management Analytic (LENT/SOMA) scoring system.
Oral Mucositis Grading using The World Health Organization (WHO) Oral Toxicity Scale Dental
Assessment of carious lesions present from clinically visible change of colour to dark brown
on any surface to open lesions in the oral cavity. Number of teeth / decayed, missed or
filled (DMFT) will be included in the clinical assessment.
Sample Analysis
UWMS saliva samples Samples will be analysed for total protein content using the
Bicinchoninic Acid Assay (BCA), targeted protein concentration by Enzyme-Linked Immunosorbent
Assay (ELISA), Periodic Acid Schiff (PAS) staining, Coomassie Brilliant blue and α-amylase
activity by the standard kinetic enzyme assay (Salimetrics).
Prior to biochemical analysis UWMS samples will be centrifuged at 10000 RPM for 5 mins at
4°C. The supernatant will be separated to be used to analyse protein content and the pellet
was preserved to perform DNA extraction.
Protein Analysis (Concentration and Secretion Rate) Mucin 5B mucin 7, IgA, α-amylase, albumin
carbonic anhydrase VI, acidic proline rich protein and statherin were selected due to their
relationship to host defence, antimicrobial, bacterial adherence, colonization, mucosal
pellicle, enamel pellicle, viscoelastic, rheological properties, lubrication, and
remineralization.
Total protein secretion rate will be calculated by multiplication of the salivary flow rate
and protein concentration in ug / min (Carpenter et al., 2000).
Mucin 5B and 7 will be quantified by PAS,α-amylase by a kinetic assay,IgA, albumin, cystatin
S, proline rich protein and statherin concentration in UWMS will be determined using ELISA.
