Last updated on February 2018

Innovative Approach to Triage Oral Precancer

Brief description of study

Oral cancer is a major health problem worldwide, accounting for 274,000 new cases and 145,000 deaths annually. On average, half of the patients die within 5 years of an oral cancer diagnosis. Most troubling, however, is the lack of significant change in prognosis for this disease over the last 4 decades, even in developed nations. Even when successful, treatment of oral cancer can be devastating due to diminished quality of life and disfigurement. The key to controlling this disease is early identification of lesions that are at high risk of progression and provide effective treatment. The overall objective of the team is to integrate clinical, pathological, molecular, and imaging data to create a robust oral cancer risk model to predict the risk of progression of OPLs and to develop population-wide cost-effective prevention strategies for high-risk oral premalignancies. The project will involve 4 specific aims as described in detail below.

Aim 1. To use molecular data to stratify low-grade OPLs into high- and low-risk groups.

Aim 2. To evaluate the cost-effectiveness of various follow-up frequency that use LOH at chromosome 9p21 as a risk marker.

Aim 3: To evaluate the specificity and sensitivity of using imaging technologies as a tool for the decision of the high-grade or high-risk biopsy site.

Aim 4. To assess the clinical utility of a miRNA expression signature derived from serum collected from patients with oral cancer and OPLs.

Detailed Study Description

  1. Patient accrual This study will be occurring at the Otolaryngology Clinic, Vancouver General Hospital. Three hundred and sixty volunteer subjects will be enrolled to participate in the study. Detailed steps of the study patient accrual are provided below.
    1. The establishment of referral pipelines for a true population-based OPL cohort in BC.
      In BC, the BC Oral Biopsy Service (OBS) and the Pathology Department at Vancouver
      General Hospital (VGH) receive biopsy and surgical specimens from the dental and
      medical communities, respectively. These centralized biopsy services offer a very
      rare opportunity to establish a population-based cohort of OPLs. The pathologists
      team will identify eligible patients through the pathology sign-out process and
      call the submitting physicians to notify the potential referral pipeline as an
      alternative management for these patients. Currently, a referral pipeline for
      severe dysplasia or more advanced oral malignancy using this model exists and has
      been established to refer surgical patients for the TFRI-funded COOLS trial (by
      Drs. Durham and Poh; H09-03090). This same system/pipeline will be used to identify
      eligible patients diagnosed with mild and/or moderate dysplasias identified from
      both medical and dental communities.

     2. Eligibility Subjects over the age of 19 attend the Dental or Otolaryngology clinic
      at the Vancouver General Hospital (Vancouver Acute) for assessment of oral lesions
      diagnosed with mild or moderate dysplasia; are willing to give the informed

     3. Recruitment & informed consent procedures A letter of invitation regarding this
      study will be mailed to the potentially eligible patients a week before their
      appointment date along with the consent document. On the day of the clinical visit,
      the research assistant will explain the study to the eligible subject and acquire
      signed consent from the participants. 400 subjects will be recruited. These
      patients will be monitored once every six months (the current standard of care).
      When clinically warranted due to signs of disease progression or at the 2-year
      follow-up mark, two 5-mm punch biopsies will be performed on lesion areas with
      different severity (as determined by imaging technologies). Two-year comparative
      biopsy at a stable lesion is current standard of care.

2. Study procedures The study is a longitudinal study following the follow-up schedule of

     the current standard of care for such lesions, i.e., once per 6 months and comparative
     biopsy once per 2-3 years. The important time points are initial visit (baseline), at
     the end of second, 5th and 8th year of follow up visits. However, the time of biopsy is
     solely based on the clinical judgment of the clinicians, i.e., signs of disease

     1. Clinical data collection After the subject has consented, they will be asked to
      complete a set of questionnaires for the collection of demographics and risk factor
      information. The subject will be assigned a study ID and no unique identifier will
      be linked to the data collected. A separate file will be used to link the study ID
      and patient identifiers. This is important to facilitate patient management and
      capture the outcome information. This file with patients' unique identifier will be
      kept in the pass-word protected file in the BC Cancer Research Centre (BCCRC)
      computer in a locked office in the BCCCRC and only PIs can access the file. The
      health status and HAI questionnaire is not for diagnostic purposes. Should the
      clinicians believe there is depression or anxiety present in the participant
      (clinicians' clinical judgment), the study clinicians in charge of this specific
      participant will communicate with patient's family doctor and refer the participant
      to a proper source for further evaluation and management.

     2. Data collection using study device

      -  The clinicians will examine the patients using WL, VELScope VX for FV
       (previously approved, R05-0116), OCT (previously approved, H09-01955), and a
       hand-held confocal microscope (H11-00011).

      -  OCT imaging: After identifying the abnormal areas for biopsy using WL and FV
       examination, the clinician will place a fiber-optic probe of the OCT on the
       oral mucosal areas of interest. The site for placement of the probe will be
       determined by PIs (Otolaryngology-head and neck surgeons (SD/DA) and/or Oral
       Medicine/Oral Pathology Specialist (Ng/Poh)). The images will be recorded by
       the machine for later analysis.

      -  Confocal microscope imaging: After OCT imaging, the clinician will apply 0.05%
       Acriflavine Hydrochloride solution topically on the oral mucosal areas of
       interest for 30 seconds prior to imaging. The clinician will place a hand-held
       confocal microscope on the mucosal surface to record the observation for later

      -  All necessary efforts will be taken to reduce any mild discomfort that could
       be associated with the probe placement inside the oral cavity of a subject.
       The OCT probe or the confocal microscope will be covered by a plastic barrier
       and disinfected by standard methods used for oral cavity instruments before
       and after subject usage. The device examination will take no more than 15
       minutes in addition to the subject's appointment time for their routine
       visits. The maximum intensity of tissue illumination for each measurement will
       be less than the Threshold Limit Value (TLV) established by the American
       Conference of Governmental Industrial Hygienists (ACGIH)11 for exposure to
       broadband light.

      -  The information obtained from polarized reflectance measurements will be
       compared with the histology and quantitative pathology (nuclear phenotype
       score) of the tissue sections from the lesion. The collected spectra data from
       normal looking areas from adjacent normal looking mucosa and contralateral
       mucosa will be used to determine patient to patient variation in the polarized
       reflectance of oral mucosa.

     3. Exfoliative brushing sample collection (previously approved, R05-0116) An Innovatec
      cytology brush (Arcona Inc) is used to collect exfoliated cells from the oral
      lesion. These brushings are transferred into PreservCyt Solution (Cytyc Corp.) and
      keep in 4C fridge.

     4. Blood sample collection In total, 12 ml (3/4 of a tablespoon) of blood sample will
      be collected in 1 SST and 1 EDTA vacutainers in the clinic by trained research
      personnel. The blood sample will be processed and serum, plasma and puffy coat
      samples will be aliquot and frozen in -80C for future analysis. The DNA samples in
      the puffy coat will be extracted and used as the normal control sample for the loss
      of heterozygosity (LOH) analysis. A separate consent will be used for this purpose.
      We anticipate that all aliquots of serum, plasma and puffy coat will be used up.
      Any remaining tissue will not be discarded or sold, but will be stored in a locked
      freezer room at the BC Cancer Agency for a period of up to fifteen years so that
      results of this study can be confirmed.

     5. Frozen tissue collection In the event of biopsy, tissue will be bisected. Half of
      the sample will be fixed in the formalin solution and sent to the pathology
      laboratory for analysis as a normal part of medical diagnosis procedure. Part of
      this tissue will be kept and used only after the diagnosis has been made. At no
      time will tissue be removed solely for the purpose of research. The donated tissue
      will be given a code for identification by the project leader, and will be kept in
      secure freezers at the BC Cancer Agency until genetic material (DNA and RNA) has
      been extracted for analysis. A separate consent will be used for this purpose. We
      anticipate that all donated tissue will be used up. Any remaining tissue will not
      be discarded or sold, but will be stored in a locked freezer room at the BC Cancer
      Agency for a period of up to fifteen years so that results of this study can be

     6. Tissue microdissection and DNA extraction. The formalin-fixed, paraffin-embedded
      tissue blocks of the initial biopsy and biopsy from the follow-up visit will be
      obtained from the Department of Anatomical Pathology, the Vancouver General
      Hospital. at the time of clinical change or at 24 months follow-up visit will be
      requested for processing. Ten 10-m thick sections for DNA sample, 2 4-m unstained
      tissue sections for quantitative histological analysis. Areas of dysplasia on the
      thick sections will be identified and microdissected. The DNA sample from the
      epithelium will be extracted and used for the LOH analysis.

Clinical Study Identifier: NCT03202810

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