Efficacy of Optically-guided Surgery in the Management of Early-staged Oral Cancer – COOLS TRIAL

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Brief Title

Efficacy of Optically-guided Surgery in the Management of Early-staged Oral Cancer - COOLS TRIAL

Official Title

Canadian Optically Guided Approach for Oral Lesions Surgical Trial - COOLS

Brief Summary

      Oral squamous cell carcinoma (SCC) is a global disease responsible for ~300,000 new cancer
      cases each year. Local recurrence (~30% of cases) and formation of second primary malignancy
      are common.2, 3 Cosmetic and/or functional compromise associated with treatment of disease
      stage is often significant. These statistics underscore the urgent need to develop a better
      approach in order to control this deadly disease.

      It is becoming increasingly apparent that oral cancers develop within wide fields of diseased
      tissue characterized by genetically altered cells that are widespread across the oral cavity
      and present in clinically and histologically normal oral mucosa. Complete removal of these
      lesions is difficult because high-risk changes frequently go beyond clinically visible tumor.
      In recognition of this, current 'best practice' is to remove SCC with a significant width
      (usually 10 mm) of surrounding normal-looking oral mucosa. However, since occult disease
      varies in size such approach often results in over-cutting (causing severe cosmetic and
      functional morbidity) or under removal of disease tissue, as evidenced by frequent positive
      surgical margins and high local and regional recurrence - a failure of the 'best practice.

      There is a wealth of literature that supports the use of tissue autofluorescence in the
      screening and diagnosis of precancers in the lung, uterine cervix, skin and oral cavity. This
      approach is already in clinical use in the lung and the mechanism of action of tissue
      autofluorescence has been well described in the cervix. Changes in fluorescence reflect a
      complex interplay of alterations to fluorophores in the tissue and structural changes in
      tissue morphology, each associated with progression of the disease.

      As one of the internationally leading teams in applying tissue fluorescence technology, we
      have shown that direct fluorescence visualization (FV) tools can identify clinically visible
      or occult premalignant and malignant lesions that are associated with lesions at risk, with
      high-grade histology and high-risk molecular change. In a recently small scaled,
      retrospective study, we have shown that FV helped surgeons in the operating room to determine
      the extent of the high-risk FV field surrounding the cancer and resulted in remarkably lower
      2-year recurrence rates (0% for FV-guided vs. 25% for those without FV-guided approach).
      There is need to design a larger scale prospective, randomized controlled (Phase III) trial
      to gather strong evidence in proving the efficacy of the surgery approach using this adjunct
      tool.

      To establish the evidence supporting the change in clinical practice using FV-guided surgery.
      There are 3 objectives.

      2.1. Objective 1 (Clinical evidence): To assess the effect of FV-guided surgery on the
      recurrence-free survival of histologically confirmed disease within the context of a
      randomized controlled trial (efficacy). Hypothesis: FV-guided surgery will increase the
      recurrence-free survival.

      2.2. Objective 2 (Quality of Life evidence): To establish the cost per recurrence prevented
      for this approach and assess quality of life issues. Hypothesis: FV-guided surgery can be
      delivered in a cost effective manner and improve the quality of life of patients 2.3
      Objective 3 (Scientific/Molecular evidence): To assess the presence of previously validated
      molecular markers (microsatellite analysis, LOH) and histological change (quantitative
      pathology) in surgical margins in a nested case-control study involving a tumor bank created
      within this project. Hypothesis: FV-guided surgery will spare normal tissue at the same time
      improving capture of high-risk tissue.
    

Detailed Description

      1.0. OBJECTIVES AND APPROACHES: 1.1. Objective 1 (Clinical evidence): To assess the effect of
      FV-guided surgery on the recurrence-free survival of histologically confirmed disease within
      the context of a randomized controlled trial (efficacy).

      Hypothesis: FV-guided surgery will increase the recurrence-free survival. Approaches: This
      Aim requires the establishment of a randomized controlled trial of 200 patients which will
      compare outcome for patients in 2 arms: one with conventional surgery with margin delineated
      under white light, and the other using FV guidance for margin delineation. Please see
      attached Appendix 1 for a step-by-step protocol. This comprises a multidisciplinary team of
      surgeons, pathologists, project coordinators, and FV Specialists. In addition to the
      presurgery assessment, all participating patients will have 3-month follow-ups for the first
      2 years and 6-month for the rest of the study period. Biopsy will occur when clinically
      warranted or at 2-year post-surgery.

      1.2. Objective 2 (Quality of Life evidence): To establish the cost per recurrence prevented
      for this approach and assess quality of life issues.

      Hypothesis: FV-guided surgery can be delivered in a cost effective manner and improve the
      quality of life of patients.

      Approaches: This aim requires the collection of economic and quality of life (QoL) data to
      establish the cost per recurrence prevented for FV-guided surgery and to assess quality of
      life impacts. To asses potential psychosocial consequences of FV-guided surgery we will
      measure global QoL. We will use the validated EQ-5D and Functional Assessment of Cancer
      Therapy Head and Neck Module (FACT-H&N) to determine the participant's QoL at each
      assessment. The questionnaires will be applied at pre-surgery baseline, and at 6-week,
      3-month, and 24-month post-surgery follow-ups.

      1.3 Objective 3 (Scientific/Molecular evidence): To assess the presence of previously
      validated molecular markers (microsatellite analysis, LOH) and histological change
      (quantitative pathology) in surgical margins in a nested case-control study involving a tumor
      bank created within this project.

      Hypothesis: FV-guided surgery will spare normal tissue at the same time improving capture of
      high-risk tissue.

      Approaches: This Aim requires the retrieval and cutting of the archive material for a nested
      control study. The estimate number of cases reach outcome is 30 (5% of FV group (100) + 25%
      of control group (100). Additionally, 60 matched controls will be selected (matched by
      gender, age, smoking habit, and anatomical site). This Aim is critical to demonstrate a shift
      in field, sparing normal tissue while catching high-risk occult tissue. Samples for the
      nested molecular analysis will be performed in Rosin's Lab (for microsatellite analysis) and
      Cancer Imaging at BC Cancer Agency (Dr. MacAulay for qualitative Pathology). The protocols
      used to analyze these samples have been published.

      2.0. STUDY TOOL - VELSCOPE® We have recently developed a simple hand-held field-of-view
      device for direct visualization of tissue fluorescence in the oral cavity. This tool is
      currently commercially available as VELScope® (LED Med Inc., White Rock, BC). We have begun a
      longitudinal study to explore the effect of FV in defining the surgical margin on outcome of
      oral cancer surgery27. Between 2004 and 2008, 60 patients with a ≤4 cm oral cancer entered
      the study. Each case was treated with surgical excision alone and was followed for at least
      12 months. Thirty-eight patients had FV-guided surgery, with the surgical margin placed at 10
      mm beyond the perimeter of autofluorescence loss. The remaining patients (control group) had
      the surgical margin placed at 10 mm beyond the tumor edge defined by standard white-light
      examination. Among those, 7 of the 60 cases (12%) have developed a recurrence of severe
      dysplasia, carcinoma in situ or squamous cell carcinoma at the treated site, all in the
      control group (25% versus 0%, P = 0.002). These data suggest the potential utility of
      autofluorescence changes within this clinical setting. There is a need to design a larger
      scaled randomized controlled clinical trial to confirm the efficacy of FV-guided surgery.

      We are also using FV to monitor the potential re-emergence of regions of autofluorescence
      loss at treated sites in the cases accrued to the longitudinal study and are currently
      completing an interim assessment of these monitoring results. Autofluorescence loss persists
      in some cases, increasing in size and intensity over time and giving rise to a clinical
      lesion containing dysplasia or cancer.

      3.0 Core members of the trial and project management We have a well-built core group with
      long-term and strong working relationships, including surgeons (Drs. Anderson (Co-PI) and
      Durham), Pathologists (Drs. Berean (Co-PI) and Zhang), and Oral Medicine (Drs. Poh (PI) and
      Williams), and are in a world-leading position in using fluorescence visualization in
      operating room and in follow-up. Dr. J. Lee, collaborator, from M.D. Anderson Cancer Centre
      and has extensive experience in clinical trials with special expertise in randomized
      controlled trial. He will be the trialist in this project, design a program for patient
      randomization, oversee the trial protocol, and work with local statistician (Prof. Chen) for
      day-to-day data management. Professor Jiahua Chen, Department of Statistics, the University
      of British Columbia will serve as the biostatistician to the trial and will be responsible
      for the data analysis and submission of interim analyses to the Data Safety Monitoring Board.

      4.0 Basic trial design The proposed study will be a double-blinded, randomized controlled
      Phase III study to evaluate the effect of FV-guided surgery in patients diagnosed with severe
      dysplasia, carcinoma in situ and invasive squamous cell carcinoma and undergoing surgery
      treatment with an intent-to-cure. The trial will randomize 200 patients -100 in the FV arm
      (using FV guided the surgery margin) and 100 in the control arm (using conventional white
      light approach). The trial period is 5 years - 2 years to complete accrual and 3 more years
      of follow-up.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Recurrence-free survival

Secondary Outcome

 Histological and molecular evidence of positive margins and quality of life

Condition

Oral Cancer

Intervention

Fluorescence visualization device

Study Arms / Comparison Groups

 A
Description:  All subjects in this study will receive surgery to treat their oral lesions. The margins (or boundaries) of the tissue to be removed during surgery will be defined by 2 different procedures (or study arms) in the operating room.
The Control arm. Surgical boundaries for oral lesions will be defined under regular white light.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

200

Start Date

January 2013

Completion Date

June 2015

Primary Completion Date

December 2014

Eligibility Criteria

        Inclusion Criteria:

          -  Patients diagnosed with severe dysplasia, carcinoma in situ, invasive squamous cell
             carcinoma (T1 or T2) of the oral cavity (ICO-D site codes: C02.0-C06.9) who will be
             undergoing curative resection (primary disease).

        Exclusion Criteria:

          -  Patients with a non-oral malignancy diagnosed (not including non-melanoma skin cancer
             and lymphoma outside of head and neck region) within the past 3 years.

          -  Patients with evidence of distant metastasis (as determined by CAT and X-ray) at the
             time of recruitment.
      

Gender

All

Ages

19 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Catherine Poh, DDS, PhD, 604-675-8057, [email protected]

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT01039298

Organization ID

H09-03090


Responsible Party

Sponsor

Study Sponsor

University of British Columbia

Collaborators

 Terry Fox Research Institute

Study Sponsor

Catherine Poh, DDS, PhD, Principal Investigator, University of British Columbia


Verification Date

September 2014