Official Title
Canadian Optically Guided Approach for Oral Lesions Surgical Trial - COOLS
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 tumour. 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 tumour bank created within this project. Hypothesis: FV-guided
surgery will spare normal tissue at the same time improving capture of
high-risk tissue.
Trial Description
Primary Outcome:
Secondary Outcome:
- Histological and molecular evidence of positive margins and quality of life
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 tumour 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 tumour 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.
View this trial on ClinicalTrials.gov
