Study design
The COOLS trial is a multicentre, double blind, randomized controlled study, comparing FV- guided surgery (experimental arm) to conventional white light (WL)-guided surgery (control arm). See Figure 1 for the schema of the study.
This study has been approved by the human research ethics committees at each of the participating institutions. Any future amendments to the study protocol will be submitted to each committee for approval. The trial has been registered at Clinicaltrials.gov (NCT01039298).
Sample size
A total of 400 subjects (240 invasive squamous cell carcinoma and 160 severe dysplasia or carcinoma in situ) will be randomized from 9 centres across Canada (from west to east): Vancouver, British Columbia; Calgary and Edmonton, Alberta; Winnipeg, Manitoba; Toronto (Sunnybrook Hospital), London, and Ottawa, Ontario; Montreal (McGill University Health Centre), Quebec; Halifax, Nova Scotia.
Target population
The study is open to patients with high-grade preinvasive (severe dysplasia/carcinoma in situ) or invasive squamous cell carcinoma (T1 or T2) of the oral cavity.
Inclusion Criteria
Patients with disease localization at oral anatomical sites that can be visualized using both white light and fluorescence visualization device (this includes ICD-10 site codes: C02.0-C06.9); patients with a clinical diagnosis of N0 or N1 as confirmed by CT scan, with the latter undergoing neck dissection; or patients with resectable locally recurrent disease diagnosed with severe dysplasia or higher grade, provided that they are at least 6 months post-treatment (this time frame will allow resolution of artefacts produced by treatment that could impact on tumor or lesion visualization).
Exclusion Criteria
Patients with concurrent non-oral malignancy diagnosed within the past 3 years (patients with non-melanoma skin cancer or lymphoma that lie outside of the head and neck region are included); patients with evidence of distant metastasis, as determined by CT and X-ray at the time of recruitment; patients with illnesses that could preclude standard diagnostic tests and post-surgery follow-up; and patients with lesions located at the base of tongue (C01) or tonsil (C09), as these sites are not readily assessable to FV.
All patients will provide written informed consent for study participation.
Key steps
Patient recruitment
Site surgeons will identify potentially eligible patients and briefly introduce the study to the patient (see key steps in Figure 2). The local site coordinator will be informed and will contact the patient to arrange an appointment to discuss the study and for a pre-surgery assessment. As part of that eligibility assessment, all patients with squamous cell carcinoma will have a CT scan from skull base to chest as a baseline to confirm the clinical nodal status and the absence of the upper alimentary and respiratory tract and lung metastasis or second primary tumor. Upon verifying all the eligibility criteria, the study coordinator will obtain informed consent from the eligible and interested patients.
Pre-surgery assessment
Prior to the assessment, the site coordinator will assist the patient to complete a set of study questionnaires covering socio-demographic factors, risk factors, comorbidity and family cancer history. Quality of life will be assessed with the EQ-5D [15, 16], the Functional Assessment of Cancer Therapy Head and Neck Module (FACT-H&N)[17, 18] and the Speech Handicap Index, a specific tool for the measurement of speech pathology. [19]
The lesion undergoing surgery will be assessed by a trained FV Specialist (FVS) using both WL and FV. The FVS will be either a dental specialist or a head & neck surgeon who will not be performing the surgery for the patient. With the assistance of the site coordinator, digital images will be obtained of the lesion under both conditions and lesion size and location will be recorded on the case report form (CRF). Both the images and the CRF will be uploaded to the trial's web-based database.
The FV assessment will be performed with an autofluorescence imaging device, marketed as the VELscope®, (LED Dental Inc., White Rock, British Columbia, Canada), using protocols described in Poh et al. [12] The examination is performed under reduced room lighting and involves the inspection of the entire oral mucosa in the same manner as the conventional intraoral examination, with special attention to the lesion site. Tissue that show a reduction in the normal pale green, appearing as dark patches, will be categorized as FV positive (FVpos). Lesions that retain the normal green autofluorescence under FV are classified as FV negative (FVneg). Both WL and FV digital images of the lesion will be recorded prior to randomization.
Intervention (Surgery)
At the time of surgery the operating surgeon will outline the boundary of the clinically visible lesion under white light. The FVS will take an image (Image 1); measure its size; and record data on the surgical tracking sheet.
a. If this is a FV-guided surgery (experimental arm)
With the operating room (OR) lights off, the FVS will use the VELscope Vx to examine the lesion and outline the FV change using a green Sharpie pen. After the FV positive boundary is outlined, images (Image 2) are taken in the dark to demonstrate the distance between FVL and clinical outline.
With the OR light back on, the FVS will measure the distance from FV boundary to the clinical boundary in 4 directions, and record this on the surgical tracking sheet. The site surgeon will outline a 10 mm surgical boundary around the clinically visible tumor and FV boundaries, whichever is wider. The FVS will take images (Image 3) under both FV and WL and record if there is any anatomical restriction for the placement of the standardized surgical boundary.
b. If this is a WL- guided surgery (control arm)
With the light off, the FVS will use the VELscope VX to examine the lesion and draw an outline on top of the surgeon's clinical boundary using a green Sharpie pen. After this step, the FVS will take another set of images (Image 2). In this case, the 2 outlines will be identical and this will be recorded on the surgical tracking sheet. The surgeon will outline a 10 mm surgical boundary around the clinical/FV boundary. The FVS will take images (Image 3) under both FV and WL and record if there is any anatomical restriction for the placement of the standardized surgical boundary.
The operating surgeon will remain outside the OR while the FVS marks the boundaries. Although it is unlikely the surgeon will remain blinded once the two markings are made, any deviation from the marked boundary will be recorded to allow assessment of deviation from the protocol.
Blood samples (5 ml in SST and 12 ml in EDTA tubes) will be collected at this time prior to the surgery. The tumor will then be resected and oriented using a suture for the anterior or right orientation. This will be indicated on the routine pathology requisition form to help the SP to orient the resected tissue. The specimen will be wrapped in a piece of cold saline gauze and kept on ice during transfer to the Pathology Department for processing.
The Site Pathologist (SP) will either use the tracking sheet or a print-out of the digital image of the excised tissue to record the tissue blocking. One-week after the diagnosis has been determined all the H&E sections will be sent to the Central Histology Review committee for histological review. If there is disagreement on the assessment between the site pathologist and the review committee, a teleconference will be arranged in order to discuss and achieve consensus. The site coordinator will upload all images, surgical and pathological CRFs and key information from pathology reports into the study database.
Follow-up
All patients will return for follow-up examinations every 3 months for two years and then every 6 months for the remainder of the study period. At each visit the entire oral mucosa will be examined under WL, with surgery sites photographed. The presence of lesions will be noted on lesion tracking sheets along with lesion size and location. Updated clinical information, digital images and data fields from the quality of life questionnaires will be uploaded to the database by the SC.
Decision to biopsy will depend on the clinical judgment of the surgeon, based on suspicion of a recurrence. If there is no significant clinical change, a biopsy will be taken at the surgery site at 2-year post surgery. A repeat CT scan is warranted if there is clinical suspicion of regional or distant diseases. If there is no clinical indication, Neck CT scan and a chest X-ray will be arranged at 2-year post surgery follow-up.
Randomization
Stratified randomization will be employed. Two stratification factors will be applied: 1) institution and 2) histological grade of the primary lesion (severe dysplasia and carcinoma in situ or invasive squamous cell carcinoma).
A randomization program has been written specifically for this trial (JJL). According to the information collected, the central database manager under the supervision of the study biostatistician (PMB) will perform the randomization. Within each stratum, the minimization algorithm will be used to achieve balanced randomization with respect to other prognostic factors, including surgeon, gender, age, smoking history, and lesion anatomical sites. [20]
The randomization will be done 1 - 2 days prior to surgery. Only the FVS will be notified of the result. The patient, research staff, operating surgeon, and the pathologist are not aware of the assignment. The allocation list will be held by the study database manager; this individual is not involved in patient care or recruitment. The allocation will only be revealed in the event of an emergency medical situation.