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Canadian Optically-guided approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized… Poh, Catherine F; Durham, J S; Brasher, Penelope M; Anderson, Donald W; Berean, Kenneth W; MacAulay, Calum E; Lee, J J; Rosin, Miriam P Oct 25, 2011

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STUDY PROTOCOL Open AccessCanadian Optically-guided approach for OralLesions Surgical (COOLS) trial: study protocol fora randomized controlled trialCatherine F Poh1,4,5,8*, J Scott Durham2,6, Penelope M Brasher3,7, Donald W Anderson2,6, Kenneth W Berean8,Calum E MacAulay4, J Jack Lee9 and Miriam P Rosin5,10AbstractBackground: Oral cancer is a major health problem worldwide. The 5-year survival rate ranges from 30-60%, andhas remained unchanged in the past few decades. This is mainly due to late diagnosis and high recurrence of thedisease. Of the patients who receive treatment, up to one third suffer from a recurrence or a second primarytumor. It is apparent that one major cause of disease recurrence is clinically unrecognized field changes whichextend beyond the visible tumor boundary. We have previously developed an approach using fluorescencevisualization (FV) technology to improve the recognition of the field at risk surrounding a visible oral cancer thatneeds to be removed and preliminary results have shown a significant reduction in recurrence rates.Method/Design: This paper describes the study design of a randomized, multi-centre, double blind, controlledsurgical trial, the COOLS trial. Nine institutions across Canada will recruit a total of 400 patients with oral severedysplasia or carcinoma in situ (N = 160) and invasive squamous cell carcinoma (N = 240). Patients will be stratifiedby participating institution and histology grade and randomized equally into FV-guided surgery (experimental arm)or white light-guided surgery (control arm). The primary endpoint is a composite of recurrence at or 1 cm withinthe previous surgery site with 1) the same or higher grade histology compared to the initial diagnosis (i.e., thediagnosis used for randomization); or 2) further treatment due to the presence of severe dysplasia or higherdegree of change at follow-up. This is the first randomized, multi-centre trial to validate the effectiveness of the FV-guided surgery.Discussion: In this paper we described the strategies, novelty, and challenges of this unique trial involving asurgical approach guided by the FV technology. The success of the trial requires training, coordination, and qualityassurance across multiple sites within Canada. The COOLS trial, an example of translational research, may result inreduced recurrence rates following surgical treatment of early-stage oral cancer with significant impacts on survival,morbidity, patients’ quality of life and the cost to the health care system.Trial Registration: Clinicaltrials.gov NCT01039298BackgroundOral cancer is a major health problem worldwide,accounting for 274,000 new cases and 145,000 deathsannually [1]. Although it occurs at a site that is easilyaccessible for examination it is often diagnosed at anadvanced stage, with 5-year survival rates ranging from30-60%, depending on the global locale. Treatment ofearly stage squamous cell carcinoma is an essential com-ponent of effective oral cancer management; a recentlarge (~190,000) randomized trial of a screening pro-gram showed the mortality rate ratio between interven-tion and control groups was 0.79 [95% CI 0.51 - 1.22][2]. However, even with treatment there are high ratesof second oral malignancies, with up to a third of thesepatients suffering a recurrence or a second primary[3,4]. There has been extensive research in the* Correspondence: cpoh@interchange.ubc.ca1Department of Oral Biological and Medical Science, The University of BritishColumbia, Wesbrook Mall, Vancouver, CanadaFull list of author information is available at the end of the articlePoh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462© 2011 Poh et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.importance of examining the field surrounding oral can-cers for risk assessment and management of this disease[5-7]. Using molecular technology, it is becomingincreasingly apparent that genetically altered cells areoften widespread across the mucosa of patients withoral cancer, extending into clinically and histologicallynormal tissue, and that these cells can drive the processof field cancerization. Recognizing this, surgeons try toremove oral squamous cell carcinomas (SCC) with a sig-nificant margin of surrounding normal-looking oralmucosa. However, the occult disease varies in size and awealth of evidence suggests that it frequently extendsbeyond the tumor clearance area [5-8]. This extensionmay be responsible for the high rate of cancer recur-rence at the primary site (10-30% of SCC cases) [9-11].Taking margins that are too large can result in over-cut-ting (causing severe cosmetic and functional morbidity)and margins that are too small may leave cancerous tis-sue behind, as evidenced by frequent positive surgicalmargins and high local and regional recurrence - a fail-ure of the ‘best practice’.Our research team has developed an approach usingfluorescence visualization (FV) technology, whichimproves the recognition of the field at risk surroundinga visible oral cancer [12,13]. Our preliminary resultsshow that using FV to define the field at risk for surgi-cal resection can result in a marked reduction in recur-rence rates at 3 years (0/38 vs. 7/22) [14]. Our goal inthis study is to rigorously evaluate and validate theeffectiveness of FV-guided surgeries compared to whitelight in a multicentre pan-Canadian randomized controlstudy.ObjectiveThe trial has 4 objectives. The primary objective is todetermine the effectiveness of FV-guided surgery inreducing local recurrence after surgical excision ofsevere dysplasia or cancer of the oral cavity. Secondaryobjectives include 1) To collect molecular and phenoty-pic evidence in margins to test if FV produces a shift insurgical field, sparing normal tissue while catching high-risk occult tissue; 2) To collect relative cost-effective evi-dence of the two arms in both the cost per avoidedrecurrence and the cost per quality-adjusted life yearsgained; and 3) To develop a knowledge translation (KT)strategy that will foster the dissemination of FV-guidedsurgery across Canada and globally.Methods/designStudy designThe COOLS trial is a multicentre, double blind, rando-mized controlled study, comparing FV- guided surgery(experimental arm) to conventional white light (WL)-guided surgery (control arm). See Figure 1 for theschema of the study.This study has been approved by the human researchethics committees at each of the participating institu-tions. Any future amendments to the study protocolwill be submitted to each committee for approval. Thetrial has been registered at Clinicaltrials.gov(NCT01039298).Sample sizeA total of 400 subjects (240 invasive squamous cell car-cinoma and 160 severe dysplasia or carcinoma in situ)will be randomized from 9 centres across Canada (fromwest to east): Vancouver, British Columbia; Calgary andEdmonton, Alberta; Winnipeg, Manitoba; Toronto (Sun-nybrook Hospital), London, and Ottawa, Ontario; Mon-treal (McGill University Health Centre), Quebec;Halifax, Nova Scotia.Target populationThe study is open to patients with high-grade preinva-sive (severe dysplasia/carcinoma in situ) or invasivesquamous cell carcinoma (T1 or T2) of the oral cavity.Eligible patient  Identification at each geographic site  Stratify FV*-guided surgery (N= 80 + 120) Randomize Conventional surgery (Non -FV-guided) (N=80 + 120) Endpoint   Local recurrence * FV: fluoresence visualization Preinvasive  high- grade lesions (N=160) Invasive cancers  (N=240)  Figure 1 Trial schema. A total of 400 subjects (240 invasive squamous cell carcinoma and 160 severe dysplasia or carcinoma in situ) will berandomized equally into FV-guided surgery (experimental arm) or white light-guided surgery (control arm). The primary endpoint is a compositeof recurrence at or 1 cm within the previous surgery site with 1) the same or higher grade histology compared to the initial diagnosis (i.e., thediagnosis used for randomization); or 2) further treatment due to the presence of severe dysplasia or higher degree of change at follow-up.Poh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 2 of 9Inclusion CriteriaPatients with disease localization at oral anatomical sitesthat can be visualized using both white light and fluor-escence visualization device (this includes ICD-10 sitecodes: C02.0-C06.9); patients with a clinical diagnosis ofN0 or N1 as confirmed by CT scan, with the latterundergoing neck dissection; or patients with resectablelocally recurrent disease diagnosed with severe dysplasiaor higher grade, provided that they are at least 6 monthspost-treatment (this time frame will allow resolution ofartefacts produced by treatment that could impact ontumor or lesion visualization).Exclusion CriteriaPatients with concurrent non-oral malignancy diagnosedwithin the past 3 years (patients with non-melanoma skincancer or lymphoma that lie outside of the head and neckregion are included); patients with evidence of distantmetastasis, as determined by CT and X-ray at the time ofrecruitment; patients with illnesses that could precludestandard diagnostic tests and post-surgery follow-up; andpatients with lesions located at the base of tongue (C01) ortonsil (C09), as these sites are not readily assessable to FV.All patients will provide written informed consent forstudy participation.Key stepsPatient recruitmentSite surgeons will identify potentially eligible patientsand briefly introduce the study to the patient (see keysteps in Figure 2). The local site coordinator will beinformed and will contact the patient to arrange anappointment to discuss the study and for a pre-surgeryassessment. As part of that eligibility assessment, allpatients with squamous cell carcinoma will have a CTscan from skull base to chest as a baseline to confirmthe clinical nodal status and the absence of the upperalimentary and respiratory tract and lung metastasis orsecond primary tumor. Upon verifying all the eligibilitycriteria, the study coordinator will obtain informed con-sent from the eligible and interested patients.Pre-surgery assessmentPrior to the assessment, the site coordinator will assist thepatient to complete a set of study questionnaires coveringsocio-demographic factors, risk factors, comorbidity andfamily cancer history. Quality of life will be assessed withthe EQ-5D [15,16], the Functional Assessment of CancerTherapy Head and Neck Module (FACT-H&N)[17,18]and the Speech Handicap Index, a specific tool for themeasurement of speech pathology. [19]The lesion undergoing surgery will be assessed by atrained FV Specialist (FVS) using both WL and FV. TheFVS will be either a dental specialist or a head & necksurgeon who will not be performing the surgery for thepatient. With the assistance of the site coordinator, digi-tal images will be obtained of the lesion under bothconditions and lesion size and location will be recordedon the case report form (CRF). Both the images and theCRF will be uploaded to the trial’s web-based database.The FV assessment will be performed with an auto-fluorescence imaging device, marketed as the VEL-scope®, (LED Dental Inc., White Rock, BritishColumbia, Canada), using protocols described in Pohet al. [12] The examination is performed under reducedroom lighting and involves the inspection of the entireoral mucosa in the same manner as the conventionalintraoral examination, with special attention to thelesion site. Tissue that show a reduction in the normalpale green, appearing as dark patches, will be categor-ized as FV positive (FVpos). Lesions that retain the nor-mal green autofluorescence under FV are classified asFV negative (FVneg). Both WL and FV digital images ofthe lesion will be recorded prior to randomization.Intervention (Surgery)At the time of surgery the operating surgeon will outlinethe boundary of the clinically visible lesion under whitelight. The FVS will take an image (Image 1); measureits 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 willuse the VELscope Vx to examine the lesion and outlinethe FV change using a green Sharpie pen. After the FVpositive boundary is outlined, images (Image 2) aretaken in the dark to demonstrate the distance betweenFVL and clinical outline.With the OR light back on, the FVS will measure thedistance from FV boundary to the clinical boundary in 4directions, and record this on the surgical trackingsheet. The site surgeon will outline a 10 mm surgicalboundary around the clinically visible tumor and FVboundaries, whichever is wider. The FVS will takeimages (Image 3) under both FV and WL and record ifthere is any anatomical restriction for the placement ofthe standardized surgical boundary.b. If this is a WL- guided surgery (control arm) Withthe light off, the FVS will use the VELscope VX toexamine the lesion and draw an outline on top of thesurgeon’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 identicaland this will be recorded on the surgical tracking sheet.The surgeon will outline a 10 mm surgical boundaryaround the clinical/FV boundary. The FVS will takeimages (Image 3) under both FV and WL and record ifthere is any anatomical restriction for the placement ofthe standardized surgical boundary.The operating surgeon will remain outside the ORwhile the FVS marks the boundaries. Although it isPoh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 3 of 9unlikely the surgeon will remain blinded once the twomarkings are made, any deviation from the markedboundary will be recorded to allow assessment of devia-tion from the protocol.Blood samples (5 ml in SST and 12 ml in EDTAtubes) will be collected at this time prior to the surgery.The tumor will then be resected and oriented using asuture for the anterior or right orientation. This will beindicated on the routine pathology requisition form tohelp the SP to orient the resected tissue. The specimenwill be wrapped in a piece of cold saline gauze and kepton ice during transfer to the Pathology Department forprocessing.The Site Pathologist (SP) will either use the trackingsheet or a print-out of the digital image of the excisedtissue to record the tissue blocking. One-week after thediagnosis has been determined all the H&E sections will besent to the Central Histology Review committee for histo-logical review. If there is disagreement on the assessmentbetween the site pathologist and the review committee, ateleconference will be arranged in order to discuss andachieve consensus. The site coordinator will upload allimages, surgical and pathological CRFs and key informa-tion from pathology reports into the study database.Follow-upAll patients will return for follow-up examinations every3 months for two years and then every 6 months for theremainder of the study period. At each visit the entireoral mucosa will be examined under WL, with surgerysites photographed. The presence of lesions will beA. Patient identification and recruitmentB. Clinical (pre-surgery) assessmentC. In OR, a step-by-step approachD. Pathology Assessment  (Tissue procurement) Key stepsE. Follow-upCliniciansSite SurgeonFV SpecialistSite SurgeonFV SpecialistSite PathologistSite SurgeonFV SpecialistRecruit and consentAssist patients to Complete surveys Coordinate with Site Surgeon, FV Specialist and Site Pathologist Site coordinatorData and specimens collectionData and specimens collectionCoordinate with Site Surgeon, FV Specialist and Site Pathologist Figure 2 Flow chart of key steps and the involvement of key personnel in each steps and site coordinator’s role.Poh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 4 of 9noted on lesion tracking sheets along with lesion sizeand location. Updated clinical information, digitalimages and data fields from the quality of life question-naires will be uploaded to the database by the SC.Decision to biopsy will depend on the clinical judg-ment of the surgeon, based on suspicion of a recurrence.If there is no significant clinical change, a biopsy will betaken at the surgery site at 2-year post surgery. A repeatCT scan is warranted if there is clinical suspicion ofregional or distant diseases. If there is no clinical indica-tion, Neck CT scan and a chest X-ray will be arrangedat 2-year post surgery follow-up.RandomizationStratified randomization will be employed. Two stratifi-cation factors will be applied: 1) institution and 2) histo-logical grade of the primary lesion (severe dysplasia andcarcinoma in situ or invasive squamous cell carcinoma).A randomization program has been written specificallyfor this trial (JJL). According to the information collected,the central database manager under the supervision of thestudy biostatistician (PMB) will perform the randomiza-tion. Within each stratum, the minimization algorithm willbe used to achieve balanced randomization with respect toother prognostic factors, including surgeon, gender, age,smoking history, and lesion anatomical sites. [20]The randomization will be done 1 - 2 days prior tosurgery. Only the FVS will be notified of the result. Thepatient, research staff, operating surgeon, and thepathologist are not aware of the assignment. The alloca-tion list will be held by the study database manager; thisindividual is not involved in patient care or recruitment.The allocation will only be revealed in the event of anemergency medical situation.Outcome evaluationPrimary endpointA composite endpoint will be used for outcome evalua-tion. The components are 1) local recurrence defined asa recurrence at or within 1 cm of the previous surgerysite, with the same or higher grade histology compared tothe initial diagnosis or 2) further treatment due to thepresence of severe dysplasia or higher degree of changeat follow-up. This is consistent with the current practiceat all participating sites that only high-grade lesions (i.e.≥ severe dysplasia) require further treatment. The end-point will be evaluated and adjudicated by the CentrePathology Review Committee (chaired by KWB) of whichmembers are blinded to the treatment assignment.Secondary endpointsIn addition to the primary endpoint, we are also inter-ested in the following endpoints.1. Failure of the ‘first pass’. A histologically-confirmedpositive margin for severe dysplasia or greater histologi-cal change, either at the intraoperative or paraffin sam-ple assessment, will count as failure of the ‘first pass’margin (surgical failure). Should this happen, an addi-tional strip of tissue will be taken during surgery or asecond surgery will be performed. For the latter case,the second surgery will be done according to thepatient’s originally assigned surgical approach (i.e., WL-or FV-guided).2. Regional or distant metastasis: At any follow-uptime point, failure of regional or distant control, i.e.,development of metastatic disease to regional lymphnodes confirmed by fine needle aspiration, CT or MRI,or subsequent pathology diagnosis.3. Disease-specific survival: Patient’s death due to dis-ease recurrence, including failure in local, regional anddistant control, is considered an event. Patients who dieof causes unrelated to their oral cancer or treatment oftheir oral cancer are censored at the time of event.Patients lost to follow-up are considered censored at thelast follow-up time.Statistical design and analysisThe trial data will be analysed by the biostatistician(PMB) who will be blinded to the treatment allocation(masked as Treatment A or Treatment B) during thestudy period.Sample sizeAssuming the survival curves follow exponential distri-butions, a 25% failure rate at 3 years in the WL arm anda hazard ratio of 0.5 (i.e. ~12.5% failure rate in the FVarm), a 36-month accrual period, a minimum of 2 yearsof follow-up, with an overall two-sided a = 0.05, a totalsample size of 350 patients is required to achieve atleast 80% power using the stratified log-rank test.Assuming 10% of patients may be lost to follow-up wewill randomize 400 patients.Two interim analyses for efficacy are planned (at one-third and two-thirds of predicted outcomes) with a finalanalysis at the end of Year 5. A Lan-Demets spendingfunction with O’ Brien-Fleming type stopping bound-aries will be employed.MonitoringA Data Safety and Monitoring Board (DSMB) will meetyearly to monitor accrual and adverse events. TheDSMB will also review the results of the interim ana-lyses and provide a recommendation as to whether ornot the trial should be stopped early for efficacy. TheDSMB will be comprised of a medical oncologist, a head& neck surgeon, and a biostatistician.Poh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 5 of 9Fidelity of the interventionThe COOLS trial examines the efficacy of using adevice. How to transfer the technique with uniformityto the participating sites across Canada is the key tosuccess.It will be necessary to establish uniform standardoperating procedures (SOPs) for all key activities; how-ever, each site will have its own unique environmentand personnel. Prior to activation, each site will be vis-ited with the delivery of study devices. During these vis-its the multidisciplinary team of surgeons, pathologists,project coordinators, and FVS at each site will betrained in all study procedures. These site visits will alsoprovide a face-to-face opportunity to build strong rela-tionships with site team members that should facilitateproblem solving throughout the study.Along with the site visits, a comprehensive trainingmanual has been created and is made accessible to eachsite through study’s web-based database. This trainingmanual includes study protocols, operation details foreach key step, how to complete and upload the scan-nable CRFs, sections for clinicians/surgeons with anatlas of clinical lesions in both WL and FV images andinstructions for the VELscope, VELscope Vx and cam-era, sections for the pathologists with details in tissueblocking and the definition of key fields in the pathologysynoptic report form. This manual will serve as a proto-type that will be evaluated and fine-tuned throughoutthe project for future knowledge translation. The studywebsite also includes a library of all study CRFs that canbe downloaded.For clinical images and the use of VELscope, all FVoperators (FVS and SS) will need to pass a 2-step con-trol process. Step 1: as part of the training process, twosets of 8 images will be provided to the site surgeonsand FVS, as a first step in calibrating their judgment onclinically visible tumor boundaries and FV positive (FVloss) boundaries. The criteria for passing the step is thatboth clinically visible tumor boundaries and FV bound-aries need to be within ± 5 mm of those drawn by theexperienced FV operators from the British Columbia(BC) site. Step 2 : to be certified, all FV operatorsrequire hands-on experience in outlining the tumor andFV boundaries on 2 real patients. The same criteria willbe used to assess this activity, with a requirement thatboth clinically visible tumor and FV boundaries bewithin ± 5 mm of those drawn by the experienced FVoperators from BC site. This time, the BC specialistswill draw on the images received from the study sites.This can be used to review the entire operation fromnew patient assessment to the completion of surgery(see Key Steps above) to ensure the high-qualityoperation.After passing this 2-step control process, a site will beready to recruit the first patient to the study. The PI(CFP) will review the first 10 patients from each site toensure the quality of images is maintained and thatmapping of clinical and fluorescence boundaries pro-ceeds as per initial training and to provide suggestionsto the site team members for any problems experiencedduring these activities. Subsequently, about 5% randomsamples from each site will be selected from time totime to check for the accuracy of boundary drawings.This can also mitigate ‘margin creep’ over time.One risk is the potential contamination of endpoint bythe surgeon, i.e., margin creep (expanding margins) inthe control arm. We are requiring that both the FV andwhite light margins be justified just prior to surgery inthe operating room with the presence of both surgeonand an independent party for FV assessment. In thisfashion, the surgical margin will be placed in a con-sented and unbiased fashion. In order to keep the studydouble blinded and avoid potential bias, the FVS will bea different person from the SS. The periodic review ofsites by central management team will also mitigate thisproblem.Data qualityThe acquisition of high quality data is key to the successof any clinical trial. We have planned a systematic strat-egy for control of data and image capture with a specialfocus on ensuring that the involved processes are effi-cient and of high quality. For clinical data, we use a setof scannable teleforms. These forms can be scanned andquickly uploaded from the participating sites to the cen-tral database. The use of scannable forms will signifi-cantly increase the efficiency of the knowledge captureand avoid transcription errors during the data collectionprocess. The central database manager will reviewuploaded CRFs for completeness and review any pro-blems with the local site coordinators who will haveaccess to the uploaded forms through a user interface.In order to maintain the high quality operation andintegrity of the study, the CPM will periodically performa random check of all processes of selected cases, withat least 1 case from each site every 3 months. The data-base will be programmed to alert the Centre and Site ifa patient is overdue for their scheduled follow-upappointment. A monthly teleconference with site coordi-nators and site PIs will share problems among sites. Wemonitor the trial activity on a day-to-day basis and acommon email account has been set up to alert urgentissues from the site. Any operational questions in theproject will be brought forward to the Steering Commit-tee. All problems and solutions will be logged for futurereference.Poh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 6 of 9A major risk to the success of this project is patientenrolment. This risk will be mitigated by requiring eachsite to develop patient pipeline strategies. This is a mile-stone driven project. With the consideration of allowingsufficient start-up time for each site to build its infra-structure, we project to recruit 400 patients over thefirst 36 months of the trial starting date.DiscussionThe COOLS trial is a multicenter, phase III randomizedcontrolled trial comparing 2 surgery approaches, oneguided with a optical device (VELscope; experimentalarm) and one without (control arm), which is differentfrom the conventional drug trial. This is a large scalepan Canadian study to validate an FDA- and HealthCanada-approved optical device to better define the sur-gical margin. We acknowledge the support and theshared vision from the Terry Fox Research Institute.The uniqueness of this trial is multi-fold. Firstly, thisis the first-ever pan Canadian surgical study of suchcalibre, involving 9 institutions across 6 provinces, morethan 70 health professionals, and 400 patients. The 9institutions are drawn from academic centres with aresidency program and affiliated to provincial canceragencies, with patient populations of interest, linkages tothe dental system (referral pathway for patients), andonsite pathology services. The catchment areas of theseparticipating sites cover over the locations from which70% of oral cancer patients come from. Every year,there are ~3,400 patients diagnosed with oral cancer inCanada and ~60% are early stage oral cancer, which arethe target population of our trial. Hence, if the resultsare validated, it can make enormous impact at thepatient level in increasing patients’ survival, morbidity,and quality of life, at the institutional level in changingthe standard of care, and at the population level inimproving the cure rate and reducing costs to the healthsystem.Secondly, this is an exceptional example of translationalresearch from bench to bedside, from discovery to clinicalimplication. With the strong support of the ongoing OralCancer Predictive Longitudinal (OCPL) Study, BCresearchers have built a strong foundation to lead this pro-spective, multicenter study. The OCPL study is an NIH/NIDCR-funded study which involves ~900 patients withoral precancer and oral cancer that have been monitoredregularly since 1999 for progression/recurrence of disease.The OCPL study has served as a pipeline for referral ofsuch patients to the trial in BC [21].Thirdly, in order to change clinical practice we needto ascertain clinical efficacy through assessment of localrecurrence at the clinical, histological and molecularlevel, assess the impact on quality of life and cost effec-tiveness, and construct a plan for KT. The moleculargoal will examine the margin to see if the tool can pro-duces a shift in surgical field, sparing normal tissuewhile catching high-risk occult tissue. The health eco-nomics goal will collect relative cost-effective evidenceof the two treatments in both the cost per avoidedrecurrence and the cost per quality-adjusted life yearsgained and last but not the least, in the knowledgetranslation (KT) goal, we plan to develop a KT strategythat will facilitate rapid scale up of FV-guided surgery inCanada and beyond. With such a comprehensive pack-age, the COOLS trial promises to collect evidence andinformation necessary for bridging the gap from discov-ery to clinical application of FV-guided surgery into anoral cancer solution for patients worldwide.The COOLS trial is a large-scale study - large numberof patients, types of health professional specialties, andgeographically widespread institutions. The site estab-lishment, personal training to standardize the protocolincluding the use of study device, and quality assuranceare critical components to the success of the trial. Toensure the quality of the trial, a multidisciplinary trialcoordinating centre has been developed to monitor thetrial operation and a web-based database application hasbeen created to facilitate the data, images, and sampleflow. A data safety monitoring board and a steeringcommittee have been formed to oversee the trial. Addi-tionally, a central pathology review committee (chairedby KWB) has been formed to document and review allthe margin pathology of the surgical samples and theadjudication of the endpoint based on the pathology ofthe follow-up biopsy.At the time of writing, September 2011, 69 patientshave been enrolled from 4 sites. It is anticipated thatrecruitment will be completed in August, 2013. Follow-up will be completed two years later with results avail-able by 2015.This trial represents a pan-Canadian partnership ofsites and investigators/surgeons and is the first rando-mized trial of the pan-Canadian Network for Oral Can-cer Control or PanCanNOC. The network, serving asthe machinery for future research idea/projects, is com-mitted to rigorously evaluating interventions in the pre-vention and treatment of oral cancer.Publication and reporting dateExpect late 2015 or early 2016.List of abbreviationsBC: British Columbia; COOLS: Canadian Optically-guided approach for OralLesions Surgical; CRF: case report form; CT: computed tomography; DSMB:data safety monitoring board; FV: fluorescence visualization; FVS; FVSpecialist; ICD: International Classification of Diseases; KT: knowledgetranslation; PanCanNOCC: pan-Canadian Network for Oral Cancer Control;RCT: randomized controlled trial; SC: site coordinator; SOP: standardoperating procedure; SP: Site pathologist; SS: Site surgeon; TFRI: Terry FoxResearch Institute; WL: white light.Poh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 7 of 9AcknowledgementsThe authors would like to acknowledge Ms. Alisa Kami for the sharing of herclinical research experience; Ms. Yi-Ping (Kelly) Liu for the preparation oftraining manual; and all the research staff at the participating centres. Wewould like to thank Dr. Stuart Peacock, Health Economics and the Co-Director of the National Centre for Applied Research in Cancer Control(ARCC), and Dr. Kitty Corbett, Knowledge Translation and HealthCommunication Specialist, for their contribution of their expertise in thesecondary objectives of the trial. The trial is supported by the Terry FoxResearch Institution (2009-24), and the development work was supported bythe Canadian Cancer Society (20336). CFP is supported by a ClinicianScientist Award from the CIHR and a Scholar Award from the Michael SmithFoundation for Health Research.Author details1Department of Oral Biological and Medical Science, The University of BritishColumbia, Wesbrook Mall, Vancouver, Canada. 2Department of Surgery, TheUniversity of British Columbia, West 10th Avenue, Vancouver, Canada.3Department of Statistics, The University of British Columbia, AgriculturalRoad, Vancouver, Canada. 4Integrative Oncology, British Columbia CancerAgency/Research Centre, West 10th Avenue, Vancouver, Canada. 5CancerControl Research, British Columbia Cancer Agency/Research Centre, West10th Avenue, Vancouver, Canada. 6Otolaryngology- Head & Neck Surgery,Vancouver General Hospital, Laurel Street, Vancouver, Canada. 7Centre forClinical Epidemiology and Evaluation, Vancouver General Hospital, West 10thAvenue, Vancouver, Canada. 8Anatomical Pathology, Vancouver GeneralHospital, Laurel Street, Vancouver, Canada. 9MD Anderson Cancer Center,University of Texas, Holcombe Boulevard, Texas, USA. 10BiomedicalPhysiology and Kinesiology, Simon Fraser University, University Drive,Burnaby, Canada.Authors’ contributionsThis project was initiated and developed by CFP, DWA. CFP, JSD, CM, JJL,MPR contributed to the design of the study and development of theprotocol. DWA, PMB, and KWB contributed to the development of the trialprotocol. All authors read and approved the final manuscript.Authors’ informationCFP, Trial Principle Investigator, is an Oral Pathologist, a Clinician Scientist atthe BC Cancer Research Centre (Departments of Integrative Oncology andCancer Control Research) and an Associate Professor at the University ofBritish Columbia (Faculty of Dentistry). She is the winner of the ClinicianScientist Award from the Canadian Institute of Health Research (2007-2010)and the Scholar Award of the Michael Smith Foundation for the HealthResearch (2007-2013). Her primary research focus involves application ofmolecular and imaging tools for screening, diagnosis, and management ofcancerous and precancerous oral tissues. Her investigations also involve theimpact of oral cancer screening in medically underserved communities. JSD,Trial Principle Investigator, is Clinical Professor and Acting Head, Division ofOtolaryngology, Faculty of Medicine, the University of British Columbia. He isalso Head and active staff of the Department of Otolaryngology, VancouverHospitals & Health Sciences Centre (Vancouver General Hospital and UBCHospital), and a Consulting Surgical Oncologist, Head and Neck TumorGroup of the BC Cancer Agency. His research interests include Head andneck oncology and oromaxillofacial reconstructive surgery. PMB, TrialBiostatistician, is a Senior Research Scientist at UBC affiliated-Centre ofClinical Epidemiology and Evaluation (C2E2) and an associate member ofthe Department of Statistics at UBC. She is the Statistical Editor for theCanadian Journal of Anesthesia and has served on several grant reviewcommittees and ethics boards. Her research interests include clinicalresearch methodology, secondary use of administrative data and statisticaleducation. DWA is Clinical Professor, Division of Otolaryngology, Faculty ofMedicine, the University of British Columbia. He is the Divisional Head ofOtolaryngology for the Fraser Health Region Hospitals, an active staff of theDepartment of Otolaryngology, Vancouver Hospitals & Health SciencesCentre (Vancouver General Hospital and UBC Hospital), and a ConsultingSurgical Oncologist, Head and Neck Tumor Group of the BC Cancer Agency.His research interests include Head and neck oncology and quality of lifepost head and neck surgery. KWB, Chair, Trial Pathology Committee, is anexperienced head and neck pathologist. He is a Consultant Pathologist atVancouver General Hospital. He is also a Clinical Professor with the Universityof British Columbia (Department of Pathology and Laboratory Medicine). Hedid his undergraduate training and medical school at the University ofAlberta and Residency in Anatomic Pathology at the University of BritishColumbia. He will be the lead pathologist in the Histology Centre ReviewCommittee and member of the Outcome Jurisdiction Committee. CEM, TrialImaging Consultant, is the Head of the Integrative Oncology Department atthe BC Cancer Research Centre. He is also a faculty member of both theDepartment of Pathology and Laboratory Medicine and the Department ofPhysics and Astronomy at the University of British Columbia. His research isfocused on automated image analysis of cell preparations, in vivo tissueimaging, quantitative microscopy, and the development of imagingtechnologies for the early detection of epithelial cancer types and one ofthe inventors of the VELScope. He is also the co-Lead of the substudy tolook for phenotypic evidence using Quantitative Pathology in margins forsurgical field shift. JJL, Trial Design Consultant, is a Professor and KenedyFoundation Chair in Cancer Research in the Department of Biostatistics,Division of Quantitative Sciences at the University of Texas M. D. AndersonCancer Center in Houston, Texas. He also serves as an Adjunct Professor atboth Rice University (Statistics) and the University of Texas (School of PublicHealth, Biostatistics). His expertise and research interests include design andanalysis of clinical trials, survival analysis, longitudinal data analysis, statisticalcomputation/graphics, statistical methods for determining drug interactionin combination studies, and cancer chemoprevention. MPR, Co-PI andScientific Director of the COOLS study, is the Director of the British ColumbiaOral Cancer Prevention Program (BCOCPP), a structure created within the BCCancer Agency that has brought together ~40 clinicians and scientists ofvery diverse disciplines experience who are engaged in leading theevolution of system-wide change in oral cancer control in BC. MPR is aSenior Scientist in the Department of Cancer Control Research at the BCCancer Research Centre. She also serves as a Professor at both Simon FraserUniversity (Biomedical Physiology and Kinesiology) and the University ofBritish Columbia (Pathology and Laboratory Medicine). She is the winner ofthe Oral Health Promotion Award of the Canadian Dental Association (2010).She has extensive experience with the development and management ofresearch projects that involve large multidisciplinary teams both globally andlocally in Vancouver. She leads the NIH-funded longitudinal study, the OralCancer Predictive and Longitudinal study, that is developing and evaluatingnew technology and molecular markers for prediction of cancer progressionand recurrence. She is the co-Lead of the substudy to look for molecularevidence using Loss of Heterozygosity in margins for surgical field shift.Competing interestsThe projects received 10 units of VELscope and 20 units of VELscope Vx(cordless version of VELscope) as an in-kind donation from the LED DentalInc., White Rock, British Columbia, Canada. The authors declare that theyhave no competing interests and no monetary fund received from the LEDDental Inc. or other companies.Received: 8 October 2011 Accepted: 25 October 2011Published: 25 October 2011References1. Ferlay J, Bray F, Pisani P, Parkin D: GLOBOCAN 2002. Cancer incidence,mortality and prevalence worldwide. IARC Cancer Base No. 5 Version 2.0Lyon, France: IARCPress; 2004.2. Sankaranarayanan R, Ramadas K, Thomas G, Muwonge R, Thara S,Mathew B, Rajan B: Effect of screening on oral cancer mortality in Kerala,India: a cluster-randomised controlled trial. Lancet 2005,365(9475):1927-1933.3. Mariotto AB, Rowland JH, Ries LAG, Scoppa S, EJ F: Multiple cancerprevalence: a growing challenge in long-term survivorship. CancerEpidemiol Biomarkers Prev 2007, 16:566-571.4. Dhooge IJ, De Vos M, Van Cauwenberge PB: Multiple primary malignanttumors in patients with head and neck cancer: results of a prospectivestudy and future perspectives. Laryngoscope 1998, 108(2):250-256.5. Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH: A geneticexplanation of Slaughter’s concept of field cancerization: evidence andclinical implications. Cancer Res 2003, 63(8):1727-1730.6. van Houten VM, Leemans CR, Kummer JA, Dijkstra J, Kuik DJ, van denBrekel MW, Snow GB, Brankenhoff RH: Molecular diagnosis of surgicalPoh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 8 of 9margins and local recurrence in head and neck cancer patients: aprospective study. Clin Cancer Res 2004, 10:3614-3620.7. Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, Kummer JA, Leemans CR,Braakhuis BJ: Genetically altered fields as origin of locally recurrent headand neck cancer: a retrospective study. Clin Cancer Res 2004,10(11):3607-3613.8. Tsui IF, Garnis C, Poh CF: A dynamic oral cancer field: unraveling theunderlying biology and its clinical implication. Am J Surg Pathol 2009,33(11):1732-1738.9. Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB: Recurrence atthe primary site in head and neck cancer and the significance of necklymph node metastases as a prognostic factor. Cancer 1994,73(1):187-190.10. Brennan JA, Mao L, Hruban RH, Boyle JO, Eby YJ, Koch WM, Goodman SN,Sidransky D: Molecular assessment of histopathological staging insquamous-cell carcinoma of the head and neck. N Engl J Med 1995,332(7):429-435.11. Tabor MP, Brakenhoff RH, van Houten VM, Kummer JA, Snel MH, Snijders PJ,Snow GB, Leemans CR, Braakhuis BJ: Persistence of genetically alteredfields in head and neck cancer patients: biological and clinicalimplications. Clin Cancer Res 2001, 7(6):1523-1532.12. Poh CF, Zhang L, Anderson DW, Durham JS, Williams PM, Priddy RW,Berean KW, Ng S, Tseng OL, MacAulay C, et al: Fluorescence visualizationdetection of field alterations in tumor margins of oral cancer patients.Clin Cancer Res 2006, 12(22):6716-6722.13. Poh CF, Ng SP, Williams PM, Zhang L, Laronde DM, Lane P, Macaulay C,Rosin MP: Direct fluorescence visualization of clinically occult high-riskoral premalignant disease using a simple hand-held device. Head Neck2007, 29(1):71-76.14. Poh CF, MacAulay CE, Zhang L, Rosin MP: Tracing the “at-risk” oralmucosa field with autofluorescence: steps toward clinical impact. CancerPrev Res (Phila Pa) 2009, 2(5):401-404.15. EuroQol - Home. [http://www.euroqol.org].16. Shaw JW, Johnson JA, Coons SJ: US Validation of the EQ-5D HealthStates: Development and Testing of the D1 Valuation Model. MedicalCare 2005, 43(3):203-220.17. Facit Classification Overview. [http://facitorg000.web108.discountasp.net/qview/class_overview.aspx].18. List MA, D’Antonio LL, Cella DF, Siston A, Mumby P, Haraf D, Vokes E: ThePerformance Status Scale for head and neck cancer patients and theFunctional Assessment of Cancer Therapy-Head and Neck (FACT-H&N)scale: A study of utility and validity. Cancer 1996, 77:2294-2301.19. Rinkel RN, Verdonk-de Leeuw IM, van Reij EJ, Aaronson NK, Leemans CR:Speech Handicap Index in Patients with Oral and Pharyngeal Cancer:Better Understanding of Patients’ Complaints. Head & Neck 2008,30:868-874.20. Pocock SJ, Simon R: Sequential Treatment Assignment with Balancing forPrognostic Factors in the Controlled Clinical Trial. Biometrics 1975,31:103-115.21. Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, Berean K, Epstein JB,Priddy R, Le ND, et al: Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000, 6(2):357-362.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/462/prepubdoi:10.1186/1471-2407-11-462Cite this article as: Poh et al.: Canadian Optically-guided approach forOral Lesions Surgical (COOLS) trial: study protocol for a randomizedcontrolled trial. BMC Cancer 2011 11:462.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitPoh et al. BMC Cancer 2011, 11:462http://www.biomedcentral.com/1471-2407/11/462Page 9 of 9

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