The incidence of cancer is expected to increase significantly with the aging of the population. In North America, 20% of the population, 80 million people, will be over the age of 65 by 2030. Half of the entire North American population will develop cancer in their lifetime and cancer deaths will increase to over 10 million per year by 2020. Projections for BC. are in line with these statistics; by 2020, there will be a 50% increase in the number of new cases per year, at a time when health care budgets are increasingly strained. To date, the majority of cancer budgets are allocated to costly chemotherapy regimens and research into already developed cancers. For instance, in the United States, less than 2% of the entire cancer budget is spent on awareness, literacy and early detection.

Early detection of disease has proven to have marked impact on the outcome of cancer. In 1949, BC introduced the first organized population-based screening program in the world for cervical cancer. Since then, the rate of death from cervical cancer has dropped by 70%. This remarkable achievement has yet to be reproduced in other types of cancer for several reasons. Roadblocks to improved early detection of disease include the limited understanding of the natural history of cancer and the fact that cancer often takes many years to develop and the tissues are constantly changing during this 15- to 25-year period.

Oral cancer is no different from other cancers in that the history of cancer development is not well understood, and there is a significant degree of uncertainty with respect to future outcomes of oral premalignant lesions (OPLs), the precursors to cancer. Despite universal recognition that a new strategy for the management of oral cancers is required, little progress has been made in the last 3 decades, even in technologically developed countries. On average, half of the 300,000 patients diagnosed yearly die within 5 years of diagnosis. Recurrence of second cancers is frequent (10-25% of cases). Even when successful, treatment of late-stage oral cancer can be devastating, associated with disfigurement, impairments in speech and eating and an overall compromise in quality of life.

Oral cancer, however, offers a unique opportunity to break through these barriers and, with effective early screening and detection tools, significantly reduce oral cancer deaths worldwide. The oral cavity is well suited for development of screening programs that can identify premalignant disease for early treatment. The site is readily accessible for visual inspection and oral premalignant lesions are known to present clinically as either white patches or, less frequently, red patches. Histologically, there are early indications of the disease comparable to other sites – such as the cervix – where screening has been an effective strategy for reduction of mortality.

The BC Oral Cancer Prevention Program is ready to take on this challenge through a multifaceted research program that is laying the scientific groundwork for a new generation of screening tools. Information on the research priorities and initiatives of the BC OCPP may be found below.

The BC Oral Cancer Prevention Program research initiative is grounded in the development of the understanding of the natural history of the disease. It focuses on 2 key areas: understanding the biology that drives the development of cancer and applying this knowledge to improve detection, risk assessment and management of the disease. This line of attack exemplifies the concept of "translation research", whereby biological discoveries are translated into the community as soon as they are validated.

Serving as the foundation of the research program is an ongoing Oral Cancer Prediction Longitudinal study, located in B.C. and funded by the National Institute of Dental and Cranio-facial Research (NIDCR) since 1999. The NIDCR, an arm of the National Institutes of Health (NIH) in the United States, considers the work in BC. as having the potential to serve as a template for more effective and potentially life saving early detection programs for oral cancer throughout Canada, the US and worldwide.

The Oral Cancer Prediction Longitudinal Study, one of the largest oral longitudinal studies worldwide, is designed to create an integrated clinical risk assessment model that incorporates clinical, pathological and molecular markers into a model that will be used to guide detection, risk assessment and management of patients with oral cancer. The study is following approximately 500 patients with high-risk oral lesions: half with cancer (at risk for recurrence) and the other half with low-grade dysplasia (at risk for progression to cancer). This is one of the richest prospective studies of oral lesions to date with a rigorous collection of clinical, pathological, demographic and molecular data.

Funded by the National Institute of Dental and Craniofacial Research, the study has triggered the development of a set of innovative technologies. These devices are meant not to replace conventional approaches to patient assessment, but rather to enrich them and to integrate them with current knowledge. The plan is to use these tools as overlapping sieves in a step-by-step fashion to progressively filter out patients in the community with high-risk oral premalignant lesion and triage them to dysplasia clinics for management.

These devices are being used in a step-by-step sequence to guide clinicopathological decisions on patient risk and treatment. They include a hand-held visualization tool which makes use of tissue autofluorescence to detect abnormal lesions and is used alongside optical contrast agents such as toluidine blue. In addition, two semi-automated high-resolution computer microscopy systems are being used to quantitate the protein expression phenotype of cell nuclei in tissue sections and exfoliated cell brushings.

Previously identified risk-associated molecular changes are being used to validate these systems as well as to establish their place in a population-based triage program that will filter out high-risk cases in the community and funnel them to dysplasia clinics, where higher-cost molecular tools will guide intervention. A critical development for the translation of this technology into community settings is the establishment of an effective methodology for education and training of health practitioners on the front lines.

Problem

The approach taken by the British Columbia Oral Cancer Prevention Program is to develop technologies that are targeted towards the key clinical decision points that are potential barriers to patient flow. One of these barriers is visualization of the lesion. Oral premalignant changes (OPLs) vary considerably in clinical appearance. It can be quite challenging for the clinician to differentiate abnormalities requiring biopsy from reactive lesions associated with other causes, such as infection or trauma. Visualization devices that facilitate the decision to biopsy can have a profound effect on outcome.

Approach

There are two basic approaches to improving lesion visualization. The first uses optical contrast agents to better differentiate diseased tissue from its normal counterpart, such as the toluidine blue (TB) stain. The second builds upon the rapid growth in optical technologies, particularly those based on fluorescence imaging and spectroscopy. Data from BC OCPP research suggest that a synergism between these two approaches will improve the ability to detect critical tissue changes in oral premalignant lesions (OPLs) and cancers. The two approaches are described below.

Visualization Advances

• Toluidine Blue (TB)

Toluidine blue has a long history of use and an established validity for assisting in the detection of oral cancers and OPLs with high-grade dysplasia. However, its value for detecting low-grade OPLs has been contentious, since only a portion of such lesions stain with the dye. The BC OCPP has shown that this selective staining of OPLs may be important. In an analysis of 100 primary OPLs being followed in the Oral Cancer Prediction Longitudinal study (OCPL), TB positive staining correlated with clinicopathologic risk factors and high-risk molecular patterns. Significantly, a >6-fold elevation in cancer risk was observed for TB-positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (p = 0.0008). The association of TB status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. These data were published in 2005 and the article highlighted as Breaking Point news by the American Association of Cancer Research. For more information on the TB study, see Visual Aids - Toluidine Blue.

• Florescence Visualization (FV)

Significant advances have also been made in the OCPL study with the use of optical devices, specifically fluorescence visualization (FV) in oral cancers and OPLs. This approach is already in clinical use in the lung and the mechanism of action and interaction of tissue autofluorescence has been well described in the cervix. The BC OCPP has developed a simple field-of-view device for the direct visualization of tissue fluorescence in the oral cavity. The device has been used to follow clinical changes to the oral mucosa of all patients in the OCPL study, with some very promising early results. Loss of autofluorescence (FVL) was detected in virtually all high-grade lesions and invasive cancers and in a substantial portion of premalignant lesions. For more information on FV studies, see Visual Aids - Fluorescence Visualization.

Problem

In addition to visualization of the lesion, a second important barrier revolves around risk prediction for oral premalignant lesions (OPLs). OPLs vary widely in potential for malignant transformation with only a fraction eventually progressing into cancer. At present, the gold standard for prediction involves the determination of the presence and degree of dysplasia in a biopsy. Severe dysplasia or carcinoma in situ (CIS), grouped as high-grade premalignant lesions, are characterized by persistence, recurrence, and high likelihood of eventual progression to invasive cancer, if left untreated. Even with aggressive surgical treatment, 30-40% of the lesions still recur or progress within 30 months. Histology has a good predictive value for such lesions. In contrast, determination of prognosis for lesions with histological changes that are less than severe is more problematic. The majority of OPLs without dysplasia or with low-grade dysplasia will not progress into cancer and histology alone does not clearly differentiate between those that will progress and those that will not.

Approach

Development of approaches that will differentiate cases with a high likelihood of progression will allow more timely intervention at an earlier stage for high-risk cases while avoiding over-treatment of lesions with little risk of progression. The BC OCPP has piloted two such approaches. One involves high-resolution computer microscopy, potentially a high-throughput, cost-effective filter for outcome. The second involves a final set of sieves based on molecular alterations in the tissue. The latter uses two approaches: 1) microsatellite analysis for loss of heterozygosity (LOH); and 2) Genome Profiling. They are described below.

Computer Microscopy / Imaging Advances

Histological assessment of a biopsy has as its basis a consensus by pathologists of the types of phenotypic changes associated with risk, with a classification system based on the presence of specific features (dysplasia) and the degree of epithelial involvement. High resolution computer imaging systems measure these same features as well as the frequency and distribution of cells, in a quantitative fashion. A Quantitative Tissue Phenotype (QTP) is derived. These helper tools allow the pathologist to use reproducible and repeatable measures of specific phenotype characteristics that make up the appearance of dysplastic cells in tissues and can be statistically associated with risk. The two systems are described below.

• Quantitative Pathology (QP)

The tissue analysis system used in British Columbia assesses quantitatively stained material for association with outcome in sectioned material. It examines 120 nuclear features in cell nuclei, the majority of which describe the distribution of DNA, unravelling very complex features into quantifiable algorithms. Preliminary data suggest that the QP system can identify nuclear changes that associate with the presence of high-risk molecular clones and with future outcome. For more information on the QP system, see Molecular Markers.

• Quantitative Cytometry (QC)

The second computer system is a noninvasive counterpart to the work station described above, using exfoliated cell brushings. Currently in development, the projected use for this device is to assist the clinician in identifying lesions requiring biopsy, to be used in conjunction with visualization devices. For more information on the QC system, see Molecular Markers.

Microsatellite Analysis/Loss of Heterozygosity

Oral carcinogenesis is a multistep process requiring the accumulation of multiple genetic alterations in the epithelium. Loss of Heterozygosity (LOH) marks this genetic instability and clonal selection and is a powerful potential risk marker. Although several laboratories have previously reported an association of LOH with progression, no longitudinal studies have validated this approach. The BC OCPP has published two LOH risk models based on retrospective analyses that suggest a strong association of specific LOH patterns with outcome. The first model examines associations of LOH patterns with risk of progression for OPLs to cancer. Three ‘Molecular Risk” (MR) patterns have been identified, MR1 (lowest risk), MR2 (intermediate risk) and MR3 (highest risk). Twenty-six percent of oral premalignant lesions with MR2 patterns and 47% with MR3 patterns progressed to cancer within 5 years. In a parallel retrospective model for recurrence of cancer from OPLs developing after treatment at the former cancer site, these same markers showed the lowest risk with pattern MR1. Relative risk for MR2 and MR3 was 23.5 and 26.1, respectively. Sixty-one percent of lesions with such LOH patterns developed recurrences within 2 years and 77% within 5 years. For more information on these data, see Molecular Markers.

Genomics Profiling

Within the scope of the OCPL study, the BC OCPP has created a system that can lead to rapid identification of candidate DNA markers of progression and recurrence through high resolution genome-wide profiling of biopsies of individuals with extensive follow-up. Novel genes frequently altered in oral cancers have been identified. Refinement of this platform has generated the first whole genome profile of oral dysplastic lesions and has led to the discovery of patterns of genetic change in oral dysplastic lesions that are associated with progression risk.

Building upon these early findings, the BC OCPP is developing a miniaturized microarray called the OPL Risk Prediction (OPL RP) chip. This chip is designed to analyze very small samples such as those collected in longitudinal monitoring of patients. Version 1 of the OPL RP chip concentrates on probes in the frequently altered regions identified in the >100 oral premalignant lesions analyzed to date. The OPL RP chip will evolve and reiteratively improve with feedback on how informative the individual regions are in predicting risk of progression.

Problem

In recognition of strong evidence that occult disease frequently extends beyond the clinically apparent tumour, surgeons excise a 1cm margin around the cancer when anatomically possible. However, tumour recurrences are frequent (10-25%) and are thought to be associated with residual disease.

Approach

Surgery Advances

An unexpected finding of the early studies of Florescence Visualization (FV) was that regions of tissue showing FV loss often extended beyond clinical boundaries and, at times, appeared at former lesion sites that were no longer clinically apparent. In 2006, the BC OCPP published data further characterizing FVL tissue that lies beyond the clinically apparent tumour, both histologically and molecularly. The study assessed 122 oral mucosa biopsies taken from 20 surgical specimens. All tumours showed FVL; in 19 of the 20 cases, it extended beyond the conventional 1-cm margin normally excised, in at least one direction. Loss of autofluorescence in these margins was strongly associated with histological change, present in 32 of 36 FVL biopsies compared with only one of 66 biopsies that had FV retained.

COOLS Trial for Better Outcomes

A pan-Canada phase III randomized surgical trial investigating the efficacy of implementing FV to guide the surgical margin for early-staged oral cancer has been recently funded by the Terry Fox Research Institute. Led by the BC Oral Cancer Prevention Program, this is a 5-year multicentric study involving 6 provinces, 8 surgical centres across Canada. The team will collect data to establish strong evidence that will direct a change in clinical practice in using FV-guided surgery to reduce local recurrence in early-staged oral cancer.

Terry Fox Research Institute Workshop for the establishment of Pan Canadian Network for Oral Cancer Control (PanCanNOCC) in Sep. 2010

Historically, the approach to the study of oral cancer has involved investigation in treatment, research and prevention; however, the pace of development has been limited by the lack of translational integration of these components. The BC Oral Cancer Prevention Program (BC OCPP) is in a unique position to break through this barrier due to the focus on team science, bringing together expertise from diverse disciplines.

A Working System

When initiating any new technology, it needs to be validated on data from high-risk clinics to establish the operating characteristics of the systems. Once this is done, the systems need to be tested in the screening population where the disease is in place. The systems currently in place in BC include:

• A centralized pathology review service for the community
• Four dysplasia clinics staffed by specialists trained in the new technology, for patient referral from the community
• Established linkage between these clinics and the clinicians in hospitals that treat high-risk cases

High-Risk Population

The BC OCPP is also beginning the process of transfer to the community in the Downtown Eastside of Vancouver, one of the city’s poorest neighbourhoods, where drinking and smoking, two well-known risk factors for oral cancer, are widespread. A high risk of disease in this community has already been identified: of 250 residents screened, 2 had cancers and 9 had precancerous lesions. A more extensive screening program has now been launched in this neighbourhood.

The Dental Community

The next step is to begin the process of Integrating screening protocols into regular day-to-day practices among community health practitioners. The 3,000 dentists in B.C. will be integrated into a screening network that will identify cases requiring follow-up and refer them forward for further assessment. Training manuals and educational modules are being created to provide hands-on training for a select number of dentists who will become leaders or the network and will work within the BC OCPP to create population-wide guidelines for screening.

Population-based Surveillance Database for Oral Cancer Management

The BC Oral Cancer Prevention Program, the BC Oral Biopsy Service and BC Cancer and its Cancer Registry are partnering with the Canadian Partnership against Cancer to develop a surveillance database within the BC Oral Biopsy Service. This database will serve as a framework that will monitor program processes and outcomes in BC, measure changes in rates of detection of disease as new technology is integrated and practices change, identify areas of improvement or harm quickly and follow the more long-term, critical indicators of change: shifts in staging, morbidity, disease recurrence and mortality. The system is being built with broad consultation to other biopsy services across Canada and internationally to facilitate future expansion across Canada.

The first steps in this process began in Fall 2010 with the creation of electronic requisition forms that will be used for biopsy submission to the OBS. These forms will be delivered on a new an e-website for the Oral Biopsy Service. Form prototypes are currently being validated in focus groups of different users and stakeholders in BC with plans for gradual deployment to all users by the Spring of 2012.