A pilot study to develop an efficacious oral cancer screening strategy for India

Lead Research Organisation: King's College London
Department Name: Cancer Studies

Abstract

Oral cancer imposes a huge burden globally, especially in low and middle income countries (LMICs) (8). This high burden of oral cancer is attributable to high prevalence of risk factors such as tobacco, areca nut (tamul) and alcohol. In most countries, cigarette smoking is the predominant form of tobacco use (9). However, in India, approximately 75% of tobacco consumption is in smokeless form (9). India has the highest burden of oral cancer globally (10). It is recognized that smokeless tobacco causes cancers of the mouth, gullet and pancreas (11). The proposed study will be conducted in Assam, where the prevalence of tobacco is 48% (12). In Assam, tamul is traditionally offered as a mark of respect and auspicious beginnings. We recently conducted a survey in Assam on tamul use. In all, 34% of subjects reported using tamul. Influencing factors were family (58%) and friends (34%). Majority of the subjects (60%) chewed tamul due to pressure at work, after food and during leisure with a mean age of initiation at 15 years. While knowledge about the ill-effects of tamul was low and willingness to quit high (77%), paradoxically, 81% of subjects had not attempted to quit the habit in the preceding 6 months.

The 5-year survival rate for oral cancer is 80% in those diagnosed at early stage and only 20% in those diagnosed at advanced stage, underscoring the need for early detection (13). In India, most oral cancer patients present with advanced disease and have survival rates as low as 3-5%. There is, therefore, a pressing need to diagnose early and ideally at a pre-cancerous stage (2).

In India and other LMICs, the current approach for oral cancer screening relies on visual inspection of the inner lining of the oral cavity (conventional oral examination [COE]) in tobacco/ alcohol users aged over 30 years (4). Yet, owing to issues with the method of screening (low sensitivity of COE) and size of the target population (ages 30+), this approach is not efficacious. For example, the eligible population for oral cancer screening in India based on COE is ~300 million, which reduces its operational feasibility and makes it cost prohibitive. Any screening system developed in LMICs should fulfill two features for optimal effectiveness: 1) The screening test should have high accuracy 2) The screening system (infrastructure, human resource and referral centres) has to be financially viable. Unfortunately, the current oral cancer screening strategy of visual inspection in India and several other LMICs fails at both these levels. Risk stratification tools for systematic identification of high-risk population could potentially drastically reduce the target population for screening.

We propose a 3-step oral cancer screening strategy to enable effective implementation of the screening program. First, a risk prediction model will be used for identification of those at greatest risk of oral cancer, thus reducing the number of screened individuals and enhancing cost effectiveness. Second, high-risk individuals will be screened using autoflourescence, a highly sensitive test for diagnosing oral cancer to rule-out disease by causing only the abnormal areas to light up. Finally, individuals positive on autofluorescence will be ruled-in through a brush biopsy to look for suspicious cells, a test that is highly specific for diagnosing oral cancer. We will validate the risk prediction model of the proposed 3-step strategy as part of this pump priming application which will subsequently lead to a large randomized controlled trial in the population of North East India to test its effectiveness. Our study will provide proof-of-principle of the 3-step screening strategy for implementation of the oral cancer screening in LMICs.

Technical Summary

We propose conducting a study in North East India (Assam), to investigate the proof-of-performance of the proposed 3-step oral cancer screening strategy. First, we propose to use a risk prediction model to identify individuals at high-risk of oral pre-cancer/ early oral cancer for inclusion in the screening program. Second, we propose to rule-out disease in these high-risk individuals using a wide-field screening adjunct with high sensitivity - autofluorescence. Third, in individuals found to be positive by autofluorescence, we propose to rule-in disease using a narrow-field screening adjunct with high specificity - brush cytology.

The study will be conducted in two phases. All healthy individuals aged between 30 to 65 years, with exposure to tobacco, areca nut and alcohol, will be included in the study. Logistic regression analyses will be utilized for the development of the risk-prediction model using data on 15,000 participants recruited in Phase I. The developed model will be applied to 15,000 participants recruited into Phase II for validation. Model-validation will be evaluated using calibration ratios (ratio of observed to expected number of cases) and discrimination (area under the receiver operating characteristic curve [AUC]).

Successful completion of this study is anticipated to lead to the design and implementation of a large randomized controlled trial to investigate the efficacy, cost and population-level effectiveness of this oral cancer screening strategy.

Planned Impact

The current approach for oral cancer screening and early detection relies on visual inspection of the oral mucosa (conventional oral examination [COE]) in tobacco/alcohol users aged over 30 years (2). COE has low sensitivity and low specificity for the identification of oral pre-cancer (e.g. oral leukoplakia, the most common oral pre-cancer) or early oral cancer (carcinoma in-situ or Stage I cancers). Owing to the low sensitivity of COE, as well as the size of the target population (ages 30+; ~300M), this approach is not expected to be efficacious.

This proposal aims to develop an oral cancer screening strategy that identifies high-risk individuals, rules-out disease through a highly sensitive screening modality, and then rules-in disease through a highly specific screening modality. The proposed 3-step approach for oral cancer screening is highly innovative because it efficiently accomplishes several desirable features of population-wide cancer screening programs, including efficiency, high negative reassurance for screen negative individuals, high positive predictive value for screen positive individuals, as well as the use of non-invasive, low-cost screening modalities. Hence, this strategy will ensure that the already strained public health systems in LMICs are able to utilize their precious resources in a more efficient manner.

Our study potentially has a high public health impact because it addresses the most common cancer in India. Further, our results would be broadly generalizable to other countries in Asia with similar high-risk exposures and high oral cancer incidence such as Pakistan, Nepal, Bangladesh, Sri Lanka and other LMICs around the world. Lastly, our study leverages investment through the existing field infrastructure in place for screening of chronic diseases (oral, breast and cervical cancer, diabetes and hypertension) led by the Government of Assam and the Tata Trusts.
 
Description A pilot study to develop an efficacious oral cancer screening strategy for India
Amount ₹30,500,000 (INR)
Organisation Tata Trusts 
Sector Charity/Non Profit
Country India
Start 09/2018 
End 12/2020
 
Title A pilot study to develop an efficacious oral cancer screening strategy for India 
Description We have developed a digital data capture tool to collect all the essential information about participants, habits, capture of clinical images, autofluorescence images with Velscope. The collection of samples and specimens have been recorded through our digital platform as well as a storage facility in the biobank. 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? No  
Impact We initiated the collection of clinical images of normal and abnormal oral precancer and cancer. In the future, it can serve as a repository for applying artificial intelligence/ Machine learning tools. Also, we have collected biospecimens mainly saliva, oral rinse, and cytology samples which in the future can lead to the development of new innovative biomarker studies or validation of point of care devices. 
 
Description A pilot study to develop an efficacious oral cancer screening strategy for India 
Organisation National Institutes of Health (NIH)
Department National Cancer Institute (NCI)
Country United States 
Sector Public 
PI Contribution Regular meetings were held with all the investigators to discuss the scientific progress of the study and in addition, frequent meetings were held virtually with members of the researchers who comprised the field team. Constant monitoring of the recruitment rate, impact of COVID, and morale of the research team were essential to keep the focus on the project and to encourage team members and investigators on the good work that had been done thus far despite many difficulties encountered on the field.
Collaborator Contribution The partnership with NCI has involved the following: a) Design of the research protocol b) Assisting in procurement of equipment and consumables c) Regular monitoring and operational feedback for research study d) Working closely with clinicians to improve the robustness of data collection e) Training and capacity building of the research team f) Developing a network of collaborators for the oral cancer study As a result of this collaborative partnership, much has been achieved despite the pandemic. The current project has enabled us to develop a new tool to screen for oral cancer in the field. We have a robust risk factor questionnaire and it is providing us with insight into the current practice of tobacco and areca nut among the community in Assam. An immense amount of training has been delivered to field staff especially to health workers who in turn have developed the capability to identify suspicious lesions by following the protocols. Our ability to capture digital images has improved tremendously. The clinical images captured both under normal light and autofluorescence will create an image bank and help us to train many community health workers in the near future. We have also established a biobank facility for the collection of specimens, mainly oral rinse and saliva. It will serve as a repository for future validation studies mainly point of care devices.
Impact Training and Development - capability building As part of the research study, a structured training program was developed in consultation with the collaborators, clinical experts and field team. The participating institutes were Tata Trusts (Mumbai), Kings College (London), Dr B Boorah Cancer Institute (BBCI - Guwhati), National Cancer Institute (USA), and Tata Memorial Centre. The training was provided to the study team consisting of dentists, healthcare workers, patient navigators, laboratory technicians. The blended learning program consisted of the classroom-based session on oral cancer, its sign symptoms, management, patient pathway, diagnostic procedure, tobacco cessation, and counselling skills. It was followed by field visits in the community both in Maharashtra and Assam. The team had an intense immersion exercise to understand the research process and handholding from the clinical experts for developing skills of screening and early detection of precancerous lesions and conditions of the oral cavity. Special training was provided on the Velscope (Autofluorescence) device to train dentists and healthcare workers in detection of precancerous lesions and differentiating from normal mucosa. There were frequent handholding guidance sessions conducted virtually through the zoom platform to enable the research team to discuss their queries, present cases, and the patient pathway. The purpose behind the training sessions was to implement proper knowledge and skillful implementation of the research in the following ways- - To have an oriented flow in the process of registration, awareness as well as the consent form section. - To have a clear picture of conventional oral examination as well as to detect any abnormality clinically. - To have a better and clear understanding of the autoflourescence( Velscope) and how to properly use it to detect abnormal lesions. - To have a clear protocol regarding the sample collection which included the saliva and the oral rinse collection - To have a patient registration code so that each and every aspect of the particular patient is safely stored as well as to take utmost care of the confidentiality of the patients' data. - To provide assistance to the lesion positive cases in BBCI as well as to take care of the diagnostic aids provided in the hospital. - And finally to have a follow-up history of each and every positive lesion detected in patients.
Start Year 2018
 
Description Engagement with the National Health Mission of Assam 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Cancer screening was suspended during the first wave of the pandemic in India. This resulted in an immediate suspension of its study. As the Government of India started to lift restrictions, the team on the ground in Assam commenced a dialogue with the National Health Mission, Healthcare workers, the public, and patients to explain the situation and jointly develop a roadmap for recommencement of recruitment which needed to be conducted in a safe and gradual manner. Key to this was engagement with policymakers in the Government of Assam who were extremely collaborative and supportive of this work and provided all the support required. The policymakers recognized the potential value of the output of the study which could have an impact on the current screening programme for oral cancer in India..
Year(s) Of Engagement Activity 2020