Screening for oral cancer: Experience in developing countries K. Ramadas MD, DNB Additional Professor Division of Head and Neck Oncology Regional Cancer Centre Trivandrum India

Screening requirements Suitable disease Important problem Can be detected in preclinical stage Effective treatment available End result improved by early diagnosis

Screening requirements Suitable test Cheap and easy to apply Valid: Sensitivity Specificity Positive predictive value Safe and acceptable

Screening requirements 3. Suitable programme settings Adequate infrastructure for Dx and Rx in health services Adequate trained manpower Adequate financial resources

OUTCOME EVALUATION OF SCREENING PROGRAMME Early outcome Stage distribution Case fatality and survival Final outcome Reduction in incidence (if precancerous lesions are detected and treated) Reduction in mortality (if early invasive disease is detected and treated)

Oral Cancer Burden Incidence Deaths World 274,000 127,200 More developed countries 91,100 30,600 Less developed countries 183,000 96,600 India 83,000 46,000 Ferlay J et al., GLOBOCAN 2002, IARC Press, 2004

Screening for oral cancer Oral cancer is a major health problem Oral cancer incidence on the increase Survival rates remain unchanged Easily accessible sites Long premalignant and early invasive phase Better Rx outcomes in early stages

Screening Tools for oral cancer Visual inspection Self Examination Toluidine blue Fluorescence imaging Exfoliate cytology/Brush biopsy Saliva Examination

Oral Visual Inspection Sensitivity 58 – 94 % Specificity 76 - 98% Most widely evaluated test Warnakulasuriya KAAS et al., Bull WHO 1984; 62: 243-250 Mehta FS et al., Cancer Detect Prev 1986; 9: 219-225 Mathew B et al., Br J Cancer 1997; 76: 390-394 Ramadas K et al., Oral oncol 2003; 39: 580-88

Toludine Blue Test Tested only in a few specified clinical settings High false negative and false positive rates

Oral Cytology Lesion has to be seen before the sample collection Yield is poor Interpretation highly subjective High false negative rates

Analysis of Saliva Increased levels 4 mRNA from the following genes Interleukin1 beta Ornithine decarboxylase antizyme1 Spermidine/spermine N1-acetyl transferase Interleukin8

Oral cancer screening – Cuban experience Screening programme in 1984 Annual oral inspection to all subjects aged 15 yrs and above in the assigned population of 1000-1200 by each dentist. In practice only opportunistic examination of subjects carried out 21% of males and 31% females underwent screening in any given year up to 1990 No evidence of any reduction in incidence or mortality from oral cancer Fernandez L et al., Epidemiology 1995; 6: 428-31

Case Control study from Cuba 33 % reduction in the frequency of advanced oral cancer in screened subjects. The protection increased to 59% in subjects who had two or more screening examinations Protection lasts for 3 years Sankaranarayanan et al., Oral Oncol 2002; 38: 131-36

TRIVANDRUM ORAL CANCER SCREENING STUDY (TOCS) Only randomized controlled clinical trial in a community setting COLLABORATIVE PROJECT OF INTERNATIONAL AGENCY FOR RESEARCH ON CANCER, LYON & REGIONAL CANCER CENTRE TRIVANDRUM & SUPPORTED BY ASSOCIATION FOR INTERNATIONAL CANCER RESEARCH (AICR),U.K

Objective To evaluate the efficacy of oral cancer screening by visual inspection of the oral cavity in detecting early stages of oral cancer and in reducing mortality To study the determinants of population compliance for intervention To evaluate the cost effectiveness of intervention Sankaranarayanan R, Ramadas K et al., Lancet 2005; 365: 1927-1933

Materials and Methods 13 Panchayaths randomized to intervention (N=7) and control (N=6) groups Between 1995- 2004, 3 rounds of screening, at 3-year intervals completed Screening carried out in subjects 35 years or older by trained health workers 96,517 subjects in the intervention group and 95,356 subjects in the control groups Ramadas K et al., Oral oncol 2003; 39: 580-88 (Continued…..)

(Continued…..) Materials and Methods Information on socio demographic factors and habits collected for both intervention and control cohorts Education on the harmful aspects of tobacco/alcohol use for the intervention and control cohorts 3 rounds of oral visual inspection at 3-year intervals provided to eligible individuals in the intervention group by trained health workers Screen positive cases referred for physician confirmation/ biopsy Precancer cases were advised, cessation of habits, medication or surgical excision Oral cancer cases were treated by radiation and/or surgery ± chemotherapy according to the stage at diagnosis

Map Showing Study Clusters INDIA TRIVANDRUM CITY Kerala Indian Ocean Bay of Bengal Arabian Sea Vakkom Kadakavoor Kizhuvilam Azhoor Mangalapuram Andoorkonam Pothencode Kazhakuttam Sreekariyam Attipra Kadinamkulam Chirayinkil Anjuthengu Intervention Clusters Control Clusters

Trivandrum Oral Cancer Screening Study Design Randomized 13 Panchayaths In Trivandrum District, India Intervention N = 7 panchayaths Control N = 6 panchayaths Door-to-door identification and interview of eligible subjects (> age 34, no debilitating disease) Consent form, Individual questionnaire, Education on tobacco and alcohol health effects Oral Visual Inspection by trained health worker Screen positives referred for inference investigations Treatment given for precancers and cancer cases Follow-up for oral cancer incidence and mortality Usual care

Screen positivity White, red, nodular lesions suggestive of leukoplakia or eythroplakia Oral submucous fibrosis Suspicious ulcer or growth

Referral investigations Clinical examination by dentist or clinical oncologist Histological examination

Monitoring and Evaluation Process measures Participation in screening Screen (test) positivity Compliance with referral for reference investigators Intermediate outcomes Detection rates of precancers and cancer Programme sensitivity Positive predictive value of screening test to detect both precancers and invasive cancer Stage distribution of cancers Survival Case fatality rate Final outcome Reduction in mortality from oral cancer

Sources of data Study database Population based cancer registry Mortality registration offices Death records from churches/mosques Active follow-up by home visits and telephone inquiries

Screening history

Compliance with screening and referral

Stage Distribution of Oral Cancers Intervention Control p < 0.05

Overall survival from oral cancer in the study groups 20 40 60 80 100 Months Intervention screen detected Intervention Interval cancer Intervention non-responders Control group Survival (%) Time to death or end of follow-up (in months) Kaplan-Meier survival estimates, by oral cancer type 25 50 75

Oral cancer incidence and mortality rates PYOs=Person-years of observation

Oral cancer incidence and mortality rates by sex PYOs=Person-years of observation

Conclusions Good participation rates for screening (~ 90%) Moderate compliance to referral (~62%) Significant detection of oral cancer at early stages (I & II) by visual inspection (41.2% vs. 23.2%)

Conclusions Significant reduction in oral cancer mortality among high-risk individuals, particularly among males Potential to prevent 37,000 oral cancer deaths world-wide Sankaranarayanan R, Ramadas K et al., Lancet 2005; 365: 1927-1933

EPILOGUE Oral visual screening reduces mortality among high-risk subjects Can be integrated into existing health services

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