Cancer prevention and early detection Lausanne-March-2011 Cancer prevention and early detection C. Sauvaget MD Screening Group (SCR)

Prevention aims to reduce mortality from cancer Lausanne-March-2011 Prevention aims to reduce mortality from cancer

Burden of cancer in less-developed countries(2008) Lausanne-March-2011 Men Women

Natural history of cancer and levels of prevention Lausanne-March-2011 Natural history of cancer and levels of prevention Pre-clinical phase Clinical phase Exposure Onset of disease Early detection Onset of symptoms and/or signs D1 Cure A B C D2 Disability Primary prevention Secondary prevention Tertiary prevention D3 Death

Early detection approaches Lausanne-March-2011 Screening: Systematic, routine application of a suitable early detection test at specified intervals in a systematically invited asymptomatic population. 2. Early clinical diagnosis: Searching for precancerous or early invasive cancer in symptomatic or asymptomatic individuals in opportunistic settings. Improved awareness and access to health services promote early clinical diagnosis.

Cancer early detection options Lausanne-March-2011 Cancer early detection options Screening programs Clinical early diagnosis Screened + Confirmed + Population Screening target Clinical early diagnosis target

Early detection is associated with: Lausanne-March-2011 Early detection is associated with: Benefits/harms Costs to Individual and the Health Services It is important to establish that benefits of early detection, particularly screening, outweigh harms and it is cost-effective in reducing incidence/mortality.

Screening Requirements Lausanne-March-2011 Screening Requirements Suitable disease Suitable test Suitable screening settings

Screening Requirements-1 Lausanne-March-2011 Screening Requirements-1 Suitable disease a) Important problem b) Can be detected in preclinical stage c) Effective treatment available d) End result improved by early diagnosis

Screening Requirements-2 Lausanne-March-2011 Screening Requirements-2 2. A suitable screening test 2.1 Adequate validity Sensitivity Specificity 2.2 Acceptability and cost

2.2 Acceptability and cost Lausanne-March-2011 2.2 Acceptability and cost In addition to adequate validity, a screening test should be: Low cost Convenient Simple As painless as possible Does not cause complications

Screening Requirements-3 Lausanne-March-2011 Screening Requirements-3 3. Suitable programme settings Adequate infrastructure for diagnosis and treatment in health services Adequate trained manpower Adequate financial resources

Successful cancer prevention programme Lausanne-March-2011 Successful cancer prevention programme Key elements Link Screening and Treatment Effectiveness of Treatment Screening Coverage Surveillance and monitoring

Evaluation of screening programmes Lausanne-March-2011 Evaluation of screening programmes Process measures Outcome measures

Evaluation of screening Programmes Outcome Lausanne-March-2011 Evaluation of screening Programmes Outcome Early outcome Stage distribution Case fatality and survival Final outcome Reduction in incidence (if precancerous lesions are detected); mortality (if invasive disease is detected)

Lausanne-March-2011 Mortality rates from invasive cervical cancer and screening coverage rate, Mexico, 1979-2004 Courtesy Dr Eduardo Lazcano

Suitable cancers for early detection in LMIC Lausanne-March-2011 Oral cancer Visual inspection by trained health workers Health education to prompt symptomatic high-risk individuals Cervical cancer Visual inspection methods and HPV-DNA testing as alternatives of Pap smear Health education on risk factors, symptoms and signs of cervical carcinoma See-and-treat approach by trained health workers and physicians Breast cancer Health education to improve awareness and to motivate high-risk women to demand early detection Clinical breast examination and mammography may then be used

Screening for oral cancer Lausanne-March-2011 Screening for oral cancer

Study design TRIVANDRUM ORAL CANCER SCREENING STUDY (TOCS) Lausanne-March-2011 Study design Randomized 13 Panchayaths In Trivandrum District, India Intervention N=7 Panchayaths 96 516 participants Control N=6 Panchayaths 95 358 participants Door-to-door identification and interview of eligible subjects (> 34 years, 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

Overall survival from oral cancer in the study groups TRIVANDRUM ORAL CANCER SCREENING STUDY (TOCS) Lausanne-March-2011 Overall survival from oral cancer in the study groups

Lausanne-March-2011 Cost-effectiveness of Visual Screening for Oral Cancer in India Results from the Trivandrum Oral Cancer Screening Study (TOCS) (1996-2004) Intervention group Control group Person-years of observation 469 090 419 748 No. of oral cancers/deaths 205/77 158/87 Mortality rate (per 100,000) 16.4 20.7 Rate Ratio: 0.79 (0.51-1.22) 95% CI Mortality rate among tobacco and/or alcohol users (high-risk individuals) 29.9 45.4 Rate Ratio: 0.66 (0.45-0.95) 95% CI Cost per cancer detected (intervention compared to control) All individuals High-risk individuals - $ 6,228 $ 9,394 Cost per life year saved* $ 457 $ 156 * GDP per Capita for India (2004) $ 2900 Sankaranarayanan et al., 2005: Lancet 365:1927-33 Subramanian et al., 2009: Bull WHO 87:200-206

Screening for cervical cancer Lausanne-March-2011 Screening for cervical cancer Source: R. Sankaranarayanan, Ramani S. Wesley. A practical manual on visual screening for cervical neoplasia (IARC Technical Publication No. 41)

Study design 131 746 Women aged 30-59 yrs in 52 clusters Lausanne-March-2011 Comparative efficacy of visual inspection with acetic acid, HPV testing and conventional cytology in cervical cancer screening: a randomized intervention trial in Osmanabad District, Maharashtra State, India Study design 131 746 Women aged 30-59 yrs in 52 clusters Cytology 13 clusters (N = 32 058) HPV 13 clusters (N = 34 126) VIA 13 clusters (N = 34 074) Control 13 clusters (N = 31 488) Diagnosis and treatment of screen-positive women Follow-up for cervical cancer incidence and mortality (passive and active) Follow-up for cervical cancer incidence and mortality (passive and active) Health education, routine existing care Sankaranarayanan et al., N Engl J Med 2009;360:1385-1394

Person years of follow-up Lausanne-March-2011 Comparative efficacy of visual inspection with acetic acid, HPV testing and conventional cytology in cervical cancer screening: a randomized intervention trial in Osmanabad District, Maharashtra State, India Hazard ratios of incidence of stage II+ cervical cancer and cervical cancer mortality with control group as the reference Group Cases Person years of follow-up Hazard ratio* (95% CI) Stage II+ cervical cancer incidence Control 82 247,895 1.00 HPV 39 268,185 0.47 (0.32-0.69) Cytology 58 250,523 0.75 (0.51-1.10) VIA 86 267,326 1.04 (0.72-1.49) Cervical cancer mortality 64 248,175 34 268,674 0.52 (0.33-0.83) 54 251,144 0.89 (0.62-1.27) 56 267,917 0.86 (0.60-1.25) CI: confidence interval * Age-adjusted Sankaranarayanan et al., N Engl J Med 2009;360:1385-1394 In collaboration with TMC, Mumbai and NDMCH, Barshi, India Study

Age-Standardized Incidence rate (per 100 000) Lausanne-March-2011 Comparative efficacy of visual inspection with acetic acid, HPV testing and conventional cytology in cervical cancer screening: a randomized intervention trial in Osmanabad District, Maharashtra State, India Cervical cancer incidence rates among screen-negative women by study group (2000-2007) Group Number of women Cancer cases Age-Standardized Incidence rate (per 100 000) HPV 24 380 8 3.7 Cytology 23 762 22 15.5 VIA 23 032 25 16.0 Sankaranarayanan et al., N Engl J Med 2009;360:1385-1394

The new HPV DNA test for low-resource settings - CareHPV Lausanne-March-2011 The new HPV DNA test for low-resource settings - CareHPV Hybrid capture 2 CareHPV

New algorithms for cervix screening Developing countries New algorithms for cervix screening Lausanne-March-2011 - ve Repeat test 5 or 10 years later? CareHPV test + ve VIA + ve - ve Cryotherapy LEEP

Screening for breast cancer Lausanne-March-2011 Screening for breast cancer NORMAL BREAST Normal female breasts: Note similar size and shape, nipples at the same level, normal nipple, areola and skin

Study design Trivandrum Breast Cancer Screening Study (TBCS) Lausanne-March-2011 Study design 275 clusters 115 652 women aged 30-69 years 142 clusters 59 808 women Control group 133 clusters 55844 women CBE once in 3 years x 3 rounds 133 clusters 55 844 women CBE once in 3 years x 3 rounds CBE +ve Triple Diagnosis Breast cancer cases Breast cancer deaths

Performance characteristics of clinical breast examination Trivandrum Breast Cancer Screening Study (TBCS) Lausanne-March-2011 Performance characteristics of clinical breast examination Test characteristics Values (95% CI) Number of women screened 50 366 Number of women screened positive 2 880 Screen-positivity rate (per 100 women screened) 5.7 (5.5 – 5.9) Breast cancer detection rate (per 10,000 women screened) 6 (4 – 8) Screen detected cancers (true positive cancers) 30 Interval cancers (false negative cancers) 29 False positive rate (per 100) Sensitivity (%) 50.8 (37.5 – 64.1) Specificity (%) 94.3 (94.1 – 94.5) PPV (%) 1.0 (0.7 – 1.5) NPV (%) 99.9 (99.9 – 100.0) CI: confidence interval; PPV: positive predictive value; NPV: negative predictive value unpublished data submitted In collaboration with RCC, Trivandrum, India

First round of screening: intermediate outcome (2006-2009) Trivandrum Breast Cancer Screening Study (TBCS) Lausanne-March-2011 First round of screening: intermediate outcome (2006-2009) Control Intervention p-value Number % Breast cancers cases 63 80 Size of tumor ≤ 2cm 4 (6.3) 15 (18.8) 0.030 Early stage breast cancers (0-IIA) 16 (25.4) 35 (43.8) 0.023 Negative axillary lymph nodes 22 (35.5) 40 (50.0) 0.084 ER positive breast cancers 23 (36.5) 28 (35.0) 0.852 Received conservative surgery 3 (4.8) 14 (17.5) 0.020 Deaths 6 (9.5) (3.8) 0.158 unpublished data * ER: estrogen receptors submitted In collaboration with RCC, Trivandrum, India

Non-suitable cancers for early detection in LMIC Lausanne-March-2011 Digestive tract cancer Endoscopy is not cost-effective nor feasible Liver cancer High fatality rate and ineffective treatment Primary prevention Lung cancer Chest radiography and sputum cytology are ineffective CT scan screening is not feasible Tobacco control Prostate cancer PSA testing with considerable over-diagnosis Early detection not recommended for developing countries Ovarian cancer Efficacy of α-fetoprotein and ultrasound is not yet known Screening is not feasible

Thank you for your kind attention! Lausanne-March-2011 Thank you for your kind attention!