Group 3 To Screen or Not to Screen: Who, Why, When and Where?

Transcription

1 Group 3 To Screen or Not to Screen: Who, Why, When and Where? Paul March Speight 4 th /5th (Chair), 2016 Omar Kujan, Toru Nagao, Kannan Ranganathan, Pablo Vargas Joel Epstein (Moderator),

2 Paul Speight PhD, BDS, FDSRCPS, FDSRCS (Eng), FDSRCS (Edin.), FRCPath Professor, School of Clinical Dentistry, University of Sheffield Chair, Group 3 p.speight@sheffield.ac.uk Omar Kujan DDS DipOPath MSc PhD Assistant Professor, Al-Farabi College for Dentistry and Nursing omar.kujan@gmail.com Kannan Ranganathan BDS, MDS, MS (oral path), PhD, FIAOMP Professor, Ragas Dental College and Hospital ranjay22@gmail.com Toru Nagao PhD, DMSc, DDS Professor, Fujita Health Science University tnagao@dpc.aichi-gakuin.ac.jp Pablo Vargas, DDS, MSc, PhD, FRCPath Professor, Piracicaba Dental School-UNICAMP pavargas@fop.unicamp.br

3 Moderator Joel Epstein, DDS, MSD Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles

4 Screening the application of a test or tests to people who are apparently free from the disease in question in order to sort out those who probably have the disease from those who probably do not. A screening test is not intended to be diagnostic Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968:

5 Screening The purpose of screening is to interrupt the natural history of a disease at its asymptomatic stage when it is treatable and progression can be halted

6 Case finding The detection of lesions with the objective of bringing patients to treatment.. or for epidemiological studies and surveys not screening, but often called screening eg. Awareness weeks, free clinics, epidemiological studies

7 Types of screening Mass (population) screening large scale screening of population groups usually by invitation Selective screening targeted screening of high-risk groups Opportunistic screening examining individuals when they attend for some other, often unrelated, purpose

8 Why screen for oral cancer and precancer?

9 Why screen for oral cancer and precancer? Current detection of early lesions is inadequate: only 50% attend a dentist many lesions are missed over 60% of patients present with late lesions high mortality

10 Why screen for oral cancer and precancer? Pattern of disease: Increasing incidence? No improvement in survival Patients still present late

11 Why screen for oral cancer and precancer? Clinical features of the disease easy to detect identifiable precursor lesion effective treatment available for small lesions

12 Criteria for screening Disease must be common and serious Disease must have a known natural history A good screening test must be available Effective treatment must be available It must be cost-effective From: Wilson and Jungner 1968

13 UK National screening committee 19 criteria

14 Oral Cancer Screening to screen or not to screen? Is oral cancer a screenable disease? Is screening for oral cancer feasible? Is screening for oral cancer cost-effective?

15 Criteria for screening Disease must be common and serious Disease must have a known natural history A good screening test must be available Effective treatment must be available It must be cost-effective From: Wilson and Jungner 1968

16 keratosis dysplasia carcinoma

17 Oral premalignant lesions Leukoplakia Erythroplakia

18 Leukoplakia A predominantly white lesion of the oral mucosa that cannot be characterised as any other definable disease, and which has a significantly increased risk of oral cancer.

19 Leukoplakia and malignancy Leukoplakia: Overall about 5% become malignant within 5 years About 1.5% /year transformation

20 Oral Cancer Screening to screen or not to screen? Is oral cancer a screenable disease?

21 Oral Cancer Screening to screen or not to screen? Is oral cancer a screenable disease? YES? OPMD exist and may progress to cancer

22 Criteria for screening Disease must have a known natural history

23 Criteria for screening Disease must have a known natural history? OPMD exist and may progress to cancer

24 Criteria for screening Disease must have a known natural history? OPMD exist and may progress to cancer BUT

25 Leukoplakia and malignancy Only about 5% overall become malignant 95% do not progress We do not know how to identify this 5%?

26 Criteria for screening Disease must be common and serious Disease must have a known natural history A good screening test must be available Effective treatment must be available It must be cost-effective From: Wilson and Jungner 1968

27 Possible screening methods Oral examination With or without adjunctive methods Toluidine blue Cytology Illumination and light-based methods

28

29 Evaluation of a screening test Systematic visual examination of the oral mucosa Positive screen: A white patch A red patch An ulcer of longer than 2 weeks duration

30 Test accuracy of oral examination 2013

31 Test accuracy of oral examination Identified 10 studies that evaluated conventional oral examination (COE) Criteria included available data on specificity AND sensitivity (reference standard applied to those screened negative)

32 Test accuracy of oral examination From: Walsh et al, Cochrane Systematic review 2013

33 Test accuracy of oral examination.. there is limited evidence of performance in each of the different settings.. which means that the current evidence base is limited. though COE has been shown to have good estimates of both sensitivity and specificity in some studies. there is some evidence that implementing COE as a component of a population screening programme can reduce mortality and produce stage-shift in a high risk population.

34 Test accuracy of oral examination.. there is limited evidence of performance in each of the different settings.. which means that the current evidence base is limited. though COE has been shown to have good estimates of both sensitivity and specificity in some studies. there is some evidence that implementing COE as a component of a population screening programme can reduce mortality and produce stage-shift in a high risk population. Kerala study

35 Evaluation of screening tests A systematic review of test performance in screening for oral cancer and precancer. Downer MC, Moles DR, Palmer S, Speight PM. Oral Oncology 2004,

36 Evaluation of screening tests n % +ive Sensitivity Specificity PPV NPV Jullien, Ikeda, Downer, Mathew, Mehta, Warn Monteiro, Nagao, (68) A systematic review of test performance in screening for oral cancer and precancer. Oral Oncology 2004, Downer MC, Moles DR, Palmer S, Speight PM

37 Meta-analysis of all screening studies Sensitivity Specificity PPV NPV % of lesions correctly identified 15% false negatives 3% false positives 70% likelihood of being right 1% likelihood of being wrong

38 Sensitivity and specificity of screening tests Sensitivity Specificity Oral examination Mammography* Cervical smear* *estimates from UK National Screening Programmes:

39 Evaluation of screening tests n % +ive Sensitivity Specificity PPV NPV Jullien, 1995 Ikeda,1995 Downer, 1995 Mathew, Three studies used non-medical health workers Mehta, Warn Monteiro, Nagao, (68) A systematic review of test performance in screening for oral cancer and precancer. Oral Oncology 2004, Downer MC, Moles DR, Palmer S, Speight PM

40 Evaluation of screening tests Jullien, 1995 Similar sensitivity n % +ive and specificity Sensitivity Specificity PPV 0.67 NPV 0.99 Ikeda, Downer, Mathew, Mehta, Warn Monteiro, Nagao, (68) A systematic review of test performance in screening for oral cancer and precancer. Oral Oncology 2004, Downer MC, Moles DR, Palmer S, Speight PM

41 Criteria for screening A good screening test must be available COE shows satisfactory sensitivity and specificity Dentists and other trained health care workers are able to detect lesions

42 Criteria for screening A good screening test must be available COE shows satisfactory sensitivity and specificity Dentists and other trained health care workers are able to detect lesions BUT criteria for a positive test (lesion) need to be established

43 Is screening for oral cancer feasible? Yes OPMD exist Dentists and health care workers are able to detect them

44 Do oral cancer screening programmes work?

45 Japan Only two significant studies of screening programmes India

46 Oral cancer screening studies in Japan Toru Nagao

47 Tokoname study Los Angeles County Museum of Art Nagoya Tokoname city Aichi prefecture Population: 52,058 Over 40 yrs : 26,856 (52%) Beckoning cat

48 Period: 1995 to 1998 Study design Objectives: to elucidate efficacy of mouth examination Method: Strategy: Subjects: by invitation Annual screening as part of general health screening 40 yrs and older 9,536 (36%) (male:32%, female:68%)(age:61±11 yrs) Total number of examinations: 3,275 ( in 1995) 19,056 (in ) (including repeat examinations) Examiners: Dentists (n=42) Calibration of screeners 1 week before

49 Programme processes in oral cancer screening in Tokoname study in Japan Community Level Primary Level Secondary Level Tertiary Level General health screening Pathology lab Hospital units - Free shuttle bus available 250 examinations per day Sc posi OMS units + Detection (1 st screening) Diagnosis (2 nd Exam) Treatment

50 Specialist vs. Screening diagnosis Screening diagnosis Specialist Diagnosis Cancer Leuko Erythro Lichen planus Others Total (M/F) Cancer 2 2 (2/0) Leukoplakia (28/9) Erythroplakia 0 * Lichen planus (9/31) Other (27/26) Normal (1/4) Total (67/70) Detected lesions confirmed by specialists: 2 of 8 cancers (25%) 27 of 40 leukoplakias (68%) 32 of 44 lichen planus (80%) 36 of 43 benign lesions (84%) Sensitivity :0.92 (95% CI ) PPV: 0.78 (95% CI ) Nagao et al. Oral Oncol. 2000;36(4):340-6.

51 Compliance for secondary testing and detection rate in organized cancer screening Colorectal cancer Screening (Fecal occult blood test) Examinees as 10,000 Breast cancer Screening (Mammography) Examinees as 10,000 Oral cancer screening Examinees 10,000 Referral for 2 nd testing 620 (6%) Referral for 2 nd testing 750 (8%) Referral for 2 nd testing 105 (1%) Examinees for 2 nd testing 419(68%) Examinees for 2 nd testing 662(88%) Examinees for 2 nd testing 72(69%) Colorectal cancer 17 (0.17%) Breast cancer 23 (0.23%) In 2013, Japan Cancer Society Oral cancer 1 (0.01%) Nagao T et al. J Med Screen, 2000;7(4): Colon polyp 157 (1.6%) OPMDs 41 (0.4%)

52 Summary of the outcomes Satisfactory participation can be obtained for annual oral cancer screening when this is coupled to a general health screening: this allows detection of new lesions including oral cancer and precancer Those with risk habits (smoking and drinking) are likely not to show-up in subsequent years. An attendance of 69% for re-examination by specialists compares well with other reported studies measuring patient compliance The performance of the Japanese dentists employed in screening was satisfactory

53 Kannan Ranganathan

54 Gold standard: Randomised controlled trial with mortality as the end point India

55 KERALA STUDY Arabian Sea Vakkom Kadinamkula Anjuthengu m Chirayinkil Kadakavoor Kizhuvilam Azhoor Mangalapura m Pothencod e Andoorkonam Intervention Clusters Control Clusters INDIA Bay of Bengal Kerala TRIVANDRUM CITY Indian Ocean Attipra Kazhakutta m Sreekariyam Kannan Ranganathan TRIVANDRUM CITY

56 The Kerala screening studies 1. Sankaranarayanan R, Ramadas K, Thara S, Muwonge R, Thomas G, Anju G, Mathew B. Long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in Kerala, India. Oral Oncol Apr;49(4): Sankaranarayanan R, Ramadas K, Thomas G, Muwonge R, Thara S, Mathew B, RajanB. Trivandrum Oral Cancer Screening Study Group. Effect of screening on oral cancer mortality in Kerala, India: a cluster-randomised controlled trial. Lancet Jun 4-10;365(9475): Ramadas K, Sankaranarayanan R, Jacob BJ, Thomas G, Somanathan T, Mahe C, Pandey M, Abraham E, Najeeb S, Mathew B, Parkin DM, Nair MK. Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India. Oral Oncol Sep;39(6): Sankaranarayanan R, Mathew B, Jacob BJ, Thomas G, Somanathan T, Pisani P, Pandey M, Ramadas K, Najeeb K, Abraham E. Early findings from a community-based, cluster-randomized, controlled oral cancer screening trial in Kerala, India. The Trivandrum Oral Cancer Screening Study Group. Cancer Feb 1;88(3): Subramanian S, Sankaranarayanan R, Bapat B, Somanathan T, Thomas G, Mathew B, Vinoda J, Ramadas K. Costeffectiveness of oral cancer screening: results from a cluster randomized controlled trial in India. Bull World Health Organ Mar;87(3): Pandey M, Thomas G, Somanathan T, Sankaranarayanan R, Abraham EK, Jacob BJ, Mathew B; Trivandrum Oral Cancer Screening Study Group. Evaluation of surgical excision of non-homogeneous oral leukoplakia in a screening intervention trial, Kerala, India. Oral Oncol Jan;37(1): Mathew B, Sankaranarayanan R, Sunilkumar KB, Kuruvila B, Pisani P, Nair MK. Reproducibility and validity of oral visual inspection by trained health workers in the detection of oral precancer and cancer. Br J Cancer. 1997;76(3):390-4.

57 Kerala study 13 districts randomised 7 intervention 6 control Subjects over 35 years Subjects screened by non-medical HWs Oral examination Positives referred to hospital Health, habits and socioeconomic data recorded

58 Results at 9 years districts clusters population >35 years Intervention arm 96,517 87,655 (91.0%) screened Control arm 95,356 5,145 positives 6.55% 3,218 attended for referral 131 cancers 2,252 precancers Total cancers in population 205 (43.7 per 100,000) Total cancers in population 158 (37.6 per 100,000) 77/205 died 37.6% 87/158 died 55%

59 Kerala study after 9 years Intervention Control Deaths NS Survival (5yr) P<0.01 Stage I & II P<0.005 Mortality rate NS

60 Kerala study after 9 years Intervention Control Males Tobacco & Alchol: Mortality rate P<0.01 Females Tobacco & Alchol: Mortality rate NS

61 Conclusions at nine years Oral visual screening can reduce mortality in high-risk individuals This has the potential of preventing at least oral cancer deaths worldwide Our findings support the routine use of oral visual screening in the reduction of oral cancer mortality in the high-risk group... Sankaranarayanan et al (2005) Effect of screening on oral cancer mortality in Kerala, India: a clusterrandomised controlled trial. Lancet, 365,

62 Results at 15 years clusters 191,872 population >35 years All subjects Intervention arm 96,517 Control arm 95,356 88,822 screened 92% 5,586 (6.3%) positive 188 cancers 2,336 precancers Total cancers in population 279 (37.1 per 100,000) Total cancers in population 244 (30.8 per 100,000) 138/279 died 50% 154/244 died 63%

63 Results at 15 years Intervention arm 45, clusters 84,942 population >35 years Control arm 39,151 High Risk Group 5,246 screened positive Total cancers in population 254 (57.3 per 100,000) Total cancers in population 232 (58.5 per 100,000) 129/254 died 51% 147/232 died 63%

64 Kerala study after 15 years ( ) Intervention Control Deaths 50% 63% NS Survival (5yr) P=0.003 Survival (10yr) P=0.003 Stage I & II P=0.002 Mortality rate NS Sankaranarayanan et al, Oral Oncology, :

65 Kerala study after 15 years Intervention Control Tobacco & Alchol: Deaths 51% 63% Mortality rate P<0.05 Advanced cancers 54% 66% P<0.05 No Habits: Mortality rate NS

66 Effect of compliance with screening Mortality (% reduction) All n (%) Tob & Alc n (%) 3 Rounds 38% 22,008 (23%) 47% 10,373 (23%) P< Rounds 79% 19,228 (20%) 81% 8,163 (18%) P<0.05 Sankaranarayanan et al, Oral Oncology, :

67 Kerala study after 15 years ( ) Summary:..a sustained reduction in oral cancer mortality.. In high-risk individuals.after 15 years Overall 12.5% were screened positive 59% of those attended follow up Significant reduction in mortality in high-risk group (39% vs 30%) BUT significant reduction in mortality & incidence ONLY in high-risk individuals attending 4 rounds NO significant reduction in the total population Sankaranarayanan et al, Oral Oncology, :

68 Kerala study after 15 years ( ) Summary:.our findings support the routine use of oral visual screening to reduce oral cancer mortality among the high-risk group....we recommend that dentists and general practitioners perform a careful visual oral examination in tobacco or alcohol users during routine clinical interactions Sankaranarayanan et al, Oral Oncology, :

69 Kerala study after 15 years ( ) Summary:.our findings support the routine use of oral visual screening to reduce oral cancer mortality among the high-risk group....we recommend that dentists and general practitioners perform a careful visual oral examination in tobacco or alcohol users during routine clinical interactions Opportunistic screening in high-risk groups may work Sankaranarayanan et al, Oral Oncology, :

70 Paul Speight

71 Oral Cancer Screening to screen or not to screen? Is oral cancer a screenable disease? Is screening for oral cancer feasible? Is screening for oral cancer cost-effective?

72 Cost-effectiveness The Kerala study also calculated costs of screening. Compared to no screening

73 Cost-effectiveness Costs * Incremental costs at 9 years From: Brocklehurst et al. Cochrane Systematic Review 2013.

74 Cost-effectiveness Costs * Incremental costs at 9 years From: Brocklehurst et al. Cochrane Systematic Review 2013.

75 Cost-effectiveness The screening cost less than US$ 6 per case The incremental cost per life-year saved was $835 Fell to $156 if only high risk individuals were to be targeted.

76 This is the first clinical prospective study to show that opportunistic screening for oral cancer may be cost-effective. Subramanian, S., Sankaranarayanan, R., Bapat, B. et al (2009) Cost-effectiveness of oral cancer screening: results from a cluster randomized controlled trial in India. Bull World Health Organ, 87,

77 Is screening for oral cancer cost-effective in a developed, low prevalence, country? The cost-effectiveness of screening for oral cancer in primary care. Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, etal. Health Technology Assessment 2006;10(14):1 144.

78 A hypothetical model of oral cancer screening Baysian simulation model The outcome was determined for 100,000 individuals entered into a 1 year screening cycle And for 100,000 individuals not screened (control) Costs calculated from record review and published cost data Outcome measured in QALYs Prevalence data and sensitivity and specificity taken from previous pilot screening programmes

79 Computer simulation model of cost-effectiveness of screening for oral cancer & precancer Complex model, including estimates of probabilities of transition between disease states

80 Result of screening high-risk group: QALYs in unscreened population = QALYs in screened population = QALYs gained = 312 Equivalent to 15 lives saved

81 Results Incremental cost-effectiveness ratios No screen 0 Opportunistic high risk screen, GDP 18,919 Opportunistic high risk screen, GMP 19,703 Opportunistic population screen, GMP 21,623

82 What is a life worth? In USA: $40,000 was the price agreed by legislation for mammography In UK NIHCE has approved 20,000-30,000 These have become benchmarks for the worth of a health care intervention

83 Costs of screening programmes per QALY Breast cancer 80,000 Cervical cancer 300,000 Colon cancer 6,500 Oral cancer 18,500 Roberts et al, 1985; Lancet i, 89-91; Gray & Briggs, NSC 1998

84 Is screening for oral cancer costeffective? Probably For opportunistic screening of high risk individuals but more research is needed

85 Omar Kujan

86 Evidence base for Oral cancer screening Systematic reviews Omar Kujan

87

88 Review of RCTs of screening programmes for oral cancer or OPMD Mortality as primary outcome Secondary outcomes: incidence stage Adverse effects costs No RCTs in any developed or low-prevalence countries Only one study met the inclusion criteria

89

90 Kerala study: Ramadas K, Sankaranarayanan R, Jacob BJ, Thomas G,Somanathan T, Mahe C, et al. Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India. Oral Oncolgy 2003;39(6): Sankaranarayanan R, Mathew B, Jacob BJ, Thomas G, Somanathan T, Pisani P, et al. Early findings from a community-based, cluster randomized, controlled oral cancer screening trial in Kerala, India. Cancer 2000;88(3): Sankaranarayanan R, Ramadas K, Thara S, Muwonge R, Thomas G, Anju G, et al. Long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in Kerala, India. Oral Oncology 2013;49 (4): Sankaranarayanan R, Ramadas K, Thomas G, Muwonge R, Thara S, Mathew B, et al. Effect of screening on oral cancer mortality in Kerala, India: a cluster-randomised controlled trial. Lancet 2005;365(9475):

91 Conclusions: The evidence from the Kerala trial is that visual screening can reduce the mortality rate in users of tobacco, alcohol or both and can produce a stage shift. visual examination could be effective at reducing mortality rates for oral cancer when used within a targeted screening programme...but the risk of bias in the included study means that further welldesigned randomised controlled trials are necessary to establish the validity of this relationship.

92 Conclusions: The results suggest that there is insufficient evidence to recommend a whole population screening programme for oral cancer. In the meantime, opportunistic visual screening by appropriately trained dentists and oral health practitioners is recommended for all patients and particularly for those who use tobacco, alcohol or both.

93 Summary and Conclusions Paul Speight

94 JADA: 2010;141:

95 ..defines screening as the process by which a practitioner evaluates an asymptomatic patient to determine if he or she is likely or unlikely to have a potentially malignant or malignant lesion.

96 ..defines screening as the process by which a practitioner evaluates an asymptomatic patient to determine if he or she is likely or unlikely to have a potentially malignant or malignant lesion. Conclusions: screening by means of visual and tactile examination in the general adult population intended to detect early and advanced oral cancers may not alter disease specific mortality..insufficient evidence to determine whether screening by means of visual and tactile examination to detect potentially malignant and malignant lesions alters disease-specific mortality...screening by means of visual and tactile examination may decrease oral cancer specific mortality among people who use tobacco, alcohol or both.

97 National Cancer Institute, USA:

98 National Cancer Institute, USA: Benefits There is inadequate evidence to establish whether screening would result in a decrease in mortality from oral cancer. Magnitude of Effect: No evidence of benefit or harm. Study Design: Evidence obtained from one randomized controlled trial. Internal Validity: Poor. Consistency: Not applicable (N/A). External Validity: Poor.

99 US Preventive Services Task Force The USPSTF.....found inadequate evidence that the oral screening examination accurately detects oral cancer..found inadequate evidence that screening for oral cancer and treatment of screen-detected oral cancer improves morbidity or mortality..concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for oral cancer in asymptomatic adults. UpdateSummaryFinal/oral-cancer-screening1

100 UK National Screening Committee UK National Screening Committee. Criteria for appraising the viability, effectiveness and appropriateness of a screening programme. London, UK: National Screening Committee, Updated 2015:

101

102 9 of 19

103 Oral Cancer Screening to screen or not to screen? Is oral cancer a screenable disease?

104 Problems: Oral Cancer Screening to screen or not to screen? The clinical appearance is not specific for a potentially malignant lesion Criteria for relevant lesions not clearly established Only 5% - 30% of screen detected lesions may be relevant to the natural history of the disease Does an oral examination work in a screening programme? Is it cost-effective?

105 OPMD and malignancy Only about 5% overall become malignant 95% do not progress How do we identify this 5%?

106 Priorities for further research

107