Screening for GI Cancer Past Present and Future. Prof. Bob Steele University of Dundee

Transcription

1 Screening for GI Cancer Past Present and Future Prof. Bob Steele University of Dundee

2 Worldwide Cancer Incidence Rates

3 UK Cancer Incidence Rates

4 Screening The detection of disease in asymptomatic subjects in order to improve the outcome of the disease in question or to prevent it.

5 Screening Opportunistic individuals Programmatic populations

6 Screening vs. Surveillance Screening average risk without known premalignant disease Surveillance high risk by virtue of genetic risk or known premalignant disease

7 Does cancer screening do any good?

8 Criteria for Programmatic Screening Disease common treatable better prognosis when early Screening process sensitive & specific acceptable affordable

9 Volunteer Bias Individuals accepting screening tend to be health conscious

10 Length Bias Screen Screen

11 Lead-time Bias Tumour Growth Time

12 Proving Screening Works Population-based randomised trials in which the whole group offered screening (including refusers and interval cancers) is compared with the control group

13 Should a Screening Programme be introduced? Does it work? RCTs How much does it cost? money harm

14 Which GI cancers should we screen for? Large bowel? Stomach? Oesphagus? Liver? Pancreas?

15 Stomach Direct endoscopy H.Pylori Pepsinogen No RCTS Gastrin 17 Gastopanel H. pylori, PGI&II, G17

16 Oesophagus Direct Endoscopy Cytology No RCTS

17 Liver Radiological imaging cirrhosis hepatitis B PBC No RCTS AFP poor sensitivity and specificity

18 Pancreas Work in progress No RCTS

19 Large Bowel

20 Disease-Specific Mortality in gfobt Randomised Trials (Relative Risks) Minnesota Annual 0.67 (CI ) Biennial 0.79 (CI ) Nottingham Biennial 0.85 (CI ) Funen Biennial 0.82 (CI ) Göteborg Biennial 0.84 (CI )

21 National UK Colorectal Cancer Screening Pilot Aim: to test the feasibility of introducing gfobt screeing into the NHS

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23 Demonstration Pilot All year olds offered FOBT screening No screening offered

24 5 Cumulative Mortality from Colorectal Cancer Rate and 95% CI (Nelson-Aalen estimates) Years since screening/matched date Invited for screening Controls

25 Rate ratio of Colorectal Cancer invited vs controls Overall 0.90 ( ) Relative reduction in CRC mortality 10% Participants only 0.73 ( ) Relative reduction in CRC mortality 27%

26 Positive Predictive Value of Screening Colonoscopy Carcinoma 14.6% No Neoplasia 49.5% Adenoma 35.9%

27 Cancers Diagnosed in the Screened Population Round 1 Round 2 Round 3 Screen -detected 351 (56.6%) True interval 193 (31.2%) Missed 2 (0.3%) Miscellaneous 66 (10.7%) Not on Registry 6 (1%) 208 (46.5%) 213 (47.7%) 4 (0.9%) 22 (4.9%) 139 (35.7%) 229 (58.9%) 2 (0.5%) 19 (4.9%) 0 0

28 Gender distribution p<0.001 %

29 Uptake - Gender and Deprivation % Women Men 0 Most Deprived SIMD Least Deprived

30 Guaiac FOBT Limited sensitivity (false negatives) Imperfect specificity (false postives) Gender and deprivation inequality Poor acceptability But it works!

31 gfobt vs FIT gfobt Based on Guaiac reaction Not specific for haemoglobin Messy to do FIT Immunological Specific for human haemoglobin Easy to do Quantitative FIT 400(80) = gfobt

32 FIT Evaluation (60.6%) participants completed a single FIT 909 participants (2.4%) with f-hb 400 ng Hb/ml (80 µg Hb/g faeces) referred for colonoscopy. 30 Screen-detected cancers 31 Interval Cancers (SCR)

33 Uptake - gfobt and FIT 80% 70% 60% Uptake, by level of deprivation and gender Males Females 50% 40% 30% 20% 10% 0% 1 most deprived least deprived

34 FIT cutoff for 2.0% positivity n=20358 n=17783

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36 Effect of lowering cut-off on IC rate 60% 50% Positivity rate Interval cancer rate 40% 30% 20% 10% 0% >0 faecal Hb concentration cut-off

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38 FIT can accommodate: Colonoscopy capacity Gender differences Deprivation differences

39 Can Screening Prevent Colorectal Cancer?

40 The Adenoma-Carcinoma Sequence

41 ICRF/MRC FS Trial (Oct 1996 March 1999) Single flexible sigmoidoscopy with removal of adenomas years High risk colonoscopy adenoma > 1cm 3+ adenomas tubulovillous or villous histology 20+ hyperplastic polyps above distal rectum cancer

42 Mortality from CRC

43 Incidence of CRC

44 Incidence of L-sided CRC

45 ICRF/MRC Study Total no: Interested : (55%) Randomised: Control: Invited for screening: Attended: (71%)

46 Flexible Sigmoidoscopy Trial Actual Results (Self selected population) Uptake : 71% Incidence reduction : 23% Mortality reduction : 31% Imputed results (Whole population) Uptake: 31% Incidence reduction : 12% Mortality reduction: 20%

47 Incidence of R-sided CRC

48 Colonoscopy No mortality or incidence data from RCTs as yet Case control studies only But highly sensitive and 100% specific for both cancer and adenoma

49 Ongoing Colonoscopy RCTs NordICC (Norway, Poland, Netherlands, Sweden) 100,000; colonoscopy vs. no-screening Screening complete 2014; 15 y f-up COLOPREV (Spain) 57,000; biennial FIT vs. colonoscopy Screening complete 2011; 10 y f-up CONFIRM (US VA) 50,000; annual FIT vs. colonoscopy Started 2013; 10 y f-up Screesco (Sweden) 200,000; c scopy vs. biennial FIT vs. no screening Started 2014, 15 y follow-up Quintero et al. NEJM 2012; Kaminski et al. Endoscopy 2012;

50 Colonoscopy mortality and incidence NHS and HPFUS 88,902 participants 22 year FU

51 Mortality No SLE SFS SC

52 Incidence No LE Polyp y -ve FS -ve C

53 Why does colonoscopy have little effect on R-sided cancer? Colonoscopy quality? Bowel preparation quality? Different biology?

54 Questions for population screening Does Endoscopy perform better than blood in stool tests? FOBT/FIT + FS? Colonoscopy? Novel tests?

55 Current position England FS offered at 55 gfobt from Opt-in to gfobt after 74 Scotland gfobt/fit from 50-74years Opt-in after 74 years

56 Flexible Sigmoidoscopy England One-off FS at 55 years i.e. before FOBT screening starts Uptake 30-40% In exams 55 cancers and 835 HRA (2% SCRN detection rate) Scotland FOBT screening starts at 50 years RCT of FS at ~ 60 years

57 Immediate future England Full roll-out of FS?Change to FIT Scotland Change to FIT?FS

58 Not-too distant future Intelligent use of FIT Differential cut-off based on age and gender? Varying cut-off and screening interval? Varying interval based on FHb conc.?

59 New approaches Multitarget faecal DNA test Peripheral blood tests Methylated DNA Tumour associated proteins Micro RNA Autoantibodies Volatile organic compounds CT/MRI colonography Capsule endoscopy

60 Multitarget faecal DNA Test Cologuard ($500) Kras mutations, abberant NDRG4 and BMP3 methylation β-actin Compared with FIT ($4) Cologuard Sens: 92.3% Spec: 86.6% FIT Sens: 73.8% Spec: 96.4% But FIT cut-off 20µg/g

61 Volatile organic compounds Breath Sensitivity 91% Specificity 99% Stool Sensitivity 97% Specificity 99%

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64 Scottish Bowel Screening Programme 1st June st October Total Invitations 1,379, , , , ,562 4,439,602 Positive results 9,207 10,361 10,929 13,762 13,825 58,084 Invasive cancers ,454 Polyp cancers All colorectal cancers ,034 3,224 Polyps 2,896 3,722 4,054 5,362 4,755 20,789 Adenomas 2,125 2,808 3,117 4,171 3,735 15,956 Dukes' stage (in %) A B C C D Not known Not stated