Screening for GI Cancer Past Present and Future Prof. Bob Steele University of Dundee
Worldwide Cancer Incidence Rates
UK Cancer Incidence Rates
Screening The detection of disease in asymptomatic subjects in order to improve the outcome of the disease in question or to prevent it.
Screening Opportunistic individuals Programmatic populations
Screening vs. Surveillance Screening average risk without known premalignant disease Surveillance high risk by virtue of genetic risk or known premalignant disease
Does cancer screening do any good?
Criteria for Programmatic Screening Disease common treatable better prognosis when early Screening process sensitive & specific acceptable affordable
Volunteer Bias Individuals accepting screening tend to be health conscious
Length Bias Screen Screen
Lead-time Bias Tumour Growth Time
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
Should a Screening Programme be introduced? Does it work? RCTs How much does it cost? money harm
Which GI cancers should we screen for? Large bowel? Stomach? Oesphagus? Liver? Pancreas?
Stomach Direct endoscopy H.Pylori Pepsinogen No RCTS Gastrin 17 Gastopanel H. pylori, PGI&II, G17
Oesophagus Direct Endoscopy Cytology No RCTS
Liver Radiological imaging cirrhosis hepatitis B PBC No RCTS AFP poor sensitivity and specificity
Pancreas Work in progress No RCTS
Large Bowel
Disease-Specific Mortality in gfobt Randomised Trials (Relative Risks) Minnesota Annual 0.67 (CI 0.51-0.83) Biennial 0.79 (CI 0.62-0.97) Nottingham Biennial 0.85 (CI 0.74-0.98) Funen Biennial 0.82 (CI 0.68-0.99) Göteborg Biennial 0.84 (CI 0.71-0.99)
National UK Colorectal Cancer Screening Pilot Aim: to test the feasibility of introducing gfobt screeing into the NHS
Demonstration Pilot All 50-69 year olds offered FOBT screening 2000-2006 No screening offered
5 Cumulative Mortality from Colorectal Cancer Rate and 95% CI (Nelson-Aalen estimates) 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 Years since screening/matched date Invited for screening Controls
Rate ratio of Colorectal Cancer invited vs controls Overall 0.90 (0.830 0.989) Relative reduction in CRC mortality 10% Participants only 0.73 (0.653 0.824) Relative reduction in CRC mortality 27%
Positive Predictive Value of Screening Colonoscopy Carcinoma 14.6% No Neoplasia 49.5% Adenoma 35.9%
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
Gender distribution p<0.001 %
Uptake - Gender and Deprivation 70 60 % 50 40 30 20 10 Women Men 0 Most 1 2 3 4 5 Deprived SIMD Least Deprived
Guaiac FOBT Limited sensitivity (false negatives) Imperfect specificity (false postives) Gender and deprivation inequality Poor acceptability But it works!
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
FIT Evaluation 40125 (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)
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 2 3 4 5 least deprived
FIT cutoff for 2.0% positivity n=20358 n=17783
Effect of lowering cut-off on IC rate 60% 50% Positivity rate Interval cancer rate 40% 30% 20% 10% 0% 400 300 200 100 75 50 10 >0 faecal Hb concentration cut-off
FIT can accommodate: Colonoscopy capacity Gender differences Deprivation differences
Can Screening Prevent Colorectal Cancer?
The Adenoma-Carcinoma Sequence
ICRF/MRC FS Trial (Oct 1996 March 1999) Single flexible sigmoidoscopy with removal of adenomas 55-64 years High risk colonoscopy adenoma > 1cm 3+ adenomas tubulovillous or villous histology 20+ hyperplastic polyps above distal rectum cancer
Mortality from CRC
Incidence of CRC
Incidence of L-sided CRC
ICRF/MRC Study Total no: 354262 Interested : 194726 (55%) Randomised: 170432 Control: 113178 Invited for screening: 57254 Attended: 40674 (71%)
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%
Incidence of R-sided CRC
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
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; www.clinicaltrials.gov
Colonoscopy mortality and incidence NHS and HPFUS 88,902 participants 22 year FU
Mortality No SLE SFS SC
Incidence No LE Polyp y -ve FS -ve C
Why does colonoscopy have little effect on R-sided cancer? Colonoscopy quality? Bowel preparation quality? Different biology?
Questions for population screening Does Endoscopy perform better than blood in stool tests? FOBT/FIT + FS? Colonoscopy? Novel tests?
Current position England FS offered at 55 gfobt from 60-74 Opt-in to gfobt after 74 Scotland gfobt/fit from 50-74years Opt-in after 74 years
Flexible Sigmoidoscopy England One-off FS at 55 years i.e. before FOBT screening starts Uptake 30-40% In 43500 exams 55 cancers and 835 HRA (2% SCRN detection rate) Scotland FOBT screening starts at 50 years RCT of FS at ~ 60 years
Immediate future England Full roll-out of FS?Change to FIT Scotland Change to FIT?FS
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.?
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
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
Volatile organic compounds Breath Sensitivity 91% Specificity 99% Stool Sensitivity 97% Specificity 99%
Scottish Bowel Screening Programme 1st June 2007-31st October 2013 50-54 55-59 60-64 65-69 70-75 Total Invitations 1,379,304 793,423 968,707 623,606 674,562 4,439,602 Positive results 9,207 10,361 10,929 13,762 13,825 58,084 Invasive cancers 234 312 473 646 789 2,454 Polyp cancers 69 106 139 211 245 770 All colorectal cancers 303 418 612 857 1,034 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 37.0 35.9 32.8 36.6 36.1 35.7 B 16.5 21.5 24.3 23.0 27.0 23.7 C1 27.4 22.7 26.3 24.4 21.6 23.9 C2 2.6 2.6 2.6 2.2 2.4 2.5 D 4.3 4.8 2.3 3.0 2.9 3.2 Not known 5.3 3.8 3.8 2.9 3.8 3.7 Not stated 7 6.9 8.6 7.8 7.8 6.3 7.4