Camberley & District Bowel Cancer Screening Exploiting science brings better medicine Prof Stephen P. Halloran
World - All Cancers Men Incidence & Mortality (2012) Women Incidence Mortality GLOBOCAN 2012 (IARC) Estimated age-standardised rates/100,000
World Top 20 Cancers Men 1 Incidence & Mortality (2012) Women 4 3 2 World - Bowel Cancer 3 rd commonest cancer 4 nd cause of Ca deaths Western Europe 2 nd commonest cancer death 2 nd commonest cancer 1 st commonest cancer in non-smoking men? GLOBOCAN 2012 (IARC) Estimated age-standardised rates/100,000
W. Europe Top 20 Cancers Men Incidence & Mortality (2012) Women 2 1 World - Bowel Cancer 3 rd commonest cancer 4 nd cause of Ca deaths Incidence Mortality Western Europe 3 nd commonest cancer 2 nd commonest cancer death 1 st commonest cancer in non-smoking men? GLOBOCAN 2012 (IARC) Estimated age-standardised rates/100,000
Bowel Cancer Incidence & Mortality (2012) Uruguay
Bowel Cancer Incidence & Mortality (2012)
% Change Incidence % Change Mortality % Change over 10 year in CRC Incidence & Mortality Arnold M, et al. Gut 2016;0:1 9
Total cancer deaths (millions) Deaths From Cancer Low - Middle Income Countries 12 High Income Countries 10 8 8.9 6 4 5.5 6.7 2 0 2.1 2.3 2.5 2005 2015 2030
UK 2013-15 Bowel Cancer age at diagnosis Europe 2012 1 in 14 men 1 in 19 women Diagnosed bowel cancer during their lifetime Diagnosed - 447,000 p.a. Die - 215,000 p.a. 83% in >60 years 94% in >50 years
Bowel Cancer Genetic Risk Two well described genetic conditions FAP - Familial adenomatous polyposis 1% of all bowel cancer - (auto rec. /dom) 100% risk by age 40-1000s of polyps) mutation Lynch Syndrome - HNPCC Hereditary non-polyposis colorectal cancer 2-7% of all bowel cancer (and other cancers) 40% risk by age 30, MSH2, and MSH6 (autosomal dominant) 1 st degree relative diagnosed with bowel cancer <50y
Diet and Exercise Red & processed meat Overweight Alcohol Low fibre diet Lack of exercise Low fruit & vegetable diet Smoking Bowel Cancer Risk Factors Responsible for 21% of all bowel cancers Responsible for 19% of all cancers Other Previous bowel cancer Diabetes Severe ulcerative colitis Crohn s disease Ashkenazi Jewish Family history Deprivation
WHO 1968 - Criteria for Screening 1968 1. The condition is an important health problem 2. Its natural history is well understood 3. It is recognisable at an early stage 4. Treatment is better at an early stage 5. A suitable test exists 6. An acceptable test exists 7. Adequate facilities exist to cope with abnormalities detected 8. Screening is done at repeated intervals when the onset is insidious 9. The chance of harm is less than the chance of benefit 10. The cost is balanced against benefit
Colorectal Cancer Pathogenesis Case for Screening Cancer Stage Screening Colonoscopy 30 to 45 mins 1 Look for polyps 2 remove (polypectomy) 3 4 Look for cancers surgery Polyp >50 years old - 1 in 4 have polyps 1 in 10 change to invasive cancer Alive - 5 years after treatment 93% 77% 48% 7% 10 years
20-15 years ago Large Randomised Controlled Trials FOBT Colorectal Cancer Screening Minnesota Nottingham Funen France Amongst those who did the tests 23% reduction in mortality Overall 16% reduction in mortality
Colorectal cancer screening: An updated review of the available options Iyad A Issa, Malak Noureddine World J Gastroenterol 2017 July 28; 23(28): 5086-5096 FOBt is still the most appropriate screening test'
England Bowel Cancer Screening 1. Day 1 Pre-invitation to be screened + literature 2. Day 8 By default - stool collection kit (Free return post) 3. Day 30 Reminder 4. and then a. No reply @ 3m repeat invitation in 2 years b. Kit Negative repeat in 2 years c. Kit Positive Hub. i. Makes nurse (SSP) appointment (5 days time) ii. Notify GP (first class mail) iii. Assessed for colonoscopy
England BCSP gfobt timeline Start 2 yearly Screening Cycle D1 Invitation Kit & Spatula Return Envelope D8 <2d +ve Result Patient & GP Letter Kit Read (1)d SSP Clinic Appointment <14d <14d D29 M3 Screening Colonoscopy Surveillance Colonoscopy 2 Years Pre-Invitation At Screening Due Date Kit Returned -ve Result Patient letter & GP letter /e-message Reminder Letter No Response GP Letter/ E-Comms Next Pre-Invitation Freephone Helpline (
Easy access to Information Access to Information Emphasis on reaching everyone!
20% 18% 2% 2% 2% 6% 7% 9% 8% 8% England Screening Outcomes Episode 1, 2 & 3 2011/12 17% 10% 11% Cancer detected High-risk adenoma 0% 0% 1% 1 st Episode (Prevalent) 2 nd Episode (Incident) 17% 13% Intermediate-risk adenoma Low-risk adenoma Abnormal finding Abnormal, no histology 3 rd Episode (Incident) 28% Normal result No result 27% 31% 16% 21% 26% Polypectomy Rate 48%
2007 2008 2009 2010 2011 2012 2013 % Uptake % Uptake - gfobt Screening (Southern Hub - Population 60 74 year) 100 90 80 70 60 50 % Uptake in all invited % Uptake following previous acceptance 61% Uptake 40 30 % Uptake following previous refusal 20 10 0 0 2 4 6 8 10121416182022242628303234363840424446485052545658606264666870727476788082848688 Date Sept 2006 April 2013
% Uptake Relationship to Socioeconomic Status First 2.6 million Invitation (BCSP - UCL Study) Male Female von Wagner C, Baio G, Raine R et al. (2011) Int J Epidemiol 40, 712-718
% Uptake FOBT kits First 2.6 million invitations in England von Wagner C, Baio G, Raine R et al. (2011) Int J Epidemiol 40, 712-718
%Uptake of FOBt screening in different ethnic groups in the Netherlands 60 50 Ethnic Dutch Other Western Surinamese & Antillean S & E Asian 40 Middle & Central East African % Uptake 30 20 10 0 Ethnic Dutch Other Western Surinamese & Antillean Uptake of faecal occult blood test colorectal cancer screening by different ethnic groups in the Netherlands M. Deutekom E J of Public Health 2009 Vol. 19, No. 4, 400 402 S & E Asian Middle & Central East African
1 st Invitation 2 nd Invitation 3 rd Invitation Very Poor Adherence Poor Adherence Full Adherence 80 70 60 50 57.4 % Uptake - 3 Episodes (E1, E2 & E3) BCSP Southern Hub 2006-8 Colorectal cancer screening uptake over three biennial invitation rounds in the English bowel cancer screening programme. Lo SH, Halloran et al Gut 2014 60.9 66.2 Adherence to screening? 70% 1 of 3 61% 2 of 3 44% 3 of 3 40 30 20 10 0 1st Episode 2nd Episode 3rd Episode At least once At least twice At least 3 times
Small effect (0.7%) on Uptake Socioeconomic gradient 1. Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening Raine R, et al. BRITISH JOURNAL OF CANCER 114(3):321-326 2. Effects of evidence-based strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme (ASCEND): four cluster-randomised controlled trials Wardle J, et al. LANCET 387(10020):751-759 20 3. Colorectal cancer screening uptake over three biennial invitation rounds in the English bowel cancer screening programme Lo SH, et al. 2nd Digestive-Disorders-Fed. Conf., London,, GUT. BMJ. 64: A373-A373 2015
Faecal Occult Blood Tests FIT Haemoglobin - Haem Globin Antibody Haem (containing recognition iron) of the tertiary Release structure of oxygen produced from H 2 Oby 2 the folding Oxidise of a the dye amino (guaiac) acid chain in the globin protein. Change in colour (blue) gfobt Haem Guaiac test gfobt Globin Immunochemical ifobt (FIT)
In good company! European guidelines for quality assurance in colorectal cancer screening and diagnosis. Chapter 4. Faecal occult blood testing. Halloran SP, Launoy G, Zappa M Endoscopy 2012; 44 (S 03):SE65-SE87
What is the Faecal Immunochemical Test? Globin Protein structure.. Unique to the humans Haem Contains iron Hb
What is the Faecal Immunochemical Test? Making the Test Reagents 1. Antibodies prepared against 2. human haemoglobin (just the globin) Hb
What is the Faecal Immunochemical Test? Test Reagents + = Anti-human Hb antibodies Particles of a latex polymer (e.g. polystyrene) Latex coated with anti-human Hb immunoglobulin
What is the Faecal Immunochemical Test? + = Latex particles coated with anti-hb antibodies Blood in faeces (human haemoglobin) Latex bound antibody-hb complexes
What is the Faecal Immunochemical Test? Light source wavelength 660-570nm Particles cross link and block the passage of light The reduction in light intensity relates to Hb Glass or plastic container (cuvette) concentration Immunoturbidimetric analysis Light measurement Photometer
Individual analyser results nghb/ml UK FIT Pilot 150 samples 600 individual measurements 5 Batches each of 30 samples, 4 analysers, 2 sites over 7 months April October 2014 1100 1000 900 800 700 600 500 400 300 200 100 y=x Line of best fit y=0.997x + 0.1122 0 0 100 200 300 400 500 600 700 800 900 1000 1100 Mean result of 4 analysers nghb/ml
Midlands & North West Hub More Deprivation Population 13.1 m gfobt Kits = 537,770 FIT Kits = 19,289 FIT Pilot 2014/5 (England) Both Hubs Population 27.8 m gfobt Kits = 1,126,087 FIT Kits = 40,930 Southern Hub Less Deprivation Population 14.7 m gfobt Kits = 588,317 FIT Kits = 21,641 FIT Pilot FIT Pilot
Uptake & All Episodes 2014 Southern, Midlands & NW Pilot Both 0 5 previous screening invitations 7.1% Increase FIT gfobt Southern Mid & NW 7.3% 7.0% 290,000 Additional screens each year! 50% 55% 60% 65% 70%
% Positivity & Screening Episode 0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0% Both Southern Mid & NW FIT Cut-off - 20 ug Hb/g Faeces Prevalent Episode Southern Mid & NW Southern Mid & NW 0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0% Both Incident Episode 0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0% Both First Screening Episode
Outcome Mean FIT Conc. ug Hb /g faeces Positives at 20 ug /g Cut-off Normal 10 (1-20) 6.9% All adenoma 14 (4-23) 9.3% Adv. adenoma 81 (37-125) 34.5% Cancer 170 (89-252) 84.6% Endoscopic Classification Histology Mean FIT Conc. ug Hb /g faeces +ve at 20 ug /g Cut-off LGD 27 14.1% HGD 197 50.0% Size < 10 mm 12 9.0% 10 mm 99 36.4% Number < 3 adenoma 14 10.1% 3 adenoma 65 26.7%
Age-Specific Incidence Rates /100,000 Population 600.0 500.0 Annual Colorectal Cancer Rates UK 2012-2014 Male Rates Female Rates Higher Risk of Harm 400.0 Benefit? Harm? 300.0 200.0 100.0 0.0 Lower Risk of CRC Age range for screening 40 to 44 45 to 49 50 to 54 55 to 59 60 to 64 65 to 69 70 to 74 75 to 79 80 to 84 85 to 89 Age Range
Cancer Detection Rate 0.45% Age & FIT Threshold Cancer Detection Rate 0.40% 0.35% 0.30% 0.25% 59-64 65-69 70-75 0.20% 0.15% 0.10% 0.05% 0.00% FIT 20 FIT 100 FIT 150 FIT180 gfobt Age Group
FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT FIRST PREVALENT INCIDENT % Cancer Detection Rate Screen Episode & FIT threshold Cancer Detection Rate 0.6% First Invitation (60 year olds) No response to previous invitations Participated previously 0.5% 0.4% 0.3% 0.2% 0.1% 0.0% FIT 60 20 40 60 80 100 120 140 160 180 200 gfobt 140 gfobt
1 st Invitation 2 nd Invitation 3 rd Invitation Very Poor Adherence Poor Adherence Full Adherence Colorectal cancer screening uptake over three biennial invitation rounds in the English bowel cancer screening programme. Lo SH, et al. Gut 2014 Adherence to screening % Uptake over 3 episodes Risk associated with screening history 60.9 57.4 Include in FIT algorithm 1. Period since last screen? 2. Previous screening outcomes 3. Surveillance details 66.2 70% 1 in 3 61% 2 in 3 44% 3 in 3 In hot countries 1. Ambient temperature 2. Travel time to laboratory All held on screening database! 1st Episode 2nd Episode 3rd Episode At least once At least twice At least 3 times
Retrospective study 2.5 million UK people Full blood count data on GP records. The algorithm offers an additional means of identifying risk of colorectal cancer, and could support other approaches to early detection, including screening
70% Ulcerative colitis Crohn's colitis 22-33% Type II diabetes 33% Gallstones 33-41% 25% Family history of colon cancer Metabolic syndrome Personal cancer history - (colon, rectum, ovary, endometrium, or breast)
21% 12% 12% 8%
Future of Quantitative FIT FIT-based Multivariate Risk Assessment Quantitative FIT concentrations & trends (ambient temp /elapse time?) Multivariate Bowel Cancer Risk Score Age & Sex Screening history Indices of Deprivation Postcode Medical History IBD, Crohns, DM, etc Stage 1-2 Assess - risk at onfit receipt invitation of FIT Referral to colonoscopy with If low improved risk PPV & cost delay effectiveness invitation Family History 1 st and 2 nd deg. relatives Life style Smoking, exercise, diet, obesity
Collaborators Jennifer Cooper, Nick Parsons, Sian Taylor-Phillips Multivariable Risk Prediction Model Logistic linear regression Artificial neural networks Machine learning Neural networks in the lead Jennifer Cooper Neural Network Feed forward 5-3-1 neural network, 18 weights. Weight decay 0.01 Risk-adjusted colorectal cancer screening using the FIT and routine screening data: development of a risk prediction model Jennifer Cooper et al British Journal of Cancer (2017), 1 9 doi: 10.1038/ bjc.2017.375
FIT An opportunity to personalise population-based screening? Better Screening by - focusing on individuals...as well as on populations? Personalising Population-based Screening 1. Intelligent use of FIT data 2. Incorporate personal risk 3. Personalised interpretation of the FIT Screen