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Bowel Cancer Screening…
Exploiting science brings better medicine
Camberley & District
Prof Stephen P. Halloran
IncidenceMortality
Estimated age-standardised rates/100,000
Men Women
World - All Cancers
GLOBOCAN 2012 (IARC)
Incidence & Mortality (2012)
Estimated age-standardised rates/100,000
Men Women
World – Top 20 Cancers
GLOBOCAN 2012 (IARC)
Incidence & Mortality (2012)
World - Bowel Cancer 3rd commonest cancer
• 4nd cause of Ca deaths
Western Europe
• 2nd commonest cancer death
• 2nd commonest cancer
• 1st commonest cancer in
non-smoking men?
1
23
4
IncidenceMortality
Estimated age-standardised rates/100,000
Men Women
W. Europe – Top 20 Cancers
GLOBOCAN 2012 (IARC)
Incidence & Mortality (2012)
World - Bowel Cancer 3rd commonest cancer
• 4nd cause of Ca deaths
Western Europe
• 3nd commonest cancer
• 2nd commonest cancer death
• 1st commonest cancer in
non-smoking men?
12
Bowel Cancer Incidence & Mortality (2012)
Uruguay
Bowel Cancer Incidence & Mortality (2012)
Arnold M, et al. Gut 2016;0:1–9
% Change Incidence % Change Mortality
% Changeover
10 yearin CRC
Incidence&
Mortality
0
2
4
6
8
10
12
2005 2015 2030
2.1 2.3 2.5
5.5
6.7
8.9
Tota
l can
cer
de
ath
s (m
illio
ns)
Deaths From Cancer
Low - Middle Income Countries
High Income Countries
UK 2013-15 Bowel Cancer – age at diagnosis
94% in >50 years
83% in >60 years
Europe – 2012
1 in 14 men1 in 19 women
Diagnosed bowel cancerduring their lifetime
Diagnosed - 447,000 p.a.Die - 215,000 p.a.
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
Bowel CancerGenetic Risk
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)
1st degree relative diagnosed with bowel cancer <50y
Other• Previous bowel cancer• Diabetes• Severe ulcerative colitis• Crohn’s disease• Ashkenazi Jewish• Family history• Deprivation
Bowel CancerRisk Factors
Diet and Exercise• Red & processed meat• Overweight• Alcohol• Low fibre diet• Lack of exercise• Low fruit & vegetable diet• Smoking
Responsible for 21% of all bowel cancers
Responsible for 19% of all
cancers
WHO 1968 - Criteria for Screening
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 benefit1968
Alive - 5 years after treatment 93% 77% 7% 48%
>50 years old - 1 in 4 have polyps 1 in 10 change to invasive cancer
10 years
Polyp
Cancer Stage1 2 3 4
Colorectal Cancer Pathogenesis
Case for Screening
Screening Colonoscopy – 30 to 45 mins• Look for polyps – remove (polypectomy)• Look for cancers – surgery
20-15 years ago…LargeRandomisedControlled TrialsFOBT Colorectal Cancer Screening
• Minnesota
• Nottingham
• Funen
• France
Amongst those who did the tests……23% reduction in mortality
Overall……16% reduction in mortality
‘FOBt is……still the most
appropriatescreening test'
‘Colorectal cancer screening:An updated review of the available options’
Iyad A Issa, Malak NoureddineWorld J Gastroenterol 2017 July 28; 23(28): 5086-5096
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
KitReturned
KitRead
+veResult
Patient & GPLetter
-veResult
Patient letter & GPletter /e-message
SSPClinic
AppointmentScreening
Colonoscopy
Freephone Helpline (
Pre-InvitationAt Screening
Due Date
D1
InvitationKit & Spatula
Return Envelope
D8
ReminderLetter
D29
NextPre-Invitation
(1)d
<2d
<14d <14d
NoResponseGP Letter/E-Comms
M3
SurveillanceColonoscopy
2 Years
Start2 yearlyScreeningCycle
Access to Information• Emphasis on reaching everyone!
Easy access to Information
9%
10%
17%
16%
28%
1%
17%
2%
7%
8%
13%
21%
31%
0%
18%
2%
6%
8%
11%
26%27%
0%
20%
2%
Cancer detected
High-risk adenoma
Intermediate-risk adenoma
Low-risk adenoma
Abnormal finding
Abnormal, no histology
Normal result
No result
3rd Episode (Incident)
1st Episode (Prevalent)
2nd Episode (Incident)
EnglandScreening Outcomes
Episode 1, 2 & 32011/12
Polypectomy Rate 48%
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10121416182022242628303234363840424446485052545658606264666870727476788082848688
% U
pta
ke
Date Sept 2006 – April 2013
2008
2009
2010
2011
2012
2013
2007
% Uptake following previous refusal
% Uptake following previous acceptance
% Uptake in all invited61% Uptake
% Uptake - gFOBT Screening(Southern Hub - Population 60 – 74 year)
% Uptake – Relationship to Socioeconomic StatusFirst 2.6 million Invitation
(BCSP - UCL Study)
Female
Male
von Wagner C, Baio G, Raine R et al.(2011) Int J Epidemiol 40, 712-718
% Uptake FOBT kitsFirst 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 groupsin the Netherlands
0
10
20
30
40
50
60
Ethnic DutchOther Western
Surinamese &Antillean S & E Asian
Middle &Central East African
% Uptake
Ethnic Dutch
Other Western
Surinamese & Antillean
S & E Asian
Middle & Central East
African
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
57.460.9
66.2
70%1 of 3
61%2 of 3
44%3 of 3
0
10
20
30
40
50
60
70
80
1st Episode 2nd Episode 3rd Episode At least once At least twice At least 3 times
2n
dIn
vita
tio
n
1st
Invi
tati
on
3rd
Invi
tati
on
Full
Ad
her
ence
Po
or
Ad
her
ence
Ver
y P
oo
r A
dh
eren
ce
Adherence to screening?
% 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
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
Haemoglobin - Haem
Haem (containing iron)
Release of oxygen from H2O2
Oxidise a dye (guaiac)
Change in colour (blue)
Haemoglobin - Globin
Antibody recognition of the tertiary structure produced by the folding of the amino acid chain in the globin protein.
Faecal Occult Blood Tests
HaemGuaiac test gFOBT
GlobinImmunochemical iFOBT (FIT)
gFOBt
FIT
European guidelines for quality assurance incolorectal cancer screening and diagnosis.Chapter 4. Faecal occult blood testing.Halloran SP, Launoy G, Zappa M
Endoscopy 2012; 44 (S 03):SE65-SE87
In good company!
Hb
HaemGlobin
Protein structure..
Unique to the humans
Containsiron
What is the Faecal Immunochemical Test?
1. Antibodies prepared
against…
2. …human haemoglobin
(just the globin)
Making the Test Reagents
Hb
What is the Faecal Immunochemical Test?
Anti-human Hb
antibodies
Particles of a ‘latex polymer’
(e.g. polystyrene)
+
‘Latex’ coated with
anti-human Hb
immunoglobulin
=
Test Reagents
What is the Faecal Immunochemical Test?
=
Latex particles
coated with
anti-Hb antibodies
+
Blood in faeces
(human
haemoglobin) Latex boundantibody-Hb complexes
What is the Faecal Immunochemical Test?
Glass or plastic container (cuvette)
What is the Faecal Immunochemical Test?
Immunoturbidimetric analysis
Light sourcewavelength660-570nm
Particles cross link and block the passage of
light Lightmeasurement‘Photometer’
The reduction in light intensity relates to Hb
concentration
0
100
200
300
400
500
600
700
800
900
1000
1100
0 100 200 300 400 500 600 700 800 900 1000 1100
Ind
ivid
ual
an
alys
er
resu
lts
ngH
b/m
L
Mean result of 4 analysers ngHb/mL
y=x
Line of best fity=0.997x + 0.1122
UK FIT Pilot – 150 samples – 600 individual measurements5 Batches each of 30 samples, 4 analysers, 2 sites over 7 months
April – October 2014
FITPilot
FITPilot
Both Hubs• Population 27.8 m• gFOBT Kits = 1,126,087• FIT Kits = 40,930
Southern HubLess Deprivation• Population 14.7 m• gFOBT Kits = 588,317• FIT Kits = 21,641
Midlands & North West HubMore 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
50% 55% 60% 65% 70%
Mid & NW
Southern
Both
FIT
gFOBt
7.0%
7.1% Increase
7.3%
290,000Additional screens
each year!
0 – 5 previous screening invitations
Uptake & All Episodes2014 Southern, Midlands & NW Pilot
50% 55% 60% 65% 70%
Mid & NW
Southern
Both
FIT
gFOBt
0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0%
Mid & NW
Southern
Both
0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0%
Mid & NW
Southern
Both
0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% 14.0%
Mid & NW
Southern
Both
% Positivity & Screening Episode
PrevalentEpisode
FIT Cut-off - 20 ug Hb/g Faeces
Incident Episode
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
Mean
FIT Conc.
ug Hb /g
faeces
+ve at
20 ug /g
Cut-off
Histology
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%
0.0
100.0
200.0
300.0
400.0
500.0
600.0
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
-Sp
eci
fic
Inci
de
nce
Rat
es
/10
0,0
00
Po
pu
lati
on
Age Range
Annual Colorectal Cancer RatesUK 2012-2014
Male Rates
Female Rates
Lower Risk ofCRC
Higher Risk of Harm
Benefit?
Harm?
Age range for screening
0.00%
0.05%
0.10%
0.15%
0.20%
0.25%
0.30%
0.35%
0.40%
0.45%
FIT 20 FIT 100 FIT 150 FIT180 gFOBt
Can
cer
Det
ect
ion
Rat
e
Age Group
Age & FIT Threshold – Cancer Detection Rate
59-64
65-69
70-75
Screen Episode & FIT threshold – Cancer Detection Rate
0.0%
0.1%
0.2%
0.3%
0.4%
0.5%
0.6%
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
FIR
ST
PR
EVA
LEN
T
INC
IDEN
T
20 40 60 80 100 120 140 160 180 200 gFOBt
% C
ance
r D
ete
ctio
n R
ate
140
First Invitation (60 year olds)No response to previous invitationsParticipated previously
gFOBT60FIT
% Uptake over 3 episodes
57.460.9
66.2
70%1 in 3
61%2 in 3
44%3 in 3
1st Episode 2nd Episode 3rd Episode At least once At least twice At least 3 times
2n
dIn
vita
tio
n
1st
Invi
tati
on
3rd
Invi
tati
on
Full
Ad
her
ence
Po
or
Ad
her
ence
Ver
y P
oo
r A
dh
eren
ce
Adherence to screeningColorectal cancer screening uptake over three biennial invitation rounds in the English bowel cancer screening programme. Lo SH, et al. Gut 2014
Risk associated with……screening history
Include in FIT algorithm…1. Period since last screen?2. Previous screening outcomes3. Surveillance details
In ‘hot countries’…1. Ambient temperature2. Travel time to laboratory
All held on screening database!
‘The algorithm offers an additional means of identifying risk of colorectal cancer, and…
…could support other approaches to early detection, including screening…‘
Retrospective study…2.5 million UK people…Full blood count data on GP records.
Personal cancer history - (colon, rectum, ovary, endometrium, or breast)
Metabolic syndrome
33-41%
70% Ulcerativecolitis
Crohn's colitis
Family history of colon cancer
25%
33% Gallstones
Type II diabetes
22-33%
8%
12%
21%
12%
Future of Quantitative FITFIT-based
Multivariate Risk Assessment
• Quantitative FIT concentrations… & trends
(ambient temp /elapse time?)
• Age & Sex
• Screening history
• Indices of Deprivation – Postcode
• Medical History – IBD, Crohns, DM, etc
• Family History – 1st and 2nd deg. relatives
• Life style – Smoking, exercise, diet, obesity
Multivariate
Bowel Cancer
Risk Score
Stage 2 - Assess risk onreceipt of FIT
Referral to colonoscopy with improved PPV & cost
effectiveness
Stage 1 - Assess risk at FIT invitation
If low risk……delay invitation
Collaborators…Jennifer Cooper,Nick Parsons,Sian Taylor-Phillips
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
Jennifer Cooper
Feed forward5-3-1
neural network,18 weights.
Weightdecay 0.01
Neural Network
Multivariable Risk Prediction Model
• Logistic linear regression• Artificial neural networks• Machine learning
Neural networks in the lead…
FIT – An opportunity to personalise population-based screening?
‘Personalising Population-based Screening’1. Intelligent use of FIT data
2. Incorporate personal risk
3. ‘Personalised’ interpretation of the FIT Screen
Better Screening by -…focusing on individuals…
...as well as on populations?
