Comparison of CRC Screening Strategies

SVIT Conference N. Segnan MD

CPO Piemonte, AOU Città della Salute e della Scienza Torino

IARC Senior Visiting Scientist

Ljiubiana

12 December 2014

Luxembourg 2010

European guidelines for quality assurance in colorectal cancer screening and diagnosis. 2010

How to compare different

screening strategies CANCER PREVENTION

• INCIDENCE and MORTALITY

• STAGE DISTRIBUTION OF SCREENING DETECTED CANCERS

• CANCER SITE BY AGE (DETECTION RATES OF PROXIMAL VERSUS DISTAL NEOPLASMS)

• COST

• SIDE EFFECTS

• PREPARATION

• PARTICIPATION

• NNS (number needed to screen)

• NNI (number needed to invite)

• ACCURACY (SENSITIVITY, SPECIFICITY, LR)

• STANDARDIZATION BY AGE

• CUMULATIVE DETECTION RATE

• CUMULATIVE COVERAGE

• TREATMENT

FOBT vs FIT

FOBT SCREENING

Test performance of G-FOBT Versus I-FOBT (≥ 100 ng/mL)

G-FOBT I-FOBT Difference

Test

performance

n % 95% CI n % 95% CI % 95% CI

Participation rate 4836 46.9 (46.0-47.9) 6157 59.6 (58.7-60.6) 12.7 (11.3-14.1)

Detection rate

intention to

screen

All advanced

adenomas and

cancers

57 0.6 (0.4-0.7) 145 1.4 (1.2-1.6) 0.9 (0.6-1.1)

Detection rate per

protocol

All advanced

adenomas and

cancers

57 1.2 (0.9-1.5) 145 2.4 (2.0-2.7) 1.2 (0.7-1.7)

Cost – performance modelling of gFOBT and FIT

Van Wilschut JA, van Ballegooijen M, et al. Gastroenterology 2011

Sygmoidoscopy vs FIT

THE LANCET

JNCI

NEJM

ITT analysis UK Flexible

Sigmoidoscopy

Trial

SCORE

Randomized

Controlled Trial

PLCO Randomized

Controlled Trial

CRC Incidence RR 0,77

CI 0,70 – 0,84 RR 0,82

CI 0,69 – 0,96

RR 0,79

CI 0,72 – 0,85

CRC Mortality RR 0,69

CI 0,59 – 0,82

RR 0,78

CI 0,56 – 1,08

RR 0,74

CI 0,63 – 0,87

Colorectal cancer incidence and mortality with screening

flexible sigmoidoscopy

Per-protocol analysis UK Flexible Sigmoidoscopy

Trial

SCORE Randomized

Controlled Trial

CRC Incidence RR 0,67

CI 0,60-0,76

RR 0,69 CI 0,56 – 0,86

CRC Mortality RR 0,57

CI 0,45 – 0,72

RR 0,62

CI 0,40 – 0,96

Colorectal cancer incidence and mortality with screening

flexible sigmoidoscopy

UK Flexisig

trial

The Lancet 2011

SCORE trial

JNCI 2012

PLCO trial NEJM 2013

INCIDENCE REDUCTION

Cumulative Events by years from randomization

≤2 ≤4 ≤6 ≤8 ≤10 >10

Control 26 44 77 105 140 152

Not Screened 9 20 31 45 57 64

Screened 21 26 32 40 47 48

0.25

0.50

0.75

1.00

1 2 3 4 5 6 7 8 9 10 11Time from randomization-years

Control Screened Not screened

Per protocol analysis-Colorectal cancer

INCIDENCE, All sites Advanced Nelson Aalen Cumulative Hazard (%) by time from randomization

RR (95%CI) =

0.54 (0.39-0.76)

PARTICIPATION RATE IN FS SCREENING

gFOBT : 49.5% FIT : 61.5% FS : 32.4%

FS : 29-39%

TC : 26.5% FIT : 32.3% FS : 32.3%

Gut. 2010 Jan

Gut. 2013 May

Gastroenterology. 2007 Jun

Segnan, et al.

Rotterdam screening trial in 15.013 average risk

screening-naïve individuals aged 50 – 74 years

gFOBT

FIT50

Sigmoidoscopy

2-step: Sigmo +

FIT50

50

62

32

57

2.8

8.1

10.2

16.8

45

42

100

6

21

33

43

% Adherence

% positive test

% true

positives*

True

positives per 1000 invited

* of those with positive test

Hol L, et al. Gut 2010, Int J Cancer 2011

Numbers needed to screen and scope to detect one

screenee with an advanced neoplastic lesion

gFOBT

FIT50

FIT75

FIT100

FIT125

FIT150

FIT175

FIT200

84

31

37

41

43

44

46

49

2.2

2.4

2.0

1.9

1.8

1.7

1.6

1.6

NN Screen NN Scope

Hol et al. Gut 2010

Cumulative uptake FIT repeated screening

Cohort 50-74 years – 4 FIT screening rounds

77,6

63,2

48,4

38,3

0,05,0

10,015,020,025,030,035,040,045,050,055,060,065,070,075,080,085,090,095,0

100,0

1 test 2 tests 3 tests 4 tests

60% of people participating in each round

Source: Crotta S, et al. High rate of advanced adenoma detection in 4 rounds of colorectal cancer screening with the

fecal immunocemical test. Clin Gastroenterol Hepatol. 2012

FEASIBILITY 20 birth cohorts of 12,000 btw 50-69 yrs

FIT SCREENING (2yrs interval) 120,000 PEOPLE AGED 50 - 69 PARTICIPATION 50% POSITIVITY RATE 5%

FS SCREENING Once only

12,000 PEOPLE AGED 58 PARTICIPATION 50% TC REFERRAL RATE 8.0%

ENDOSCOPIC WORKLOAD

3000 CT (9000 FS)

ENDOSCOPIC WORKLOAD

6000 FS + 480 CT

ENDOSCOPIC WORKLOAD 3-year follow-up - FS programs

0,0%

2,0%

4,0%

6,0%

8,0%

10,0%

12,0%

14,0%

16,0%

18,0%

20,0%

22,0%

24,0%

1 2 3 4 5 6 7

proportion of endoscopic exams attributable to surveillance TCs

ENDOSCOPIC WORKLOAD 3-year follow-up FIT programs

N.Segnan, Italy

Detected lesions (organized screening

programmes Italy 2010)

First screen Subsequent screen

Screened 631.460 824.562

Cancer 1.464 1.041

Staged cancer 72% 71%

Advanced adenoma 6.930 6.205

N.Segnan, Italy

Cancer stage distribution at diagnosis

* Malignant adenoma treated with endoscopic resection

Stage

FIT FS

programmes

(n=23) First screen

(n=1052)

Subsequent

screen (n=740)

I 35,5 42,3 56,5

I* 8,9 10,1 17,4

II 29,9 21,1 8,7

III-IV 25,7 26,5 17,4

N.Segnan, Italy

Lesions treated only with endoscopy

(71% of cases)

Mean 10°-90° percentiles

All cancers 12,1% 0 – 26%

pT1 Cancer 27,2% 0 – 46%

Advanced adenoma 95,7% 89 - 100%

N.Segnan, Italy

Operative TC mean Range Standard

Bleeding 3.2‰ 0.0 – 18.4‰ <25‰

Perforations 0.7‰ 0.0 – 5.2‰ <25‰

Endoscopic complications

Not operative TC mean Range Standard

Bleeding 0.6‰ 0.0 – 10.9‰ <5‰

Perforations 0.3‰ 0.0 – 5.4‰ <5‰

COST ANALYSIS

FS : 110 Euros

FIT : 26 - 20 Euros

Including costs incurrred by

NHS for :

Screening

Assessment

Recruitment / organisation

2005 Jan

FIT - Detection rate

AMONG NON ATTENDERS TO FS

* 1000

3,0

14,8

0,0

1,0

2,0

3,0

4,0

5,0

6,0

7,0

8,0

9,0

10,0

11,0

12,0

13,0

14,0

15,0

CRC ADVANCED ADENOMA

FIT DETECTED

20% OF ALL CRCs

8% OF ALL ADVANCED

ADENOMAS

NNS

ADVANCED NEOPLASIA MEN : 34 WOMEN : 91

(ADVANCED ADENOMA+CRC)

DO WE HAVE TO CHOOSE ?

• FS once in the lifetime:

about 4 hours devoted to screening, to

reduce by 33% the risk of getting CRC

• Proportion of regular participants in FIT

screening is about the same as with a

single FS

so comparable impact on risk reduction at

the population level, but likely higher

among FS attenders

• Reduced NHS and patient’s costs

26,6%

33,5%29,2%

32,5%37,2%

45,0%

11,4%

7,3% 15,7%12,0%

20,6%

11,7%

0,0%2,5%5,0%

7,5%10,0%12,5%15,0%17,5%

20,0%22,5%25,0%27,5%

30,0%32,5%35,0%37,5%40,0%

42,5%45,0%47,5%50,0%52,5%

55,0%57,5%60,0%

WOMEN -

TORINO

MEN - TORINO WOMEN - THE

NETHERLANDS

MEN - THE

NETHERLANDS

WOMEN -

VERONA

MEN - VERONA

FS FOBT

OR SHOULD WE COOPERATE ?

Combined strategies can

• favour patient’s preferences

• overcome limitations of each single test

Pilot studies aimed to evaluate different

combinations of the tests

Targets FIT refusers

screenees with negative FS

Outcomes population coverage

incremental CRC risk

reduction

PERSONAL INVITATION LETTER WITH

PRE-FIXED APPOINTMENT MAILED

TO MEN AND WOMEN AGED 58 – 60 *

ATTENDERS

NON ATTENDERS

INVITED FOR

BIENNIAL FIT

PERFORM FS

MAIL REMINDER

NON ATTENDERS

SCREENING FLOW (Piedmont Screening Programme (Italy) (4,400,000 inhabitants)

* 58 years old invited in Piedmont

Diagnostic Yield of Colonoscopy and Fecal Immunochemical Testing (FIT), According to the Intention-to-Screen Analysis.

Quintero E et al. N Engl J Med 2012;366:697-706

Diagnostic yield CTC vs Colo (number of subjects with advanced neoplasia)

CC CTC P-value RR

(95%CI)

n/100

participants

8.7 6.1 0.02 1.46

(1.06-2.03)

n/100

invitees

1.9 2.1 0.56 0.91

(0.66-2.03)

Stoop E et al. Lancet Oncol 2011

Proteus 2 – trial flow

AIMS

To compare the participation rate of

Flexible Sigmoidoscopy (FS) vs. CT

Colonography (CTC) in a population-

based colorectal cancer (CRC)

screening program in Turin, Italy.

Second-generation colon capsule endoscopy compared with

colonoscopy

Cristiano Spada, MD, Cesare Hassan, MD, PhD, Miguel Munoz-Navas, MD, PhD, Horst Neuhaus, MD,

Jacques Deviere, MD, PhD, Paul Fockens, MD, PhD, FASGE, Emmanuel Coron, MD, PhD, Gerard Gay, MD, Ervin

Toth, MD, PhD, Maria Elena Riccioni, MD, PhD, Cristina Carretero, MD, Jean P. Charton, MD,

Andrè Van Gossum, MD, PhD, Carolien A. Wientjes, MD, Sylvie Sacher-Huvelin, MD, Michel Delvaux, MD, PhD,

Artur Nemeth, MD, Lucio Petruzziello, MD, Cesar Prieto de Frias, MD, Rupert Mayershofer, MD, Leila Aminejab,

MD, Evelien Dekker, MD, PhD, Jean-Paul Galmiche, MD, FRCP, Muriel Frederic, MD, Gabriele Wurm Johansson,

MD, PhD, Paola Cesaro, MD, Guido Costamagna, MD, FACG

Rome, Italy; Pamplona, Spain; Düsseldorf, Germany; Brussels, Belgium; Amsterdam, The Netherlands; Nancy, France;

Malmö, Sweden

Colon capsule study

Aims

Sensitivity and specificity of PILL-CAM COLON2 for • advanced adenomas • CRC among FIT positive screened subjects Complete and rapid videos assessed

• A sample size of 400 subjects, considering a 33% (8% CRC and 25% advanced adenomas) of FIT and assuming the colonoscopy results as the gold standard, would allow to achieve a precision oPPV f the estimated Pill-Cam sensitivity equal to + 8% for advanced adenomas and + 5% for CRC+ advanced adenomas • For unblinded comparisons, we can estimate the relative performance of PillCam and TC, taking advantage of the paired design, which would allow to detect differences of at least 5% in the DR

Study size

Random sample of target

population 50-69 yr

FIT

Participation,NNS,NNI

ADENOMAS AND

CANCER DR

3yr-5 yr surveillance

and interval cancers

FIT and

serum markers

(Participation)

Adenomas and

cancer DR

Serum markers

Participation ,NNI,NNS

ADENOMAS AND

CANCER DR

RANDOMIZATION

Comparative effectiveness

Phase 4

Multitarget Stool DNA Testing for Colorectal-Cancer Screening

Thomas F. Imperiale, M.D., David F. Ransohoff, M.D., Steven H. Itzkowitz, M.D.,

Theodore R. Levin, M.D., Philip Lavin, Ph.D., Graham P. Lidgard, Ph.D., David A.

Ahlquist, M.D., and Barry M. Berger, M.D.. NEJM 2014

Extrapolation of Findings to a Population of 10,000 Persons Undergoing Screening with a Multitarget Stool DNA Test and FIT.

C. Senore N.Segnan

N Engl J Med 2014;371:184-188.

How to compare different

screening strategies CANCER PREVENTION

• INCIDENCE and MORTALITY

• STAGE DISTRIBUTION OF SCREENING DETECTED CANCERS

• CANCER SITE BY AGE (DETECTION RATES OF PROXIMAL VERSUS DISTAL NEOPLASMS)

• COST

• SIDE EFFECTS

• PREPARATION

• PARTICIPATION

• NNS (number needed to screen)

• NNI (number needed to invite)

• ACCURACY (SENSITIVITY, SPECIFICITY, LR)

• STANDARDIZATION BY AGE

• CUMULATIVE DETECTION RATE

• CUMULATIVE COVERAGE

• TREATMENT

Thank you for the attention

Dimensions of comparison and/or integration of CRC screening

programmes with FIT and/or FS

1. Outcomes by age and length of time :in the general and in the screened

population

- incidence and stage distribution

- mortality,

- overall (cumulative) detection rate,

- interval cases for FIT (cumulative) and FS

………Time: effect of screening in 10-30 years interval for FS and FIT

2. Population perspective: observed cumulative uptake and detection rate of

advanced adenomas and cancer in FIT screening and FS screening,

from age at FS and before

3. Individual perspective: expected risk of incidence and mortality of CRC at

individual level for FIT and FS screening by age and gender.

4. Endoscopy workload: FS workload, cumulative proportion of

colonoscopies in FIT and FS screening (including postpolypectomy

surveillance), overall endoscopy workload (range)

5. cost of FIT per screen detected advanced adenomas and cancer,

according to cumulative detection rates at screening, and cost of FS per

screen detected lesions

6.Screening strategies in areas with no active organized screening programme

7. Screening strategies in areas with active organized screening programme

- active and high coverage FIT screening programme

- active and low coverage FIT screening programme

- active FS low coverage screening programme

- active FS high coverage screening programme

8.Screening with integration of FS and FIT:

- sequential approach (invite to FS and offer to the FIT to refuters)

- individual choice (FS or FIT )

- combined approach (Five FITs between 50- 58 years and than once only FS)

- combined approach ( FS at 58-60 years and FIT every two years up to 70-75 yrs)

- any other combination

9. Which studies, pilot studies and/or monitoring systems

PARTICIPATION RATE

gFOBT : 50% FIT : 62%

N.Segnan, Italy

2009 standard

Positive RS (%)

advanced adenoma

other

4.6

6.4

<6-8%

Adenoma DR at RS (%) 19.6 >7.5-12.5%

DR (‰) cancer

advanced adenoma

2.6

43.7

>3-4‰

>35-40‰

RS+ PPV for proximal

neoplasia (%)

10.3

>7-10%

RS Programmes

Proteus I Study design to compare

detection rates