The Dutch bowel cancer screening program Relevant lessions for Ontario

The Dutch bowel cancer screening program Relevant lessions for Ontario Ernst J Kuipers Erasmus MC University Medical Center Rotterdam - The Netherlands 1

Ismar Boas (1858 1938)

Colorectal cancer screening is rapidly expanding Schreuders E et al. Gut 2015

Annual number of German men undergoing colonoscopy screening Brenner H et al. Gastroenterology 2015

Asia-Pacific Working-Group on CRC Screening Guidelines Sung JJ, et al. Gut 2014 Hong Kong, June 9-10, 2013

Map of Ontario versus Netherlands 17 million 6

Density of Netherlands compared to North American cities The Netherlands is not a densely populated country, but rather a thinly populated city Nederland 17 miljoen 13-11-2017 7 7

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Bowel cancer screening in NL; stakeholder positions in 2005 Ministry of Health: Reluctant Impact of breast and cervical cancer screening uncertain This also pertained to other national programs, such as ongoing campaign to reduce smoking Uncertainties on optimal bowel cancer screening strategy Worries about capacity issues and costs

Pictures of colorectal cancer screening process 10

More pictures of colorectal cancer screening program 11 11

Bowel cancer screening in NL; stakeholder positions in 2005 Ministry of Health: Reluctant General population: Unaware 12

Bowel cancer screening in NL; stakeholder positions in 2005 Ministry of Health: Reluctant General population: Unaware Health insurers: Not interested 10-20% of population annually switch insurer Long-term benefit of screening for population of one insurer thus unclear 13

Bowel cancer screening in NL; stakeholder positions in 2005 Ministry of Health: Reluctant General population: Unaware Health insurers: Not interested Physician organizations: Opposed >90% of endoscopies performed by gastroenterologists Shortage of staff, waiting lists 14

Effect of rising chemotherapy cost on the cost savings of colorectal cancer screening Screening costs and treatment savings per individual US$ HemII FIT FSig Cscopy Lansdorp-Vogelaar I et al. JNCI 2009 15 15

Recommendation National Health Council and Dutch Cancer Association 2005 Seriously consider introduction of a national CRC screening program...but first provide insight into the following issues; optimal screening-strategy population participation program organization role primary care physician quality assessment program

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The impact of colorectal cancer screening The impact of screening on CRC incidence and mortality rests on: the (repeated) uptake of the test the ability to detect CRC at all stages and locations the ability to detect advanced adenomas at all locations Kuipers EJ et al. Nat Rev Clin Oncol 2013

The impact of colorectal cancer screening The impact of screening on CRC incidence and mortality rests on: the (repeated) uptake of the test the ability to detect CRC at all stages and locations the ability to detect advanced adenomas at all locations Impact defined by: Accuracy of screening test Proportion of the population covered / screening status up to date Kuipers EJ et al. Nat Rev Clin Oncol 2013

The impact of colorectal cancer screening The impact of screening on CRC incidence and mortality rests on: the (repeated) uptake of the test the ability to detect CRC at all stages and locations the ability to detect advanced adenomas at all locations Impact defined by: CRC incidence and mortality population trends over time CRC incidence and mortality among screened vs non-screened Kuipers EJ et al. Nat Rev Clin Oncol 2013

The incidence of colorectal cancer in Italian regions related to their timing of introduction of CRC screening Zorzi M et al. Gut 2015; 64:784-90

The impact of colorectal cancer screening The impact of screening on CRC incidence and mortality rests on: the (repeated) uptake of the test the ability to detect CRC at all stages and locations the ability to detect advanced adenomas at all locations Impact defined by: Screening Uptake (%) x Positivity Rate (%) x Pos Predictive Value (%) = Number of screenees diagnosed with advanced neoplasia per 1000 invited Kuipers EJ et al. Nat Rev Clin Oncol 2013

The Dutch pilot; a close combination of randomized studies and simulation modeling Randomized trials in screening-naive population with follow-up Pre-randomized designs (i.e. first randomization, then approach for consent and participation) Comparison between different screening methods and screening intervals Use of low cut-offs for colonoscopy referral

CRC screening in average risk screening-naïve individuals aged 50 74 years in Rotterdam area % Adherence % positive test % true positives* True positives per 1000 invited gfobt 50 2.8 45 6 FIT 50 62 8.1 42 21 Sigmoidoscopy 32 10.2 100 33 Hol L et al. Gut 2010

CRC screening in average risk screening-naïve individuals aged 50 74 years in Rotterdam area % Adherence % positive test % true positives* True positives per 1000 invited gfobt 50 2.8 45 6 FIT 50 62 8.1 42 21 Sigmoidoscopy 32 10.2 100 33 Sigmo + FIT 50 57 16.8 43 Kuipers EJ et al. Nat Rev Clin Oncol 2013, Hol et al. Gut 2010, Hol et al. Int J Cancer 2011

van Dam L et al. Lancet Oncol 2012 The price of autonomy; should screenees be offered a choice?

The Dutch pilot; a close combination of randomized studies and simulation modeling MISCAN microsimulation modeling to assess screening scenarios in terms of: Screening age-range (age to start and stop screening) Screening interval Cut-off of screening test Number of tests per screening round

Screening strategies; opportunities to tailor based on local needs and resources FIT screening strategies: Targeted age-range Test cut-off Screening interval Number of tests per screening round

MISCAN-Colon model for CRC screening ADENOMA Preclinical CANCER Clinical CANCER No lesion adenoma <=5 mm adenoma 6-9 mm preclinical stage I preclinical stage II preclinical stage III clinical stage I clinical stage II clinical stage III death colorectal cancer adenoma >=10 mm preclinical stage IV clinical stage IV Data sources: Adenoma Autopsy studies Endoscopy studies Preclinical Cancer gfobt trials Clinical Cancer Cancer registries Death Cancer registries National Statistics Buro

Cost performance modelling of gfobt and FIT Van Wilschut JA, van Ballegooijen M, et al. Gastroenterology 2011

CRC screening in average risk screening-naïve individuals aged 50 74 years in Rotterdam area % Adherence % positive test % true positives* True positives per 1000 invited gfobt 50 2.8 45 6 FIT 50 62 8.1 42 21 Sigmoidoscopy 32 10.2 100 33 CTC 34 8.6 71 21 Colonoscopy 22 8.7 100 19 Kuipers EJ et al. Nat Rev Clin Oncol 2013, Hol et al. Gut 2010, Stoop et al. Lancet Oncol 2011

Diagnostic yield of colonoscopy Prevalence of advanced neoplasia Primary screening colonoscopy: 5 10% Symptomatic patients: 10 15% Secondary secondary screening colonoscopy in FIT-positives: 30 60%

Comparison of CRC screening in average risk screeningnaïve individuals aged 50 74 years in Rotterdam area % Adherence % positive test % true positives* True positives per 1000 invited gfobt 50 2.8 45 6 FIT 50 62 8.1 42 21 Sigmoidoscopy 32 10.2 100 33 CTC 34 8.6 71 21 Colonoscopy 22 8.7 100 19 3-round FIT 50 70 19.8 24-42 43 4-round FIT 50 73 22.8 24-42 45 33 Hol et al. Gut 2010, Stoop et al. Lancet Oncol 2011, Kapidzic et al. AJG 2014, Grobbee et al. In preparation

Two-round FIT50 screening with 1-, 2-, or 3-year interval; advanced neoplasia detection rates Detection rate of advanced neoplasia % N = 6111; Van Roon A, et al. Gut 2012

Four biennial rounds of one- versus two-sample FIT screening; positivity rate 35 30 * 29 1-FIT 2-FIT 25 * P<0.05 20 19 15 10 5 8.4 * 12.7 * * 10.8 9.6 * 8.3 7.3 5.8 5.5 0 Round 1 Round 2 Round 3 Round 4 Cumulative Schreuders E et al. Submitted

Four biennial rounds of one- versus two-sample FIT screening; detection rate Detection rate advanced neoplasia PPV advanced neoplasia 5 4 % % 50 1-FIT 2-FIT 40 3 30 2 20 1 10 0 0 Round 1 Round 2 Round 3 Round 4 Round 1 Round 2 Round 3 Round 4 Schreuders E et al. Submitted

True positives with advanced neoplasia per 1000 invited Round Cumulative 1 2 Cumulativ Colonoscopies 3 4 needed e 1-FIT 2157 12 9 134 15 57 2- FIT 2760 11 9 194 14 60 Schreuders E et al. Submitted

Cost-effectiveness of one versus two sample FIT testing 180 160 140 Life years gained 120 100 80 60 40 20 0 1sFIT 2sFIT(both pos) 2sFIT(mean pos) 2sFIT( 1 pos) Eff. Frontier 0 200 400 600 800 1000 Costs (x1000 euro's) Van Roon AH et al. CGH 2011, Goede L et al. Gut 2013

Uptake of colonoscopy among FIT-positives in the Rotterdam pilot 92 96%

Randomized trial to assess impact of advance notification on uptake of FIT screening Advance notification increased adherence from 61.1 to 64.4% Costs per additional detected advanced neoplasia 957 euro Van Roon AH et al. Prev Med 2011

P a rtic ip a tio n (% ) Participation per screening round in the pilot 8 0 6 0 4 0 re s p o n s e a fte r re m in d e r re s p o n s e in itia l in v ite 2 0 0 1 2 3 4 S c re e n in g ro u n d Van de Vlugt M et al. Br J Cancer 2017

Gradual invitation of subsequent birth cohorts

FIT tender FOB-Gold (Sentinel, Italy) won public tender over OC-Sensor (Eiken, Japan) A cut-off for referral to colonoscopy of 15µg/g was chosen

Mailing

www.rivm.nl Protocol for the authorization and auditing of colonoscopy centres and endoscopists

Colorectal cancer screening in NL Kuipers EJ et al. Nat Rev Clin Oncol 2013

FIT positivity and detection rates in the Netherlands Pilots cut-off 10 µg Hb/g National program 1st phase cut-off 15 µg Hb/g Participation (%) 50-62 68 FIT positivity (%) 6.4 12.0 Detection of CRC* 4.5 5.9 Detection of AN* 28.3 36.2 PPV for CRC (%) 8.2 6.7 PPV for AN (%) 51.6 40.2 NN Scope for AN 1.8 2.5 *N per 1000 screened Penning C et al. In preparation; results of first 638.935 invited

Waiting list in 2014 for colonoscopy after positive FIT 100% 90% 80% 70% 60% 50% 40% 30% 20% 6 wk 5 wk 4 wk 3 wk 2 wk 10% 0%

Consequences for the Expected Colonoscopy Demand

Reduction in number of invitations

Positivity rate (%) Problem analysis: comparison between national programme and pilot studies positivity rate Programme Pilot Grobbee EJ et al. Gut 2017

Detection rate (%) Problem analysis: comparison between national programme and pilot studies detection rate Programme Pilot Grobbee EJ et al. Gut 2017

Detection rate (%) Problem analysis: comparison between national programme and pilot positivity vs detection rate Pilot Positivity rate (%) Programme Grobbee EJ et al. Gut 2017

Options to meet colonoscopy demand Increase colonoscopy capacity Reduce colonoscopy demand Slow down rate of invitations Change implementation scheme Increase cut-off value Increase screening interval

Model-based calculations for the most optimal reduction in colonoscopy demand Toes-Zoutendijk E et al. Gastroenterol 2017

FIT positivity and detection rates in the Netherlands Pilots cut-off 10 µg Hb/g National program 1st phase cut-off 15 µg Hb/g National program 2nd phase cut-off 47 µg Hb/g Participation (%) 50-62 68 72 FIT positivity (%) 6.4 12.0 7.2 Detection of CRC* 4.5 5.9 5.0 Detection of AN* 28.3 36.2 25.4 PPV for CRC (%) 8.2 6.7 9.5 PPV for AN (%) 51.6 40.2 48.1 NN Scope for AN 1.8 2.5 2.1 *N per 1000 screened Toes-Zoutendijk E et al. Gastroenterol 2017

The best laid plans: Adaption is an essential part of going from efficacy research to program implementation Levin T. Gastroenterol 2017

Longer-term implications of the national programme: colonoscopy demand

Waiting list in 2014 for colonoscopy after positive FIT 100% 90% 80% 70% 60% 50% 40% 30% 20% 6 wk 5 wk 4 wk 3 wk 2 wk 10% 0% 59

Number of CRCs diagnosed in 2013 and 2014, listed per year of birth Screening started in 2014; first approaching subjects born in 1938, 39, 47, 49, and 51 CRC incidence increased 12% from 13.400 (2013) to 15.000 (2014) Toes-Zoutendijk et al; results of first 638.935 invited

Results of 2016 1.5 million persons invited 1.0 million participants 57.000 positive test results 47.000 persons underwent colonoscopy: - 3.700 colorectal cancers - 20.000 advanced adenomas

Participation rate 2016 First round Second round 71.8% 75.9%

Positivity rate 2016 First round Second round 6.1% 4.5% Cut-off level 47 µg Hb/g

Yield of colonoscopy First round Second round 20% 8% 7% Colorectal cancer 25% Advanced adenoma 5% 6% 35% Non-advanced adenoma 45% Serrated polyps 22% 27% No polyps or tumours

Positive predictive value First round Second round CRC 8.3% 6.6% CRC + AA 53.7% 42.1% Toes-Zoutendijk E et al. Submitted

Detection rate First round Second round CRC 4.1 22.3 CRC + AA 2.4 13.0

Stage distribution of colorectal cancer Screen-detected CRCs have a more favourable stage distribution percentage (%) 0 10 20 30 40 50 (stage I and II) than symptom-detected CRCs (67% versus 40%) I II III IV screen-detected I II III IV percentage (%) 0 10 20 30 40 50 I II III IV symptom-detected I II III IV

Uptake of colonoscopy among FIT-positives in the national program 82.8% (- 89%)

Complications in 47.257 colonoscopies

Interval cancers in subjects undergoing multiple rounds of FIT screening 27 / 157= 17% FIT cancer miss rate Van de Vlugt M et al. Gastroenterol 2017

Interval cancers in subjects undergoing multiple rounds of FIT screening Van de Vlugt M et al. Gastroenterol 2017

0 / 0 Number of cancers = Interval cancers in FOBT-based colorectal cancer population screening programme: implications for stage, gender and tumour site 1 st round: 618 2 nd round: 447 3 rd round: 389 Steele RJC, et al. Gut 2012 Target population 317,000, 3 biennial rounds of gfobt screening

Interval cancers in subjects undergoing colonoscopy screening 14.064 patients diagnosed with CRC and having had a screening colonoscopy, 12.084 (91%) were diagnosed at the screening colonoscopy 1.260 (9%) were diagnosed within 3 years after the screening colonoscopy Baxter NN et al. Gastroenterol 2011

Risk of advanced neoplasia depends on baseline FIT, even at low levels in the negative range 40 0 µg Hb/g 0-2 µg Hb/g cum. incidence of AN (%) 30 20 10 p<0.001 >2-4 µg Hb/g >4-6 µg Hb/g >6-8 µg Hb/g >8<10 µg Hb/g 0 0 1 2 3 4 5 6 7 8 years 0 4927 4185 3639 2852 2410 2090 1485 726 Subjects at risk >0-2 1874 1672 1587 1427 1291 1177 470 94 Subjects at risk >2-4 436 376 333 286 247 220 101 34 Subjects at risk >4-6 214 171 151 125 105 94 54 16 Subjects at risk >6-8 106 87 78 65 56 47 18 4 Subjects at risk >8-<10 78 70 58 44 35 29 18 7 Subjects at risk

Potential relevant lessons for Ontario Focus on one dominant screening strategy and lower threshold to participate as much as possible If FIT-based: Mail kits to home address Consider pre-invitation letter Mail reminder with 2 nd kit in case of non-response Make mailings stand out and use image of mailing in all communications With respect to colonoscopy: Target limited capacity towards optimal impact Risk of AN FIT-positives > symptomatic patients > healthy subjects! Quality assurance and accreditation, for instance linked to reimbursement

Conclusions Nearly all European countries are implementing CRC screening They use different approaches Primary colonoscopy screening tends to be associated with low participation, and thus little impact on CRC incidence and mortality Guaiac-FOBT based programs are being replaced by FIT programs FIT programs have the highest population participation Modeling can help to devise the most optimal program for a particular country or region for optimal use of available resources, participation, 76

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