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The impact of National Bowel Cancer Screening Program in Australia
The impact of National Bowel Cancer
Screening Program in Australia
Lowy Cancer Research Centre
Jie-Bin Lew1,2, James St John3, Dayna Cenin4 , Xiang-Ming Xu1, Veerle Coupe5,
Marjolein Greuter5, Michael Caruana1,2, Emily He1,2, Karen Canfell1,2
1.University of NSW, Australia 2. Cancer Council NSW, Australia 3. Cancer Council Victoria, Australia, 4. Cancer Council Western
Australia, Australia 5. VU University Medical Center, The Netherlands,
Email: jiebin.lew@nswcc.org.au
Background
 Bowel cancer (also known as colorectal cancer) is the second
most common cancer in males and females in Australia
 In 2011:
 ~15,200 new bowel cancer cases (ASR: 67.8 per 100,000 persons)
 ~5,000 bowel cancer deaths (ASR: 17.8 per 100,000 persons)
Data source: AIHW 2015. Australian Cancer Incidence and Mortality (ACIM) books 2015
0
100
200
300
400
500
600
Rateper100,000person
Age group (year)
Australian bowel cancer incidence rate in 2011
Male
Female
0
50
100
150
200
250
300
Rateper100,000person
Age group (year)
Australian bowel cancer mortality rate in 2011
Male
Female
Background : National Bowel
Cancer Screening Program (NBCSP)
Phase Year
Age cohort invited to NBCSP (years)
50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74
1 2006-2007 √ √
2 2008-2012 √ √ √
3
2013-2014 √ √ √ √
2015 √ √ √ √ √ √
2016 √ √ √ √ √ √ √ √
2017 √ √ √ √ √ √ √ √ √ √
2018 √ √ √ √ √ √ √ √ √ √ √
2019 √ √ √ √ √ √ √ √ √ √ √ √ √
2020 and later √ √ √ √ √ √ √ √ √ √ √ √ √
NBCSP phases and target population
Data Source: AIHW 2014. National Bowel Cancer Screening Program: Monitoring Report 2012-2013
By 2020, full
implementation of the
biennial screening
program for 50-74years
Screening program began
Prior estimates of predicted costs
and impact
• Pignone et al 2011:1
 Estimated annual gross cost of a biennial iFOBT screening program for 50-74 years as ~ $150 million
(did not consider surveillance and cancer treatment costs).
 Assuming screening program would reduce mortality from bowel cancer by 15-25%, undiscounted
cost per LYG of screening was estimated to be $25,000-41,667.
• Cenin et al 2014:2
– Estimated that accelerated implementation of the screening program to 2020 (as now occurring) will
be associated with a cumulative deaths prevented of 70,000 (equivalent to 1,750 deaths prevented
per year) between 2015-2055.
– Total 4.9 million colonoscopies (equivalent to 125,000 per year) over the period between 2015-2055.
– Did not consider costs
• No prior work has involved a comprehensive evaluation of the health
outcomes, health services utilisation and costs over time.
Data Source:
1. Pignone MP, Flitcroft KL, Howard K, Trevena LJ, Salkeld GP, St John DJ. Costs and cost-effectiveness of full implementation of a biennial faecal occult blood test screening
program for bowel cancer in Australia. Med J Aust 2011;194:180-5.
2. Cenin DR, St John DJ, Ledger MJ, Slevin T, Lansdorp-Vogelaar I. Optimising the expansion of the National Bowel Cancer Screening Program. Med J Aust 2014;201:456-61.
Study Aims
To evaluate the impact of the fully rolled out
NBCSP on health outcomes, resource utilisation
and costs*.
*Excluding program overheads and costs of targeted initiatives – considering costs
related to direct health services use only.
Methods: Adenoma and Serrated Pathway
to Colorectal Cancer (ASCCA) model
Source: Greuter MJ, Xu XM, Lew JB, et al. Modelling the Adenoma and Serrated
pathway to Colorectal CAncer (ASCCA). Risk Analysis 2014;34:889-910.
• First CRC model to incorporate the
serrated pathway
• Microsimulation (individual-based)
model.
• Simulates 20 million virtual
individuals per age-cohort through
life from age 20-89 years.
• Calibrated to the Dutch Colonoscopy
versus Colonography Screening
(COCOS) trial data, including age-
and sex-specific rates of:
• Adenoma prevalence by lesion size
• Adenoma multiplicity
• % of adenoma with HG dysplasia
• % of adenoma with villous
characteristics
• Prevalence of advance adenoma
• Advance adenoma multiplicity
• Prevalence of HPs by size
• Prevalence of SSAs by size
• HPs multiplicity
• SSAs multiplicity
• Overall SA multiplicity
• % of CRC developed via each pathway
Data sources
• Follow-up of positive FOBT and colonoscopic surveillance intervals was modelled
based on guidelines.1,2
• Cost assumptions:
– Screening, diagnosis and treatment were obtained from MBS, DRG-AG and published literature.3,4
– Program overhead cost and general program administrative cost not included
• Test characteristics of FOBT were informed by literature review and finalised via
calibration to the overall observed FOBT positive rate in Australia in 2012-13.
• Test accuracy of colonoscopy was obtained from published literature5,6
• Base case screening participation for 2006-2013 based on the observed participation
rate.
• Base case screening participation for 2014 onwards based on current rates,
interpolated rates for new age cohorts.
Reference:
1. Cancer Council Australia Colonoscopy Surveillance Working Party. Clinical Practice Guidelines for Surveillance Colonoscopy – in adenoma follow-up; following curative resection of
colorectal cancer; and for cancer surveillance in inflammatory bowel disease. Cancer Council Australia, Sydney (December 2011).
2. Barclay Karen, Cancer Council Australia Surveillance Colonoscopy Guidelines Working Party. Colonoscopic Surveillance Intervals – Adenomas. 2013
3. Pignone MP, Flitcroft KL, Howard K, Trevena LJ, Salkeld GP, St John DJ. Costs and cost-effectiveness of full implementation of a biennial faecal occult blood test screening program for
bowel cancer in Australia. Med J Aust 2011;194:180-5.
4. Ananda SS, Tran B, Kosmider S, Field K, Gibbs P. Calculating the rapidly escalating cost of treating colorectal cancer: time for an increased focus on prevention and screening. Poster
session presented at: Australia Gastrointestinal Trials Group 11th Annual Scientific Meeting. 26–28 August 2009; Brisbane, Australia
5. van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol 2006;101:343-
50
6. Pickhardt PJ, Hassan C, Halligan S, Marmo R. Colorectal cancer: CT colonography and colonoscopy for detection--systematic review and meta-analysis. Radiology 2011;259:393-405.
Model calibration results: Australia
Data sources:
•Bowel cancer incidence and mortality rate: AIHW 2015.
Australian Cancer Incidence and Mortality (ACIM) books 2015
•Distribution of CRC in sections of bowel: Forman D, Bray F,
Brewster DH et. al. (2013). Cancer Incidence in Five Continents,
Vol. X (electronic version). Lyon: IARC. Available from:
http://ci5.iarc.fr , accessed [03/02/2015].
•Stage distribution of symptomatically-detected and screen-
detected CRC: Ananda SS, McLaughllin SJ, Chen F et al
(2009). Initial impact of Australia’s National Bowel Cancer
Screening Program. MJA 191(7):378-81
•5-year survival of patient with symptomatically-detect4ed
cancer: Morris M, Iacopetta B, Platell C (2007). Comparing
survival outcomes for patients with colorectal cancer treated in
public and private hospitals. MJA 186(6):296-300.
•Relative 5-year survival of screen-detected CRC patients
vs. symptomatically-detected CRC: Gill MD, Bramble MG, Hull
MA et al (2014). Screen-detected colorectal cancers are
associated with an improved outcome compared with stage-
matched interval cancers. BJC 111(11):2076-81
Baseline results: Fully rolled out NBCSP
Model predictions Overall estimated
number in the period
over 2020-2035
( 15 years)
Overall estimated
number in the period
over 2015-2055
( 40 years)
Estimated per annum
number in the period
over 2015-2055 ( 40
years)
# of bowel cancer deaths prevented 37,700 138,100 3,500
# of FOBT returned 30.5 million 85.4 million 2.1 million
# of individuals had a colonoscopy 2.0 million 5.6 million 140,000
# of individuals needed polypectomy 973,400 2.7 million 67,500
Cenin et al (2014)
predicted over 2015-
2055:
•A total of 70,000 deaths
prevented. (equivalent
to 1,750 deaths
prevented p.a.)
•A total of 4.9 million
colonoscopy (equivalent
to 125,000 p.a.)
Reference:
Cenin DR, St John DJ, Ledger MJ, Slevin T, Lansdorp-Vogelaar I. Optimising the expansion of the National Bowel Cancer Screening Program. Med J Aust 2014;201:456-61.
Conclusion
• We have constructed a comprehensive platform for
evaluation of bowel cancer screening in Australia
• In this initial evaluation, using the most recent data on age-
specific participation, we found that after the full
implementation of the biennial screening program in 2020:
– 138,100 lives would be saved in 2015-2055: 3,500 per year on average
– 5.6 million individuals would undergo colonoscopy +/- polypectomy: 140,000
per year on average
• The biennial FOBT screening program is considered highly cost-
effective when compared to a $50,000/life-years saved willingness-
to-pay threshold in Australia.
Acknowledgement
This work was funded via:
Australia Postgraduate Award (APA) PhD Scholarship for JBL
Translational Cancer Research Network (TCRN) Top-up
scholarship, supported by Cancer Institute NSW for JBL
Prince of Wales Clinical School/NHMRC PhD Scholarship for EH
NHMRC Career Development Fellowship for KC
An initial seed funding grant from the Cancer Programs Division of
Cancer Council NSW
The University of NSW, Australia

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The impact of National Bowel Cancer Screening Program in Australia

  • 2. The impact of National Bowel Cancer Screening Program in Australia Lowy Cancer Research Centre Jie-Bin Lew1,2, James St John3, Dayna Cenin4 , Xiang-Ming Xu1, Veerle Coupe5, Marjolein Greuter5, Michael Caruana1,2, Emily He1,2, Karen Canfell1,2 1.University of NSW, Australia 2. Cancer Council NSW, Australia 3. Cancer Council Victoria, Australia, 4. Cancer Council Western Australia, Australia 5. VU University Medical Center, The Netherlands, Email: jiebin.lew@nswcc.org.au
  • 3. Background  Bowel cancer (also known as colorectal cancer) is the second most common cancer in males and females in Australia  In 2011:  ~15,200 new bowel cancer cases (ASR: 67.8 per 100,000 persons)  ~5,000 bowel cancer deaths (ASR: 17.8 per 100,000 persons) Data source: AIHW 2015. Australian Cancer Incidence and Mortality (ACIM) books 2015 0 100 200 300 400 500 600 Rateper100,000person Age group (year) Australian bowel cancer incidence rate in 2011 Male Female 0 50 100 150 200 250 300 Rateper100,000person Age group (year) Australian bowel cancer mortality rate in 2011 Male Female
  • 4. Background : National Bowel Cancer Screening Program (NBCSP) Phase Year Age cohort invited to NBCSP (years) 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 1 2006-2007 √ √ 2 2008-2012 √ √ √ 3 2013-2014 √ √ √ √ 2015 √ √ √ √ √ √ 2016 √ √ √ √ √ √ √ √ 2017 √ √ √ √ √ √ √ √ √ √ 2018 √ √ √ √ √ √ √ √ √ √ √ 2019 √ √ √ √ √ √ √ √ √ √ √ √ √ 2020 and later √ √ √ √ √ √ √ √ √ √ √ √ √ NBCSP phases and target population Data Source: AIHW 2014. National Bowel Cancer Screening Program: Monitoring Report 2012-2013 By 2020, full implementation of the biennial screening program for 50-74years Screening program began
  • 5. Prior estimates of predicted costs and impact • Pignone et al 2011:1  Estimated annual gross cost of a biennial iFOBT screening program for 50-74 years as ~ $150 million (did not consider surveillance and cancer treatment costs).  Assuming screening program would reduce mortality from bowel cancer by 15-25%, undiscounted cost per LYG of screening was estimated to be $25,000-41,667. • Cenin et al 2014:2 – Estimated that accelerated implementation of the screening program to 2020 (as now occurring) will be associated with a cumulative deaths prevented of 70,000 (equivalent to 1,750 deaths prevented per year) between 2015-2055. – Total 4.9 million colonoscopies (equivalent to 125,000 per year) over the period between 2015-2055. – Did not consider costs • No prior work has involved a comprehensive evaluation of the health outcomes, health services utilisation and costs over time. Data Source: 1. Pignone MP, Flitcroft KL, Howard K, Trevena LJ, Salkeld GP, St John DJ. Costs and cost-effectiveness of full implementation of a biennial faecal occult blood test screening program for bowel cancer in Australia. Med J Aust 2011;194:180-5. 2. Cenin DR, St John DJ, Ledger MJ, Slevin T, Lansdorp-Vogelaar I. Optimising the expansion of the National Bowel Cancer Screening Program. Med J Aust 2014;201:456-61.
  • 6. Study Aims To evaluate the impact of the fully rolled out NBCSP on health outcomes, resource utilisation and costs*. *Excluding program overheads and costs of targeted initiatives – considering costs related to direct health services use only.
  • 7. Methods: Adenoma and Serrated Pathway to Colorectal Cancer (ASCCA) model Source: Greuter MJ, Xu XM, Lew JB, et al. Modelling the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA). Risk Analysis 2014;34:889-910. • First CRC model to incorporate the serrated pathway • Microsimulation (individual-based) model. • Simulates 20 million virtual individuals per age-cohort through life from age 20-89 years. • Calibrated to the Dutch Colonoscopy versus Colonography Screening (COCOS) trial data, including age- and sex-specific rates of: • Adenoma prevalence by lesion size • Adenoma multiplicity • % of adenoma with HG dysplasia • % of adenoma with villous characteristics • Prevalence of advance adenoma • Advance adenoma multiplicity • Prevalence of HPs by size • Prevalence of SSAs by size • HPs multiplicity • SSAs multiplicity • Overall SA multiplicity • % of CRC developed via each pathway
  • 8. Data sources • Follow-up of positive FOBT and colonoscopic surveillance intervals was modelled based on guidelines.1,2 • Cost assumptions: – Screening, diagnosis and treatment were obtained from MBS, DRG-AG and published literature.3,4 – Program overhead cost and general program administrative cost not included • Test characteristics of FOBT were informed by literature review and finalised via calibration to the overall observed FOBT positive rate in Australia in 2012-13. • Test accuracy of colonoscopy was obtained from published literature5,6 • Base case screening participation for 2006-2013 based on the observed participation rate. • Base case screening participation for 2014 onwards based on current rates, interpolated rates for new age cohorts. Reference: 1. Cancer Council Australia Colonoscopy Surveillance Working Party. Clinical Practice Guidelines for Surveillance Colonoscopy – in adenoma follow-up; following curative resection of colorectal cancer; and for cancer surveillance in inflammatory bowel disease. Cancer Council Australia, Sydney (December 2011). 2. Barclay Karen, Cancer Council Australia Surveillance Colonoscopy Guidelines Working Party. Colonoscopic Surveillance Intervals – Adenomas. 2013 3. Pignone MP, Flitcroft KL, Howard K, Trevena LJ, Salkeld GP, St John DJ. Costs and cost-effectiveness of full implementation of a biennial faecal occult blood test screening program for bowel cancer in Australia. Med J Aust 2011;194:180-5. 4. Ananda SS, Tran B, Kosmider S, Field K, Gibbs P. Calculating the rapidly escalating cost of treating colorectal cancer: time for an increased focus on prevention and screening. Poster session presented at: Australia Gastrointestinal Trials Group 11th Annual Scientific Meeting. 26–28 August 2009; Brisbane, Australia 5. van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review. Am J Gastroenterol 2006;101:343- 50 6. Pickhardt PJ, Hassan C, Halligan S, Marmo R. Colorectal cancer: CT colonography and colonoscopy for detection--systematic review and meta-analysis. Radiology 2011;259:393-405.
  • 9. Model calibration results: Australia Data sources: •Bowel cancer incidence and mortality rate: AIHW 2015. Australian Cancer Incidence and Mortality (ACIM) books 2015 •Distribution of CRC in sections of bowel: Forman D, Bray F, Brewster DH et. al. (2013). Cancer Incidence in Five Continents, Vol. X (electronic version). Lyon: IARC. Available from: http://ci5.iarc.fr , accessed [03/02/2015]. •Stage distribution of symptomatically-detected and screen- detected CRC: Ananda SS, McLaughllin SJ, Chen F et al (2009). Initial impact of Australia’s National Bowel Cancer Screening Program. MJA 191(7):378-81 •5-year survival of patient with symptomatically-detect4ed cancer: Morris M, Iacopetta B, Platell C (2007). Comparing survival outcomes for patients with colorectal cancer treated in public and private hospitals. MJA 186(6):296-300. •Relative 5-year survival of screen-detected CRC patients vs. symptomatically-detected CRC: Gill MD, Bramble MG, Hull MA et al (2014). Screen-detected colorectal cancers are associated with an improved outcome compared with stage- matched interval cancers. BJC 111(11):2076-81
  • 10. Baseline results: Fully rolled out NBCSP Model predictions Overall estimated number in the period over 2020-2035 ( 15 years) Overall estimated number in the period over 2015-2055 ( 40 years) Estimated per annum number in the period over 2015-2055 ( 40 years) # of bowel cancer deaths prevented 37,700 138,100 3,500 # of FOBT returned 30.5 million 85.4 million 2.1 million # of individuals had a colonoscopy 2.0 million 5.6 million 140,000 # of individuals needed polypectomy 973,400 2.7 million 67,500 Cenin et al (2014) predicted over 2015- 2055: •A total of 70,000 deaths prevented. (equivalent to 1,750 deaths prevented p.a.) •A total of 4.9 million colonoscopy (equivalent to 125,000 p.a.) Reference: Cenin DR, St John DJ, Ledger MJ, Slevin T, Lansdorp-Vogelaar I. Optimising the expansion of the National Bowel Cancer Screening Program. Med J Aust 2014;201:456-61.
  • 11. Conclusion • We have constructed a comprehensive platform for evaluation of bowel cancer screening in Australia • In this initial evaluation, using the most recent data on age- specific participation, we found that after the full implementation of the biennial screening program in 2020: – 138,100 lives would be saved in 2015-2055: 3,500 per year on average – 5.6 million individuals would undergo colonoscopy +/- polypectomy: 140,000 per year on average • The biennial FOBT screening program is considered highly cost- effective when compared to a $50,000/life-years saved willingness- to-pay threshold in Australia.
  • 12. Acknowledgement This work was funded via: Australia Postgraduate Award (APA) PhD Scholarship for JBL Translational Cancer Research Network (TCRN) Top-up scholarship, supported by Cancer Institute NSW for JBL Prince of Wales Clinical School/NHMRC PhD Scholarship for EH NHMRC Career Development Fellowship for KC An initial seed funding grant from the Cancer Programs Division of Cancer Council NSW The University of NSW, Australia

Editor's Notes

  1. Bowel cancer (also known as colorectal cancer) is the second most common cancer in Australia In 2011, ~15,200 new bowel cancer cases and ~5,000 bowel cancer deaths in Australia This type of cancer is more common in 50 year-old or above and it is more common in men than women (Source: http://www.aihw.gov.au/cancer/ )
  2. After a pilot phase, The National Bowel Cancer Screening Program commenced in 2006, offering free self-sampling iFOBT screening for cohort turning 55 and 65 years. The program has been expanding since then and the full rollout of biennial screening for Australians aged 50-74 years is targeted for 2020 Currently, the overall screening participation rate is ~36% . This rate varies across age group Higher participarion rate are found in women and in 60 & 65 year-old
  3. Pronounciation: Pignone - bi neoh- neh - There are two prior studies on the cost and effectiveness of bowel screening in Australia. A paper published by Pignone and colleagues estimated an annual cost of 150 million to provide biennial iFOBT screening for 50-74 years and colonoscopy follow-up for positive FOBT The cost of surveillance and cancer treatment were not considered in the study The study also estimated that that bienniel bowel cancer screening program is associated with an ICER of $25,000-41,667 undiscounted cost per LYG Another study by Cenin and colleagues estimated that accelerated implementation of the screening program to 2020, as now occurring, will prevent 70,000 bowel cancer deaths and associated with a total of 4.9 million colonoscopies over the period between 2015-2055. This is equivalent to 1,750 deaths prevented per year and 125,000 colonoscopies per year However, the study did not consider costs None of these prior works have involved a comprehensive evaluation of the over time health outcomes, health services utilisation and costs.
  4. This study has two aims: 1… 2…
  5. We have developed a comprehensive NH model in collaboration with VU University Medical Center in The Netherlands The ASCCA model is used in this study to simulate the natural history of colorectal cancer development via adenoma-carcinoma pathway and serrated pathway in individuals This model is a micro-simulation model. It simulates 20 million virtual individual per single age-cohort from 20 to 89 years old The model has undergone extensive calibration process to calibrate its predictions to a series of outcome of COCOS trial, including The age- and sex- specific prevalence of the polpys The multiplicity of the lesions And the proportion of CRC developed via each natural history pathway
  6. I would like to quickly go through some of the model assumptions and data sources: We modelled screening and surveillance based on guideline recommendations The cost data were obtained from MBS, DRG and published literatures. Program overhead cost and general administrative cost are not included- Test characteristics of FOBT were informed by literature review and finalised via calibration to the overall observed FOBT positive rate in Australia Test accuracy of colonoscopy were obtained from published literature 5,6. - The base case screening participation in the period between 2006 and 2013 was modelled based on the observed rate. - The screening participation for 2014 onwards were based on current rates, interpolated rates for new age cohorts.
  7. - I would like to show you some of the model calibration results. The model has calibrated to the age-specific bowel cancer incidence and mortality in men (the blue lines) and women (the red lines) observed in Australia. The model predictions are plotted in dotted lines. They are in a close agreement with the observed data, which are plotted in solid lines The model has also calibrated to the distribution of cancer in sections of bowel reported by IARC The stage distribution of in symptomatically-detected CRC and screen-detected CRC observed in Australia
  8. The first two graphs on shows the model predicted overtime cancer incidence rate and cases and cancer mortality rate and cases. The graphs contains two vertical axes. The axis on the left represents the age-standardised rate and the axis on the right represents the case number. The red lines and bars are the result predicted in female and the blue lines and bars are results predicted in males After the full biennial program were rolled out in 2020, the age-standard rate of cancer incidence and mortality was estimated to decrease under the effect the of screening. However, the case number were predicted to increase overtime due to the expansion in size of the projected future populations We have also predicted the overtime cost and number of use of FOBT, colonoscopy and polypectomy. These numbers are also predicted to increase overtime due to the expand in population size The fully rollout program was predicted to savce ~3.5K lifes a year Associated with a about 2.1million individuals being screened by FOBT a year and a need to perform 136 k colonoscopies a year to follow-up positive FOBT and to provide surveillance. This is equivalent to 600 needed to screened per cancer death prevented and 39 colonoscopies per death prevented These predicted numbers are higher then the estimates of the recent paper published by Cenin and colleagues It is likely due to the differences in how the surveillance program and future screening participation and the cancer survival were modelled in the two studies The cost-effectiveness of biennial bowel screening program was found to be $3,800/life-years saved when compared to no screening. The screening program is therefore considered to be highly cost-effective when compared to an indicative $50,000/life-years saved threshold in Australia. (Additional information – not for presentation) 0f the $2,162 million p.a. ~$59 million (3%) related to FOBT screening ~$464 million (21%) related colonoscopy services to follow-up positive FOBT and surveillance program ~$1,639 million (76%) related to cancer treatment If surveillance stop at 74 year, the number of colonoscopy will decreased by ~15% but the overall cost may increase due to the increase in cancer cases
  9. - We have constructed a comprehensive platform for evaluation of bowel cancer screening in Australia - In this initial evaluation, we found that 31,158 lives would be saved and 2.3 million individuals would undergo colonoscopy +/- polypectomy in the first 15 years after the implementation of the biennial screening program. This is equivalent to 2,000 lives saved per year and 154,000 colonoscopy per year average The biennial bowel screening program for 50-74 years is considered highly cost-effective in Australia -
  10. I would like to thank the funders of this work, listed in this slide