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Screening for H. Pylori – finding out if it prevents stomach cancer
19/09/2018 Screening for H. Pylori – finding out if it prevents stomach cancer Nicholas Wald Wolfson Institute of Preventive Medicine London Adult Medical Screening Conference 29 November 2002 Version 2 – created (27/11/02) for Adult Medical Screening Conference 29 November 2002 19/09/2018 © N.Wald - HP001 _ 1 © N. Wald
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Five leading causes of cancer death worldwide
Million/year* Lung 1.10 Stomach 0.65 Liver 0.55 Colon/rectum 0.49 Breast 0.37 * In 2000 Parkin et al 2001 Int J Cancer 19/09/2018 © N.Wald - HP001 _ 2
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Stomach cancer in five different countries
Age-adjusted death rates per 100,000 Male Female From Cancer mortality statistics in 33 countries 1953 – 1992, Tominaga, Kuroishi & Aoki (Eds), IUCC, 1998 19/09/2018 © N.Wald - HP001 _ 3
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Prevalence of H. Pylori infection
Colombia 95% India 80% Peru Mexico 75% Japan 70%* UK 40%* France Italy * At about age 55 Marshall 1994 , Hazel 1994 19/09/2018 © N.Wald - HP001 _ 4
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Prevalence of H. Pylori infection
19/09/2018 © N.Wald - HP001 _ 5
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Epidemiology of H. Pylori infection
Infection acquired in early childhood It is associated with Number of siblings Birth order: last born is most likely to be infected 19/09/2018 © N.Wald - HP001 _ 6
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H. Pylori 19/09/2018 H. Pylori infection and number of siblings, and other children, at home (up to age 12) Total children at home Odds of being H. Pylori positive 1.00 1 1.01 2 1.09 3 1.38 4 2.03 5 2.50 6 3.89 7 8.42 results from the BUPA study 19/09/2018 © N.Wald - HP001 _ 7 © N. Wald
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Prevalence of H. Pylori infection according to age
Prevalence of infected persons <20 15% 20 – 49 35% 50 – 69 50% 70+ 65% JMS, 1999 19/09/2018 © N.Wald - HP001 _ 8
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Does this mean that the incidence of infection increases materially with age?
NO The age relation is a “cohort effect” – the infection occurs in childhood and the chance of children being infected has decreased over the last century. 19/09/2018 © N.Wald - HP001 _ 9
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First prospective study of H. Pylori infection and stomach cancer:
19/09/2018 First prospective study of H. Pylori infection and stomach cancer: BUPA study and Caerphilly study Risk of stomach cancer was about three times higher in H. Pylori positive men than in negative men (OR 2.77, 95 CI 1.04 – 7.97) Forman et al, BMJ, 1991 Not sure what is relationship of “BUPA study and Caerphilly study” to rest of title. Is the colon right? 19/09/2018 © N.Wald - HP001 _ 10 © N. Wald
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Nested case-control design
H. Pylori 19/09/2018 Nested case-control design Advantages of a prospective study Economy of a retrospective study Collected blood and stored serum samples on about 25,000 men Receive notification of cancer and deaths from ONS Retrieve stored serum samples on stomach cancer cases and matched controls Should it be “case-control”? What was sig of bracketing on N’s original? Tenses don’t agree. The results were clear with only 29 cases! 19/09/2018 © N.Wald - HP001 _ 11 © N. Wald
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All showed a higher risk in H. Pylori infected people
12 prospective studies All showed a higher risk in H. Pylori infected people Helicobacter and Cancer Collaboration Group Gut, 2001 19/09/2018 © N.Wald - HP001 _ 12
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Lower oesophageal/cardia cancer
H. Pylori 19/09/2018 Lower oesophageal/cardia cancer A non-significant case-control study (Chow et al, 1998) found a lower risk of this cancer in infected people (OR 0.7, 95% CI 0.4 – 1.1) suggesting that infection may be protective. Results from a subsequent meta-analysis showed no effect (OR 1.0, 95% CI 0.7 – 1.3). Is title correct incl capitalisation? 19/09/2018 © N.Wald - HP001 _ 13 © N. Wald
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Association between H. Pylori infection and non-cardia stomach cancer is greater if people are surveyed many years before the cancer occurs. Tested for infection Relative risk if infected 10 years before cancer develops 5.9 10 years before cancer develops 2.4 Helicobacter and Cancer Collaboration Group Gut, 2001 19/09/2018 © N.Wald - HP001 _ 14
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The bacterium, over many years, destroys its own habitat.
Why? Because the H. Pylori infection tends to be lost with the atrophic gastritis that the organism causes. The bacterium, over many years, destroys its own habitat. 19/09/2018 © N.Wald - HP001 _ 15
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H. Pylori and stomach cancer
H. Pylori infection causes about 60% of the 7000 deaths a year from stomach cancer in the UK 19/09/2018 © N.Wald - HP001 _ 16
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H. Pylori and peptic ulcer
H. Pylori infection causes >70% of gastric ulcers and >90% of duodenal ulcers About 4,500 people per year in the UK die from the complications of such ulcers (haemorrhage or perforation) 19/09/2018 © N.Wald - HP001 _ 17
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H. Pylori 19/09/2018 Two randomised endoscopy studies on H. Pylori positive subjects in China Triple therapy Placebo Changle Yantai 819 294 809 292 7 5* 11 9* 12 20 Subjects Gastric cancers after 5-7 years Fujian – province, Yantai – medium city, Changle – Small city * Includes dysplasia 19/09/2018 © N.Wald - HP001 _ 18 © N. Wald
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Helicobacter pylori screening study
A randomised prevention trial HPSS 19/09/2018 © N.Wald - HP001 _ 19
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HPSS Does H. pylori screening and the treatment of those with positive results prevent stomach cancer and, if so, to what extent? 19/09/2018 © N.Wald - HP001 _ 20
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Cancer Research Campaign (now part of Cancer Research UK)
HPSS A unique example of UK medical research conducted as a university – private sector collaboration Funding: Cancer Research Campaign (now part of Cancer Research UK) BUPA Foundation 19/09/2018 © N.Wald - HP001 _ 21
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There is sufficient evidence that it is
HPSS The trial is not intended to show whether H. Pylori infection is a cause of stomach cancer There is sufficient evidence that it is The trial is intended to see if eradication of H. Pylori infection in middle-age can reverse the risk, or is it too late? 19/09/2018 © N.Wald - HP001 _ 22
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Randomised by week of attendance at BUPA
HPSS Recruitment Men aged 35 – 69 Women aged 45 – 69 Randomised by week of attendance at BUPA UK Residents, registered with an NHS GP 19/09/2018 © N.Wald - HP001 _ 23
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HPSS 45 40 85 7,000 (25%) HP Positive 28,000 Screened 21,000
H. Pylori 19/09/2018 HPSS 85 40 45 Expected gastric cancers with no treatment 21,000 HP Negative 7,000 (25%) HP Positive 28,000 Screened 56,000 People 28,000 controls © N. Wald
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HPSS 62 85 45 22 40 85 7,000 (25%) HP Positive 22 HP positive 45 HP
H. Pylori 19/09/2018 HPSS Expected gastric cancers with treatment 7,000 (25%) HP Positive 62 85 45 22 22 HP positive 45 HP 40 HP negative P = 0.005 P = 0.06 28,000 Screened 21,000 HP Negative 40 56,000 People 85 test sera at end of study 28,000 controls © N. Wald
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Nested randomised trial
Application of the nested case-control concept to a randomised trial Saves cost Increases statistical power 19/09/2018 © N.Wald - HP001 _ 26
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Statistical power of HPSS
Assuming 50% reduction in gastric cancer among H. pylori positive individuals, the study has 80% power of detecting a difference at p<0.05 level of statistical significance. Recruitment is expected to take 5 years with a follow-up period of 15 years through ONS records. 19/09/2018 © N.Wald - HP001 _ 27
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The treatment is: Lansoprazole 30mg Metronidazole 400mg
H. Pylori 19/09/2018 The treatment is: Lansoprazole 30mg Metronidazole 400mg Clarithromycin 250mg Twice daily for 7 days Hmm. Not sure if we can get it undistorted – it’s a bit close-range. Maybe worth another try. Also, we need to open the pack and photograph the contents too – but not till we are sure we are finished with it unopened! Provided free of charge to HPSS by Wyeth 19/09/2018 © N.Wald - HP001 _ 28 © N. Wald
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Intervention is simple and acceptable
H. Pylori 19/09/2018 Conclusions First and only example of a randomised trial of primary prevention of a cancer through screening One of only a few randomised trials of primary cancer prevention by any means Intervention is simple and acceptable Potential impact worldwide could be great This is really the last slide 19/09/2018 © N.Wald - HP001 _ 30 © N. Wald
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