A trial in almost 1,000 people with high hereditary risk of a wide range of cancers has shown a major preventive effect from resistant starch, found in a wide range of foods like oats, breakfast cereal, cooked and cooled pasta or rice, peas and beans and slightly green bananas. The astonishing effect was seen to last for 10 years after stopping taking the supplement.
The international trial, known as CAPP2, involved almost 1,000 patients with Lynch syndrome from around the world and showed that a regular dose of resistant starch, also known as fermentable fibre, taken for an average of two years, did not affect cancers in the bowel but did reduce cancers in other parts of the body by more than half. This effect was particularly pronounced for upper gastrointestinal cancers including oesophageal, gastric, biliary tract, pancreatic and duodenum cancers.
The astonishing effect was seen to last for 10 years after stopping taking the supplement.
The study, led by experts at the Universities of Newcastle and Leeds, published in Cancer Prevention Research, a journal of the American Association for Cancer Research, is a planned double blind 10-year follow-up, supplemented with comprehensive national cancer registry data for up to 20 years in 369 of the participants.
Previous research published as part of the same trial, revealed that aspirin reduced cancer of the large bowel by 50%.
“We found that resistant starch reduces a range of cancers by more than 60%. The effect was most obvious in the upper part of the gut,” said Professor John Mathers, professor of Human Nutrition at Newcastle University. “This is important as cancers of the upper GI tract are difficult to diagnose and often are not caught early on.
“Resistant starch can be taken as a powder supplement and is found naturally in peas, beans, oats and other starchy foods. The dose used in the trial is equivalent to eating a daily banana; before they become too ripe and soft, the starch in bananas resists breakdown and reaches the bowel where it can change the type of bacteria that live there.
“Resistant starch is a type of carbohydrate that isn’t digested in your small intestine, instead it ferments in your large intestine, feeding beneficial gut bacteria – it acts in effect, like dietary fibre in your digestive system. This type of starch has several health benefits and fewer calories than regular starch. We think that resistant starch may reduce cancer development by changing the bacterial metabolism of bile acids and to reduce those types of bile acids that can damage our DNA and eventually cause cancer. However, this needs further research.”
Professor Sir John Burn, from Newcastle University and Newcastle Hospitals NHS Foundation Trust, who ran the trial with Mathers, said: “When we started the studies more than 20 years ago, we thought that people with a genetic predisposition to colon cancer could help us to test whether we could reduce the risk of cancer with either aspirin or resistant starch.
“Patients with Lynch syndrome are high risk as they are more likely to develop cancers so finding that aspirin can reduce the risk of large bowel cancers and resistant starch other cancers by half is vitally important.
“Based on our trial, NICE now recommend aspirin for people at high genetic risk of cancer, the benefits are clear – aspirin and resistant starch work.”
Long term study
Between 1999 and 2005, nearly 1,000 participants began either taking resistant starch in a powder form every day for two years or aspirin or a placebo.
At the end of the treatment stage, there was no overall difference between those who had taken resistant starch or aspirin and those who had not. However, the research team anticipated a longer-term effect and designed the study for further follow-up.
In the period of follow-up, there were just five new cases of upper GI cancers among the 463 participants who had taken the resistant starch compared with 21 among the 455 who were on the placebo.
The team is now leading the international trial, CAPP3, with more than 1,800 people with Lynch syndrome enrolled to look at whether smaller, safer doses of aspirin can be used to help reduce the cancer risk.
The research is funded by Cancer Research UK, the European Commission, Medical Research Council and the National Institute for Health Research.
Study 1 details
Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up.
John Mathers, Faye Elliott, Finlay Macrae, Jukka-Pekka Mecklin, Gabriela Möslein, Fiona McRonald, Lucio Bertario, Gareth Evans, Anne-Marie Gerdes, Judy Ho, Annika Lindblom, Patrick Morrison, Jem Rashbass, Raj Ramesar, Toni Seppälä, Huw Thomas, Harsh Sheth, Kirsi Pylvänäinen, Lynn Reed, Gillian Borthwick, Timothy Bishop, John Burn.
Published in Cancer Prevention Research on 25 July 2022
Abstract
The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomised double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomised to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33–0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non–colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32–0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non–colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62–1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non–colorectal cancer cancers for patients with LS.
Prevention relevance
Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers.
Study 2 details
Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.
John Burn, Harsh Sheth, Faye Elliott, Lynn Reed, Finlay Macrae, Jukka-Pekka Mecklin, Gabriela Möslein, Fiona McRonald, Lucio Bertario, Gareth Evans, Anne-Marie Gerdes, Judy Ho, Annika Lindblom, Patrick J Morrison, Jem Rashbass, Raj Ramesar, Toni Seppälä, Huw Thomas, Kirsi Pylvänäinen, Gillian Borthwick, John Mathers, Timothy Bishop, Alex Boussioutas, Carole Brewer, Jackie Cook, Diana Eccles, Anthony Ellis, Shirley Hodgson, Jan Lubinski, Eamonn Maher, Mary Porteous, Julian Sampson, Rodney Scott, Lucy Side.
Published in The Lancet on 13 June 2020
Summary
Background
Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population.
Methods
In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol.
Findings
Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43–0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39–0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34–0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31–0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43–0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously.
Interpretation
The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results.
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