Professor John Burn, from the Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK, said that he believed that he and his colleagues might have uncovered a simple way of controlling cancer stem cells, which are essential to the formation of malignant tumors.
The clinical trial, which involved 1071 carriers of the Lynch syndrome mutation in 42 centers worldwide, randomized participants to a daily dose of 600mg aspirin and/or 30g Novelose®, a resistant starch that escapes digestion in the small intestine. “Although there were many reports that aspirin might have a beneficial effect in a range of cancers,” said Prof Burn, “they were from case control and epidemiological studies. We decided that the only way to achieve conclusive proof was to undertake a randomized trial in a high risk population.”
Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is a rare type type of inherited cancer of the digestive tract that increases a patient’s risk of cancer, particularly the colon and rectum. People with Lynch syndrome have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women carriers also have a high risk of developing endometrial and ovarian cancers.
These patients tend to develop cancer quickly, so the scientists expected to see answers at an early stage. The first results were disappointing, however; at an average of 29 months after randomization the scientists saw no evidence of the benefits of aspirin in the high-risk population studied.
“Our original design allowed for long term post trial follow-up,” noted Prof Burn. “We have managed to track down most of those who completed the trial – around 75% of the original consent cohort – with information extending up to 10 years from randomization. We found that, around four years after randomization, there was a divergence in the incidence of cancers between the aspirin and placebo groups. To date, there have been only six colon cancers in the aspirin group as opposed to 16 who took placebo. There is also a reduction in endometrial cancer. This is a statistically significant result and we are delighted – all the more so because we stopped giving the aspirin after four years, yet the effect is continuing, and is directly correlated with the duration of aspirin use on the trial.”
Although scientists believe that diet is a major factor in the prevention of colorectal cancers, there are no randomized trial data which can prove it, since running proper, controlled trials of diet is extremely difficult. However, there is a strong inverse relationship between colon cancer and how much starch people eat. Resistant starch, after escaping digestion in the upper gut, is fermented in the colon and forms short chain fatty acids, which are powerful anti-cancer agents.
“Our very large colon probably evolved to capture such nutrients from our forefathers’ diets,” explained Prof Burn. “Because we were giving starch as well as aspirin we would also have expected to see a decrease in cancers in the placebo group. However, there could be a number of reasons for this result – perhaps patients didn’t take the starch every day, or that it simply wasn’t resistant enough.”
There were minor problems due to aspirin side effects; out of over 1000 people, 11 in the aspirin group had notable gastro-intestinal bleeds or ulcers as opposed to nine in the placebo group. But this was counter-balanced by fewer strokes and heart attacks in the aspirin group.
The mechanism by which aspirin protects against cancer has yet to be elucidated, but the scientists believe that cancer stem cells are involved. “We do not think that the mechanisms discussed to date are likely to provide an explanation,” said Prof Burn. “For example, the inflammatory enzyme COX2(Cyclooxygenase-2), a protein that acts as an enzyme and specifically catalyzes the production of certain chemical messengers called prostaglandins, is over-expressed in early cancer, but our results suggest an effect that predates the cancer, and may even predate the adenoma which precedes it. We believe that aspirin may have an effect on the survival of aberrant stem cells in the colon. These cancer stem cells are normally resistant to chemotherapy, but if a stem cell mutates but does not reveal its potential until an adenoma is formed, and if aspirin reduced the chances of such cells surviving, this would explain our results.”
The team intends to undertake a further study to see whether a smaller dose of aspirin would have the same beneficial effect or not. “We are planning to ask people with Lynch syndrome to agree to ‘toss a coin’ and take, say, either one or two aspirin tablets per day. Then we can see whether the people on the lower dose have the same protection, with fewer side effects. The problem is that, to have a significant result, this will need about 10 times as many people as we needed for our first trial, but the good news is that everyone gets treated,” said Prof Burn.
For more information:
- Abstract no: 6000, Gastro-intestinal malignancies, colorectal cancer session, Monday 11.00 hrs CEST (Hall 2)
Also read these PubMed abstracts:
- Hua A, Mackenzie GG, Rigas B. The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin. Int J Oncol. 2009 Oct;35(4):837-44.
- Barry EL, Sansbury LB, Grau MV, Ali IU, Tsang S, et al. Cyclooxygenase-2 Polymorphisms, Aspirin Treatment, and Risk for Colorectal Adenoma Recurrence--Data from a Randomized Clinical Trial. Cancer Epidemiol Biomarkers Prev. 2009 Sep 15. [Epub ahead of print]
- Lang DL. Aspirin as Colorectal Cancer Adjuvant Therapy. Gastroenterology. 2009 Aug 22. [Epub ahead of print]
- Neugut AI. Aspirin as adjuvant therapy for colorectal cancer: a promising new twist for an old drug. JAMA. 2009 Aug 12;302(6):688-9
- Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, et al. Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology. 2008 Jan;134(1):21-8. Epub 2007 Sep 26.
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