Antibiotics Use and Increased Risk of
Colon Cancer?

Pam Harrison

August 21, 2019

Editor's Note: This story was updated on August 23, 2019.

Even a single course of antibiotics was found to be associated with an increase in the risk of developing colon cancer nearly a decade later, results from a matched, case-control study suggest.

This risk was particularly apparent for cancers in the proximal colon and with the use of anti-anaerobic antibiotics, the study found.

This finding that oral exposure to anti-anaerobic antibiotics produced the most significant effect on colon cancer risk is intriguing, the authors comment, as these agents "markedly disrupt" the gut microbiome, which is predominantly composed of anaerobes.

"It is [therefore] possible that the disrupted microbiota enables acquisition or development of a carcinogenic colon microbiota," the authors suggest.  

"Whether antibiotic exposure is causal or contributory to colon cancer risk, our results highlight the importance of judicious antibiotic use by clinicians," they conclude.

"The primary message of this study is the importance of antibiotic stewardship: not treating common viral infections with antibiotics, using them for the shortest time period possible, and using targeted antibiotics rather than broad spectrum ones," senior author Cynthia Sears, MD, professor of cancer immunotherapy at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, said in a statement.

The study was published online yesterday in the journal Gut.

For the study, Sears and colleagues analyzed data from the Clinical Practice Research Datalink (CPRD) in the United Kingdom, the world’s largest primary care database, according to the authors.

The team identified 28,980 cases of colorectal cancer (CRC) across a period of 23 years (1989–2012) and matched them with 137,077 controls. They then looked at various risk factors of CRC, which included the use of oral antibiotics, and compared these between the patient and control groups.

As would be expected, the individuals who developed CRC were more likely than those in the control group to have risk factors for the disease, including being overweight (35.2% vs 33.8%) and obese (18.6% vs 16.4%), to have a history of smoking (49.9% vs 46.9%), have moderate to heavy alcohol use (13.8% vs 11.4%), have a history of diabetes (8.8% vs 7.7%), and to undergo colonoscopy (3.5% vs 2.9%); patients with CRC were less likely than controls, the researchers found, to have chronic nonsteroidal anti-inflammatory drug (NSAID) use (7.2% vs 9%).

However, the team also found that, at a median follow-up of 8.1 years, participants who went on to develop colon cancer were significantly more likely to have taken an antibiotic (at 71.3% compared with controls at 69.1% (P < .001).

Although this difference between the two groups was statistically significant, it was small — about 2% greater antibiotic use in those who developed CRC.

Sears commented to Medscape Medical News: "I agree that this is a small difference but that is the overall descriptive data, uncontrolled for confounders."

Once the team adjusted for potential confounders, including smoking and alcohol use, the data show "an association between 16+ days of total antibiotic exposure and a dose-dependent increase in colon cancer risk of about 15% by 30 to 45 days of total antibiotic exposure" Sears explained.

"Of those with known CRC location, participants with proximal colon cancers were more likely to have antibiotic exposure, particularly those with anti-anaerobic effects, whereas participants with distal colon cancers had similar antibiotic exposure to controls, regardless of antibiotic spectrum," the authors observe.

There was little difference in antibiotic exposure between participants who developed rectal cancer and those who did not; in this case, antibiotic exposure use was the same in the two groups, at 67.1% in the rectal cancer group and 67.2% in the control group.

Participants who used antibiotics for over 60 days had a 15% lower risk of developing rectal cancer over the study interval compared with participants who did not use antibiotics, at an odds ratio of 0.85, researchers point out.

Differences by Tumor Location

The effect size of antibiotic exposure on CRC risk as well as the pattern of use differed by tumor location.

"For colon cancers, exposure to antibiotics was associated with substantially increased risk, with the effect increased after minimal antibiotic use and reaching a plateau after 60 days of cumulative exposure," the researchers write.

This was true for cancers in the proximal colon, but again, not for cancers in the distal colon, they add.

For rectal cancer, "there was a reduced risk of cancer associated with cumulative exposure to any antibiotic," they emphasize, an effect that was not seen until after 30 days of cumulative antibiotic exposure and which plateaued after 90 days of exposure.

When asked about the difference between the apparent impact of antibiotic use on the risk of cancer in the colon when compared to the rectum, Sears commented, “We think these differences highlight the differences in biology and likely the microbiome between these two cancer sites. Hence we hypothesize that antibiotics impact disease at these sites differently.”

Class of Antibiotics

Almost 60% of participants in the cohort study had been prescribed more than one class of antibiotics.

However, antibiotics with anti-anaerobic properties were associated with a significantly greater risk of colon cancer, especially colon cancer in the proximal colon (P < .001).

This was again not true for rectal cancer, where all classes of antibiotics appeared to have a protective effect against its development, regardless of their effects on the gut anaerobes.

Indeed, exposure to tetracyclines appeared to have a particularly protective effect against rectal cancer, the researchers point out.

Among the different classes of antibiotics, "the use of penicillins was associated with an increased colon cancer risk…particularly in the proximal colon, but not cephalosporins, quinolones, macrolides, or sulfa/trimethoprim," the authors observed.

The penicillins also affected colon cancer risk in a dose-dependent manner (although not rectal cancer risk).

The penicillins also did not affect distal colon cancer risk, an "intriguing" finding, the study authors suggest, as the proximal colon is the site first exposed to antibiotics that are not absorbed in the small intestine and before drug modification or degradation in the colon.

In their discussion, the authors say that previous studies have suggested a link between antibiotic use and colorectal cancer, but note that this is the "largest analysis of antibiotic–CRC association to date."

Association Was Not "Particularly Strong"

In an expert reaction to the new study, posted on the UK Science Media Centre website, a statistician says that the association between antibiotic use and bowel cancer rates "was not particularly strong."

"In most cases, antibiotic use of various kinds didn't change the risk of various cancers (measured in odds) up or down by more than about 15% in relative terms, in either direction," notes Kevin McConway, PhD, emeritus professor of applied statistics at The Open University in Milton Keynes, UK.  

"Out of every 100 men in the UK, about 7 will be diagnosed with bowel cancer at some time in their life, and the corresponding figure for women is about 6 in every 100," he comments.

"A relative 15% increase in the chance (odds) of bowel cancer, if it applied to everyone, would mean there would be about one extra case in every 100 men, and also about one extra case in every 100 women. Not a vast increase," he says.

McConway says the "study has many strengths, and in particular it used a large UK database that's generally considered to be representative of the UK population."   

However, he emphasizes that this is an "observational study, and like all such studies it can't establish what causes what beyond reasonable doubt. The problem is that people who have taken oral antibiotics will differ from people who haven't taken them in several ways, and it remains possible that one of these other differences might be the explanation for any differences in cancer rates, and not the actual effect of the antibiotics at all."

"The researchers adjusted their statistical results quite extensively to allow for some of these other differences," McConway continues. "Such adjustments can never be perfect, and adjustments can't be made for factors on which the researchers have no data. The researchers acknowledge that this could matter — for instance they point out that they had no data on what the participants ate, their physical activity, or their family history."

"All these things are known to relate to bowel cancer risk, and if for some reason they happened to be different in people who had and hadn't used antibiotics, that could interfere with the estimates of the effects of antibiotics on risk," he says.

The study was funded by the Johns Hopkins Fisher Center Discovery Program and Bloomberg–Kimmel Institute for Cancer Immunotherapy. Sears has disclosed no relevant financial relationships. Several coauthors  have disclosed relevant financial interests; these disclosures are listed in the original article.

Gut. Published online August 20, 2019. Full text

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