This is the first part of an article that just appeared in Asterisk magazine. You can read the whole thing here.

One of the first things internet writing teaches you is that you don’t get to choose what other people like. But this article represents, I don’t know, 40 or 50 grugs of effort? Plus more from Asterisk’s fabulous editors and fact-checkers? So if you wanted to try to like it…

Colonoscopies are the first-line method for preventing colorectal cancer in America —and almost nowhere else. But do they work? We finally have a comprehensive trial, but it’s left gastroenterologists with more questions than answers.

Colorectal cancer is the second-most deadly cancer, killing over 1 million people per year around the world — 1.7% of all deaths. In the United States, where colorectal cancer causes 50,000 deaths per year, the foundation of the fight against it is the colonoscopy. Getting one periodically is recommended for everyone over the age of 45.

Colonoscopies are rarely used for screening elsewhere but have been standard in the U.S. for decades. There are many reasons to think that they should work. But they are also expensive, invasive, unpleasant, and rarely — but not that rarely — have serious side effects. Are they worth it?

Until recently we didn’t have any randomized controlled trials that directly tested how well colonoscopies work. We finally just got one and the results were — how can I describe them? Confusing? Ambiguous? Frenzy-inducing?

Let’s try to understand what to make of this trial, and why American gastroenterologists were so quick to criticize it.

Reminders About Tubes

After you swallow food, your body uses rhythmic waves of contractions to send it on a 4-meter (13-foot) journey through your esophagus, stomach, and small intestine. These extract most of the food’s nutrients and render it into a pulpy acidic fluid called chyme. The chyme then travels through your colon, a 1.5-meter (5-foot) tube that reabsorbs water and electrolytes, creating a solid mass that is then moved to your rectum for storage and eventual disposal. Yay!

The outermost layer of your inner colon is a single layer of epithelial cells whose job it is to let the good stuff through and keep the bad stuff out. Stem cells deeper inside the colon constantly divide to make new epithelial cells, which climb to the surface and live for four or five days before committing “suicide.”

Colonoscopies rest on the adenoma-carcinoma hypothesis. The idea is that errors can arise in the DNA, resulting in epithelial cells that don’t die on schedule. If they do anything too weird, your T-cells will kill them. But some mutations fly under the radar,  causing little clumps of cells to grow on the surface of the colon. These clumps, or “polyps,” are usually not cancer — they grow slowly, and won’t (yet) spread to neighboring tissues. But if these persist for many years, they can acquire additional mutations that make them start spreading.

To prepare for a colonoscopy, you must empty your colon. This is achieved by drinking some chemicals and enduring some spectacular biological functions. Then a doctor threads a 1.5-meter (5-foot) flexible tube with a light and camera to look at the entire colon and remove or sample any polyps. The idea is not just to detect cancer but, by removing precancerous polyps, prevent it.

The primary alternative to colonoscopies for colorectal cancer screening are “occult blood tests” that look for spooky hidden blood in the stool. The oldest of these use an extract of the guaiacum tree and have RCTs showing they reduce colorectal cancer mortality by 9%-22% when used for screening. Newer tests look for antibodies and/or genetic mutations. These are more sensitive, though we don’t yet have RCTs estimating how much they help with mortality.

Another alternative is an older procedure called a sigmoidoscopy, which is basically a “mini” colonoscopy with a 0.6-meter (2-foot) tube. Compared to colonoscopy, it is quicker, safer, less painful, and cheaper, but it can only look at the lower (“sigmoid”) colon. Still, randomized trials have shown that screening sigmoidoscopies reduce colorectal cancer deaths by 26%-30%.

In principle, colonoscopies should be better than either of these tests. Unlike blood tests, colonoscopies try to remove polyps before they become cancer. And unlike sigmoidoscopy, colonoscopies can examine the whole colon.

But how much does it actually help to remove precancerous polyps? Gastrointestinal doctors often point to the National Polyp Study, but this is not a true randomized comparison — the study did colonoscopies on all subjects and concluded, based on comparisons to base rates in other “similar” populations, that removing polyps helped. And how much does it help to screen the whole colon? Cross et al. compared sigmoidoscopy to colonoscopy in English patients with suspected colorectal cancer and found that sigmoidoscopy was sufficient to detect 80% of cancers.

Because of the cost, the lack of direct evidence for efficacy, and the fact that it’s hard to convince people to do colonoscopies, they are rarely used for cancer screening outside the United States and some parts of German-speaking Europe. So it would be really useful to have an RCT that tested how well screening colonoscopies work.

The Trial

That brings us to the star of our show. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a huge randomized trial aimed at rigorously measuring how much colonoscopies reduce cancer and death.

Here’s what the researchers did: Between 2009 and 2014, they identified 85,179 subjects mostly in Poland (64.1%), Norway (31.2%), and Sweden (4.3%), drawn at random from population registries of people between 55 and 64 years old. They invited one-third of them to a one-time screening colonoscopy. Of those contacted, 42% accepted the invitation and underwent a colonoscopy, while 58% refused the invitation. The other two-thirds of people were not contacted and seemingly never knew they were in the trial. The researchers then followed everyone (invited or not, colonoscopy or not) for a median of 10 years and checked government records to see who had been diagnosed with colorectal cancer, died from colorectal cancer, or died from any cause.

This was an “intention-to-screen” analysis. That means that it compared the control group to the whole invited group, including both the 42% of people who agreed to a colonoscopy and the 58% who refused. (If that seems strange, keep reading.)

These were the main results:

The 18% reduction in colorectal cancer incidence was statistically significant, while the 10% reduction in colorectal cancer mortality and 1% reduction in overall mortality were not.

So the reductions — they are small. This was a surprise.

The study had a huge sample and simple, reliable statistics. The authors seemed to expect a stronger showing for colonoscopies. When that didn’t happen, they made no excuses — they just followed their preregistered statistical plan and published the results. We want research to be reproducible, right? Well, then this is what we want people to do.

The Debate

This paper was greeted with gastroenterological bedlam. […]

Continued on Asterisk’s page. Or, if tubes bore you, you might prefer one of the other articles:

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