Debating the Clinical Trial Upending Colonoscopy Practices

Hello, and thank you for joining us today for what promises to be a lively discussion about screening for colon cancer. My name is Perry Wilson. I am an associate professor of medicine at the Yale School of Medicine and director of Yale's Clinical and Translational Research Accelerator. My new book, How Medicine Works and When It Doesn't is available for pre-order now anywhere the books are sold. I'm joined by two wonderful experts.

Dr. David Johnson is a professor of medicine and the Chief of Gastroenterology at the Eastern Virginia School of Medicine. He is the past president of the American College of Gastroenterology. And I'm very encouraged to see that he's won a National Education Award for his efforts in gastroenterology. I'm also joined by Dr. Kenny Lin. He's a frequent contributor to Medscape and WebMD. He's a family physician and public health consultant from Lancaster, Pennsylvania and deputy editor of the Journal of the American Family Physician.

He's also a teacher of residents and students at Lancaster General Health and the Penn Medicine Family Medicine Residency program. So we have two great educators with us today to help, hopefully, teach us something about colon cancer and colon cancer screening. As a bit of background, guys, first of all, thank you for joining me today.

Thanks for having us.

Great to be here.

So colon cancer, the second leading cause of cancer mortality in the US, around 50,000 people, a little bit more than that die every year in the United States due to colon cancer. And I would have said a month ago that there was pretty broad consensus, at least, from my perspective, that people should be getting their colonoscopies. That's what we tell our patients. And then something happened. That paper came out in the New England Journal of Medicine, very prestigious medical journal, that has caused a lot of consternation, I'll say, certainly, online.

And I've gotten questions from patients and family members about it as well. Can we talk about this randomized trial of screening colonoscopy for colon cancer and why it has caused so much, maybe, confusion or so much change and concern out there? Dr. Johnson, give us a brief overview of this trial. What was this trial all about?

Well, this is a randomized trial looking at screening colonoscopy versus no screening, no test whatsoever. And they looked at the outcomes of prevention of cancer and the prevention of colon cancer-related death. The short answer it was disappointing as it relates to colonoscopy. And a study done in the four countries in Europe, three of which are part of this particular report in the New England Journal, got a lot of attention because it surprised a lot of people, saying maybe it wasn't quite as good as we thought it was.

They tried to correct that by looking at the numbers of patients that didn't get their colonoscopy screening, and they still showed value. But it was less than value that we've seen before. Lots of reasons for that, and one we'll hopefully have time to discuss that, key issues for patients.

Yeah, absolutely. Now this was a bit of an interesting trial design. I think I'm correct, Dr. Lin, that this was really the first randomized trial of screening colonoscopy. But they didn't really randomize people to get a colonoscopy versus not get a colonoscopy. Can you tell us why this differed from what I would have thought is a simpler design of a study?

That's a-- it's definitely an important point to highlight about the study. So it was really the randomization to an invitation to get a screening colonoscopy. When the trial was set up, they actually randomized people before they knew which group they were in, rather-- sorry, before they were asked whether they wanted to participate in the study. And if you did it the other way around, if you ask them whether they wanted to be in the study first, then you randomize them.

You would have assured that more of them probably would have gotten the colonoscopy. But in this case, they were really more interested in if you have a national program of screening colonoscopy. And then if you invited people, what would be the real-life response because we know that everyone that you recommend to get a colonoscopy doesn't necessarily want to do that or forgets to do it or something happens that they don't actually get it.

So in terms of measuring the effectiveness of the colonoscopy, and I think, we we'll talk more about this, perhaps, it wasn't the greatest type of study to do that. But I think it did provide some information about what would happen if you invited people to get colonoscopy in terms of how many would do it and the results, overall, for that population.

So Dr. Johnson, looking at the data, it looks like about 42% of people who were in that invitation arm actually followed through and got their colonoscopy. You're a gastroenterologist. Does that seem low? Is that about right, or do about half of people who should get a colonoscopy end up getting one?

No, it's low. And certainly, in the United States, we see the numbers that are probably in the 70% range. Certainly, the test doesn't work for people that don't get the test performed. So 42% that actually got the colonoscopy that we're randomized to that really leaves the vast majority of patients that never got the test.

Right. Certainly, we wouldn't expect impressive results if they don't get the tests. But on the other hand, I imagine that people, who choose to get the test when they're invited, are a different breed. These are probably people who maybe are more health conscious. Do you think maybe they're living in other healthy ways? Is that something we should worry about when we look at these results?

I don't think you can stratify based on this study looking at other ethnicities, diet. All those things weren't really explained in this particular study. The key element that will hopefully have major take home here is quality. It's not just the test. It's how the test is done.

Interesting. Well, so let's start with the big picture. This was a study that looking just at everyone invited, so not the subgroup of people, who actually got the colonoscopy, but the real randomized study. Dr. Lin, the study did show that that invited group had a lower risk of colon cancer over the next 10 years. Is that-- that's a good thing, I imagine.

I think that's a significant benefit. Actually, if you follow them, initially, in the first few years, they had more colon cancers diagnosed. But that's probably because they were-- those were cancers that were already existing. They couldn't be prevented by the test. But then over the years, as you saw, that curves crossed. And by the end of the average 10 years that they were followed, there were significantly lower rate of colon cancer as being detected as you would expect because you're finding polyps and removing them before they became colon cancer.

So Dr. Johnson, is that the natural history of colon cancer? It starts out as a polyp that maybe is something that can be easily removed, doesn't require more therapy. And is that why screening colonoscopy is helpful?

Well, the ultimate goal of screening is prevention of cancer. So it's not detection of cancer. And that's by identification and complete removal of the polyps that we find that are precancerous. But the key is A, detection and B, resection. And the adequate resection comes down to some very significant issues of quality questions that I'd raised in this particular study. And we can talk about that momentarily.

Sure, absolutely. Let me go through just the two other big findings in this study. Dr. Lin, fewer cases of colon cancer over 10 years seems good. But colon cancer mortality was not significantly different in the two groups. Now, of course, we know that not everyone got a colonoscopy. I would have expected, though, if you had less colon cancer, you'd have less death from colon cancer. Dr. Lin, any-- why the disconnect? Any thoughts there?

Well, I think that you could-- there are a couple of possible explanations. I think one explanation is that you just didn't follow the people long enough. Colon cancer takes a long time to go from an adenoma all the way to cancer and from cancer to something that would actually cause the patient's death. So you may need to follow them for longer than the 10 years that most of these patients were followed to see that benefit. And I think there probably will be one after a while because just because if you are removing colon cancers that otherwise would have progressed and metastasized, you ought to see a benefit.

But I think we also have to consider the other possibility and that not all the polyps removed necessarily were going to progress to advanced cancer. And therefore, you weren't seeing the death benefit because not every polyp that was removed was necessarily going to cause health consequences.

Sure, sure. You're removing things. You have no way of knowing in advance what are the really bad ones and what aren't. Dr. Johnson, you have mentioned several times now that the quality of colonoscopy matters here. So I'm intuiting that it's not one size fits all. It's not all the same. What do you mean by quality of colonoscopy, and what was the quality of colonoscopy in the New England Journal study?

Sure. So the quality of colonoscopy is really the quality of the whole process, the clean-out-- the warm-up, if you will, and the clean-out for the procedure. And then that certainly has to allow the colonoscopies then to be able to identify precancerous polyps. We call them adenomas. There are other precancerous polyps called sessile serrated lesions. But these identification of adenomas is extremely important.

And this ties to a small increase in the detection of those precancerous polyps from studies that have been well done, in particular, looking at large databases, show that a small increase, 1% increase in the adenoma detection qualifies as a risk reduction for colon cancer by 3% decrease in colon cancer and 5% decrease in colon cancer-related death. A huge array of effect, when we talk about small increases in the adenoma detection rate.

Now let's go back to this individual study. If we base quality on the individual performing the study and say that the colonoscopy is A, achieving-- getting all the way around the colon, only about 18% of the patients of the physicians in this study were not able to get around the colon. And that really starts to raise the question about quality. In the idea that adenoma detection is important, studies from this reports from this large group, again, have shown that the adenoma detection rates have been way below the national thresholds.

So again, raising the issues of, did they find the polyp, and then did they respect the polyp? They don't tell us where these cancers were, but nonetheless, raises a lot of questions about the colonoscopy quality. It's not the instrument. It's the process.

Understood. Dr. Lin, colonoscopy with the prep and anesthesia and whatnot is not the only colon cancer screening method we have. In fact, there are a bunch. What else is out there that can allow for the early detection of colon cancer? I think we're on board saying, it's probably better to detect colon cancer early than not detect it. But what are our other options aside from colonoscopy?

So for most of my career, there were three options that I presented patients with. The first was a fecal test. It used to be, do you have the initial hemoccult test that had been mostly replaced by fecal immunochemical test. But they're just basically looking for the presence of blood in the stool. And anyone who had a positive test would be referred for a diagnostic colonoscopy. The other test besides colonoscopy that's been largely phased out in the United States, although it is still very much used in Canada and much of Europe, is flexible sigmoidoscopy.

And until this study, the tests that were supported by randomized controlled trials were really the fecal tests and flexible sigmoidoscopy. And interestingly, when you look at, there was a recent systematic review of flexible sigmoidoscopy looking at the four trials and their effects over 15 years. They showed not only a reduction in colon cancer, but a reduction in colon cancer mortality and even a small reduction in all-cause mortality.

These trials were not done-- I think three out of the four were done, where the patients were consented, then randomized, so they had a higher uptake of the procedure, which may-- but when you make the comparison to the colonoscopy trial, it really isn't that impressive that you would expect a much larger benefit because obviously, you're looking at the entire colon. But you really didn't see that. That it was-- at best, it was maybe equivalent to sigmoidoscopy, but not a whole lot better.

So Perry, can I interject one other comment here?

Please.

You mentioned sedation. It's really important to understand that in this particular cohort of Norway, Sweden, and Poland that the-- it's very much the norm to not get sedation for your colonoscopy. Any of the listeners that have had colonoscopy will tell you that they are not ones to say, don't give me sedation, 11% in Norway. And Sweden, it's maybe 23%. Poland, it may be is around 45%. So the examiner and the patient were never really super comfortable.

And I've done 50,000 colonoscopies in my career. I've done many nonsedated, but when you take the comfort factor of taking time-- we know that taking time increases the finding of polyps and the adequate resection and identification. So that ability to really perform, again, a high quality is very subject to when the patients aren't comfortable, and you want them to come back, and again, raises the issues about quality.

Dr. Johnson, we brought up flex sig or flexible sigmoidoscopy. For the patients watching, who are-- their doctors talking to them about screening colonoscopy, what's the difference from their perspective?

Well, flexible sigmoidoscopy is just a short scope examination. So you see about a third of the colon. What we've seen is that there's a progressive-- and I've been in the field for 45 years, progressive increase in the development of cancers above that bottom third of the colon to the higher end, the two-thirds of the colon that you would miss without doing a full colonoscopy. So a flexible sigmoidoscopy typically is not paid-- does not get covered for sedation.

And again, if you're going to do the exam and find something, then you're going to have to come back and do an adequate resection with the colonoscopy. So one-stop shopping, colon cancer screening is not about detection of cancer. It's prevention of cancer. And that's what colonoscopy does.

Dr. Lin, how are your patients in your family practice handling this study? Have conversations changed around colon cancer screening? What are people asking about these days?

I don't think the conversations have changed in my practice that much. When patients ask about this study, we do discuss the limitations that it wasn't designed to assess the maximum benefit of getting a colonoscopy because majority of people assigned to that group didn't get colonoscopy. But I think it is an opportunity in primary care to consider the way we present the options to patients because I would say, probably a majority of primary care physicians, when they present the options, they say, colonoscopy is the gold standard. You should get colonoscopy.

And they only offer fecal testing to patients who don't want the colonoscopy or really refuse. That hasn't been my practice. I'm usually more agnostic about the event because there are both harms and benefits. I mean, if you get a fecal test, the chances of you having a complication for colonoscopy is automatically lower because most of those people will not get colonoscopy. And when you're doing screening colonoscopy, everybody's getting a colonoscopy. Now obviously, the complications are pretty rare. And they're usually self-limited. But they do exist. And if you're doing lots and lots of these, eventually, I mean, probably all primary care physicians have patients who've had a complication from colonoscopy and may or may not have regretted it depending on how the information was presented. But I feel like this study reinforces my feeling that we ought to be presenting these, not saying one is superior than the other or one is inferior to the other and just base it on what the patient's priorities are.

Is your priority finding every single cancer? Is your-- do you want to know exactly what the benefit is? Because I think for colonoscopy, we're still trying to figure out exactly what the benefit is, whereas we can say it pretty confidently for fecal tests because we have those randomized trials.

So Dr. Johnson, I think patients who are watching need to know, first of all, that if they do the fecal test route, a positive fecal test does lead to colonoscopy. And in some sense, all roads lead to colonoscopy once you have a positive screening test. And so I can certainly see the value of just skipping to that point. But what about this risk versus benefit relationship-- colonoscopy, albeit a relatively safe procedure is still a procedure. There is some risk associated with it.

If we can get the same benefit from yearly FIT testing, stool testing yearly, is that a better choice, potentially, at least, for patients at average risk?

Well, the whole idea of screening is about the prevention of cancer. The stool-based testing are really more effective for detection of cancer. That's not screening. That's detection of cancer. Our goal in screening is to prevent them. The fecal-based testing, including the stool-based DNA, misses the majority of precancerous polyps. And the fecal-- FIT tests that Dr. Lin just mentioned misses virtually all of them. In the context of prevention, we really want to get to the implicit prevention, meaning identification of polyps and removal; prevention of cancer, not just screening for cancer.

Do you see anything on the horizon that could unsee colonoscopy as the-- to quote Dr. Lin, "the potential gold standard for screening for colon cancer"?

Well, I think not in the horizon for identification of polyps and removal of polyps. That's really the gold standard. Technology continues to advance. We'll see what happens. But on the short horizon, in the intermediate horizon, colonoscopy is going to be needed. And we're talking about these other tests, not for patients that have had polyps. I think what we're finding is that some patients are starting to acquiesce to stool-based testing because they can do it at home. Maybe they don't have to do a prep.

We're talking about screening here as Dr. Lin was mentioning, not about follow-up of patients that have family history, patients that have colitis, patients that have colon polyps and other reasons. Stool-based testing is not an option as it relates to follow-up of those patients. We're talking about screening only. And convenience testing in the face of COVID also has thrown a wrench in the stay home and maybe do these tests at home. Again, we need to be proactive, not reactive. We want to prevent cancer, not detect it.

Dr. Lin, I am 42 years old. I am at I don't believe at any increased risk of colon cancer based on my family history or other risk factors. I'm three years away from when the United States Preventive Services Task Force tells me I should potentially consider starting to screen for colon cancer. 45 is-- that has recently been moved down from 50 years old. So it's on my mind. I'm coming there. What do you advise your patients on the younger side? I can't call myself a younger patient right now.

Patients who are younger, who are approaching 45, what are you advising them right now in terms of screening for colon cancer?

Well, so assuming that you don't have any of the risk factors that Dr. Johnson mentioned, in which case, I would recommend screening colonoscopy as the initial test. I present it as we have a couple of different fecal tests. There's the traditional one that just looks for blood. Then there's the newer one that also adds DNA, which is more sensitive for colorectal cancer, but a little less specific, which is a problem just because there are more false positives.

So there's that versus the colonoscopy, which you have to only need to get done ideally every 10 years if there are no findings, is more complete and theoretically, would, as we've been talking about, also prevent as well as detect early cancers. So it's really your preference, I think, in terms of how much things that come into play are convenience of the test, your level of concern about cancer. I do tell patients that family history of cancer is not terribly predictive of whether you get-- whether or not a lot of people, unfortunately, who develop colorectal cancer, have no previous family history.

Diet will come into play to some extent. There are some things that point to increased risk for colorectal cancer if you have a high red meat diet and things like that. But ultimately, it really is up to the patient. And I just lay out the options. And whatever they choose, I'm happy to pursue. But I won't-- but the most important thing, I think, is they do some test because doing no test is not going to help anyone. And I do agree with the notion that the best test is the test that gets done.

Absolutely. I think the New England Journal article supports that, even when we're talking about colonoscopy. Dr. Johnson, you've had some criticisms about this study in the New England Journal. I think they make sense. At the same time, the first randomized trial of colonoscopy, so it's the only data we have. Are we going to get better data? Is there other studies going on out there that might help shed some light on what's turning out to be a complicated issue?

Yes, there are ongoing studies. In comparison with-- not within the United States that you couldn't get through a no-screening option trial, there are comparative studies that are probably still five years away, looking at stool-based testing. Again, recognize that if you do these alternative tests that were eloquently discussed by Dr. Lin, not the colonoscopy, which would be every 10 years, high quality performance, that you have to annualize or do them in sequence. And it's important, then, you have to follow up on those with regularity.

It's not just a one-time test every 10 for these individual tests. And any time that those tests are ordered, the patient should be instructed that if it's positive, you need a colonoscopy. We're seeing a lot of slippage on that for these stool-based testing. Convenience is not the answer. It's getting the job done.

Would you agree, Dr. Johnson, that for patients that really don't want to do the colonoscopy for one reason or another, you've done your best, you've explained what you think the risks and benefits are, would you-- you'd rather have them get something than nothing, I assume.

Absolutely. But I still make that explicit. If it's positive now that we've gone through those checkpoints, it's not just the-- it's a team effort. And the idea of the decisions have to be evidence-based. But what I recommend and then what you decide, but the idea that if it's positive, we agree that you understand that that's really the next step.

Great. Dr. Lin, I will turn the last word over to you as the person who is probably discussing the choice of screening modalities more than any of us before someone would get to someone, like Dr. Johnson. What's your final take home about the New England Journal of Medicine study and the state of colon cancer screening in the United States?

Well, so I think my take home points about the study are that there were some limitations. But it is good to have finally a randomized trial of colonoscopy screening two decades after we really started doing that in the United States. So it won't immediately change-- I don't think it should immediately change the way we practice and discussing different options.

I think that some of Dr. Johnson's points about making sure that whoever's doing the colonoscopies for your practice is doing high-quality colonoscopy is really important, just as it's important to if you're doing the fecal tests that make sure that all patients who have positives get expeditiously referred for colonoscopy.

So Perry, can I make one concluding comment just as the gastroenterology expert in this discussion as well? I've had countless questions from my patients and my peers. And I tell them the following, don't let the headlines mislead you. So when you come back to this particular study, the instrument is not so much the question. We know that getting the test is the first step in colon cancer screening. But we also know that getting the best test done with the best quality performance in the highest quality providers is really the key to optimizing the true value of colonoscopy for colon cancer prevention.

So please, please, don't lose sight of this. When reading the headlines and the media around this study, we really need to analyze the true characteristics of what we call a quality performance is that's what drives the success. That's what prevents colon cancer.

Dr. Johnson, Dr. Lin, thank you very much. I'll sum up by saying, I guess, if you're getting a colonoscopy, make sure it's a good one. But do get screened. I appreciate you spending time with me here today, and all the best.

Thanks for having us.

Thank you.