00:00:00: Egle Dieninyte: Hello everyone, my name is Egle and I'm the host of UEG podcast, educational and hopefully fun dive into GI world and beyond. We're happy to have you with us for another exciting episode. So today we're talking about young colorectal cancer and the recent data on some epidemiological trends. How serious it really is and should we change our perspective? What drives these trends and what needs to be done or maybe not done? I'm very happy to introduce today's guest, the driving force behind the widely discussed Nordic study and the study group, world-renowned authority in colorectal cancer and screening, Professor Michael Bretthauer. Welcome to UEG podcast, Professor.

00:00:37: Michael Bretthauer: Thank you, Egle. Good to be here.

00:00:39: Egle Dieninyte: We're very, very happy today to have you and discuss young colorectal cancer. And to start with, is it really such a big thing or are we just psychologically driven and scared? Because no one wants to be the doctor who misses a cancer, but especially in a young patient. So do we really have to be worried about the recent publications?

00:01:00: Michael Bretthauer: Yeah, you're going right to the heart of this topic. Well, to be honest, I'm not very scared by the epidemiology. behind colorectal cancer in young individuals. Having said that, and I can explain to our listeners what I mean with that. Having said that, there is an increase in the incidence of colorectal cancer in young people. And here young people is usually defined people who are younger than 50 years of age. That's where we usually make the threshold between younger people and older people. There is an increase in most Western countries for the risk of colorectal cancer in these people who are below 50 years of age. Why do I say I'm not super worried? Because that increase is not very large. It's not a very high increase. It's not very dramatic. It is an increase. And we should discuss why we see this increase and what we can do about it. But still, even the new numbers, with that increase, the risk of getting colorectal cancer for people who are younger than 50 years of age is much, much lower compared to the people who are 50 years or older. And I think that's very important to have in mind, especially for us gastroenterologists and endoscopists who see, of course, some of these young patients. And. it makes an impression on us that we see young patients and maybe some more patients than we used to see 10 or 15 years ago. It makes an impression there is suffering. You don't want that for your patients. You don't want to overlook a cancer in a young patient in particular. But that doesn't mean that the risk in general for young people is very high. It is not. Okay.

00:02:47: Egle Dieninyte: But is there a true, true increase or is it more that we are just diagnosing it? Do we detect it more?

00:02:56: Michael Bretthauer: Yeah, that's a great question. That's a great question. And nobody really knows. You know, we know that the workload for colonoscopy has been going up in many, many Western countries. And this is true for the people who are 50 years or older, at least here in Europe, who are usually participating in screening programs, or at least there is an offer. But it's also true for younger people. And, of course, if you do more colonoscopies, you find more cancer. You find more polyps and you find more cancer. So some of the increase may be related to the fact that we are doing. more colonoscopies. However, I don't think that's the whole increase. I think there is a real increase in the younger people. It's just that on an absolute scale, that increase is very, very small. So if I give you just some numbers from Scandinavia where there are very good population registries. So measuring risks in the population for certain diseases is very easy in Scandinavia because they have these great registries. So in people who are younger than 50 years of age, the risk of getting colon cancer has increased from 5 per 100,000 to 7 per 100,000. That's an increase of about 25%. If you say it's an increase of 25%, it sounds high. But from 5 to 7 per 100,000, that risk is very, very low. So 5 per 100,000 is the same as 0.005%, which is very low. Even if you go from 0.005% to 0.007%, which is what we see, it's an increase, definitely. But it's an increase from a very, very, very small risk to still a very, very small risk.

00:04:50: Egle Dieninyte: Well, okay, let's agree it's incremental and it's not that bad on a statistical or epidemiological level. But from the clinical practice point, should. we adjust in some way? Because I grew up with the notion that patients under 45 without alarm symptoms could be treated without testing and then the course could be adjusted. But the young cancers, at least from my understanding, they do present quite differently and there might not be any worrisome symptoms and we suddenly are at stage 4. So should we adjust somehow our diagnostic and treatment algorithm in our heads?

00:05:32: Michael Bretthauer: Yeah, it's a great question. I have not seen any data that convinced me that the biology and the symptoms for colon cancer is different in younger people as compared to older people. And that is, of course, we're talking about sporadic cancers. We're not talking about people who have Lynch syndrome or people who have IBD. That's a different category. But the sporadic cancers, I haven't seen any convincing data that tells us that these cancers are symptomatically different to the older patients. So I think the same approach applies. If there are alarm symptoms, even if a patient is 38 years old, you do a colonoscopy. If there are no alarm symptoms, you probably don't do a colonoscopy. So I don't think we should change. our algorithm with regard to that.

00:06:16: Egle Dieninyte: Okay. But you're saying that you are not convinced that these cancers are biologically different. How then can we explain localization diagnosis at a very late stage? Why there are more rectal and distal cancers?

00:06:32: Michael Bretthauer: Yeah. So there's two different topics you bring up. The late stage diagnosis is, I think, because some doctors may be reluctant to order a colonoscopy in young patients regardless of alarm symptoms. That's wrong. It has always been wrong and it's still wrong. So you have a young patient with alarm symptoms. You have to order a colonoscopy. So that's number one. Number two, with regard to the location. And I agree, this is interesting and I don't think we have the full explanation for this. But let me remind our listeners that there are two very nice papers from a group in the United States, Dr. Montminy and coworkers, that have looked at these young cancers or these cancers in young individuals. and what they see is, because often when you look at these epidemiology studies, many studies look at cancers defined by topography. So everything which is in the colon and the rectum is defined as colorectal cancer. However, these guys looked at the histology and what they found is a certain percentage of these people who get cancer at a younger age, it's not adenocarcinoma, but it's carcinoid tumors. Okay. So it's neuroendocrine tumors.

00:07:45: Egle Dieninyte: Entirely different entity.

00:07:46: Michael Bretthauer: It's a different entity, exactly. With another prognosis, you know, with a different biology, so especially in the people who are very young, 20 to 30, a large proportion of what we believed until recently is colorectal cancer. is that increase. A large proportion of that is not really adenocarcinoma, but it's carcinoids. And how do you find carcinoids? Well, because you do colonoscopy. It's an incidental finding. Most of these do not give you any symptoms. As you know, neuroendocrine tumors first give symptoms when there is liver metastasis. So these are incidental findings during a colonoscopy for something else.

00:08:25: Egle Dieninyte: Interesting. But I'm wondering, at least as I was taught, that cancer progresses and, let's say, arises around 50 to 60 years traditionally because of the cell mitosis and accidental mistakes accumulating. So what happens then? biologically? that it happens, let's say, twice as quick in young people? Or is it the same old person's cancer or? older patient's cancer in a younger body? What accelerates the process? Do we know?

00:08:58: Michael Bretthauer: Well, I think, again, I don't think we have any evidence that these cancers grow faster. They grow in younger people. But that's two different questions. So I don't think, at least I haven't seen anything that makes us believe that these cancers in younger people grow faster than cancers in older people. But why are they coming in an increasing rate at younger people? Well, nobody knows. But I think the most logical explanation, if you take out all the, you know, the neuroendocrines, you take out the increased diagnostic, and you only look at what else. And I think you have to look at the risk factors. And what are the risk factors for colorectal cancer in people in general, young and old and everybody? Well, it's the same risk factors as for cardiovascular disease. It's overweight, obesity, smoking. So it's lifestyle factors. And, of course, we all know that many people in the Western world are obese more so than, let's say, 20 years ago or even 15 years ago. So I think at least some of the increase can be explained by. more lifestyle risk factors in the younger population as compared to one or two decades ago.

00:10:09: Egle Dieninyte: So you're basically saying that those traditional risk factors apply to the younger people just because our societal shift into sedentary lifestyle, ultra processed foods and things like that.

00:10:22: Michael Bretthauer: Yeah, that's the most logical explanation.

00:10:25: Egle Dieninyte: And what about, I'm wondering, because I read a study that people who were born in the year I was born have twice as high risk of colorectal cancer than those born in 1950. So can you all attribute everything to those traditional risk factors or could there be something more?

00:10:48: Michael Bretthauer: Yeah, I mean, I don't know. It's just speculation. But what else could it be? I mean, the genetic pool of your generation as compared to the 1950 generation is the same. The genetics in the population do not change in 50 or 60 years. The genes don't change. So it must be something environmental.

00:11:09: Egle Dieninyte: Okay.

00:11:09: Michael Bretthauer: What it is, if it's obesity or what it is, you know, it's that speculation. But it must, it cannot be genetics.

00:11:16: Egle Dieninyte: Could there be any merit to microbiome changes? There was also studies about colibactin and Escherichia coli producing colibactin that. has effect on DNA damage. Are we exposed to more antibiotics, ultra processed foods and microbiome is a key player in this trend?

00:11:35: Michael Bretthauer: Yeah, many people are speculating in that and a lot of research groups are looking into that. I don't think we have found that needle in the haystack yet. But of course, you know, the microbiome and changes in the microbiome are also closely related to, just as you said, changes in lifestyle and environmental factors. For example, the exposure to antibiotics. Obesity. We know that obese people have different microbiomes than people who are not obese, etc. Ultra processed food. You mentioned all this changes the microbiome and it changes the environmental risk factors. So I think it's all related to each other.

00:12:11: Egle Dieninyte: Okay. Since we got off on the notion that these young cancers are the same as the traditional age group cancers. If we stratify by the stage of the disease, should we approach the treatment in any other way than the regular case?

00:12:29: Michael Bretthauer: Good question. The treatment should be related to, just as you said, the stage of disease and comorbidities. And of course, the good thing with younger people is that they. have less comorbidities, so they tolerate more treatment and more aggressive treatment. But other than that, I don't think that age in itself should be a factor that we need to consider. We need to consider the cancer and its features with regard to staging. And then we make our treatment decision regardless if a patient is 55 or 47 years old.

00:13:02: Egle Dieninyte: Now I will take my chance and ask you a little bit off-topic question. But what are you trying to do with the ECOPOP consortium and for the project? Could you please expand on the idea and the aims of the project?

00:13:16: Michael Bretthauer: Yeah, so the ECOPOP project is a large research project which is funded by the European Union with several European countries involved. And the idea of ECOPOP is to test less invasive treatment for colon and rectum cancer. And more specifically, to move or to test if endoscopic treatment can be as good as surgical treatment of colon and rectal cancer. Because as we all know, endoscopic treatment is less invasive. It's cheaper. It often reduces the length of stay in hospital. So if endoscopic treatment can be as good with regard to oncological outcomes as surgery, then I think there is a good argument for moving away from surgery as the primary treatment of colon cancer, which it is, and also of some rectal cancer. So this is the idea behind ECOPOP and the core of that project is three randomized trials where standard surgical techniques are compared to newer endoscopic methods to remove two trials for colon and one trial for rectal cancer. It's a very exciting project and it's ongoing. The first patients are randomized, but it's still a long way to go. It will still take two or three years to finish the trials.

00:14:33: Egle Dieninyte: Okay, it's a very exciting notion. We're actually trying to spare as much as we can the patient's organs and overall health.

00:14:42: Michael Bretthauer: Yeah, absolutely.

00:14:44: Egle Dieninyte: And be both effective and sparing in this case. I'm really looking forward to the results.

00:14:51: Michael Bretthauer: I agree. I agree. Me too. The question is, is the oncological safety the same? Because as you know, if you do a hemicolectomy for a colon cancer, you can look at the lymph nodes or the pathologist can. If you do, for example, a full thickness endoscopic resection, you do not know if the stage of the. cancer is N0 or N1 because you leave the lymph nodes inside and you cannot assess them pathologically. So there is an uncertainty in that treatment approach. And that's why we believe it needs randomized trial with long-term endpoints to assess if patients have a good oncological outcome. If you remove the tumor only with an endoscopic resection, leave the lymph nodes behind, cannot assess them even. You don't know if it's N0 or N1 and you don't know if they're going to be metastasis or not. And that's what we're going to try to find out. We believe that it will be the same, but it remains to be investigated. Indeed.

00:15:56: Egle Dieninyte: It's such a tricky situation when you have an early colorectal cancer and you tell the patient the odds of node metastasis and the options for treatment. But basically, it's the patient's decision currently. What's accepted risk for them in current situation and in the long-term outcomes?

00:16:13: Michael Bretthauer: It is. Absolutely. I agree. And again, we have to talk to patients about the absolute risk of getting metastasis. And if you have a T1 colon cancer, the risk of metastasis is very, very low. Some people even have N1. But of the people who have N1, also those, the risk of getting metastasis. Because N1 is not really... Clinically, a patient doesn't care about N0 or N1 as such. It's only a matter of the risk factor to get metastasis because nobody dies of a positive lymph node. But many people die of the liver metastasis. So that's why we are in the trials in ECOPOP looking for metastasis as one of the endpoints.

00:16:58: Egle Dieninyte: Lovely. Really, really looking forward to the results to help to solve this risk-benefit ratio with the patient.

00:17:06: Michael Bretthauer: Absolutely.

00:17:07: Egle Dieninyte: Professor, talking about that margin of below 50, 45, in regards to trends in colorectal cancer, should we follow suit the Americans and lower the age of screening?

00:17:19: Michael Bretthauer: No, I don't think so. And again, there is an increase in the younger people, so the people below 50. But that increase is so small on an absolute scale that I think it is not high enough to lower the screening age. I think if we lower the screening age, like the Americans have done, we will do a lot of negative colonoscopies. I don't think it's worth it at this point in time. If the increase gets even bigger in the future, we can reassess this. But right now, even with the increase, the risk is so low that I don't think it's worth it to lower the screening age.

00:17:54: Egle Dieninyte: Okay. So let's hold on to that for future epidemiological data. So to sum up, I got the impression that the young colorectal cancer, as dramatic as it might be in case-by-case basis in the certain patient, it is not a devastating problem overall on a population basis. What kind of concepts or notions would you like to leave our audience with regarding these trends and also maybe sometimes overly dramatized headlines in Medscape or other outlets?

00:18:27: Michael Bretthauer: Yeah, and I certainly have seen the headlines and I don't think it's helpful. I think it scares people unnecessarily because, as I said, the risk increase is not very dramatic. So I think we as medical doctors, we as experts and we as people who believe in science and evidence, I think we should not participate in such fear-mongering. We should explain to people what risks are and how we approach them. And I think we should contribute in that way and not instilling fear to the population. for this disease. I don't think that's very helpful. I don't think it's scientific. And I don't think it contributes to a good debate about these issues.

00:19:13: Egle Dieninyte: Okay, so basically we just need to keep being good and diligent doctors and keep calm in the storm of dramatic headlines.

00:19:22: Michael Bretthauer: I think so. For the clinician, and I'm a clinician myself, it is always devastating to have a patient and also a young patient with cancer or with some serious disease. It's not about diminishing the suffering and the seriousness of the patients that we see that do have or are diagnosed with cancer. It's not about that at all. These are all terrible cases. It's just that from seeing these terrible cases, it is not a very good idea oftentimes to jump right to saying, wow, this must be a big problem. We have to do something about it on a population level. That is not logical. It is emotional. And it's not something that we should pursue as medical doctors.

00:20:07: Egle Dieninyte: Okay, thank you, Professor. So let's keep calm, eat fiber and look forward to the Ecopop results. Thank you so much for your time.

00:20:16: Michael Bretthauer: Thank you, Egle.