Advances in Stage 4 Colorectal Cancer Treatment

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic Directing the Taussig Early Cancer Therapeutics Program and Co-Directing the Cleveland Clinic Sarcoma Program. Today I'm very happy to be joined by Dr. Michael Valente, an Associate Professor, Program Director for the Colorectal Surgery Residency Program, and Director of the Peritoneal Surface Malignancy Program and Center for Metastatic Colorectal Cancer. He's here today to talk to us about advances in stage four colon cancer. So welcome.

Michael A. Valente, DO: Thank you so much, Dale. Great to be here.

Dale Shepard, MD, PhD: So remind us a little bit, you've been on a previous episode. Remind us again though, about what you do here at the clinic.

Michael A. Valente, DO: Sure. By training, I'm a colorectal surgeon, general surgeon who did specialized training in diseases of the colon and rectum. And then I've been at the Cleveland Clinic for 12 years now. I mostly focus on colon and rectal cancer, but also appendiceal cancers and cancers that have spread to the peritoneum. We do a combination of both open laparoscopic robotic surgeries here, and I also have a practice that involves endoscopy, performing colonoscopies as well. So kind of the full spectrum of colorectal disease, but concentration on the cancer part of it.

Dale Shepard, MD, PhD: Excellent. So we're going to focus on late stage, stage four colorectal cancer. Give us a little bit of an idea, when we think about colon cancer, it's certainly pervasive. I would not be opposed if you want to put in a quick bid for screening, but people who unfortunately show up with late stage disease. Historically, how have we thought through managing late stage disease?

Michael A. Valente, DO: Sure, sure. We'll start with the screening part real quick. And March is Colon Cancer Awareness Month. So they always ask me when I give an interview during this month is who qualifies for a colonoscopy? And that's everyone that has a colon. So if you have a colon out there at some point in your life starting at age 45, you should be getting colon cancer screening with a colonoscopy. That is the best test that we have.

Now moving on to stage four. So stage four is a complex topic and we're going to dedicate this episode to that. And historically, when you hear about stage four, you think the worst and you think it's the highest stage. There's four stages, stage four being the worst with spread to different parts of the body. Let that be the peritoneum like we talked about, the liver, the lung, the nervous system, the brain, et cetera. Traditionally, we're talking over the past decades, over the last 50 years, not a lot of treatments have been proven to be very effective in the past, but over the last 5 years, 10 years, 20 years even, the advances that we have in both surgery, in medicines, chemotherapeutic drugs, radiation treatments, and we'll talk about some of these newer molecular things like immunotherapy, have really changed the landscape of stage four. And in many cases we're able to definitely increase someone's life expectancy. In certain cases, patients are curable and we could talk about those today.

Dale Shepard, MD, PhD: Excellent. So I guess if you think maybe on the medical side, on the surgical side, what are the things that stand out as the biggest breakthroughs of the recent years? Where have we made the biggest advances? You mentioned a couple, but let's hone in on that.

Michael A. Valente, DO: Yeah, sure. I mean, starting with the medical side, quite a few breakthroughs with chemotherapeutic agents, but also a thing called immune therapy for some patients, we'll talk about that now is in the past when someone came to us, they would be just maybe only receiving chemotherapy and that's the only option that they had. Now with a combination of drugs, newer drugs, and then maybe addition of surgery or other techniques in conjunction with treatment, we've been able to do some great things. So in terms of the medical side, there are the standard chemotherapeutic agents, and you may hear about first line, second line, even third line treatment. So folks with stage four or metastatic colorectal cancer usually go through several rounds, if you will, of chemotherapy. And some of them work right away and some of them may not work. And then we switch to a different one.

There is a subset of patients out there that have a certain genetic profile, meaning that some genetic testing was done on their tumor and we found that they're actually missing some things inside the DNA of the tumor. And those folks, we've found out that immune therapy or immunotherapy has been quite revolutionary in the treatment of these patients. In some instances, having a cure. Now, unfortunately, the vast majority of colorectal cancer does not fit into getting immune therapy, maybe 5%, at the most maybe 10% of colorectal cancers can receive this treatment currently. But for those patients who are receiving them, those immunotherapy treatments, we've seen complete responses, meaning that there's no cancer left. We've given the patient six months, maybe a year of immune therapy, we take them to surgery and all the cancers essentially gone, just scar. Those are some great scenarios. I've had several patients like that. Lots and lots of work being done on immune therapy.

There's actually some studies out there and a lot of research now looking at immune therapy for the other 90% of colorectal cancers that maybe would not normally fit into immune therapy, but they're working on some breakthroughs over the next, hopefully a year or two where maybe folks who wouldn't qualify for immune therapy would then qualify. So a lot of stuff on the horizon with that.

Dale Shepard, MD, PhD: When you think about most colon cancer, we're at a really specialized center, and even more so here on main campus, a lot of the colon cancer of course being treated in the community. Do you see these things like immunotherapy testing early to try to get those patients that might respond to immunotherapy go to see you have complete responses? Do you think we're getting enough people tested early enough?

Michael A. Valente, DO: Yeah, great question. I think we've been increasing it dramatically over the last six months, year, two years. With the Cleveland Clinic main campus, and then we have the east and west side, south side, I think we're well integrated and our medical oncology teams and surgical teams really understand this and have been testing early. I think it does make a huge difference, putting a note out there for all the people listening, medical oncologists out in the different communities or in different states or whatever. If we're not checking these things, we're never going to know. So I think the landscape has changed and it's pretty much standard of care to be checking for these different mutations, if you will, or genetic defects that may allow us to give immune therapy.

Dale Shepard, MD, PhD: I mean, sometimes it seems like it's too much force of habit to give FOLFOX and think about doing testing later, be that for EGFR or KRAS mutation or whatever.

Michael A. Valente, DO: I have seen a lot more upfront testing. I wouldn't call it standardized, but we get folks from all 50 states and some big cities and small cities, and I have seen medical oncologists really upping their game, if you will, and checking for these markers. And while we're on the topic of that, I would say a big advancement I think over the last 10 years since I've been here or so, is these patients even getting to a surgeon or even getting to a multidisciplinary tumor board.

In the past, these stage four were deemed inoperable or untreatable or would just have one line of therapy and they were never getting to institutions where they could do multi-modality treatment. So I think that still needs some work. And I see this a lot with the peritoneal cancers, with the cytoreductive surgeon, HIPEC, that we talked about last time. Still, I think the vast majority of patients with some of these stage fours may never get to a center or hear an opinion from another team of experts and multidisciplinary team where they may be some options for them. And like I said, not everyone can be cured, but with proper medicines, with aggressive surgical techniques or other kind of things that we'll talk about, we can make these patients live much, much longer and have actually really good quality of life as well. So I think getting the patients to us is critically important.

Dale Shepard, MD, PhD: It's huge. And you're exactly right. I mean, it seems as though oftentimes people in the past had a colonoscopy, you think about surgery, but then you do staging and there's a couple of things in the liver and you're like, "Eh, nevermind." And you go to chemo. That's maybe not the right way of the world. So tell us a little bit about some of those multi-modality treatments, some of those more focal therapies that might make sense.

Michael A. Valente, DO: Sure. The biggest organ, the most prominent organ that gets colorectal metastasis will be the liver and then the peritoneum and then the lungs. So we'll talk about the liver. Great advances have been done in liver surgery, and we have a fantastic team here of both liver surgeons and liver transplant surgeons who do a phenomenal job and they're an integral part the team. They're part of our multidisciplinary tumor board. They listen in on all our cases. As I said, liver metastases are the most common. And like you said, you would have a sigmoid colon cancer or even a rectal cancer and they see two or three liver metastases and they would just go to chemotherapy and sometimes maybe just beyond chemotherapy forever. They wouldn't even get to us.

However, when I was in training, not that long ago, but let's say 20 years ago, there was a limit on the amount of surgery you could possibly do on the liver. You can only do maybe if there was three or four maximum metastasis, that's all you could take care of at one time, and those patients would be deemed inoperable if there was more.

The liver world has changed drastically, and nowadays it's not so much how much cancer is in the liver, is how much good liver is there? And how much after the operation, how much good liver will be left behind? And our guys and girls are really pushing the envelope and doing these things. So say you have a liver metastasis and it's maybe three or four, five spots and they're small, one or two or three centimeters. Those are kind of situations that we would have aggressive options, chemotherapy of course, immune therapy if they qualify, but chemotherapeutic options. And then in conjunction with our liver surgeons, we would sometimes do combined operations where I go in and take out the primary tumor and then the liver surgeons would go in and wedge out or non-anatomically take these little sections out. If there's a more solitary or unifocal lesion, they would maybe do a more formal liver resection at that time as well, plus me doing the colon operation at the same time.

And then some patients have innumerable liver metastases, maybe by low bar on both sides. And this is maybe a situation where ablation techniques come into play. Radiofrequency ablation, microwave ablation, SBRT, stereotactic body radiotherapy where our radiation team comes into play as well and does some radiation to the area.

So there's a lot of different variations that can occur. You could go from the spectrum of a solitary liver lesion and a colorectal cancer, and we can knock that out in one operation, take out the liver piece, take out the colon, put them back together. All the way to the other side of the spectrum where you have replaced liver with cancer. And where that patient, and we could talk about it now, I guess, is they may even go on to liver transplantation, which is an extremely aggressive, but something that has been done here on numerous occasions. When I say numerous, probably about 13 to 15 patients here, but that's some of the most numbers in the world besides some of the Scandinavian countries. And we have our team here that for the right patient, for the right disease process at the right time, liver transplantation may be something that you could qualify for. So there's so many different options now that weren't even thought about 5 years ago, 10 years ago, that it's really exciting.

Dale Shepard, MD, PhD: If you were to sort of think of a prototypic patient, again, a lot of different people might be listening and ideally, who would you like to see for second opinions?

Michael A. Valente, DO: Honestly?

Dale Shepard, MD, PhD: Anybody with a-

Michael A. Valente, DO: Anybody.

Dale Shepard, MD, PhD: A met and a colon cancer.

Michael A. Valente, DO: But I should say everyone with metastatic disease should be at least evaluated by a surgeon at some stage in the game because if you're, and I say this for the peritoneal disease, I would say probably 75% of the folks out there with peritoneal only disease never make it to a peritoneal surgeon. So I see that also with the liver. You see someone who's been on chemo for two years and their liver's getting toxicity. Maybe it's time we go see a surgeon to see if this is resectable or abladable or maybe we could get them off chemo for a while. You know what I mean?

Dale Shepard, MD, PhD:

Sometimes they have relatively stable lesions, you don't even know what you're treating.

Michael A. Valente, DO:

Correct. And sometimes you don't even know if it's still cancer there.

Dale Shepard, MD, PhD: Correct.

Michael A. Valente, DO: Right. It could just be calcified and fibrosis, especially with immune therapy now.

Dale Shepard, MD, PhD: Right. There is an episode, we talked about peritoneal disease and HIPEC and things, but just briefly remind us kind of the role of that.

Michael A. Valente, DO: Sure. The second most common site of metastasis is the abdominal cavity, or the peritoneum. The peritoneum is a few cellular thick membrane that covers all of the internal organs and the lining of the abdominal cavity. Actually, it's one of the first lines of defense from tumors or bacteria or infections. What happens is the colon cancer, appendiceal cancer, et cetera, perforates or just grows through the wall and then spreads into the abdominal peritoneal circulation, and then that could set up shop and implantation and make new stuff and grow. And what we do, and this is not for everyone of course, but patients who have a limited amount of peritoneal disease can undergo an aggressive form of surgery called cytoreductive surgery, and then plus minus what we call hyperthermic intraperitoneal chemotherapy. Essentially it's a two-part operation where we debulk or "strip" all the areas on the peritoneum, remove any organs that may have the cancer in it, colon, rectum, appendix, small bowel, et cetera.

And then when that procedure has been completed and we verify that all the disease is out, then you can add a heated or very hot hyperthermic liquid chemotherapy that essentially bathes inside the abdominal cavity for an hour and a half or so. What that does is hopefully directly kill the cells, direct contact because peritoneal disease, systemic or IV chemotherapy has been very difficult to get to some of those hard to reach areas where there's not a lot of blood flow blood supply there. So we go at it directly, and that's been shown to do great things, increase survival, cure in up to 15% of patients, but once again, patient selection, the amount of disease, what type of disease there is, what type of cancer. So a lot of things to consider, but once again, why people should be seen in a that does these operations and also with a multidisciplinary tumor board where there's not just one or two surgeons saying something, but it's the whole team of medical oncologists, radiation oncologists, nurses, doctors, everyone.

Dale Shepard, MD, PhD: We've talked a little bit about management of the liver, for instance, peritoneum. What's the current view about resection of primaries in people that have metastatic disease and even extensive disease, liver disease? When does it make good sense to take out that primary?

Michael A. Valente, DO: Yeah. Don't have the exact answer, but we go back and forth with it. But one thing that patients sometimes don't understand initially they're like, "Why can't you just take this thing out? I got this thing in my colon. It's there."

Dale Shepard, MD, PhD: This is where it started. Why are you leaving it there?

Michael A. Valente, DO: And it makes sense. It makes sense. Generally speaking, if we have a patient that comes in with say, rectal or sigmoid cancer, any colon cancer and they have liver metastasis, one of the first things we're going to do is start chemotherapy or some treatment form, immunotherapy, et cetera, mostly chemotherapy. And then the patient's primary tumor, unless it's causing complications like a blockage, like an obstruction, or if it's bleeding, then we would have to do something with it because it's more urgent and it's causing complications. But the vast majority don't. Generally speaking, we would say you want to treat the whole body first. We want to get the liver under control, the lung or wherever the metastasis are, even the peritoneum as well, because we need to get that chemotherapy. And going right to surgery is not the right answer because we know that there's more than just what's there. Potentially there's microscopic disease floating around the bloodstream, et cetera. So we want to treat the whole body.

Well when do we take the primary out? That's a great question. As I was kind of saying before, if we're going in for liver surgery or lung surgery or peritoneal surgery and our job is not going to be too vast, meaning that the liver is not going to be too much involved, we would then go ahead and do the liver part and then take out the primary as well. If the liver disease is extensive or the lung disease is extensive, usually we would want to take care of that first, maybe give them a break, maybe put them back on chemotherapy even, and then address the primary tumor down the road. Why is that? And we would say, and maybe from your experience too, is the colon mass is not the main problem right now. There's bigger fish to fry, if you will. There's more important things to worry about than that colon cancer that's not doing anything, but the one that's already been spread from the lymph nodes into the bloodstream, into the liver, that is much more important and we need to attack that first.

Dale Shepard, MD, PhD: And again, that's the importance of patients seeing someone like yourself, because that is a fundamental thing. If it started here, why are we leaving it there?

Michael A. Valente, DO: Yeah. And there has been that-

Dale Shepard, MD, PhD: From that perspective from surgery.

Michael A. Valente, DO: Yeah, no, and there has been some data and some literature out there that's saying that at some point, taking the primary tumor out is a good thing to do as well because maybe treatments may work better and whatnot. But for the most part, if you come in with stage four, assuming chemotherapy should be the first thing that gets started, almost always, but not always.

Dale Shepard, MD, PhD: So when we think about where we've been, where we might go, you mentioned in the old days very recently when you were training that oftentimes there is a relatively limited amount of things you did in the liver, and now there's a lot of things you do in the liver. I guess the question is what led to that plateau shift and then where's next? I mean, what's going to be the next break that says now we can do even more crazy things that we haven't even maybe even thought about?

Michael A. Valente, DO: Yeah, I think the technologies have evolved, obviously. Even in terms of radiotherapy, the types of radiation we give, how we give it, how it's pinpoint and precise as opposed to radiation 30 years ago or there were so many side effects from it. Now we have precision instrumentation and people who really specialize in this. Patients are doing better from chemotherapy overall. So what's next?

I think, and this is probably for all cancer, is this tailored treatments, precision medicine, we talked about getting molecular profiling, genetic profiling of tumors, and that's really where I think everything's going to be going is patient A versus patient V versus patient C. They have colorectal cancer with liver metastasis, but all three of those can be completely different. And it's like taking a shotgun approach and just giving everyone the same chemotherapy. What's going to happen is we're going to tailor it to each person's tumor, and it's happening more and more every day in the laboratories and the research areas around here and around the world. That's where we're going to be.

And even like we're doing now for some rectal cancers, like anal cancers were in the 70s and the 80s, up to 30% of my rectal cancers aren't even getting to the operating room anymore because chemotherapy and radiation are curing them. So I'm already doing 30% or so less rectal resections than I was 5 years ago, 10 years ago. So I think really getting the profile of the tumor, and I think that's really where it's going to be going for everything. Not just colorectal cancer.

Dale Shepard, MD, PhD: So I guess to summarize, really important to actually ... We talked a lot about metastatic disease, and of course the big thing is you don't get metastatic disease if you don't get an advanced cancer in the first place, right?

Michael A. Valente, DO: Correct. Correct.

Dale Shepard, MD, PhD: Screening is important.

Michael A. Valente, DO: Screening is paramount.

Dale Shepard, MD, PhD: Screening is important. Colonoscopies, like you said, are huge. When they ask me what to do for a screening, I tell them, "Colonoscopy or anything you'll do."

Michael A. Valente, DO: Correct. Yeah. And folks out there have heard about the Cologuard or other similar screening tests out there, which I would say if you're weary or not wanting to undergo a colonoscopy, then that is definitely needed to be done. You have to do something. Now, understand, if a Cologuard comes back positive, you're going to need a colonoscopy. If a CT colonoscopy comes back as positive, you're going to need a colonoscopy. So the end result of all of these tests is still a colonoscopy because it's a beautiful test because you could diagnose and potentially treat. And the thing about colon cancer screening is we could find pre-cancers and early cancers and address them with the scope, with a minor procedure even. And before this even becomes stage two, three, or four. So if we could take it out before it even becomes a problem, that's the best prevention.

Dale Shepard, MD, PhD: And then as you've let us know that lots of things that are our options and not forget you guys as surgical colleagues in terms of treatment options.

Michael A. Valente, DO: Absolutely. And just get that point across one more time. If you have stage four colon cancer, colorectal cancer, it is okay to get a second or third opinion at various places. Talk to as many people as you can. There's a lot of variation in how things are treated. My recommendation is always go to a center that has a multidisciplinary team approach where surgeons, abdominal surgeons, colorectal surgeons, liver surgeons, lung surgeons are all part of the team and are part of the daily weekly kind of tumor board kind of environment.

You'd be surprised how many patients, like I said, who have been going around for a year and a half, two years, and they're doing well, but they could do more and we could maybe do an operation, maybe alleviate some suffering, or maybe give better quality of life. So if we can't cure the patient, which is always our goal, but then we want to be able to either increase their life expectancy and at the same time have a good quality of life. So I think all those things can be achieved in the vast majority of patients, but we've got to get them to the right place at the right time.

Dale Shepard, MD, PhD: You are doing fantastic work with an important disease, so thanks for being with us.

Michael A. Valente, DO: Thanks for having me. Appreciate it.

Dale Shepard, MD, PhD: To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

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