IBD Drive Time: Jordan Axelrad, MD, on Malignancy Risks and Care for Patients With IBD

In this episode of IBD Drive Time, Jordan Axelrad, MD, and hosts Raymond Cross, MD, and Millie Long, MD, discuss the risks of malignancies among patients with inflammatory bowel disease, and how to care for patients with IBD who develop cancer.

Jordan Axelrad, MD, is assistant professor of medicine at the NYU Grossman School of Medicine and director of Clinical and Translational Research at the Inflammatory Bowel Disease Center at NYU Langone Health in New York City. Millie Long, MD, is professor of medicine, vice-chief for Education and Fellowship Program director in the division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill. Raymond Cross, MD, is professor of medicine and director of the Inflammatory Bowel Disease Program at the University of Maryland School of Medicine in Baltimore, Maryland.

TRANSCRIPT:

Dr Millie Long:

Hello, and welcome to IBD Drive Time. This is Millie Long, I'm one of your cohosts at University of North Carolina, and Ray Cross is with me today as well from University of Maryland. And we're excited to have our first guest of 2023, Dr. Jordan Axelrad, who is Assistant Professor of Medicine at NYU Grossman School of Medicine. So Jordan, welcome to IBD Drive Time.

Dr. Jordan Axelrad:

Thank you. Thanks for having me.

Dr Long:

Oh, of course. Well, we are excited to talk to you today about a topic that is really important for many, many clinicians, which is this association between malignancy and inflammatory bowel disease and how to manage these patients and better understand how to counsel patients on the effects of our drugs. So I'm going to jump into it and start with a first question, which is that as you know, some of our advanced therapies for inflammatory bowel disease are associated with malignancy, and can you summarize to the listeners what these therapies are and what the approximate risk is?

Dr. Axelrad:

Sure. So as you mentioned, cancer is extremely common, right? Separate from inflammatory bowel disease it's one of the most common causes of disease worldwide and one of the most common causes of deaths worldwide. And in inflammatory bowel disease, we tend to divide cancers into 2 major categories, those due to chronic intestinal inflammation—so from the underlying IBD itself—and from the therapies that we use to manage IBD, so the immunosuppressive therapies that may promote immunosuppression-related malignancies. And both are actually very important and it's important for us to explain these risks to patients. In terms of IBD therapies, different drug classes or combinations have been associated with different cancer risks. And overall immunosuppression may be associated with cancers, carcinogenesis, due to a couple of mechanisms. Those include directly altering DNA, impairing immune control of chronic infections, such as EBV and HPV, and of course reducing immunosurveillance of dysplastic or cancerous cells.

So for thiopurines, there's been a lot of literature demonstrating a link with lymphoma. There's also been associations with nonmelanoma skin cancers, basal and squamous cell cancers, and in some population-based studies, urinary tract cancers as well. Anti-TNF therapies have been associated with lymphoma as well. And also in certain studies, melanoma. Combo—thiopurine plus an anti-TNF—has been associated with all the aforementioned malignancies, but also a very rare type of lymphoma, hepatosplenic T-cell lymphoma, which tends to be limited to younger men.

For all of our other agents, we actually have very limited data. So for the anti-IL-12/23 class, most of our data on malignancy is from the psoriasis literature and in many of their registries and databases, including a large registry called PSOLAR. We don't see an increased risk of cancers. For anti-integrins like vedolizumab. Again, in our studies, we have not seen an increased risk of any malignancies. For JAK inhibitors, this is sort of an evolving area.

While in the IBD literature, we have not seen an association with malignancies in the non-IBD population, there have been reports of lymphoma, lung cancer, and nonmelanoma skin cancers, so that's something to keep in mind. And for S1P receptor modulators, another sort of novel oral small molecule, again, limited data available, nothing yet seems to suggest malignancy.

Overall, when thinking about what the actual excess risks of cancer are due to these various therapies, they're extremely rare. So we're talking about a handful of cases in 10,000 that may be attributed to drug directly. And some of our more robust estimates come from larger population-based studies. So for example, there's a study from the French National Health Insurance database published a couple of years ago in JAMA, and this specifically looked at lymphoma and anti-TNF agents, and essentially exposure to anti-TNF therapies had a 2-fold increase risk of lymphoma compared to those who were unexposed to these agents. And when combo therapy was used, that was increased to a 6-old increased risk.

In absolute numbers, though, we're talking about very few cases. In this whole population from the French study, they looked at almost 200,000 patients, but only had a couple of hundred cases of lymphoma and only 30 of those were in anti-TNF, 70 in thiopurine users, and 14 in combination. So the actual number of cases in absolute numbers is quite low, and we're really only talking about relative risks that are increased.

Dr Long:

I think you make a great point. You just described the risk in a number of different ways, relative risk and absolute risk. And I think for me, for my patients, when I tell them it's rare, they say, "Oh, I have a rare disease, so rare I could be that 1 in a million." How do you counsel your patients? Which one of these numbers do you really use when you're describing the risk? Because that may help our listeners as they're having some of these similar conversations.

Dr Axelrad:

So I always use absolute risks, right? Because it's very hard for me to say, "Oh, you have a 6- times greater odds of lymphoma in your lifetime on combo therapy." That's sometimes hard to really comprehend, but I'll usually say that we're talking about 3 or 4 extra cases in 10,000 patients. Maybe talk about a stadium. If you're sitting in Yankee Stadium and X number of patients have IBD and X number are going to be exposed to this drug, we're talking about 5, 6, extra cases of lymphoma. That's a lot easier to conceptualize rather than just talking about increased risks or odds of increased risks, so that's how I usually communicate that.

Dr Long:

I totally agree. And then I think it also helps to put it in context, too. What their absolute risk, for example, if they have Crohn's Disease is of needing a surgery in the next 5 years, if we don't treat their disease appropriately, et cetera. Because obviously that's more like 5,000 out of 10,000 rather than that handful that you described.

Dr Axelrad:

And you just hit on the head the sort of importance of the conversation overall, which is balancing risks and benefits. So we all know that the risks of uncontrolled IBD, uncontrolled Crohn's and colitis, is extreme, right? Patients require steroids, hospital visits, surgeries, and that needs to be weighed against very rare risks of a therapy related malignancy. So that's important.

Dr Ray Cross:

Millie and Jordan, one thing that Steve Hanauer taught me that I've been using a lot, and I think it really helps, is I think he described it as anchoring the risk of therapy with something that happens in everyday life and certainly surgery for Crohn's. But one of the things that I mentioned is a woman has a 1 in 8 lifetime risk of breast cancer. A man has a 1 in 9 lifetime risk of prostate cancer. There's some funny risk estimates like risk of dying from drowning or choking, it's like one in 250. So I always anchor it with something like that. And it's usually watching their face. It's very reassuring to when you tell them what their risks are of just being a man or a woman that swims and eats in our society. So it can be helpful.

Dr Long:

No, absolutely. Yeah, I think that anchoring is a great point. One of the reasons we're asking you all of these questions is because you're one of the principal investigators of the SAPPHIRE study. Would you mind telling our listeners what SAPPHIRE is and if they had a patient who met criteria, could their patient be enrolled?

Dr Axelrad:

Sure. So the SAPPHIRE Registry is a registry that actually developed from the New York Crohn's and Colitis Organization, which is a consortia of academic IBD centers in New York City. And many years ago, we studied retrospectively our patients with IBD who had a history of cancer and examined their risks of new or recurrent cancer exposed to various therapies that were available at that time. And so from that preliminary data, which demonstrated that IBD therapies did not seem to increase the risk of new or recurrent cancer in patients with a history of cancer, we decided to study this prospectively. And this is especially important as newer agents with different mechanisms are becoming available to our patients. And as you know, this is one of the number one questions that patients ask us, one of the number one concerns is this cancer question, and which is especially important in patients who already have a history of prevalent cancer.

And so this is a registry, the main site is Mount Sinai and NYU, and we're prospectively following patients who have a history of cancer within the last 10 years who do not yet have a new or recurrent cancer who are exposed to various therapies or no therapy. And certainly, patients can be enrolled from anywhere across the United States. And they can either reach out to me or my collaborator from Mount Sinai, our research coordinator, Cristina Villagra. She can also help and connect folks so we can sort of get that information out there to refer patients in. But we're definitely still recruiting and we're definitely still following patients.

Preliminarily, some of our data's been presented at DDW. We're looking to present data in a manuscript form, some interim data soon. But essentially we've confirmed our retrospective data from many years ago that IBD therapies and of various types now, not just thiopurines and anti-TNF, but anti-IL-12/23, anti-integrin, JAK inhibitors, do not seem to increase the risk of new or recurrent cancer in patients with a history of cancer. There are still many caveats to this, we're sort of grouping lots of cancers together, but on the whole it looks like these agents are safe, which is what we anticipated from our retrospective data.

Dr Long:

No, that's great. I have one follow-up question to that and then I'm going to turn it over to Ray because I know he has questions for you as well. In that patient with the prior history of cancer who you're kind of selecting a new therapy, what are the factors you're considering when you're choosing that next therapy? Are you thinking about how long it's been from their cancer? Does it depend on the type of cancer? If you don't mind just talking us through that, I think it would be helpful for our listeners.

Dr Axelrad:

Sure. Well, I think there's a couple of important considerations and then I'll tell you what my real only consideration is. So of course the obvious considerations are is the prior cancer completely eradicated? And if I give an IBD therapy, am I somehow going to reactivate that malignancy? Or are patients going to be at risk for new cancers? And those are sort of the 3 main considerations. And unfortunately, trials of IBD therapies generally excluded patients with active or recent malignancy, and so we really had very limited data, at least in our trials of therapy exposure.

The reality is that the single greatest risk factor for cancer is the stage and type of a patient's previous cancer. It's not their IBD therapy, it's not the combinations or types or durations of IBD therapy. It is their cancer history. And so when I'm making a consideration about initiating therapy in patients with a history of cancer, of course I want to know about their cancer history, stage, type, molecular subtypes, what therapies they received for their cancers.

But most importantly, I want to know what their IBD activity and severity is, right, because that's really my main target. We have emerging and data demonstrating that most of our IBD therapies are very safe in patients with a history of cancer. So my major consideration is the IBD activity and severity and what I need to do to get that patient into remission of their IBD. Now of course, there's other considerations around that. I'm oftentimes having conversations with the patient's oncologist if they have a recent malignancy, but that's the major consideration is what does the patient need for their IBD and targeting that.

Dr Cross:

Just I'm going to ask you a few questions, Jordan, this has been great. Just a reminder to our listeners that IBD Drive Time is sponsored by Advances in IBD and the GI Learning Network and we do have an in-person regional AIBD coming up in March. So be on the lookout for more details about that.

So Jordan, in a patient unfortunately who develops a cancer, a liquid or a solid organ cancer while on treatment, what's your approach? So when do you stop therapy? When do you continue? Does it depend? How do you approach that?

Dr Axelrad:

So it depends on a couple of considerations. One is the cancer type and molecular subtype and of course the stage of the cancer. And I would look at something like a breast or prostate cancer very different than a lymphoma, for example. So, if the patient is on an IBD therapy and they have a malignancy that could be associated with their underlying therapy, I'm having a conversation with the oncologist to discuss what the plan of attack is. And generally speaking, most oncologists are actually quite comfortable with continuing IBD therapies through a cancer diagnosis and treatment and after. But there needs to be an open discussion about that, especially if there's even a remote consideration that the IBD therapy was somehow associated with the incident malignancy.

For the majority of patients, since I'm really basing my treatment decisions on the patient's IBD activity and severity, if they've come to a cancer diagnosis and they're only on topical therapies like mesalamine for mild colitis, I'm making no changes to their treatment. If they're on combo therapy, I will generally stop the thiopurine just to try to simplify their regimen, remove a class of medications that are thought to be associated more closely with malignancy, and just sort of focus on monotherapies and I'll continue the anti-TNF. If they're on monotherapy with a biologic or monotherapy with a small molecule, I'm generally continuing those therapies and again, in conversations with the oncologist to make sure everyone's on the same page. And that's why I approach the patient. If they flare while they're on these therapies—so if they're on their existing therapies, they have an active cancer that's being treated or managed and they flare—I'm doing the same thing I would normally, giving corticosteroids when needed, escalating therapies, adding topical therapies, doing whatever I need to do to get their disease under control.

Dr Cross:

So Jordan, you taught me this because you've published the most in this area. We know that patients that get hormonal therapy, radiation therapy, and certainly if they're getting a checkpoint inhibitor that those are not protective, they're not going to induce a remission and they're not going to maintain a remission in patients with Crohn's and colitis. But in the patients that are truly getting systemic chemotherapy, do you need to even continue the advanced therapy that they're on while they're getting chemotherapy?

Dr Axelrad:

Yeah, it's a good question. So we do have some data, it's not exceptionally robust even though I published it, but we do have data demonstrating that certain types of cancer therapies may influence the IBD activity. So as you suggest, we know that cytotoxic therapies, so drugs like cyclophosphamide or platinum-based agents, may actually improve the underlying IBD. They're sort of broad immunosuppressives, they may actually help the disease activity. And in that patient who may be exposed to lots of cytotoxic therapy for their cancer, they may not need an ongoing IBD therapy, especially if they're already in remission and there's going to be a monitoring strategy, that may be someone who you could observe while they undergo cytotoxic treatments. Increasingly, cytotoxic therapies are being used less and we're seeing more immune therapies being used, checkpoint inhibitors. And these drugs, however, as suggested, have the adverse reaction of actually exacerbating or causing IBD-like findings, causing colitis.

So again, this is completely different. So if you have folks who are going to be exposed to checkpoint inhibitors, immune therapies, that's a patient that you actually want to be aggressive with their underlying IBD to ensure that they're going to be in remission and unlikely to experience flare during or after their therapies. You also mentioned hormone therapies. So we have some data and actually Millie’s published some data on hormone agents, OCPs. There's likely a relationship between hormone therapies, hormone agents, and underlying IBD and mucosal immunity and mucosal immunology. And what we've seen from cancer studies is that those who are exposed to hormone deprivation therapies used for common cancers like breast and prostate, that these patients seem to flare a bit more than others. And so again, another class of cancer treatment that providers need to be aware of for closer monitoring of patients as disease IBD may flare. And so again, that may be a group that you want to be more aggressive about their IBD, similar with checkpoint inhibitors.

Dr Cross:

So before the fun question, Jordan, I was just thinking about health maintenance strategies and for malignancy, we recommend seeing a dermatologist as we get older, wear the big hats, sunscreen, the SPF shirts, things like that. You do what you can do and certainly we recommend dysplasia surveillance for colonoscopy, but you and I are writing an article for the Red Journal coming up on when to stop surveillance. As we get older, then our patients are aging with us. So regarding dysplasia surveillance, how do you decide when to stop doing surveillance?

Dr Axelrad: 

So this is a very individual conversation. I think that there's not just one age cutoff for all patients and we know that there's increasing emphasis placed on things like frailty rather than sort of numerical age. And for me, with my patients who are aging, it's a conversation about what's the right time to stop based on other comorbidities, other expectations, whether a cancer was identified or if dysplastic lesion was identified, would patients be able to go to subsequent evaluations for monitoring and further surveillance, potentially cancer treatments. So I think this is the conversation with the patient about what the expectations are, what their wants are towards later-in-life decision making. And it's not really about that numerical 75-year cutoff, just you're after that. And it really depends on lots of different factors, comorbidities, wants of the patient, and it should be a conversation.

Dr Cross: 

Yeah, I completely agree. I mean, there's some 80-year-olds that look like they're going to live to be a hundred, and there are 65-year-olds that you're like, oh my gosh, I don't think they're going to be around until they're 66. So age, I generally start to have that conversation in the mid-‘70s or sooner if they're really frail. But you and I are completely aligned on this. So Jordan, this has been awesome. This is the fun question and tell the listener something about yourself that they may not know. Something maybe even that Millie and I may not know about you.

Dr Axelrad: 

I always make a joke that if it wasn't medicine, I'd work in finance. And I don't know if I only say that because I live in Manhattan and there's lots of interaction and influence here. But I really think if I was not going to be in medicine, if I did not have my job, I would hands down be like a food and travel critic.

Dr Long: 

Excellent.

Dr Axelrad: 

Yes, yes, for sure. And in fact, maybe I'll still do this at some point after this career, but that's definitely something people don't know about me. But I'd love to travel, love to eat ,and love to explore new restaurants and places in the world. So that's definitely something I think I would-

Dr Long: 

Okay. Normally, we only get one fun question, but I'm getting a follow-up question out of this. So you clearly have loved to travel. What is your favorite place you have visited and why?

Dr Axelrad: 

Favorite place, I don't know, there's a couple. I'll give 2. I really, really, really, really loved actually visiting Peru. I spent quite a bit of time in Peru. I think that's kind of a fascinating place. Different cultures, different history, different food, really fascinating. I think for relaxing, probably the best place I've ever visited for relaxing, I would say is there's a whole beach community in Uruguay, which is really sort of undiscovered by a lot of Americans and which makes it a lot more pleasant when you visit as an American. And I'd say that that's super beautiful, really undiscovered, really laid back, lots of influence that's not American. So that's probably the nicest place to relax, to visit.

Dr Long: 

Oh, this is great. Not only do we have a great conversation about malignancy and IBD, but I've now got 2 new places on my bucket list because I've never been to Peru or Uruguay. So that's fantastic.

Dr Cross: 

d you've opened yourself up for travel- and food-related questions for the rest of your career. So there you go, Jordan.

Dr. Jordan Axelrad: 

Yes, yes, there you go.

Dr Long: 

Exactly. Well, with that, we'd like to wrap things up. Thanks so much for joining us. Thanks to our guest, Jordan Axelrad, and we'll see you hopefully in the next... Or not see you, but you'll hear us in the next few weeks for the next IBD Drive Time.