Carol A. Burke, MD, on Eflornithine+Sulindac for Treating Familial Adenomatous Polyposis


In this podcast, Carol Burke, MD, discusses her team's latest research on treatment options for patients with familial adenomatous polyposis (FAP), how eflornithine plus sulindac affected disease progression over 2 years, and how patients may be able to stave off surgery.

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Carol A. Burke, MD, is codirector of the multidisciplinary Hereditary Cancer Clinic and practitioner in the Department of Gastroenterology, Hepatology, and Nutrition at the Cleveland Clinic in Cleveland, Ohio.



Amanda Balbi: Hello everyone, and welcome back to Podcasts360—your go-to resource for medical news and clinical updates. I’m your moderator, Amanda Balbi with Consultant360 Specialty Network.

Today we’ll be discussing familial adenomatous polyposis (or FAP), which is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps. A new study investigated a combination treatment strategy for delaying FAP progression vs each drug alone.

With us today to discuss the findings of this study, as well as how FAP affects patients, is lead study author Dr Carol A. Burke, who is the codirector of the multidisciplinary Hereditary Cancer Clinic and a practitioner in the Department of Gastroenterology, Hepatology, and Nutrition at the Cleveland Clinic in Cleveland, Ohio.

Thank you so much for joining me today, Dr Burke.

Before we get into your study, let’s talk a little bit about FAP. What are the current treatment options and how efficacious are they?

Carol Burke: The current treatment options for FAP include mostly single agents, including nonsteroidal anti-inflammatory medications. There have been some nutraceuticals that have been looked at, including fish oil, lyophilized black raspberries, and most recently, in the last number of years, more than just a single agent.

The utility of 2 agents given at the same time, and eflornithine is one of the drugs that have been looked at in combination with an anti-inflammatory medication called celecoxib in the past, and in the current study, we looked at its utility eflornithine with sulindac, and we can talk a little bit about the use of sulindac over the years for FAP. There have been other combination studies with the use of—really, it's a chemotherapy drug— erlotinib or erlotinib with sulindac in FAP, and that showed success.

So, I think that these days practitioners who are caring for patients with FAP are looking for safe and effective medical management of all the colon polyps once someone’s had their colon removed or, of course, in select individuals or in individuals that are for some reason trying to delay the time to having their colon removed.

In terms of how efficacious these medications are, since the 1980s, clinicians have been using off-label sulindac, which is an old anti-inflammatory medication that, quite frankly, was a serendipitous finding when an individual with a rheumatologic condition with FAP had been given sulindac. The astute FAP provider said, “Gosh, your polyps left in your rectum have receded. What are you doing differently?” And the only new edition was the use of the sulindac—the anti-inflammatory medication.

We know that the COX enzymes are upregulated in colon polyps and colon cancer in FAP, as well as in sporadic colon polyps and sporadic of colon cancer. And so nonsteroidal anti-inflammatories, of which sulindac is one (a very old one) has been efficacious. Now, how efficacious is sulindac?

There have been some studies that suggest that it wasn't as effective as we had hoped, but I would say in my clinical practice and many FAP experts’ clinical practices, it is very effective to decrease the number of polyps and hold them at bay for a while. It hasn't been studied in very large FAP populations, because it's an old medication, but more recently, other anti-inflammatories, like celecoxib, have been studied.

In short-term trials, which most of the FAP trials had been prior to ours, about a 25% reduction in the colorectal polyp burden. In individuals that were given celecoxib for 6 months, a 22% reduction in a study that looked at a certain formulation of free fatty acids. Something that you might get in fish oil. And in another 6-month study, the combination of sulindac with erlotinib also had a pretty stunning reduction in not only duodenum polyps, but there was some impact on colorectal polyps. Particularly, most of these studies are done in patients that mostly have had their colon removed.

So, not a silver bullet, but it is effective in select patients, and practitioners use it when needed to try to control the polyp burn mostly people have had their colon removed and have a rectum intact or have an ileal pouch anastomosis.

Prior data from a trial in patients with sporadic colorectal polyps utilize the combination of sulindac and eflornithine. This study was published years ago, and the combination of those 2 agents showed a significant 95% reduction in the recurrence of advanced adenomas—those adenomas that are the type that are most likely to turn into cancer.

When you think about the molecular pathways from polyp to cancer in the sporadic population or in the FAP population, it's the same pathway: the chromosomal instability pathway. And that was the impetus, in part, for utilizing this combination in FAP because of the strength of the effect that the combination had in the sporadic polyp-prevention trial.

In addition, we know from animal models with FAP, as well as some tissue related models, that inhibiting a secondary pathway that leads to polyamines, that those are substances that can be produced by the enzyme ornithine decarboxylase gives rise to polyps in FAP. Eflornithine’s action is by inhibiting ornithine decarboxylase, so we lower the levels of polyamines and the polyamines then can't act to increase adenoma growth.

There is a synergistic effect between eflornithine with its effects on ornithine decarboxylase and polyamine expression, as well as sulindac, which affects COX and non-COX pathways. The 2 of them not only diminished polyamines, but the sulindac helps export polyamines out of the tissue. So, a very interesting mechanism of synergistic action.

Amanda Balbi: Now, for your study, you and your colleagues investigated the efficacy and safety of combination therapy with eflornithine and sulindac, compared with either drug alone, in the role of delaying disease progression in patients with FAP. Can you tell us more about how your study came about and why it’s so important for patients with FAP?

Carol Burke: FAP is a systemic, serious hereditary colorectal cancer syndrome that results in hundreds to thousands of colon polyps, and in most cases, the onset of colorectal cancer by the age of 40.

There’s also troublesome polyps in other parts of the gastrointestinal tract, including the duodenum with duodenal polyposis and gastric polyps, gastric polyposis, duodenum polyps, or gastric polyps can lead to duodenal or gastric cancer.

Then patients with FAP do have other extra-intestinal tumors both benign and malignant. When most patients with SAP have had their colon removed, but yet they continue to form polyp in other parts of the intestinal tract or in the rectum or in the illegal pouch, surgery is not always a great answer. So, the study is important to see if we can actually diminish recurrent surgery in patients with FAP.

The few novel things about our study, other than being the largest, the longest, and international study is that the endpoints that were looked at in our trial included FAP-related events—clinically important events—in the patient as a whole. Most of the other trials in the past, when they're evaluating the efficacy of drugs, have looked only at the number of polyps or the size of polyps. So, this was a really innovative design that wanted to see if in a patient we could impact disease progression.

One of the things about our study that might have affected the results is, based on historical data, we presumed that over a 2-year period, the FAP patients in the trial that were having their lower endoscopies and upper endoscopy every 6 months, 70% of them would have some FAP-related event if they were in the single-agent arm.

In our study, we compared sulindac, which is not FDA approved for its impact on colorectal polyps in patients with FAP but used by providers, and eflornithine, also known as DMFO. Eflornithine in and of itself has not been shown to be effective in FAP, but it does impact a different pathway then sulindac does or other anti-inflammatories does. It affects ornithine decarboxylase. So, there was some thought that potentially eflornithine alone might have some effect, but the study was designed to say, “In these patients that get one of those agents, they would have a 70% event rate by 2 years, and if we combined sulindac with eflornithine that the event rate at 2 years would be only 30%.”

And what we found at 2 years is the events rates in any arm of the study were nowhere near 70%. Basically, they were all about 30%, so when we designed and powered our study,

we enrolled the number of patients to look at change in the event rate. And we actually over-estimated the event rates in the monotherapy arms.

With that being said, when we looked over time, the number of events or time to events in an FAP patient as a whole, so all of these disease areas, were not substantially different. When you look a little bit closer at the data, and I think what’s most compelling about our study, is that the combination arm—when you looked at the patients that had their colon intact before they had it removed or those that had most of their colon removed and have the small intestine hooked up to the rectum (they have an ileal rectal anastomosis, so a rectum that still has polyps in it) or that have had their whole colon and their rectum removed and have the ileal rectal anastomosis with polyps in it—and in the combination arm out 4 years of the study, no patient in the combination arm needed surgery on the colon, where that was not proven in the monotherapy arm.

So, what was a really exciting and important finding is that this combination of an old anti-inflammatory and eflornithine seem to impart a significant benefit, way over what sulindac has shown in the past and shown in this trial to be effective.

Amanda Balbi: Your primary end point for the analysis was disease progression. How did you and your colleagues define disease progression?

Carol Burke: The primary efficacy endpoint was looking at, as I said before, patients as a whole. So any FAP-related event in the duodenum or in the colon, and it's interesting.

We looked at a variety of endpoints: a composite of major surgery, needing the colon removed, needing the rectum removed, needing the pouch extracted. We also looked at the need for excisional snare resection of large polyps, either in the duodenum or in the lower GI tract. We looked at the need for upper gastrointestinal surgery, including duodenectomy. And we also looked at the diagnosis of high-grade dysplasia in the rectum or pouch, as well as the progression of benign duodenal disease, which was based on at least 1 stage increase in the Spiegelman classification.

So this was really a novel, as I mentioned before, and global composite of endpoints of anything that would have clinical impact on the patient in the upper GI tract, which is problematic in the duodenum or in the colon.

When we looked at the efficacy in terms of duodenal progression, we didn't really find that the combination arm and part of benefit there. As I mentioned before, we see that there is very compelling and significant decrease in the need for surgery, which is the first study that shown obviating the need for surgery in patients that have had FAP.

Amanda Balbi: As you mentioned, your team found that the incidence of disease progression was not significantly lower with combination therapy than with either drug alone. How might these findings impact clinical practice and/or change the way FAP is managed in the future?

Carol Burke: Most providers are looking for things to add to their armamentarium to treat select individuals with FAP who have already undergone colectomy and have polyposis in their rectum or polyposis in their pouch.

As an FAP provider, I see a lot of young individuals that are heading off to college. They're doing sports in the summer—of course in the pre-COVID era. They're planning their family. They're starting a new life, and they would like to delay surgery as much as possible. The very compelling and statistically significant results that we saw in obviating the need for surgery in FAP is something that clinicians would believe is important to be able to have access to the eflornithine to add to sulindac in order to provide clinical benefit to the patients.

So I believe that practitioners seeing patients with FAP that need a chemo-preventive agent will look forward to using the combination, hopefully with FDA approval for the colorectal disease burden that the majority of these individuals are struggling with.

Amanda Balbi: So, what would you say is the overall take-home message for specialists managing patients with FAP?

Carol Burke: The overall take-home message for the providers that are managing patients with FAP is that there are innovative combinations of medications that seem to have a synergistic effect, particularly in the lower GI tract.

The results of what we've seen in the lower GI tract had not been replicated in other studies before, and in particular, I'm referring to looking at obviating the need for surgery as one of the endpoints.

And so I think that gives both the clinicians and patients hope that as time goes on, we're learning more about the molecular pathways to disease and that combination of agents that not only are efficacious, but also say for use.

We can't dismiss the importance of safety when we're managing any patient with any disease state. There had been some concerns about changes and hearing or ototoxicity with the eflornithine use. Quite frankly, in our study, there was no obvious signal that there was a lot of adverse events related to ototoxicity or chronic problems with hearing related to the drug.

In our study, most of the other adverse event rates were similar between the arms. I think that we found a combination of agents that has a compelling effect on the need for surgery and seems to be safe as well as effective.

Amanda Balbi: Thank you so much for joining me today and answering all my questions.

Carol Burke: I appreciate the opportunity to talk to you today, Amanda. Thank you so much.