Navigating the Evolving Landscape of Neuroendocrine Tumors

An Interview with Erik Mittra, MD, PhD

Associate Professor of Radiology, focusing on Nuclear Medicine, at Oregon Health and Science University

Dr. Erik Mittra presented on the evolving landscape of neuroendocrine tumors, specifically “PRRT: Sequencing and Navigating the Treatment Armamentarium,” at ASCO GI 2019. He discussed with Doximity his presentation and the challenges of clinical trials in the US. The full transcript is below. The accompanying video interview is soon to come.

Doximity: Can you tell me about the key takeaways and clinical applications from your presentation?

Erik Mittra: One of the big topics in our field, one of the advancements that’s happened over this past year, is one of these radiopharmaceuticals was FDA-approved almost exactly one year ago. This radiopharmaceutical, the full name of it is Lutetium-177 which is the isotope attached to a ligand called dodatate. So Lutetium-177 dodatate — the brand name is Lutathera — and it’s approved for the treatment of patients with gastroenteropancreatic neuroendocrine tumors. And so this was a long time coming because it had been under research and in clinical trials, smaller clinical trials for almost 20 years and it finally got the FDA approval last year.

And so now subsequent to that, it’s been a big push to make that available to as many patients in the US who have this disease and who needed the therapy. And prior to the approval, it had been only available for the patients in Europe, for the most part, and one or two institutions in the US. So the focus of my talk at this meeting today was to talk about this therapy. The other name for it is the PRRT or peptide receptor radionuclide therapy.

So now we’ve been using it clinically for one year and so in my talk, I was discussing the clinical applications, how to pick patients for this therapy and so forth. Then, also, one of the most difficult aspects is knowing how to choose this therapy over other types of therapies that are also available for these patients with neuroendocrine tumor.

Doximity: Can you elaborate on these therapies?

Erik Mittra:  A neuroendocrine tumor is interesting because it starts out very slowly, and a lot of patients don’t know that they have this cancer for many, many years. So often times it’s not uncommon for patients to have this for five to 10 years before they are diagnosed.

Unfortunately, in that time, the disease can metastasize to other areas before it’s found. So often times it’s more advanced and over the last, I would say 10 years or so, there’s been a lot of advancements of different types of therapy but depending on the distribution of the metastasis, [that] is what directs the different therapies.

So typically after this is diagnosed, most patients go into what you call the watchful waiting pattern, waiting for this to continue to progress even further. After that, we use some systemic therapies which are called somatostatin analogs. A lot of what I’ll talk about with my research and so forth is related to somatostatin receptors which are overexpressed neuroendocrine cells. And somatostatin analogs are a non-radioactive form of that treatment. So typically patients will go on that.

Then comes in PRT, which uses those somatostatin analogs but is now attached to a radionucleotide, so extra killing power essentially. And then beyond that, there are a lot of other therapies. Many patients have metastatic disease to the liver primarily. So you can do a lot of liver-directed therapies such as radioembolization, chemoembolization and surgery is a major component of the treatment for these patients both removing the primary tumor as well as debulking large metastases within the liver or elsewhere.

And then there’s many other systemic therapies that are growing as well. So it becomes a challenge to figure out which of these things to use first and which one to save for later.

Doximity: Can you comment broadly on how NET prognosis and treatment has changed since you started your career?

Erik Mittra: Yeah. So again over the last 10 years is primarily when a lot of these different medications have been FDA-approved. So prior to that, there really was very, very limited number of options but in the last 10 years, there have been so many different things that are slowly growing that the prognosis is definitely been changing.

One of the other speakers at the session this morning was talking about — he is an oncologist — how for neuroendocrine tumors it’s really changing from this diagnosis of cancer to one of chronic illness and I can definitely see what they’re saying because you have so many different tools for these patients and to be honest these tumors are often very slow-growing to begin with, even though they are metastatic.

And so the combination of those two things allows us really to prolong the life and really that’s what we’re after, we’re not after a cure for these diseases. We’re never going to get to a point where we completely remove it but as long as it’s something that can be tolerated and patients can go on and have a good quality of life.

Doximity: What are some other future directions that you are particularly excited about in the field in general and in your own research?

Erik Mittra: Okay. There are so many different things I could talk about related to that actually, but I will try to hit on some of the highlights. So related to PRRT specifically, even though it’s taken 20 years for us to get this FDA approval, we are so excited that it’s actually just the start of the process because there are many different things that we can do.

Some of these are, for instance, if a patient responds well to the first cycle of the therapy — given as four different treatments every two months, so to go through one whole treatment cycle is actually takes eight months. But if they do well with that then it’s possible, we can re-treat them once they progress subsequently. There’s different delivery methods that we can use for the PRRT, either intravenously or through specific access to arteries that feed the tumors, such as within the liver.

There’s different receptor ligands that are coming down the pipeline which have higher binding specificity to the ones that we are currently using. So those are just some of the examples. Probably the biggest one that a lot of the research is going on, and again, was the focus of my talk at this meeting, was figuring out how to do combination therapies because as I mentioned, there’s all of these different options.

One of the things other than sequencing is to determine whether we can actually use them in combination. Some of the agents are actually radiosensitizers and so they would make our radiation more effective than others. Then, more generally in the field of radionucleotide therapies, it’s kind of been revitalized at this point because of some of these things that are coming down the pipeline. One of the major concepts is this concept of theranostics which is unique to our field. It combines the words diagnostics and therapies to get theranostics and we can do treatments for a variety of different types of cancers using this same approach. It’s perfect for what the entire field of oncology is currently interested in, in terms of precision or personalized medicine, because we use the imaging component to select patients for a specific therapy and then we can do the therapy using the same compound but using a different isotope.

So it’s a very powerful technique and the next one that’s coming down the pipeline, probably — we’re just beginning the clinical trials on it — is for prostate cancer. It’s called PSMA or prostate-specific membrane antigen. There’s a lot of excitement about that in a similar story that it had been used in Europe for a few years now but we are just beginning the clinical trials in the US.

Doximity: Why do you think we are so far behind Europe?

Erik Mittra: I’ve thought about that question a lot because I hate being behind Europe for that long, both for personal reasons but also for patient access. So my two things that I understand is one: that there’s different regulations in local regional hospitals in Europe, as compared to the United States, [which] is under the blanket of the FDA. We don’t have special access to different regulations within the institutions. And second is a funding problem.

So again, in the US no individual hospital or individual person is sitting around with a large amount of cash that can do these very expensive studies. Whereas in Europe, they have that access to specific sources of income that they can get through these patients.

So they have this program that’s much more available there than in the US called Compassionate Use which is that if you have a new agency like PSMA where you really feel like this is going to be helpful for a specific patient and the specific patient doesn’t have any more options left, in the US oftentimes nothing can be done at that point. But in Europe, under Compassionate Use, they will allow them to use this research agent very early on and then that way they can build up a lot of data.

Doximity: What do you think are some concrete things that individual physicians can do to get the US to catch up?

Erik Mittra: That’s a good question. I feel like as an individual, it’s difficult to lobby for a change like this but through our national societies and original societies and so forth, we can become a more powerful voice. For instance, in my field, I work very closely with the Society of Nuclear Medicine and Molecular Imaging. We are all volunteers for this organization. They don’t pay us or anything but I personally feel it is a very important contribution that I do and I spend a fair amount of time doing it because we need to come together as a community.

Currently, for instance, there’s actually some issues going on with access to these types of therapies, related to who is appropriately trained to do so. So the Nuclear Regulatory Commission is evaluating possibilities for different approaches for this process and we as a community are coming together to try to lobby for what is most important. So perhaps through those different types of approaches.

I would also say that over even the course of my career, over the last 10 years, we have worked closely with the FDA and are beginning to make some of those changes. Because one of the misconceptions is that radiopharmaceuticals are drugs, and they’re not drugs. We would give them in trace amounts attached to this radioactivity so they don’t affect biology in the same way that drugs do. However, we are treated by the FDA as drugs and so we have to go through the same regulatory process which is much more difficult than we really need to, especially when it comes to diagnostic radiopharmaceuticals.

Doximity: Is there anything else you want people to know?

Erik Mittra: I think in the field of oncology over the next 10 years, just like the prior 10 years, we’re going to see many more of these types of therapies that will become available.

So one of the challenges for us is going to be, as a field, to actually figure out how to deliver these appropriately because many people who are trained in, as I said Nuclear Medicine is a subdiscipline of Radiology in the United States so we don’t necessarily have the Oncology training, and Oncologists don’t have the Nuclear Medicine training. So really, it’s not a bad thing, but we need to figure out how to work best together to provide this care in the best way for all of the patients.

Illustration by April Brust

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