Paolo Tarantino is a leading researcher in the field of breast cancer, with over 50 papers published on the topic. He’s currently pursuing an advanced research fellowship at Dana-Farber Cancer Institute and at Harvard Medical School (Boston, MA). He is also concomitantly pursuing a PhD in clinical research at the University of Milan. His research focuses on the study of the HER2 oncoprotein, the emerging HER2-low subgroup of breast tumors and the development of novel antibody-drug conjugates to treat every subtype of breast cancer.
Dr. Ayal Aizer is a radiation oncologist in Boston, MA at Brigham and Women’s Hospital and Dana-Farber Cancer Institute.
Dr. Aizer is an Assistant Professor of Radiation Oncology at Harvard Medical School who serves as the Director of Central Nervous System Radiation Oncology at Brigham and Women’s Hospital / Dana-Farber Cancer Institute in Boston, MA.
He completed medical school at Yale School of Medicine in 2009 before pursuing radiation oncology residency at the Harvard Radiation Oncology Program, which he completed in 2014. Dr. Aizer specializes in the management of brain metastases and his research efforts seek to improve outcomes in this population. He leads several prospective clinical trials involving patients with brain metastases and has published both retrospective and large data-based studies centered on the management of patients with this condition.
Dr. Ayal Aizer (Parts 1-5)
Welcome to those who are joining us today. I am patient advocate, Lianne Kraemer, and we’re going to be doing an interview with Dr. Ayal Aizer. He is the assistant professor of radiation oncology at Harvard Medical School who serves as the Director of the Central Nervous System, Radiation Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts.
He completed medical school at Yale School of Medicine in 2009 before pursuing radiation oncology residency at the Harvard Radiation Oncology Program, which he completed in 2014. Dr. Aizer focuses his clinical research efforts on the management of brain metastasis. He leads several prospective clinical trials involving patients with brain metastasis and he published both retrospective and large database studies centered on the management of patients with this condition. His career is devoted to improving the understanding of management and outcomes in patients with brain metastasis.
Thank you for joining us, Dr. Aizer, it is an absolute pleasure to have you here with us today.
Thank you, Lianne, that was a lovely introduction – and it’s funny that we’re talking more formally than we have been known to do. –
I know. And for those watching Dr. Aizer is actually my radiation oncologist and just on a personal note, he is a truly wonderful human and radiation oncologist. And, just, you know, a wealth of knowledge. And I always think you’re so special because it’s such a niche area that you work in that not only do you specialize in brain, but you specialize in brain metastasis. So it’s kind of like this niche within the niche, at least that’s how I look at it.
So why don’t you start by telling us what you do as a radiation oncologist?
Well, just to respond very briefly, I would say that it’s our relationship and that definitely goes both ways. And of course, a privilege and honor to interact with you in any way, shape or form that we have the opportunity to do so.
So to answer your first question about what our radiation oncologist does – so radiation oncologists train relatively broadly in oncology. The training program is typically about four years in life. And we actually rotate through all of the relevant disease sites. And that can be helpful with giving us a background, not only in radiation, but also in oncology in general.
And I think when it comes to the brain, one thing that is nice from a radiation standpoint, is the ability to try to put everything together as best routine: the radiation to drug therapy, the surgical therapy, as well as the supportive care and quality of life issues. Not to say that we’re an expert in all of those things, many ways, far from it, at times, but it’s nice to be able to try to counsel patients from an oncology standpoint, not just purely on a radiation standpoint.
So ultimately the treatment we provide is radiation to patients with brain tumors. However, a lot goes into the question of, should we radiate, in addition to how we radiate. So typically, you know, every radiation oncologist will be different, but the brain, it’s definitely a site where we try to bring it all together.
So when do you become involved in a patient’s care? As far as, when a patient is diagnosed with metastatic breast cancer, that is, you know, spread to the brain. So how do you become involved in their care?
It’s a great question. So typically we’ll get a referral from either a neurosurgeon, if there was a consideration regarding surgical therapy as a first step, or a medical oncologist, or a palliative care physician.
So one of the patient’s team members will often reach out to us and ask us to take a look at the case and weigh in on radiation and other elements of management. So we typically look at a referral from one of those sources and that includes inpatient performance as well.
So it sounds like it’s really important too, that if you’re getting a referral, if how you typically start with a patient is through a referral from a surgeon or an oncologist, that the importance exists to work really as a team, than with those professions.
That’s a great point, Lianne. So, increasingly, radiation is just one component of therapy and a team effort is really integral. So, whether that’s multiple doctors in the same room with a patient, or multiple independent visits where the doctors are talking behind the scenes, I completely agree that, you know, optimal management is really multidisciplinary in nature, spanning medical oncologists, neurosurgeons, radiation oncologists, palliative care physicians, and other doctors as well.
Video #2 – Types of Radiation to Treat Brain Mets
So when we hear the discussion of radiation to the brain, we hear two terms, mainly, we will see the abbreviation, SRS or HBR. Can you talk to what SRS is? Especially the different machines that are used. We hear people talking about CyberKnife and Gamma Knife and just a brief kind of explanation of what that is.
Sure. It’s a great question. So SRS stands for stereotactic radiosurgery. What that means, essentially, is that there’s focused radiation being administered to one, or more, parts of the brain, but it’s targeted to a specific area, rather than encompassing the entire brain, for example.
The nomenclature can be confusing because, you know, SRS is typically thought of as radiation given in a single day to the brain, but that radiation can be delivered in multiple days, when a single day is just not safe or viable. And a number of names exist for that; some people call that fractionated SRS. Some people will call that SBRT, or stereotactic body radiation therapy. Some people will call that SRT or stereotactic radiotherapy. But all of those refer to focused radiation given over more than one day, still to a limited number of targets, typically.
In terms of how the radiation is actually done, the specific technology – you allude to a great point. So there’s, you know, multiple different technologies used to administer SRS or SRT, for example. There’s Gamma Knife, there’s CyberKnife, there’s linear accelerator-based SRS. There are new modalities, like ZAP. But ultimately one of the most important elements is not the technology that’s chosen, especially for this reason, but rather, that a team that’s instilled in the delivery of radiation is overseeing the care. Because it’s more than just which technology has been selected – those differences tend to be relatively subtle. Some of the randomized data has told us that, for example, including an Italian randomized study that compared Gamma Knife versus a new accelerator-based treatment with really very little difference.
But, I think one thing we all would agree on is that you want to go to a center that has experience, that the given patient feels comfortable in not only with the doctors, but also the nurses and therapists and other people who are involved in the care of that patient. And not just say that we’re selecting one specific technological modality.
So I think it’s like driving a car, you know, there’s Toyota or Honda or Buick. And they’re all fine cars. But what probably makes the biggest difference on the road is who’s the driver or drivers of that car. So that’s how it looks.
That’s a really, really great analogy. I think in discussing radiation with other patients, sometimes the focus really can be on which machine or which modality of radiation is best – should I get CyberKnife or should I have them do Gamma Knife. And what I’m hearing you say is it really doesn’t matter so much which one is used, more or so that you’re comfortable with the team that is going to be utilizing that form of radiation to treat your brain metastasis.
That’s well-stated. I completely agree.
Really, and that’s really interesting. So what about whole brain radiation? Can you talk a little bit about that? How is that different from SRS?
Sure. So with whole brain radiation, now, the radiation encompasses the entirety of the brain. So rather than treating individual tumors in the brain, the radiation covers the entirety of the brain. That includes the tumors that are seen on the scan, that also will include microscopic areas of disease. So microscopic tumors, meaning tumors that are so small that you can’t even really see them on the scan. And the radiation encompasses everything. And while that sounds good, in some respects, it also has some unique toxicities which have to be balanced, and I’m sure we’re going to get into that later. But rather than a focused administration of radiation, now we’re treating the entirety of the brain and I’m sure we’ll get into this later. There are some spinoffs of that treatment that may allow certain areas to be excluded, but ultimately the entirety of the brain is being targeted.
It’s typically a treatment that’s given, not in one day, but between one and three weeks. When people do larger numbers of treatments the dose per day typically falls. So it’s roughly equivalent, whether it’s one week, two weeks, three weeks, it’s really up to the patient and the radiation team to work that out. And also other factors that go into that – how quickly does the patient need to get back to drug therapy, among other individual considerations. But yes, it’s typically a longer treatment and, of course, treating the entire brain rather than individual brain tumors.
So when you’re talking about whole-brain radiation, a term you’ll hear is hippocampal avoidance or hippocampal sparing. How does that fit into what you’re discussing?
Sure. Very great question, Lianne. So I can share this screen and sometimes a visual is helpful. You asked appropriately about hippocampal sparing in whole brain radiation and what that treatment is, is that the entire brain is treated with radiation with the exception of the hippocampi, and that’s the plural for the hippocampus. There’s one hippocampus on the right. We also look at imaging backwards. So you’ll see the mouse clicker on the left side, but we’re actually referring to the right.
So there’s one hippocampus on the right, and there’s one hippocampus on the left. And what you’re looking at here is the right and left hippocampus. You’re looking at an MRI in the top row, a CT in the bottom wall, you’re looking at different views. So the left is sort of a horizontal cut and the center and right are up and down cuts of different pictures.
And what you’re seeing is that the radiation dose, which is this kind of shaded cloud, doesn’t include the hippocampus. It doesn’t mean it doesn’t get any radiation, it just gets a much lower dose of radiation than the rest of the brain does. And the reason that this is considered is because one of the most significant side effects of whole brain radiation is cognitive problems after treatment. And sparing the hippocampus can preserve cognitive function among such patients.
This was proven relatively definitively in a randomized trial, published by Paul Brown and colleagues a little over a year and a half ago. And what they did was they took patients who needed whole brain radiation and they were randomized to receive either conventional whole brain radiation, where the hippocampus is included in the radiation field. Or hippocampal sparing radiation, where it’s excluded.
And what they found was that there was better cognition and better memory, better thinking in the group that had hippocampal sparing radiation. And it’s important to also note that everyone on both the control arm and the hippocampal sparing arm … and that’s another way to preserve cognitive function. And that was proven back in a 2013 study to get benefit.
So in patients who are candidates for hippocampus sparing whole brain radiation, it’s advantageous to use it. Now, the question comes about who is a candidate. So candidates are typically patients who don’t have tumors in or near the hippocampus. They’re being defined as typically five millimeters or less, As well as patients who don’t have leptomeningeal disease, and patients who can wait at least a few days before starting radiation, because regular whole brain radiation can be started typically in a few hours or a day. But hippocampal sparing, because it’s more complicated, typically takes longer. So if there’s an urgent need to use radiation, hippocampal sparing probably isn’t appropriate.
But assuming those criteria and a few other rare ones are met, hippocampal sparing is a more advantageous way to get over radiation than the historical way, which is conventional hippocampal radiation.
And so you were talking about the reason for avoiding the hippocampus for memory and cognition. And that made me think of a drug that’s often paired with whole brain radiation. I’m not exactly sure how you pronounce it. I think it’s Memantine? Is that correct?
That is right.
Can you talk a little bit to that?
Absolutely, so, Memantine is a drug which is thought to help cognition, meaning thinking and memory, in patients who have problems in those domains who may not even have cancer. So that’s where that drug started. And then about a decade ago, someone had the good idea of looking at that drug in patients with brain metastasis who are getting whole brain radiation.
So a randomized study was published by Paul Brown in 2013, looking at whole brain radiation with, or without Memantine. And the way that Memantine worked was they gave it in increasing doses over a few weeks, and then kept people on it for about six months. And what they found is that, in general, the Memantine group had better memory function and cognitive function.
People have spliced and diced this in different ways, but the main take-home message was that Memantine probably helps with thinking, memory, attention and other measures of cognitive function, after whole brain radiation.
The obvious next question is, well, what are the side effects? They didn’t see any bad side effects when they compared Memantine to placebo in that study. Lower grade side effects is less clear, but there don’t appear to be any significant side effects for the vast majority of patients.
So, are you able to use whole brain radiation more than one time?
Yeah, it’s a great question and it does come up a lot. So really we want to try to avoid as best as possible repeat whole brain radiation. Because whole brain radiation given the first time can really have a lot of side effects. And then the idea of giving it the second time can be a lot for patients to tolerate. If it’s absolutely necessary, it is an option. We have occasionally resorted to it.
But there’s a number of things to factor in. One is that when you give whole brain radiation a second time, you’re often using a lower dose. So if tumors that were there at the time of first whole brain radiation have grown through that radiation, giving whole brain radiation a second time, maybe less optimal because they’re often using a lower dose for a tumor that’s often more aggressive.
In addition, the toxicities can really be quite significant. More and more and more, rather than consider that treatment, we either maximize focused radiation or stereotactic radiation. We typically will really push the envelope with that because we want to avoid repeatable brain radiation. Or increasingly in oncology there’s drugs that have, you know, some degree of efficacy in the brain. Then we try to really max out those drugs before resorting to another intense form of radiation. So this is an area that really needs more investigation. We don’t know what’s best, but we’re really shying away from using whole brain radiation as best we can.
So, uh, you’re looking at using – let’s say you’ve had a patient who has had whole brain radiation and they are present with more lesions and you are looking more so at doing SRS again, rather than full brain radiation or does it just depend on the patient’s needs.
Increasingly, we’re using SRS as much as we can.
There’s a couple of rationales for it. SRS carries more radiation dose than does whole brain. So, although it’s given over a smaller number of days, biologically, it’s a stronger amount of radiation. So we’ve tried to utilize that a lot more without real upper limits in terms of the numbers that we’re going to treat.
If there are a hundred tumors, it just isn’t possible. But, you know, we’ve certainly had cases where, you know, you’re down 20, 30, 40, 50, 60 tumors, if need be. And we utilize that most often if it’s a tumor that was there at the time of whole brain and it grew through the whole brain. And the patient just doesn’t have drug options to even attempt at that point. And they still want to pursue aggressive care after they talk with their families, nurses, doctors, other people who are involved in their care.
So you were mentioning just about the number of tumors that you can, you know, radiate the second time. What about radiating, making a decision between SRS and whole brain radiation – like the very first time a patient is referred to you, the number of lesions – how does that factor in your decision-making between SRS or using whole brain radiation?
It’s a great question. And most of the guidelines have focused on patients with a “limited” number of brain tumors versus a non-limited number of brain tumors and what’s appropriate.
I think we should be clear that all of the data, until very recently, has focused on patients with four tumors or less. By “all of the data,” I mean the highest quality of data, which are the randomized studies. So there’s been a multitude of randomized studies that have asked the question: “Can we use local therapy, like SRS, instead of whole brain radiation?” Meaning, can we omit whole brain radiation. And the answer to that question was largely, yes. As long as there’s a limited number of tumors.
Very recently, there was a study published in abstract form at the time of this recording, that went up to 15 brain tumors. But that was a study out of MD Anderson. There were a smaller number of patients included. We’re all eagerly awaiting that publication. And there are some ongoing trials that will test the question of how many metastases should we be thinking about with regard to SRS versus whole brain? I would add that it’s not just a number. It’s what drug options are there? How quickly are they developing? Is this someone who had no metastases a month ago and now has 15? Is it someone who’s always had 15, for the last year. You know, these are other factors to consider when weighing which treatment is most helpful.
So we spoke a little bit about the number of lesions that help you to decide what’s the best as far as whole brain versus SRS. What about looking at a lesion, say you’ve been referred a patient from a medical oncologist and looking at them and deciding whether radiation is best or whether they need to be sent maybe to a neurosurgeon for surgery rather than radiation.
Yeah. That’s another point that comes up a lot, Lianne. So I’m glad you asked about that.
You know, it’s obviously important to have a multidisciplinary discussion about all options. And I think, we want to include the surgical team on all of these decisions about who should be going to the operating room – who might be able to – who could we get away with radiation with or who might not need either, just drug therapy, for example.
But, classically, the patients that we’ve considered referring to neurosurgery or who really would benefit from it, concretely – would be patients where there’s diagnostic uncertainty in the brain, meaning, like, you don’t know what is in the brain. We see something, we’re not sure what it is, it’s of a significant size, and we’re not super thrilled about watching it.
Because sometimes we see these little small areas in the brain and just end up watching. But if there’s something like two and a half centimeters in size, we think it could be an abscess or it could be a brain met. You know, that’s the type of patient that really needs to see a neurosurgeon, and quickly.
In addition to those patients, among patients who we strongly suspect have brain metastasis – if patients are having neurologic symptoms, especially if steroids are not helpful or helpful enough, those patients should almost always see a surgeon because surgery is by far the best therapy to make symptoms go away quickly. And that can be important for the future quality of life.
In addition, if there’s a patient who has a tumor that’s faulty,we pretty much refer all of those patients for a surgical evaluation because the likelihood of getting control with radiation is much lower. And often there’s not a long leash to try a drug out, because if there’s swelling around that piece of the tumor, that patient could quickly get a lot of symptoms, and we don’t want them to have that. So, we often will refer those patients to surgeons as well.
And then lastly, you know, if you look at the group of patients that have just one brain tumor, and there’s nothing in the body, we see this occasionally in breast cancer, it happens more in lung cancer. Sometimes even if it’s just one centimeter in size, we’ll refer to a surgeon, even if they’re having no symptoms because we kind of have wonder – I say wonder because the data supporting this is relatively weak – whether taking that tumor out, radiating the cavity after, is more beneficial to the patient long-term than just doing radiation by itself. So that’s another softer reason that we would refer them to a surgeon.
So you just mentioned about radiating the tumor bed afterwards. Can you speak a little bit more to that? Because even when you refer for surgery, it seems that you are often involved in one way or another, even when they are surgically removed.
That’s a great point. So, you know, there’s two factors to consider when someone has had surgery to remove a brain tumor, you know, a brain met, in this case. The question, should we radiate, and if so, how should we radiate? So the first question, should we radiate? You know, there’s a nice study out of MD Anderson by Anita Mahajan and her colleagues that looked at the question in someone with a resected brain metastasis – does radiating the cavity help? And it certainly did when it came to the likelihood that the tumor would grow back. And that’s certainly one reason to strongly consider radiation.
The thing with brain surgery is that it’s a little different than having a mastectomy, for example, because, you know, their surrounding tissue is so vital that it’s often difficult, or even not recommended, to remove everything in one piece with a margin of normal tissue around, because you’d be removing normal brain which nobody would recommend.
As a result, you know, there’s often little cells left over at the cavity rim, even if you can’t see them on a scan. And that probably amounts to about a 60 or 70% chance that a tumor will come back at that site, if you don’t radiate. If you do radiate, it lowers significantly, but this is where “how should you radiate” comes about.
You know, historically we’ve used whole-brain radiation, even with one cavity. The data tells us we shouldn’t really do that anymore based on a couple of really great studies that were published a few years ago. But then the question comes about: should we use SRS like one day of radiation, or should we be a little bit more broad with our fields and use like five days of radiation or three days of radiation. But we don’t have to give an enormous amount in a single day. We can be a little bit more generous with our volumes and we can, you know, ideally, prevent recurrence in a safe way. Because essentially what the data has told us, as long as we hit the right target, the recurrence rates are pretty low, but when people have looked at SRS, the recurrence rates seem to be pretty significant.
So, really the answer that we’re going to get to this question, SRS versus SRT, one day versus more than one day, will come from an ongoing Alliance randomized study which is occurring very well, and that’ll compare SRS versus SRT to cavities, and I think that will be enormously impactful for them.
One thing to factor in, Lianne, and I’ll share the screen again, is when we do cavity radiation, I think it’s important to recognize that a lot of the recurrence risk is along the lining of the brain. And I think this is where we want to be pretty generous with the radiation fields.
So this is an example of a cavity and you can see the cavity in green. And you can see there’s no white area around it. There’s no contrast happening. But, you can see these other nodules that develop afterwards and they’re circled in red. And this is a tumor that’s occurring along the lining of the brain. And this is something that we think complicates surgery about eight or ten or twelve percent of cases, at least with a single institution series. That number can vary based on a number of factors. But when we design our radiation fields, we really want generous coverage of that lining of the brain to try to minimize the likelihood that the tumor’s coming back at that area that’s greatest risk.
Now, that example that I showed you, trying to include all that in a preemptive radiation field is too much, but I think the point is that we want a generous margin along the line of radiation.
And I just want to clarify that when you talk about the cavity, that image was showing where a tumor used to be. When you say cavity, you’re saying that there used to be a brain metastasis there that you have removed. And so, what is left is referred to as the cavity.
That’s exactly right. So there used to be a brain metastasis here. There’s not, it’s just a cavity. And that’s a perfect description of it.
So I wanna move on to side effects, but because we know that with radiation, it doesn’t come without some side effects. So let’s start with SRS and the side effects that you see, both immediately following SRS, and anything down the line, long-term, that you might see as a side effect.
Yeah, that’s a great point. So I’m going to try to focus, Lianne, on the side effects that are most relevant, because I think you can always go down a laundry list of what could happen, and that’s what we definitely do when patients consent to radiation. But I want to focus this on what actually really matters.
Like, not temporary side effects that’ll go away, or side effects that are not of great impact to the patient. But focus more on the side effects that could really impact how someone does on a day-to-day basis. So I always think of a couple of side effects in the short-term and then one side effect in the long-term, but it can manifest in different ways.
So in the short-term, the side effects are seizures and bleeding. Those are thankfully very rare. It’s hard to quantify that risk, but it’s probably about one percent. We sometimes use preventative seizure meds for like a week, to minimize that risk. Some people use shorter or longer courses. That’s all reasonable.
Some people don’t use it at all – that’s also reasonable because there are certain areas of the brain that can’t really generate seizures. So if a given patient’s doctor didn’t recommend seizure meds, that can be totally fine. The other risk is bleeding, and thankfully that’s also about a 1% risk in terms of a meaningful bleeding – one that the patient will know is happening.
And you know, typically we don’t see that very much in breast cancer. We see that more in tumors that are prone to bleeding, like melanoma or thyroid cancer or some ovarian cancers, as well as kidney cancer. And we still look at things like platelets and are people on blood thinners, but for the most part, that risk is also really quite low, thankfully with breast cancer.
The overwhelming long-term risk is something called radiation necrosis and it’s hard to quantify the risk of that because everybody has a slightly different definition of what that is. But what it basically means is that there is some inflammation and/or injury to the part of the brain that was treated with radiation.
And the first thing that can happen, and, I’ll share the screen one more time. The first thing that can happen, that we may not know that it’s radiation necrosis right away. Cause radiation necrosis can sometimes mimic the tumor. At least initially. So one thing that can come up is, you know, someone has, something that grew in an area that there was a tumor, for example, this is a patient who had a tumor here in the right parietal lobe, had radiation, and on the next grid there, now the top center image, that responded beautifully to radiation, but what you can see over time is that there was this increasing, fluffy, cloudy, enhancement, the whiteness, around the tumor. And this was radiation necrosis, meaning there’s no tumor there anymore, it’s all radiation injury.
You know, when we looked at this in another example, this is a patient who had this tumor treated and over a long time, it grew and then it grew more. And when you look at the bottom row, you see this other white stuff, which is swelling. So this is a sequence called a flare that’s just swelling really well.
And this can impact patients because it’s not just an area that is taking up contrast. It’s all of the swelling that can accommodate, and that can go along for the ride. So, you know, this can basically cause symptoms that are general in nature, like headaches or seizures, or it can relate to the specific area of the brain that was injured.
And this is a process that goes on for a while. It eventually will stop in the vast majority of patients. It might get a little better over time, but this is like a chronic process. It almost becomes a chronic disease. And this is one of the reasons that when we think about, you know, SRS to large numbers of tumors, and this is an example of a case where we did, you know, SRS to total about a total of 60 tumors, over three sessions, pink, blue and dark blue. You know, this is a fair amount of radiation given to the brain and some of these things, as you can see, have a decent amount of bulk to it. So this is probably the side effect that concerns us most about focused radiation. It is manageable, there are things we can do about it, but it does become a chronic disease that needs a lot of attention and even treatment options aren’t always perfect.
Is there something that increases or makes the occurrence of radiation necrosis more likely – like the size of the tumor – or is there anything that makes someone more likely to develop this?
You’re spot on, Lianne, so the size of the tumor is an important consideration. Bigger size means more likelihood, no question about that. Prior radiation to the same area. So if this area has been radiated before, that will increase the risk of radiation necrosis. And then, other things like drug therapy given at the same time of radiation probably plays somewhat of a role.
Immunotherapy is increasingly relevant in cancer and in the breast cancer world. Some of the triple negative patients, and maybe some of the other patients who aren’t triple negative are getting immunotherapy. Sometimes standard, sometimes in the context of a trial. And we do think that that probably increases the risk of radiation necrosis to some extent. And so, you know, there’s a number of factors, but really size prior radiation and then maybe a third one is what drugs are they receiving, you know, play into that.
Well and usually when you’re getting radiation, aren’t those drugs being held for that reason? Aren’t you told to stop your treatment, or something like that?
You make a really good point and we do often hold treatment for that reason. But there are some treatments that just can’t really be held. For example, immunotherapy is a good example. The half-life of most immune drugs is several weeks. So the idea of waiting three half-lives before you radiate the brain, doesn’t always seem viable.
The other notion is that sometimes it’s immunotherapy after the radiation that can be just as impactful as the immunotherapy that preceded the radiation. So, you know, yes, we try to hold when we can. Sometimes it’s just not possible or viable.
So, how do you differentiate on a scan what is actually tumor necrosis versus what is a tumor – like the regrowth of the tumor or the failure of the tumor to respond to the radiation? Is there a test? Is there a way to know the difference?
Another great question, Lianne. So, you know, the gold standard is to take that area out. And then you’ll know under the microscope what it is. However, we don’t want to do that every time something grows after radiation because a lot of the times they’ll be removing radiation change that otherwise would have stopped anyway. And it may be before the patient even became symptomatic. Like you can see it on the scan, and sometimes it just stops growing. In fact, most of the time it stops growing before the patient even knows that it’s there. So, you know, to go and remove it preventatively, is sort of overkill for most patients.
There are advanced imaging tests that can be used. None of them are perfect and they’re all better than a coin flip. Are they a physician’s best guess, you know, based on other factors – hard to know. But tests like dual phase PET, MRI spectroscopy, MRI perfusion, we’re doing a study looking at the treatment response assessment map, which looks at the clearance of contrast over time and making an inference as to what that represents.
As promising as these tests are, they do have their limitations and they’ve been evaluated to different degrees. A lot of the times you can make sense of it based on the MRI. Initially, we really don’t know what’s going on, but over time, they’ll fork in the road, so to speak, there’ll be a classic necrosis appearance, there’ll be a tumor appearance, and most tumors, most areas will separate along those.
Sometimes it’s difficult to tell, and sometimes it can be a mix – like you can have both tumor and necrosis in the picture. So it really varies from person to person, but this is a really, really common problem in a brain radiation oncology clinic because we just see it everyday. .
Yeah. So it sounds like it’s a really hard thing to delineate on a scan what the difference is. Is there anything happening with research that’s trying to look at this problem and solve this for patients. Cause, you know, obviously it’s really difficult if you can’t tell the difference between, or aren’t sure, exactly what is happening and the option to surgically remove the area to look at it doesn’t exist.
Yeah. That’s a great point, Lianne. So, you know, the best way to avoid radiation necrosis is to minimize the use of radiation, unless you feel like the benefit is better. A lot of times the benefit is there, but it’s important to think about that every time when you’re that patient. In addition, the technical elements of the radiation can be helpful in terms of minimizing risks. Trying to minimize the margins that are used, trying to do other things to try to keep the risk of radiation necrosis down. Holding drug therapy, as you astutely mentioned, can be helpful. You know, on the diagnostic side, as I touched on, there are some increasingly utilized diagnostic tests that can try to make this delineation noninvasively, but not are really perfect at this point.
And on the treatment side, you know, there’s a number of treatments for necrosis. There’s steroids, there’s a drug called Avastin which has been explored in breast cancer before, for example. And there are other treatments like hyperbaric oxygen and different drugs. But, ultimately, it becomes challenging. And I think, hopefully avoiding the problem in the first place is the best way to prevent it from manifesting, but a lot of the time you don’t have that choice. And thankfully we haven’t talked about those incidents, and thankfully this is more rare than common.
So we spent a lot of time talking about necrosis. On average 5, 10 or 15% of our patients will get necrosis when we radiate in a focused manner. So this isn’t something that happens 80% of the time. This is something that happens relatively infrequently on a per metastasis basis. And a lot of that 5, 10, 15%, people are asymptomatic. So, you know, I don’t want to overblow the problem, but at the same time, this is probably one of the most significant drawbacks of stereotactic radiation, especially when given to large numbers of tumors or both tumors.
Yeah. I mean, when it’s a problem, it’s definitely a big problem. So even though that’s great to hear the risk of it occurring – the percentage – isn’t as high as maybe we think it is, but when it does happen, it’s definitely problematic. What about whole brain radiation? Is there a risk of necrosis with whole brain radiation?
It’s extremely rare. You know, it’s been reported, we’ve seen a few cases of it, but it’s exceedingly rare. If something grows after only whole brain radiation, meaning there was no SRS, no SRT given, that it really should be thought of as tumor growth, unless proven otherwise.
Again, we have seen over many, many, many cases in the denominator, a handful of necrosis cases with only whole brain radiation, but they are quite, quite rare. Whole brain radiation has its own side effects, so to keep it on the areas that are most relevant. In the short term, there is a lot of fatigue that goes along with whole brain radiation. It can happen with stereotactic radiation too, but you know, typically when smaller numbers of targets are radiated, it’s not as big of an issue.
So fatigue is a big one. That fatigue can last for a few months or sometimes longer. Appetite is a problem that can also be impaired for a few months, sometimes longer. And sadly hair loss, not in a focused manner, but a whole head of hair, can happen with whole brain radiation
When hippocampal sparing techniques are used, sometimes the hair loss is more gentle or some people actually don’t get much hair loss, which is an interesting byproduct of the hippocampal sparing that certainly a lot of patients appreciate it.
But, with conventional whole brain radiation and even some cases of hippocampal sparing, there is hair loss and that takes typically months to come back. The hair may be different when it comes back. It may not be as thick, or as vibrant, it may be curly where it once was straight, it may be brown where it once was different colors. So that’s another thing to factor in.
Long-term, I think the side effects I think about are the cognition that we talked about. And unfortunately, the long-term side effects are more permanent in nature, so cognitive problems, people’s balance can take a hit with whole brain radiation. And we see a lot of people who don’t have impeccable balance after that treatment.
And then sometimes there could be some hearing loss. But usually, that’s not a major effect. So, you know, those are the three short-term and three long-term side effects that I think matter most. You know, fatigue, appetite loss, hair loss in the short-term. Cognitive problems, balance problems and hearing loss, to some extent, in the long-term.
Not everything happens in every patient. A lot of our patients don’t get much of that at all, but those happen commonly enough that they, you know, impact a fair number of patients. So unlike stereotactic radiation where we’re talking 1%, 5%, 10%, with whole brain radiation, many of these things can happen – it’s just to what extent. And that’s certainly an issue to consider.
I want to go back to hair loss because with, you know, women that’s, you know, that’s a really important thing. And being able to anticipate what is going to happen with your hair before you have radiation and knowing what to expect, I think is really helpful for women. So, you know, you talked a little bit about with whole brain radiation, in general, you’re going to lose all of your hair, I think you might’ve mentioned. What about in SRS?
SRS really varies a lot and it really comes down to this in surface dose, and just factors that are random from person to person – some people get side effects that others don’t. But typically a larger tumor near the skin surface, maybe along where the brain touches the bone of the skull, more likely to cause some hair loss. Something deeper, less likely to cause hair loss.
We mention it to all of our patients, cause you never really know. But it tends to be more of a factor of the tumors that are closer to the skin surface. It tends to be patchy though. So, you know, unless a lot of tumors are treated and the beams are coming in and out from many, many different directions, it tends to be areas that are smaller. You can cover it up more readily depending on hairstyles. So it tends to be a less significant problem. Still an important one, but a less significant one and one that often resolves more quickly, as well.
How long does it take for the hair to start to regrow? Is there a period of time where you expect that hair to start to regrow in both SRS and whole brain?
Yeah, you make a good point. And the first thing is how long does it take to fall out? Cause people, you know, they finish radiation and the hair’s intact, and then it’s like, oh, maybe they won’t get it. But you know, the hair loss won’t start typically for 2, 3, 4 weeks after we do the first treatment. It’s a somewhat delayed effect.
So, you know, all of our patients finish SRG with the same hair that they had when they started five days prior. And certainly for SRS, that’s a hundred percent true – it’s just a one-day treatment. But then the question also comes about, how long does it take to grow back? And this varies in terms of like, which treatment was given. Whole brain radiation tends to be a little longer. Stereotactic is really variable depending on what the skin actually got.
But typically, sometimes we tell patients, 8 weeks, 10 weeks, 12 weeks, you might start to see something coming back and, you know, it varies from person to person. Some people get it back at 6 weeks. Some people, it takes 4 or 5 months. Everyone’s a little different.
And then with whole brain radiation, well women, you know, who’ve had chemotherapy and they’ve lost all their hair, and when it starts to regrow, it generally regrows all at the same time. Like your hair comes in, you know, in your forehead and the whole scalp at the sort of the same rate, just like, as if you’ve shaved it, it might be really slow. But I think it’s a bit different, or more patchy with whole brain radiation. Is that true?
That is definitely the truth. It depends on how the whole brain radiation was given. Is it hippocampal sparing, is it not? Was there scalp sparing, was there not? What metrics were trying to be achieved on the radiation plan versus not? But yes, that’s classically with whole brain radiation, you know, you sometimes had a dose distribution that led to most dose kind of right at the top with it, where there’s the thinnest amount of tissue for the radiation to pass through. And that means that this is the area here, that the radiation, you know, this is the area that the hair loss comes. This is the area where the hair regrows last. So people would have hair coming back in other parts, but the top center, and in the middle, the hair is not coming back very well. So the reality is it really depends on how the radiation was done to know what to expect. Thankfully, with hippocampal sparing, you know, the hair loss does appear to be more gentle in nature, than with non-hippocampal sparing techniques.
There have been some metrics published, from Anand Mahadevan, has done a beautiful job. You know, a number of years ago, reporting in a small subset of his patients that were getting this technique initially, that they were actually keeping all of their hair and he reported his metrics. We’ve tried to emulate those metrics. Not a perfect system, but you know, the actual dose that the skin is getting and the scalp is getting, plays a big role.
Yeah, I was just thinking, you know, obviously I’ve had radiation a couple of times. I haven’t had whole brain radiation. I know something that comes up in discussion a lot is the use of steroids. Steroids can be a really challenging drug to be on. As far as – do you have to use steroids in stereotactic radiation versus whole brain? What are the indications for use of it? When can it be avoided so that patients don’t have to use it? Can it be avoided?
Yeah, it’s a great question. And it’s going to vary a lot based on a number of factors. I think the first factor is does the patient need steroids even before they go into radiation? And do they have neurologic symptoms, or not? And if patients don’t, then the question becomes, do you want to add steroids? Increasingly, we are not utilizing steroids.
So for example, in my practice, and this is not right or wrong, I never preventatively give steroids. If patients develop symptoms that warrant steroids, then we’ll give them steroids. But in an effort to minimize the side effects that patients go through, I try to avoid steroids. Increasingly –
Is that both SRS and whole brain that you’re trying to avoid using steroids?
SRS and whole brain. That’s right. Increasingly in the immunotherapy route, we’re even more concerned about giving steroids out of concern that steroids will blunt the effect of immunotherapy. The process of giving steroids can make immunotherapy not work.
Now I want to ask you a question that is common amongst, our community, is driving, and how radiation affects, you know, the ability to drive. Can you drive after you receive radiation?
This is another tricky issue and there’s no right answer. I think in general, for a given patient, it’s not going to be a one size fits all situation. I think it’s important to talk to your doctor or your team. Whoever is on your team, it could be a PA or a nurse practitioner, or a nurse, or anyone who you feel like you feel comfortable to ask guidance on this issue from.
But the concern with driving in patients with brain tumors, including those who have radiation, are a couple of fold. One is that either the tumor itself or the treatments can impair someone’s ability to act accordingly. For example, if there’s a tumor in an area that’s controlling the right foot, and most of us use our right foot to go from gas to break, that inherently poses a challenge, whether you’ve radiated or not.
The other factor is seizures, and we worry that our patients with brain tumors can develop seizures. Thankfully most do not, the vast majority do not. When we’ve looked at this in our data, you know, if patients, about 10% of our patients with brain metastasis will have a seizure at diagnosis. And then if they don’t, about 10% will develop one thereafter. So taken another way, the majority of people will never develop a seizure. So I don’t want people to think that they’re prone to get a seizure, that’s not the intention. But the concern is that, what if someone’s behind the wheel, and all of a sudden, they, you know, are not aware of the surroundings, or they lose consciousness and that can be a significant issue.
So radiation, especially when given in a stereotactic manner carries some risk of seizures. It’s small. The estimates are not well listed. But it’s probably on the order of a low single digit percent. 1%, 2%, 3%, something like that. Some centers give preventative seizure meds with radiation to prevent that seizure for a short period of time.
But I think most of us would acknowledge that around the time people are getting SRS or SRT, we probably shouldn’t be – they probably shouldn’t be driving because of that small risk of this. In people who are getting whole brain, sometimes you just don’t feel up to driving. Like if the patient is tired or nauseous or, you know, is just feeling sluggish, it just may not be the right time to drive. So in general, around the time people are getting brain directed radiation, for brain metastasis, we generally advise not to drive. And, you know, thereafter, it really depends on the individual circumstances. And again, this ends up getting sort of into a discussion.
Once you have finished radiation, whether it’s whole brain, or it’s SRS, what is the timeframe to when you do an MRI, to look at what the radiation did?
So, Lianne, that’s a great question. And there’s a number of factors to consider. So, I think if people are following guideline-based care, such as NCCN guidelines, you know, a consideration would be to do a repeat brain MRI in about three months after whole brain, or potentially two months after stereotactic radiation, with the shorter time interval for stereotactic radiation, being out of concern for the development of new brain metastasis. But, I think, you know, doctors and nurses and patients and therapists, and other people who manage brain metastasis, often recognize that one patient is so different from another.
So you have patients that have rapidly progressive brain metastasis, and they’re not going to jive with a two or three month follow-up. They may need a one month follow-up. You have patients who’ve had a long track record of having smoldering brain metastasis, meaning things barely changed with time. And even if we end up using radiation, we might not do the next scan for four months after because we really understand the trajectory of the disease and what we would expect.
So, it varies a lot from patient to patient and there are other factors to consider as well. But I think the most, kind of, standard would be about a couple of months after stereotactic radiation – you know, about two, or maybe, three months after radiation.
Gotcha. I think that sticks with the theme of brain metastasis – that it depends. That seems to be the overarching theme that connects all answers about treatment and radiation – is it really is an individual thing. Is there any problem to screening too soon?
Doing a scan a little bit too early?
So it’s a great question. And, you know, largely the answer is no. You know, there are some costs potentially to patients in the system. There’s the inconvenience of the scan. In patients with kidney function is it optimal, or if they have stage three, four, or five of the disease, the contrast that we use with the MRI, the gadolinium poses some risk, not a lot of risk, but a small amount of risk.
And then a recent discovery is that some of this contrast isn’t being entirely cleared by the body, in patients. But the ramifications of what does that actually mean on a day-to-day level remain highly unclear. So we have not been telling patients that they should refrain from scans for any of those reasons. If they have, for example, really poor kidney function, we will maybe do a scan without gadolinium. But, you know, largely, apart from those minor issues, doing a scan too soon, usually there’s not a lot of downside.
Okay. So when you’ve completed radiation and you do the scan, what are you looking for? What is the goal of radiation therapy? What are you hoping to see? Is there something that you hope to see on the scan?
You know, it’s another really helpful point to talk about. And radiation is different than drug-based therapy in terms of what we expect to see in the scan. I think with most drug-based therapy whether it’s chemo or targeted therapy or HER2 directed therapy, hormonal therapy, you generally would assume that when things shrink it’s optimal and when things grow, it’s not. With radiation, it doesn’t really work that way all the time.
Initially, we can see some growth after radiation, just due to irritation of the tumor, by the radiation. So if we did a scan in a given patient five days after we finished radiation, oftentimes things would be larger. And that’s one of the reasons we don’t scan that early.
The other factor is that a lot of tumors will remain controlled, even if we can see them on a scan after they’ve been radiated. Because what we’re seeing on the scan may not be viable tumor anymore. It could be dead cells or cells that are non-functional, or there could be, you know, radiation induced changes that are mimicking what the tumor used to look like. So after radiation, scan interpretation is tricky and it does require a lot of thought and expertise and a team effort to try to interpret some of these scans because one of the most classic things that happens is that we do SRS or SRT for a patient and then a year later, things are larger and we’re trying to delineate – is this tumor growth, is this a late radiation tumor enlargement, called radiation necrosis.
And these are difficult to delineate. And as a result, you know, it’s the type of thing where, you know, now that reports are immediately accessible to patients, that’s wonderful in many ways, but it also can be problematic for some patients, because they’ll read “enlargement of this site” in a given part of the brain. And I think the immediate conclusion that some patients make is that the tumor’s growing, when in reality, that may not be the case a lot of the time.
So it’s really important to talk to your oncologist, your radiation oncologist, about what your particular results mean. And it sounds like, over time, it may vary in what you’re saying. When you say controlled you’re meaning that there’s not growth. Am I correct?
Okay. So it isn’t necessarily an expectation that your scan needs to show shrinkage and then complete disappearance of the tumors in order to indicate that you’ve had success with radiation.
That is entirely true.
Okay. I think that’s an expectation we see a lot with those in the breast cancer, brain mets community, is expecting that those tumors will completely disappear. And when they don’t, it can be confusing.
So let’s move on to research. Is there anything happening right now in the field of research for radiation and brain mets that would be helpful to know about?
Yeah, there’s a lot going on, and I think, ultimately, this is a good thing for patients. And you know, there’s different types of questions being asked and, you know, at a higher level, there are questions being asked – who needs radiation and who doesn’t, which types of patients may be managed with drugs alone versus with radiation. And this extends a little bit beyond breast cancer, sometimes, because each drug and each type of cancer has its own drugs, some of which will work, some of which may not, in the brain specifically. So the questions kind of vary from disease site to disease site. But that’s certainly an ongoing issue.
And then, there’s a lot of questions focused on how do we make radiation either more effective in patients who need it to be more effective, or less toxic, if the radiation has a track record of yielding some side effects. Some examples would include, you know, ongoing studies trying to delineate who really can get away with stereotactic radiation, SRS, or SRT. Whole brain radiation there are multiple ongoing studies of that kind. There are studies looking at using radiation with a radiosensitizer – so a drug designed to make the radiation work better. We have a study open at our center on that front where we have patients who have historic, or tumors that have historically not displayed the greatest control range with radiation, and they can receive a radiosensitizer in some of these studies that ideally makes the radiation work better, but doesn’t impart some of the toxicities that might be seen if we just increased the dose, for example. None of this has been definitively established, but that’s why it’s done in the context of the study.
I think there’s a lot of interest, on a separate note, patients who need surgery for a brain metastasis and this comes up in breast cancer a fair amount because of the historical lack of screening MRIs. In patients who need surgery, when we give radiation after surgery, based on the way it’s been done in studies, which is a single day to an entire cavity, the results have not been as ideal as we would have hoped. More people are recurring in the cavity than we would have expected. The surgery can propagate tumor cells beyond the cavity and that radiation can’t account for that anymore. And then there can be necrosis because they’re often radiating a generous size area with a single day of high dose radiation.
So there have been a number of studies looking at fractionating radiation, like breaking it up into multiple doses. And those are ongoing currently. And a really exciting concept is doing the radiation pre-op. So, giving the radiation and then taking the patient into surgery, with the idea that you’re treating their tumor and even if the surgery, you know, disperses some of those tumor cells, they’ve been treated by the radiation and hopefully, are less likely to propagate elsewhere because essentially they’re non viable. This is a paradigm that’s used in other cancers and the question is can we apply it in brain mets.
So there are other exciting concepts as well. There’s drug plus radiation concepts… ability of radiation and drugs to work together to manage a given patient. And, thankfully, there’s more and more studies being conducted each year. But I do want to emphasize that in brain metastases, we do lag behind other cancer entities with similar incidents.
So if you look at the number of brain metastasis per year, it’s roughly the same as the number of breast cancer diagnoses per year, or colorectal cancer diagnoses per year, lung cancer diagnoses per year or prostate cancer diagnoses each year in the United States. But when you look at research output, whether you measure that in terms of active clinical trials, completed trials, abstracts presented at major conferences, we lag behind in this field.
So as much as is being done to promote the health and wellbeing of patients with brain metastasis, there is an even bigger need to do more. So I think this is where we need, you know, patients, nurses, doctors, funding agencies, companies, coming together to try to dedicate studies to patients with brain metastasis.
That’s a really interesting point that you make. Do you have any kind of thoughts on why that is?
Well, you know, I think there’s a number of factors to think about. The field has gotten better in many ways, but historically, not only did we have not have a lot of trials for patients with brain metastasis, but if patients had brain metastasis, they weren’t even eligible to get a drug designed to look at the effect in the body.
And thankfully, we see the transition from that, to allowing those patients to be on study if they get the tumor treated beforehand. To now, what’s really exciting is studies testing whether a drug can work in the brain among patients with active brain metastasis. And I think that’s come a long way forward. But, historically, I think, funding agencies and companies are a little reticent to put patients on their studies because of the concern that the brain would progress while the body remains controlled. And that might not reflect well on a given drug or may prematurely terminate a drug from development that otherwise was promising.
So I think that’s been a historical issue. I think, in the past there hasn’t been as much attention given in the literature to the unique nature of brain metastases. They’re different than liver metastasis or bone metastasis and lung metastasis, they have inherent challenges and issues associated with them. And I think increasingly we’re seeing more awareness. We’re seeing things like dedicated meetings for brain metastasis patients. A few years ago, SNO had, for example – that’s the Society for Neuro Oncology – had the first dedicated meeting for specifically brain metastasis. And that was a huge success.
There are other brain metastasis meetings that are upcoming. For example, this year there’ll be the first conference dedicated to clinical trials relating to brain tumors which is sponsored by ASCO/SNO and a lot of those studies include brain mets-specific studies, so I think that’s exciting. And so I think the future is bright, but we definitely have a long way to go in terms of promoting research in this population.
I agree. We do. I wanted you to jump back to one of the studies that you mentioned, just out of curiosity, about reversing when the radiation occurs and that now you typically do the radiation after surgery occurs, and then you discuss that research is looking at doing radiation before surgery. Why would you need to do surgery if you have gone ahead and radiated the tumor? Isn’t that just like getting SRS and waiting for it to shrink?
That’s a great question. And so you – this would come up if you’ve made a determination that the patient needs surgery. And typically you’ve made that determination based on – the most common scenario is a larger tumor that’s causing a bunch of symptoms and that steroids have not yielded good enough effect for.
So you’ve made the determination that the patient needs surgery and then the current standard is to get the radiation after. Here, what you are going to say is, okay, we understand that. We understand that the radiation is probably not a good long-term strategy by itself because it’s a little bit more difficult to control a bigger, bulkier tumor. You’re giving less dose. These often behave more poorly than smaller tumors. And, you know, ultimately the patient may have symptoms that aren’t going to get better anytime soon if it’s just radiation alone. If it’s surgery then it can quickly be compressed. So you’ve made that determination the patient needs surgery and then now you’re adding that, you know, preoperative radiation. But you make a really good point – you could say like, why not? And that would typically be for the patient who just doesn’t quite need surgery yet, you know?
Makes sense. Yeah, thank you for that clarification.
Dr. Peter Fecci is a neurosurgeon and Director of the Center for Brain & Spine Metastasis at Duke University. He performs surgeries to treat brain tumors including the emerging technique called LITT or laser interstitial thermal therapy. He is also a cancer researcher and serves as the Director of the Brain Tumor Immunotherapy Program also at Duke.
Peter Fecci, MD PhD, is currently an Associate Professor of Neurosurgery, Pathology, Immunology, and Biomedical Engineering at Duke University, where he also serves as the Director for the Duke Center for Brain and Spine Metastasis, as well as for the Duke Brain Tumor Immunotherapy Program.
A neurosurgeon-scientist, Dr. Fecci focuses clinically on intrinsic brain tumors, both primary and metastatic. In the research realm, he heads an NIH-funded laboratory that focuses on integrating strategies for reversing cancer-induced T cell dysfunction with current immune-based platforms. For his research contributions, he was a recent recipient of the Cancer Research Institute Lloyd J. Old STAR Award and was likewise inducted into the American Society for Clinical Investigation.
Dr. Fecci also serves as multi-PI for the Duke R25 training grant. His recent work on brain tumor-induced T cell sequestration and exhaustion has produced numerous high profile publications. He is now actively engaged in exploring novel drug targets and therapeutics that his group has uncovered for side-stepping brain tumor-imposed immune dysfunction and for newly licensing immune-based approaches in this patient population.
Dr. Peter Fecci #1
Hi, my name is Christine Hodgdon. I’m a metastatic breast cancer patient and advocate. And I’m here today with Dr. Peter Fecci, and I’m very excited to talk with him today about his work on brain metastasis. Dr. Fecci is a neurosurgeon and Director of the Center for Brain and Spine Metastasis at Duke University.
He performs surgeries to treat brain tumors, including the emerging technique called LITT or Laser Interstitial Thermal Therapy. He is also a cancer researcher and serves as the Director of the Brain Tumor Immunotherapy program also at Duke. Thank you so much, Dr. Fecci, for joining us today.
Thanks for having me. I appreciate it.
I want you to take a step back. We said that you’re a neurosurgeon. Can you tell us what a neurosurgeon is and what role they play in the treatment of cancer?
Sure. In general neurosurgeons are those that operate on either the brain or the spine, and that can include pathologies that range from things like a herniated disc, all the way up to brain tumors, spine tumors, aneurysms, et cetera.
And we tend to all specialize quite a bit. From my perspective, I’m specifically a brain tumor surgeon. I have colleagues that operate on metastases or other tumors within the spine, but I focus specifically on either primary brain tumors which are tumors that arise in the brain, things like glioblastoma meningiomas, et cetera, or brain metastases; cancers that have traveled to the brain from either common places like the lung, the breast or the liver. And of course, breast cancer, being the topic of conversation here, tends to be the second, most common cancer that travels to the brain.
Yes. And what kind of surgeries do you perform on breast cancer patients specifically with brain metastasis?
In certain instances, those tumors can actually be removed or we say the word resected from the brain. When we look at a patient, basically what we’re trying to decide is a tumor that they have in their brain, more amenable to just radiation upfront or is it a tumor that should actually be removed prior to radiation.
The reasons we might consider one versus the other have to do with things like location in the brain. Is it safe to operate? How large is the tumor? If it’s particularly small, maybe less than a centimeter and a half or a centimeter, it’s not frequent that we would go in there surgically. Often we would reserve something like that for radiation, because it might be very effective against such a small lesion.
If tumors are larger, maybe larger than two or three centimeters, they’re in an area of the brain that we can go to safely and they’re causing a lot of symptoms in particular, then it’s often beneficial to take them out. Number one, to relieve the symptoms that the patient might be experiencing and also to make subsequent radiation therapy work better because that radiation tends to work better when a lot of that mass has been removed. In general, however, if someone has a lot of tumors, taking out one, isn’t going to make a big difference. So oftentimes people that have either, not very many tumors in the brain or maybe have one larger lesion, the remainder and that large lesion is causing symptoms those are the instances when we’re more likely to consider surgery prior to radiation.
Got it. And we are actually going to interview some experts in the field of radiation oncology as well. So we’ll definitely be answering questions that folks may have about that type of treatment. So what I’m hearing is that it really is going to depend, which we hear this a lot as a metastatic breast cancer patient.
I hear all the time we don’t really know exactly because every person is so unique. So what I’m hearing is that surgery is really going to depend on the size of the tumor, the location of the tumor and whether it’s causing symptoms.
Dr. Peter Fecci #2
And what kind of surgeries? I know that there are craniotomies, is there some other type of surgery that you can perform in the brain? And is one more common than the other?
Yes, craniotomy, as you were referring to, is essentially where we make an incision in the scalp.
We make an opening in the bone where we take that portion of bone out. That gives us access through the dura, which is the protective covering over the brain into the brain itself. There are kinds of various specifics to how we do that. That probably goes beyond what people want to hear about. But once that tumor’s out and, and we tend to try to get it out in one piece, if we can, then we put that bone back on.
We use little titanium brackets frequently, and then we close up the scalp over the bone and that’s what a craniotomy means. That’s kind of the most invasive type of surgery we do to get a tumor out. But there are minimally invasive procedures. You mentioned in the introduction of me, a procedure called LITT, which stands for Laser Induced Interstitial Thermal Therapy.
That’s just fancy talk for basically using a laser to cook the lesion. And it’s a very small incision, usually a centimeter or less. And then we drill a very tiny three to four millimeter hole in the skull. We lower a biopsy needle down a trajectory that we use navigation systems kind of like what’s in your car to kind of fix a trajectory.
Then we can take that biopsy needle out. Once we have a piece and replace it with a laser catheter down the same trajectory, and then use that laser to cook the lesion.It’s done in a kind of a clever fashion. We can essentially convert a regular MRI machine in the operating room into a giant thermometer.
And we can use the MRI data real time to give us temperature data. And so we’ll know when we’ve successfully cooked the lesion with the laser. And it’s a boon. It’s very common. We’ve been using it at Duke for about the last five years. That’s kind of been the period of time when it started to really gain popularity.
It’s great for a variety of instances where the role of craniotomy may be less clear, or it might be a little bit more dangerous. So usually where we use the laser now, or in patients who have already had either surgery and/or radiation for metastasis in the past, and it’s perhaps come back or perhaps there’s a radiation side effect called radiation necrosis, which is an inflammatory response that can happen many months later.
And the role of surgery for recurrent tumors or for radiation necrosis, the role of a craniotomy is a little less clear and perhaps a little troublesome or there’s risks because of wound healing issues that follow radiation, et cetera, et cetera. And in those instances, doing a much smaller surgery with the laser is sometimes advantageous.
And so most of the time when we’re using the laser in metastatic patients, it’s when a tumor has come back where, when we’re concerned that there might be something called radiation necrosis, which perhaps hasn’t responded to medical therapies like steroids,
Okay, I didn’t realize that you can use LITT on radiation necrosis.
So you can do both. It can be used on a brain metastasis or to treat radiation necrosis, which as you mentioned is kind of a side effect that can happen from radiation to the brain. And it sounds like what I really love about this procedure is that you can actually get a biopsy. So you don’t have to go through the full craniotomy to get a biopsy.
And so often brain metastases patients aren’t able to get a biopsy because surgery, I don’t think is that common. And so this allows you a chance to see what kind of cancer you’re dealing with. You know, we know that the receptors can change. And so, and I know one of your colleagues, Dr. Sammons did some work on the HR positive breast cancer, actually gaining that HER2 mutation in the brain.
So I just think it’s very interesting that you actually are able to see what kind of cancer you’re dealing with. And maybe that could change treatment options. It depends, especially if you have a HER2 positive brain met. I’m glad you explained that.
I wanted to ask one more question: Is LITT FDA approved?
It is FDA approved. It’s not FDA approved specifically for brain metastasis for, breast cancer, brain metastasis. It is approved for use in the brain to treat soft tissue lesions. Which of course includes things like brain metastasis, primary brain tumors, et cetera. It’s not an experimental therapy despite that statement that is made at times, and there’s a good amount of literature out there to support its use.
And like you said, a major advantage is that we can get a tissue diagnosis at exactly the same time. What it has done in our practice is it’s allowed us to offer people that type of diagnosis earlier. So in the past an MRI often cannot tell the difference between radiation necrosis, maybe many months after someone’s had radiation to a brain metastasis.
It cannot tell the difference between that or whether or not the tumor has come back. The MRI is just not sensitive enough to give us a difference. And sometimes it’s a mixture of both. And so rather than try to guess, or use medicines that may or may not work to see how people respond. This allows us to now just say, well, let’s just go in there and figure it out.
We’ll get a biopsy. We know that we have the laser at our disposal. It can treat either biopsy results, just fine. And people tend to leave either same day or the next morning with a bandaid on their head. Pretty much unable to tell that they’ve had a surgery. So it’s really, really a fantastic procedure.
So I’m thinking like a patient right now.
I’m curious, do you know if there are going to be issues with the breast cancer patient trying to get insurance to cover a procedure like this? Because it’s not specifically FDA approved for brain meds and breast cancer. I’m just curious.
So I won’t tell you that there are zero issues, but I will tell you that the majority of our patients are able to actually obtain approval without issue.
And then I’ll tell you a few things. So Medicare and Medicaid have no problem whatsoever with it. Actually, some of the private insurance coverage companies that have been stating that they feel that this is experimental. But those dominoes are starting to fall as well. I’ll tell you that I actually wrote, in conjunction with one insurance provider in North Carolina, that very first specific policy to cover LITT in patients with recurrent brain metastasis, radiation, necrosis, and other brain tumors.
And now other insurance companies are following suit because there’s a precedent. We actually at the neurosurgical societies, the tumor section, for instance, we’ve just started to put forth, position statements that allow us to kind of advocate for this with insurance companies. There is a code being issued to this procedure that will also help.
And the NCCN has now included LITT and it’s guidelines as well for the first time this year. So, even if there have been issues in the past, I think fewer and fewer of those issues will persist.
That’s really great to know because there’s many metastatic patients already on Medicare. So that is very good information for them.
And my next question as a patient, is it widely available? Will I be able to find this at my local cancer institution or do I have to travel to actually get this procedure?
In general, most academic centers will have the LITT procedure. And then there are some of us that are the leaders across the country right now. As far as places that perform the most of these, I would recommend going somewhere where the people are quite familiar with the procedure.
It’s like anything surgical, the more people do the better they are. Typically, smaller centers, smaller hospitals, community hospitals,I don’t think you’ll find this procedure available. So although you may have to travel, there are enough academic centers around the United States that have it that hopefully you shouldn’t have to travel too far.
Dr. Peter Fecci #3
Switching gears a little bit. I’m just curious in general, could you just talk about a patient who might be considering surgery and they’re nervous about the side effects. You just gave us two examples. We’ve got craniotomy, we’ve got laser surgeries. One’s a little more invasive than the other.
Can you tell us what the recovery time is like for each and maybe what kind of side effects patients might be dealing with?
Sure. I think that you know, obviously what I’m about to say is not true for everybody. There’s variation across the board. If I perform a craniotomy on someone, which is the larger, more invasive option, of course, typically I would say most people leave the hospital two days after surgery.
There are some folks that are just really motivated to get out of the hospital. Certainly COVID has served that motivation purpose in the last year and a half, who often will leave the hospital even the day after the surgery. . But some folks of course need to be there longer than that, a few nights. And then overwhelmingly, most people are able to be discharged home, but depending on where the tumor was and what some of the swelling in and around that area may cause symptom-wise for a period of time after the surgery, some people may need brief stays in rehab facilities to get some of their strength back, et cetera.
For the laser procedure everything’s a little faster, not surprisingly. So that’s where the patient might spend one night in the ICU after craniotomy. They are unlikely to see the inside of an ICU after the laser procedure. Typically, I said, we send people home the following morning, but also with COVID we’ve increasingly been able to successfully send people home the same day as the procedure.
And so it’s usually at most one night in the hospital. Of course, again, same issue. If someone’s having some weakness due to some swelling, et cetera, they may need to stay longer and they may need a brief stay at rehab, but that’s pretty unlikely.
I think most people feel that after a craniotomy, which is again, that larger procedure that by two weeks most people feel that they’re about 90%. And then I always tell people that the last 10% of your energy levels take another four to six weeks to come back. So most people are out of work for, I’d say on average, about four weeks after craniotomy. Those periods of time are shorter for the folks that undergo the laser procedure.
It just, it just kind of amazes me that we can go into somebody’s brain and people can leave the next day or two weeks later. It’s pretty amazing. And when you said weakness, does that mean people have trouble like, maybe walking, lifting up their arms, doing things for themselves? Is that when you, when you mentioned weakness, is that what you see?
Generally, you know, in the brain, one side of the brain tends to control the other side of the body. . So a lot of the lesions that we intervene upon are located near areas in the brain that control strength and the opposite side of the body.
And so there may be a period of time, for instance,in the days after surgery, where there’s some swelling around that. And the way I explain it to patients is, look, if I operated on your ankle, you expect to have a swollen ankle the next day. The brain is no different. And if we operate on your brain, it’s going to swell a little bit.
And that swelling in the brain looks a little different than a swollen ankle. So I say, if you had a swollen ankle, you may limp, well, this is the brain limping, it’s producing a little bit of weakness, maybe some hesitant speech. And it all really matters where that lesion is in the brain that we’re operating on.
So for instance, for lesions that are right near those, what we call eloquent areas or areas that are really important for what they control. The swelling into those areas may produce symptoms that take a little bit, a little time,days, maybe even weeks to resolve. And that’s kind of what we’re talking about.
Okay. Thank you. What are the risks? There must be a few risks involved in brain surgery. You just mentioned swelling. Are there other risks involved, maybe more long-term side effects that patients might experience?
I think when I, when I provide risks to a patient, I kind of divide them up into a few different categories.
So I say first things first, all surgeries have some risk and no matter where we’re performing surgery, there’s a few things that are common to all of those surgeries. Number one, surgery tends to hurt. So we’ve put folks on pain medication before, during and after. You mentioned how we can go into the brain and people do well, the brain doesn’t have pain receptors, the brain doesn’t hurt.
Now, the scalp hurts and the dura hurts, but that’s really about it. So most people tolerate the surgery better than say, like a big belly or chest surgery where we really are sore and can’t move around afterwards. People are up walking around the next day, maybe with a dull headache, but that’s about it.
So pain doesn’t tend to be too bad for brain surgery. There are some exceptions of course, but we’ll just leave that as a broad statement. Bleeding, all surgery produces some bleeding, but in general, the bleeding from brain surgery is pretty minimal. And the chance that you would require something like a blood transfusion is almost next to zero, barring getting into an artery or something that really causes some blood loss, but that’s unusual.
And then all surgery has a risk of infection. We usually say about a 1% chance of infection following a surgery. So we put people on antibiotics just around the procedure, but not for very long. All surgery and the brain produces some additional risks. It can cause strokes or seizures, because we are in your blood vessels that feed parts of the brain.
We as surgeons try to avoid those blood vessels. And so we try to reduce the risk of stroke on our own. And as far as seizures are concerned, I tend to put patients on anti-seizure medication for a period of a couple of weeks after surgery. Those practices vary across surgeons, and just to kind of stave off evil spirits if you will, but it’s the far minority of patients that have issues with that.
And then the biggest risk that we kind of talked a little bit about is that swelling that can cause things like weakness or speech deficit confusion or dizziness all depending on where that tumor is in the brain. But there’s of course a risk that if we’re near those structures that are so important, we can cause more permanent deficits, more permanent neurological deficits.
That’s what we’re of course, really trying to avoid being exceedingly careful in our surgery. And I would say overwhelming, and the majority of our patients do not have long-term effects with the surgery if the surgery is done well.
Okay, great. I think it’s just important for patients to remember that, when we talk about the uniqueness of each individual patient, that really you are taking into consideration all of those factors as to whether or not a patient may experience long-term side effects, depending on the location of the tumor.
So. Yes, there’s risk involved, but like you said, there’s risk in every surgery. So, thank you for sharing all of that information.
Dr. Peter Fecci #4
I wanted to know if you had any success stories. I’m curious if, how successful is surgery in the brain? I personally don’t know many patients that have had brain surgery, many of the brain mets patients I work with have radiation therapy. So I just wanted to know if you had any success stories and how successful these surgeries are in the brain.
So I think it’s important to recognize that the field has changed a bit, really, even in the last 10 years. When I was in training, which I won’t date myself here, but it wasn’t all that long ago. It was a “knee jerk” on neurosurgeons to kind of send folks with brain metastasis for radiation. And not too long ago, the only real form of radiation that people got was whole-brain radiation, which is now kind of a bad word in the brain metastasis realm.
Now there are more advanced radiation techniques that are focused beams of radiation called stereotactic radiosurgery that only hit the lesion itself and not the surrounding brain. That, of course, has advantages for not exposing the normal brain around a lesion to unwanted radiation. There are still instances where whole-brain radiation is appropriate, of course. But stereotactic radiosurgery is really the gold standard for treatment of patients with even numerous brain metastases now, and that represents a shift in the last few years.And that’s a good shift, frankly. So every patient will get radiation because that is the gold standard, but certain lesions now, as we realize that people are surviving longer and longer with brain metastases, that role of surgery in making radiation more effective by what we’d say, cyto reducing or reducing the size of that lesion by removing it, reducing the number of tumor cells that are still there.
It really can impact that radiation. And so surgery plays a role there. And like we talked about surgery really may be helpful to remove a larger lesion that radiation might not be as effective against, or that might be causing problems for the patient, ifit’s pushing on important structures and it’s causing weakness or speech deficits or anything like that.
And so as our surgical techniques improved too, we can operate in areas of the brain now that people once thought were dangerous to go into. Now I don’t recommend doing that everywhere. And I would recommend sticking to academic or experienced centers that have a lot of these advanced technologies and surgeons who specialize in this.
But some of the success stories I can remember are patients that are told at various hospitals that they have inoperable brain tumors. They have weeks to live, months to live, go home, make yourself comfortable, and put your affairs in order. I just spoke to one of those folks who we took two lesions out of their motor ship, which were deemed inoperable at a place.
She was given a couple of months to live. We operated on her. I think it’s about three years ago now and she’s doing just fine. So you know, there are plenty of success stories because the combination of surgery and radiation, when surgery is appropriate can offer, 80, 90, 95% local control rates for breast cancer metastases in the brain, depending on those histologies, those molecular markers, et cetera.
And so we have many patients surviving years, following even brain metastases with no evidence of recurrent disease anywhere in their body. That’s far different than what I was taught even a decade ago where we would offer people a three and six month prognosis. That’s just not, it’s just not the case.
It’s inappropriate to tell people that they don’t have options at this point.
I just want to highlight the value of getting a second opinion, and especially getting a second opinion at an NCI designated cancer center can really make a huge difference. And so we’ll make sure to highlight that on our website as well, because it is an invaluable thing.
You can’t, you, you just can’t replicate that. You really need to make sure that you’re hearing from other doctors. So I’m really glad. Thank you for sharing that.
Dr. Peter Fecci #5
So speaking of how far we’ve come, it’s nice to hear that since you started, when you were in training and to now that you’re seeing a lot of improvements. Are there any other emerging research, is there any other emerging research in the neurosurgery field that patients should know about? I know that you also run a lab and you’re a researcher. And so anything you can highlight that would be of interest to patients living with brain metastasis.
I won’t bore people with some of the surgical techniques stuff, but you know, we’re always trying to make our procedures less invasive.
So there’s, there’s ways to do things through smaller and smaller openings, so the surgeries are more tolerated. We have a lot of technologies that allow us to visualize things in three dimensions during the surgery. And in fact, there’s a technology now that instead of having to look through a microscope and crane my neck, everything’s out on large screen TVs in 3D.
We wear 3D glasses in the surgery, and then we have technologies that allow us to manipulate things like a white matter tracks, which are the kind of wiring in the brain that connects important structures. So we can actually plot trajectories that really thread a needle through areas that are pretty treacherous in the brain, but we can now get there safely based on a lot of these techniques, particularly combining them with things like mapping that allow us real-time in surgery to detect that a specific area of a person’s brain is functional and that we shouldn’t touch it or disturb it. So I won’t go through all that. It gets a little technical and boring.
Very interesting. I didn’t realize that.
I can remember giving a talk to one of the clinical heads of our cancer center.
Well, he was in the audience. I gave a talk recently highlighting all these new technologies and showing videos of all these cool things. This is someone that’s been around for a long time and certainly refers patients to us for surgery. But even afterwards, he just said, wow, I just can’t believe the stuff that you guys can do these days.
He’s been around the block, of course. So I think there are a lot of new, exciting things that are coming out. I think that’s on the surgical side, but more importantly, frankly, as far as impacting patients and their survival and their quality of life are the types of therapies that are coming out.
And I think you and I were talking earlier about the notion that previously patients who, you know, developed a brain metastasis, let’s say while they were on a clinical trial, kind of got booted off the trial and for a variety of reasons, none of which really matter. But that shouldn’t be the case anymore.
And in fact, one of the things we’ve done in building a center at Duke is we’ve focused,and that was always our motto from forgotten to focus. Right? So we took patients who were getting booted off these studies and said, no, we’re going to focus on these patients because there’s a lot to be done here to help them.
And so now instead we have clinical trials that the criterion to be on the trial is that you have a brain metastasis.We have over a dozen of those open at our institution. And I think you’ll start to see that via trend. And a lot of those are treatments that are meant to get into the brain or are meant to treat cancer regardless of histology, et cetera, et cetera.
And so I think there’s just a lot out there now that is available to folks as long as they’re willing to, like you said, get a second opinion or kind of do their homework and are willing to travel or what have you.
And also to participate in a trial. I think if we can get more patients participating, that’s going to help as well.
But the truth is part of the work that I do is we need more trials. There’s so many that are excluding the patients. I’ve seen a lot of trials where they say’ “Oh, sure, brain mets can participate.” We really want trials that are specific to brain metastasis and frankly leptomeningeal disease.
So I’m really happy to hear that Duke has a dozen or so. We’re going to highlight those on the website as well. I think that was all I had today. Did you have anything else that you wanted to add?
I’ll certainly mention a few things that I think are exciting. We have, as we’ve built our center, really tried to focus on all areas.
We do focus on leptomeningeal disease. We’ve published on it. We have a researcher at Duke, who has uncovered some of the mechanisms of leptomeningeal spread. We actually have submitted recent research proposals on it too, to try to understand that late stage of metastasis, again, to say these are folks that people perhaps are giving up on.
We don’t want to do that. We want to discover the next path forward. And, and so a lot of those things are occurring at various institutions, not just Duke. The key point here is these patients, patients with brain metastases are now becoming a focus of medicine. It’s important to recognize that part of that is because as people survive longer with cancers, as our therapies get better, larger proportions of people will survive long enough to develop these kinds of late stage portions of cancer, where the cancer can travel to the brain or the spine.
And so now we really need to focus our effort on tackling that problem. We do a lot of research. I, myself, am engaged in some really exciting research projects where we have some novel therapies that are perhaps just a couple of years away from getting into the clinic. I work with a Nobel Laureate there, and we have discovered a novel target.
We have drugs that are coming out for that. And I think it’s an exciting time to be in medicine, and it’s an exciting time in so much as it can be exciting to be a patient with this problem where previously you may not have felt there were options, but now there really are. And there’s a group of people out there who are looking to make your symptoms better or your lives better and your treatments better.
I think I’d like to include myself in that group, but I know there’s a variety of other folks out there doing this.
Well, that is wonderful. That is music to my ears, and probably many other patients to know that there are therapies coming down the pike. I think we’re all very excited and I’m very grateful for you coming here today and chatting with us.
And I’m grateful for the work that you do. So thank you so much.
Dr. Priya Kumthekar is a neuro-oncologist from Northwestern University who treats primary brain tumors, but has a specific interest in metastatic disease to the brain from cancers like breast cancer. She leads multiple clinical trials to advance the field of neuro-oncology to improve care for patients.
Dr. Kumthekar is a UCNS certified neuro-oncologist from Northwestern University dedicated to patient and care and moving the field of brain tumor forward primarily through her leadership on clinical trials.
She is currently involved in and leads many clinical trials including being the overall principal investigator of five investigator initiated treatment trials as well as the site principal investigator (PI) of over a dozen additional collaborative brain tumor treatment trials. Dr. Kumthekar is the planned study chair/overall PI for a multicenter, international breast cancer leptomeningeal clinical trial scheduled to open in Q4 2020.
Dr. Kumthekar has also been actively involved in the NCI funded clinical trials for many years. Within the NCTN (National Clinical Trials Network) and serves in leadership roles, particularly with the Alliance for Clinical Trials (Alliance”) for several years.
In 2016, Dr. Kumthekar was appointed as the national Executive Officer of Neuro-Oncology at the Alliance. In this role, she oversees the conception and development of clinical trials in these two areas from early phase through registration studies. Dr. Kumthekar has teamed with various scientists both at Northwestern and at other institutions with the goal of using translational research to advance the field. These partnerships allow for cutting edge scientific discoveries to be successfully brought to the clinic for brain tumor patients to benefit.
Thank you for joining us today. My name is Christine Hodgdon. I’m a metastatic breast cancer patient and advocate, and I’m here today with Dr. Priya Kumthekar. And I am very excited to talk with her about all the wonderful work she does, especially for patients living with brain metastasis.
A little bit about Dr. Kumthekar. She is a neuro-oncologist from Northwestern University. She primarily treats brain tumors, but has a specific interest in metastatic disease to the brain from cancers like breast cancer. She leads multiple clinical trials, which we’ll talk about a little bit later, and all these trials advance the field of neuro-oncology to improve care for patients. So Dr. Kumthekar, thank you so much for joining us today.
Thanks for having me.
The first question is just very simple. Not everybody might know what a neuro-oncologist is. Could you explain what you do specifically and how it relates to breast cancer?
Absolutely. So neuro-oncologist is almost exactly as it sounds. So, we are interested in the treatment of patients with both primary brain tumors, so tumors that start in the brain, as well as secondary brain tumors, so tumors that start in the body and then go to the brain. And so that’s where it relates to breast cancer because we’re often treating patients with breast cancer that then spreads to the brain and in and around the brain, as breast cancer is one of the primary cancers that leads to brain metastasis.
And I know that some cancer centers don’t always involve neuro-oncologists when they’re caring for their breast cancer CNS disease, but it can depend on the hospital. Do you have any comments about that? Is that something that a patient should be concerned about?
No, I don’t think that patients need to necessarily be concerned about not having a neuro-oncologist involved in their care. It’s just an added dimension and an added specialty that can be quite helpful. Not all hospitals actually physically have a neuro-oncologist onsite to have, to be able to include in their care. But we’re a pretty small network of doctors. As a specialty, we’re quite small compared to say medical oncology or breast oncology. And so if there are questions about neuro-oncologists and neuro-oncologists in your area, we can often connect you with those folks because we’re often connected in one network anyway.
That’s great. And so we commonly hear the term brain metastasis. I think we’ve mentioned that already today. But there is this separate type of metastasis called leptomeningeal disease. And I was hoping you could explain to us what leptomeningeal disease is and how it differs from brain metastasis.
Yeah. So brain metastasis is pretty straightforward, right? It’s metastasis that go to the brain itself. But what a lot of people don’t know anatomically, is that, the brain and the spinal cord live in this fluid, right. This basically floats in this fluid and that fluid is called Cerebrospinal fluid. And so what leptomeningeal disease is, is essentially the involvement of cancer in that fluid. So basically it’s the presence of cancer cells in your Cerebrospinal fluid.
The name of that space is called the subarachnoid space. I don’t want to get too detailed on the anatomy, but I think just generally speaking, the way to think of leptomeningeal disease is cancer cells that are in the fluid that surround the brain and spinal cord.
I think that’s an excellent explanation. I think many people, we often in the advocacy community hear people kind of using that term, lepto, when in fact it might actually be brain metastasis. So I just think it’s important to make that distinction. And I wanted to ask too, can patients present with both brain metastasis and leptomeningeal disease? Is that possible?
Absolutely. Similarly to having, you know, two sets of metastases, let’s say to liver and lung, present at the same time, it’s just the same concept except different anatomical spaces. So absolutely, you can have brain and leptomeningeal disease present at the same time, just like any other metastatic site.
Understood. Like you can have metastasis in your liver and you can have in your brain. And for patients that are living with brain metastasis, is there a risk factor then of developing leptomeningeal disease, or is that unrelated?
So yeah, there is a little higher risk factor of developing leptomeningeal disease. We’re still understanding the depths of that. And we do know that some subtypes are more likely to then go on to develop leptomeningeal disease. So it’s really hard to target that exactly.
Similarly, you know, we know that patients with lung mets are at greater risk of, let’s say, developing brain metastases, but we can’t quite pinpoint who they are. And that’s kind of the same analogy for brain to lepto. It’s hard to say and to complicate things further, you can have leptomeningeal disease alone, without having brain metastasis. So, really they’re truly, you know, separate anatomic compartments that you can get metastasis in.
Are there any other risk factors that you are aware of for developing leptomeningeal disease?
Yeah. There are a few different ones and they’re very similar to that of brain metastasis. So, in terms of subtypes, very frequently, we might see this in the HER2+ population or the triple negative population, basically populations that we know that have a predisposition for the central nervous system.
I see. I think I’ve even heard, so correct me if I’m wrong, does lobular breast cancer have a propensity to potentially develop into leptomeningeal metastasis?
Yeah, absolutely. That can as well. I mean, truly it’s – any breast cancer could. So even outside of the two examples that I provided, any breast cancer subtype could. But the top two of that list would be HER2+ and triple negative.
Understood. And speaking of that, how common is leptomeningeal disease in breast cancer patients? I don’t know if we have a statistic on that.
Oh, we do. I mean, I would say for all comers, if you’re looking at breast cancer as a whole, it’s a very small minority, right. We’re talking like five percent-ish, you know. But it’s, again, those risk factors that you refer to. So, for example, in the HER2+ population, depending on what statistic you’re looking at, 30 to 50% of patients with HER2+ disease have CNS mets. And of that, you know, a fraction of – a significant fraction of that – is leptomeningeal disease. So, you know, the subtypes really do matter. But all comers, it’s actually a much smaller risk.
But I think – are brain metastasis more common than leptomeningeal disease?
We’re going to see more brain mets than we will lepto.
Correct. So even in that figure of 30 to 50% of HER2+ disease going on to develop CNS or central nervous system metastasis, it’s still just probably around, you know, depending on what you read, 15 to 25% of that, then that goes on to develop lepto. So it’s still going to be a minority population, even within the CNS population.
Okay. And I think I’ve also heard and read that we are now seeing metastatic breast cancer patients living longer with their disease. So might that incidence actually increase as we might start to see more CNS, brain metastasis, lepto.
It’s a very insightful question and it’s actually totally accurate. And we’ve already started to see that over the past, you know, a handful of years plus. And beyond that… so the answer to your question is yes. And then beyond that, we’re seeing a lot more patients who are dealing with disease only in their CNS compartment, be it brain mets or lepto, because of exactly those same reasons.
So, I think we’re doing great as a field, as a breast cancer field, moving forward with great new therapies and advancing the field. It’s not necessarily an exact parallel advancement in the brain, although there are CNS advancements occurring as well. But for that reason, we see a lot more patients who, with the given therapies, are doing great systemically or, neck down, if you will. And we’re really primarily dealing with the CNS, or central nervous system disease.
Yes. I think this is really why we started this whole project and website is because we want to see the advancements that we see in breast cancer in the central nervous system as well.
I want to switch gears just a little bit. And I’m wondering if you can tell us about the symptoms of leptomeningeal disease. Some patients may be concerned that they’re experiencing something that might be indicative of lepto, but maybe they’re similar to brain metastasis. So maybe you can comment on that.
Yeah, they are similar, but there are a few distinctions that we like to keep in mind. So, you know, similar to brain mets, you can get kind of focal neurologic symptoms, your quote, unquote sort of stroke-like symptoms, where your thinking, speech and motor deficits and so forth, depending on the location of the mets.
But lepto is similar, but a little bit different. So when again, when you go back to that original question of “where is leptomeningeal disease?”, that’ll help guide us to what the symptoms are. So if you’re talking about the fluid that surrounds the brain and the spinal cord, what lives in that fluid are various nerves that control functions around your face and head. So those are called the cranial nerves.
And then through your spine, the coming out of your spine, are spinal nerves that float in that fluid, that live in that fluid. So they can be impacted by cancer cells in that space. So, you see a lot of, what we call cranial nerve symptoms. So that’s things like numbness on your face, on your chin, you know, difficulty chewing, swallowing, facial weakness, double vision. So a lot of – and hearing changes – so a lot of things dealing with your cranial nerves, because those nerves are affected because they’re in that space.
And then spinal nerves. So that can control things like neuropathic pain. So numbness, tingling, you know, pain that you can get from spinal nerves. And then your lower down spinal nerves that control really critical functions with your bowel and bladder. So you can see some changes there as well.
Additionally, because it’s the fluid that this is living in, sometimes with these patients, we can get a fluid buildup. So we get this pressure, if you think of it. Pressure increase. And with that, we can see things like headaches, nausea, and vomiting. So there are a variety of symptoms that leptomeningeal disease can bring upon. But those are kind of the basics 101 of symptomatology.
I love that visual that you provided, because I think I always just kept thinking of it in the brain, but we have to remember that lepto really affects the brain and the spinal cord and it’s that fluid. So I really liked the way that you described the cranial nerves, you’re going to have some different symptoms, versus if the lepto is around your spinal cord.
Cause I’ve worked with lepto patients who have trouble walking. So I thought that that was the main symptom, but it really does seem to kind of run the gamut. So thank you for that explanation.
How is lepto typically diagnosed? I had trouble finding this. I just tried to do some quick internet searches and it just seems like everybody does something different. So I’m curious to hear, you know, how you are able to diagnose this.
So there are three, basically, three methodologies that we use to diagnose. The gold standard, sort of, standard of care, is CSF cytology. So, as I mentioned, lepto is cancer cells in that fluid. So we sample that fluid via, typically a lumbar puncture. You sample that fluid, and you look at it under a microscope to see, are there cancer cells present? So that’s CSF cerebrospinal fluid cytology. That is the sort of textbook answer.
But ancillary to that, providing support are things like imaging. So MRI of your brain and your spinal cord, as well as clinical symptoms. So it’s all three together right now that are guiding our diagnostics. CSF cytology being sort of number one, and then MRIs, and clinical symptoms. And that, three, kind of trilogy together is what we use for the diagnostics.
I will say that, as a field, we know that there are shortcomings to those diagnostics and we are trying to look at the next generation. And beyond just improving upon treatments, we really want to improve upon diagnostics. That’ll help us so many fold, right? It will help us, of course, diagnose sooner, better, earlier. It will help us follow patients along their treatment courses better. And, you know, it really can revolutionize how we design and plan clinical trials, if we have a better foundational understanding of our diagnostics.
So there is how we currently do it, which is important to know, but also how we plan to improve upon those diagnostics. Because there are challenges to our current diagnostic paradigm.
Absolutely. I really, I like that there’s three different modalities by which you can really make a diagnosis. And I wanted to ask this, because I think I’ve heard this from other doctors. Do you only need one lumbar puncture to prove, like if you get a negative result, do you recommend doing more than one lumbar puncture, or is one really sufficient?
So it’s a great question. And the answer would be dependent on the situation. So the reason why people say that is because the sensitivity of a lumbar puncture and CSF cytology is not that great with one lumbar puncture. So depending again, on what you read, it could be 50 to 60, 66%. So that means that a third of the time, plus, we might be missing a positive result. So we might have a false negative. That sensitivity increases with subsequent lumbar punctures.
So after a lumbar puncture number two, you might be up to like 70, 80%. And then maybe with three, maybe 85, 90, depending on which paper you’re reading. But we never really get past that 90% even after three lumbar punctures.
But the reason why my answer to you isn’t yes, do a second one, is because it’s very situationally dependent. If I have a patient who is – I have a negative CSF cytology, but I have clear symptoms and clear MRI imaging, I might sit down with that patient and decide, you know, it’s not going to impact how we manage your care and I don’t need to necessarily, you know, have you go through another lumbar puncture, let’s go this way.
Versus if there was nothing on the MRI and, you know, we were really still on the fence and it was going to impact further care. Then I might suggest in that situation that, hey, you know, we need more data to stand on solid footing with our treatment decisions. Then I might say, yes, let’s proceed with another lumbar puncture. So it’s really, you know, the whole patient, keeping kind of the whole patient in mind.
Yeah. And that I think as metastatic patients, we’re kind of used to this. It’s a, “it depends” answer, you know, it’s like, it really does depend on the situation. It depends on many different factors, but I just wanted to ask if there was a straightforward answer. And I think what we’re learning with leptomeningeal disease is that there really aren’t a lot of straightforward answers and we’re going to get to the research that’s been ongoing.
How is leptomeningeal disease treated, then? We know how it’s diagnosed. How do you manage this disease in patients?
Yeah, and I laugh only because this is another, “it depends” answer. But there are multiple modalities that can be used to treat leptomeningeal disease. Historically, the primary modality has been radiation-based.
If you think about leptomeningeal disease, again, going back to that very first question. Anatomically, is something that surrounds the brain and spinal cord. You can imagine that some of our fields for radiation can be quite large. And so we often do radiation if we need to palliate symptoms, if we need to make symptoms better quickly, I like to lean on radiation for that primarily.
Other modalities that we might utilize either instead of, or after, could be things like intrathecal therapy. And this might be something I’m not sure if the listeners are familiar with it. But essentially, with intrathecal therapy, there are two ways to administer it. You can either do it via a lumbar puncture where you’re in that fluid space and then you can inject chemotherapies.
And more commonly what we use, is basically a port that we surgically place, similar to like a port that you would have chemotherapy go into, into your bloodstream. This is a port that communicates directly with your ventricular system, or that CSF fluid system, where we’re able to directly administer drugs to the CSF.
So we’ve talked about radiation, intrathecal therapy, and a third modality is systemic therapy. So that’s just chemotherapy, or medical therapy, directed therapy, that can be orally administrated, can be orally given, can be given via IV, so in different manners. Just like traditional chemotherapy that you think of for breast cancer.
Got it. And I just wanted to mention the intrathecal delivery, when you were talking about that port. That’s called an Ommaya port. Is that correct?
Okay. I just wanted to make sure I had that right. I’m curious, just for myself. How often do you use whole brain radiation? I think again, you’re going to tell me it depends on where the lepto is located. Cause I know I’ve definitely seen patients get radiation to the spine cause they’re having trouble walking. But do you use whole brain radiation often?
We do. And I can’t quote you a number because it’s kind of different site to site, patient to patient, you know? In terms of across the board, across the world or the country. I couldn’t tell you a percentage, but absolutely we do. We use whole brain radiation. We might use skull-based radiation where a lot of those cranial nerves are.
You know, leptomeningeal disease can look very different from patient to patient. It could have more bulky or nodular disease, or it could be diffuse and quite thin. And those are situations and various factors that we use in mind to decide treatment. So I think what I might sort of mold this question into is, what are the different factors that influence what we decide to do for our lepto patients?
So that includes things like the symptomatology of patients. So, what are the symptoms that that specific patient has, and is the treatment that we give going to alleviate or help those symptoms? It really is going to depend also on what’s happening throughout the rest of the body. Because we might be able to come up with a treatment regimen that can ideally kill two birds with one stone that addresses the systemic disease and the brain disease.
Proximity to when radiation was, is very important in deciding intrathecal therapy or what kind of chemos we might use. And the functional status of a patient – how well a patient’s doing, how are they functioning day to day and what sorts of treatments can they endure? So there’s a lot of different factors that go into that “it depends” answer.
Yeah. And it sounds like you can actually use a combination of some of these different treatments as well. Is that right?
Now I want to get to – this is the juicy stuff. I think this is what people want to know about. What is the emerging research in leptomeningeal disease? And I would love for you to comment on clinical trials. I know you lead many, and I would like to hear if there’s any lepto trials ongoing right now. That would be wonderful.
Please let us know.
Absolutely. So that in and of itself is a long talk, but I’ll mention a few that I think are kind of nice to keep on the horizon. And what I also want to say is that the clinical trial portfolio that we have on clinicaltrials.gov, across the country, across the world, changes on a daily, weekly, monthly basis because these things open and close.
So, I could mention things now and the status of them could be really different by the time this recording happens, or by the time you watch this recording. So please take it with a grain of salt, depending on the time that you’re seeing this. And I would encourage everyone to go to clinicaltrials.gov and you can type in leptomeningeal disease and find out everything that’s open at that given moment. So…
And we’ll also have a trial search on our website that, you know, you can actually input the data of your subtype, all of that information. It’s just a little bit easier to manage than the clinicaltrials.gov website. But I’ve definitely used it and leptomeningeal is such a distinct term that you can definitely find some trials.
No, absolutely. So then I guess to answer your question, there are many trials ongoing right now. There are a few dozen in the US that are going on. And some include novel administrations of intrathecal therapies. So, for example, there’s an intrathecal nivolumab study, ongoing. There’s an intrathecal combination of trastuzumab and pertuzumab ongoing.
Okay. So that would be for HER2+ patients?
That one’s HER2+ disease. There’s also an ongoing study with pembrolizumab for all solid tumor patients. There’s a novel compound that had very positive phase two results that was published last year. And so there’s going to be actually the first planned registration study, phase three, randomized registration study, in leptomeningeal disease with the drug called ANG1005. It’s called the ANGLeD study. That’s planned to open early next year.
So there’s a lot of forward movement and many, many more that I’m leaving out. And so there’s an ongoing one, actually with tucatinib. Which I know you were talking about earlier with the HER2+ study.
So there are, I feel bad for the many studies that I’m leaving out right now. But it’s just to say, you know, we’re encouraged and we’re moving forward. And there are more studies now than there were a few years ago, more than there were a year ago. And we do need to just keep that momentum going and keep adding more and more to lepto and brain metastasis studies.
Absolutely. We just need more trials in general. And I think that’s the other piece of this whole initiative, is that we want to advance research for patients living with central nervous system disease.
So, all these trials will be listed in our website. So don’t worry if you’re forgetting any. I just wanted to comment though, that you had mentioned, a few of the drugs you mentioned were actually immunotherapy drugs. And so in some of them, some of what you talked about would be administered through that Ommaya port that we talked about before. So that’s one type of trial. But I was very interested in the – I’m not sure how you said it – ANG 1005. Is that –
And, is that actually chemotherapy? That’s a chemotherapy drug, right?
It’s an antibody drug conjugate. So what that means –
Yeah. So it’s an antibody that’s basically meant to help cross blood brain barrier and blood CSF barrier.
And then it’s an antibody that’s bonded to three compounds of paclitaxel, which is a chemotherapy. So it actually gets the chemotherapy to the location that it’s intended to get to.
Video #7 – Note: This video is posted under the Advice Section on the website
Do you have any recommendations for patients newly diagnosed with leptomeningeal disease?
Yeah, absolutely. I would say a few things. So, I think, listen to your doctors. They have treated this before, they’ll guide you properly. Listen to the facts. You know, I know that we all are comforted by facts and science and reading.
But what I always tell my patients is, I give them statistics that they might want, the facts that they might want, and then I graciously tell them to crumple it all up and toss it in the wastebasket because we’re all our own statistic. And so, my advice to you would be, take in all the information, science is what moves us forward, and then gently push it aside and continue, you know, continue that hope because I believe in that.
And then I would also say lean on others. And that can look really different to different people, cause we all lean on others differently. That could look like online support groups, that can look like one-on-one support, that can look on online support.
There’s just so many different ways that we each need that. So do what feels right to you, but know that there are multiple avenues of that support. I think this website itself is fantastic. So there’s a lot of different, great resources out there. And I think that if you’re in a situation where you want to meet with a neuro-oncologist, there are many different ways to do that as well. I’m sure if you talked to your doctor that they could help facilitate that as well. If you didn’t have someone in your own institution.
Dr. Nancy Lin is a medical oncologist in Boston, MA at Brigham and Women’s Hospital and Dana-Farber Cancer Institute. She specializes in the care of patients with all stages of breast cancer. Her research focuses upon improving the outcomes of people living with metastatic breast cancer, including a particular focus on the challenge of breast cancer brain metastases. She has led multiple clinical trials which have led to new treatment options for patients with breast cancer that has metastasized to the brain.
Dr. Nancy Lin is a medical oncologist at Dana-Farber Cancer Institute (DFCI) and Associate Professor of Medicine at Harvard Medical School.
Dr. Lin received her medical degree at Harvard Medical School and subsequently completed her residency in Internal Medicine at Brigham & Women’s Hospital and a fellowship in Hematology/Oncology at Dana-Farber/Partners Cancer Care. Since 2018, she has served as Associate Chief of the Division of Breast Oncology at DFCI. Dr. Lin’s focus is on developing novel targeted therapies for patients with advanced breast cancer and exploring mechanisms of drug resistance, with a particular interest in patients with breast cancer that has metastasized to the brain.
Dr. Lin is leading multiple ongoing and planned clinical trials evaluating a variety of targeted approaches in patients with metastatic breast cancer. Her work is highly collaborative and involves close working relationships with clinicians, laboratory investigators, and patient advocates. Dr. Lin’s honors and awards include a Young Investigator Award and Career Development Award from the American Society of Clinical Oncology. She is a member of the Massachusetts Medical Society, American Society of Clinical Oncology, Alliance for Clinical Trials in Oncology, and Translational Breast Cancer Research Consortium.
Dr. Nancy Lin – Video #1 – Medicine Based Treatments for Breast Cancer
So I just want to welcome everyone that’s joining us today. My name is Lianne Kraemer. I am a patient advocate and we are going to do an interview today with medical oncologist, Dr. Nancy Lin. And before I formally introduce her, I’m going to read her bio to you. Dr. Lin is a medical oncologist specializing in the care of patients with all stages of breast cancer.
Her research focuses upon improving the outcomes of people living with metastatic breast cancer, including a particular focus on the challenge of breast cancer, brain metastasis. She has led multiple clinical trials, which have led to new treatment options for patients with breast cancer that has metastasized to the brain.
Dr. Lin received her MD from Harvard Medical School in 1999. She completed her residency in internal medicine at Brigham and Women’s Hospital, and went on to complete fellowships in medical oncology and hematology at Dana Farber. In 2005, she joined the staff of Brigham and Women’s and Dana Farber where she is medical oncologist and clinical investigator in the breast oncology center.
So it was wonderful to have you join us.
Thank you for having me Lianne.
Of course. For those who probably don’t know, Dr. Lin is actually my oncologist and she is wonderful and does specialize in the treatment of brain metastasis. But you treat as your bio mentioned, all stages of breast cancer. Can you tell me a little bit about your role as a medical oncologist, what you do?
So as a medical oncologist, our focus is on the medicine-based treatments for breast cancer, whether early stage breast cancer or metastatic breast cancer. And so those medicine-based approaches can be medicines like hormonal therapy, chemotherapy, or targeted therapy. And in general, except for the initial part of therapy where often the breast surgeon is the so-called quarterback for much of the rest of the course of treatment. In patients with metastatic breast cancer, in general, the medical oncologist serves as a sort of quarterback of the team.
So after early stage treatment ends or with a diagnosis that begins with metastatic breast cancer, can you talk a little bit about what happens with metastatic breast cancer?
Right. So with metastatic breast cancer, our goals are to try to help people live the longest and best quality of life possible. And we do that really in cooperation or collaboration with the patient usually going from one treatment to another in hopes that each treatment will work for a good period of time and that we can string out one treatment after another to allow people to live long lives in many cases, although not all cases, even with a diagnosis of metastatic disease.
So early stage, there’s a curative intent where with metastatic breast cancer, it has spread beyond the breast. And at that point the intent is to provide care that can extend life.
That’s right. So in general, for metastatic breast cancer, never say never, but in general, our goals are not so much to cure the cancer, but to really keep the cancer under control for as long as possible so that people can experience sometimes extended survival, even in the setting of metastatic disease.
Dr. Nancy Lin – Video #2 – What are Brain Metastases
So when breast cancer spreads, it likes to go to a couple different places. It likes to go to the brain, the bones, the liver, the lungs. Can you tell us a little bit about what brain metastases are?
Right. So brain metastasis are tumor cells that have come from some part of the body.
In the case of breast cancer, usually originally from the breast although the cells could have migrated from breast cancer that’s gone to the liver or breast cancer that’s gone to the lung, but ultimately those breast cancer cells land in the brain. And when they do that, they can either land in the so-called parenchyma of the brain, which is the actual brain tissue itself.
It shows up generally as lumps or spheres in the brain, or it can land in the spinal fluid. This is otherwise known as the CSF and that leads to something that we call leptomeningeal disease, which is cancer that is basically floating in the spinal fluid. And even though they’re both, in some ways, brain metastases or cancer in the central nervous system, they are quite distinct in the kinds of symptoms that people have and also in the types of treatments that we offer.
One of the common questions that comes up is: What’s the difference between a primary brain tumor and breast cancer brain metastasis? And the reason we care where the cancer came from is because the cancer keeps the characteristics of where it came from. So a breast cancer still responds to breast cancer treatments, even though it’s in the liver or the bone or the brain.
And it’s not going to respond to treatments necessarily for cancers that start in the brain or start in the bone. That’s why we put so much attention on pathology. Like, where is this cancer from? Because it really affects what we think about for effective treatment.
Thank you so much for mentioning that as somebody with brain metastasis are often by myself, you know, describing to people what that difference is, it’s hard sometimes for people to understand.
That was a brilliant explanation. How common are brain metastases?
So for people who have early stage breast cancer, it’s not that common as the first place for cancer to show up. So, you know, for somebody who has either stage one or stage two breast cancer, less than 5% of the time the cancer will show up first in the brain.
So that’s a reassuring number if you have early stage breast cancer. For people who have inflammatory breast cancer, that chance is higher, probably like 10% to 15%. And for people who have metastatic breast cancer, at least when the metastatic breast cancer is first diagnosed, maybe about 5% to 10% of the time is there cancer in the brain. It’s not any more than that, but over time, the chance can increase.
And so for people who have HER2 positive breast cancer, for example, if we look from the time somebody is diagnosed with metastatic breast cancer, to the time they die of breast cancer over that period of time, about half of people will develop cancer in the brain. And similarly, if we look at patients with triple negative breast cancer, that’s already metastatic, somewhere around at least a quarter and in some cases up to half. Somewhere in that general ballpark of patients will develop brain metastasis over time. It’s actually less common in people who have estrogen receptor positive breast cancer that’s HER2 negative. In that case, the lifetime risk of developing brain metastasis, even in the setting of advanced or metastatic breast cancer is estimated at about 10% to 15%.
So you mentioned that when you receive your initial diagnosis of having metastatic breast cancer, that it’s not as common to have it as a first site when you’re diagnosed.
Why does it become more common over time?
We think that it probably becomes more common over time as people live longer, because it’s almost like a chance happening. Cancer has to break off, find its way into the blood vessels, get into the brain, figure out how to cross the blood brain barrier and set up shop.
And, you know, cancer cells are breaking off into the bloodstream all the time, but very few managed to do all of those steps, but the longer somebody lives with their metastatic breast cancer, the more time there is for these repeated attempts to be – I hate to use the word successful to make it to the brain.
So we see that, for example, in HER2 positive breast cancer, where, you know, many people survive more than five years after a diagnosis of metastatic disease. That’s I think why we’re seeing a part of why we’re seeing an increased risk, but on top of that, HER2 itself probably has, and we don’t know why yet, but there’s some reason scientifically that HER2 from a biological standpoint, seems to allow cancers to get into the brain and set up shop there more easily because even people with ER, positive HER2 negative breast cancer, who also, you know, very commonly will survive five or more years after a metastatic diagnosis, they’re still at lower risk of brain metastasis than patients with HER2 positive disease surviving for the same amount of time.
Dr. Nancy Lin – Video #3 – How are Brain Mets Diagnosed
How are brain mets typically diagnosed?
Right now, the most common way that brain Mets are diagnosed is if a patient reports symptoms, and then that prompts usually an MRI scan of the brain to look to see why those symptoms appeared. A lot of people ask me about whether memory loss or forgetting where the keys are, you know, are a sign of brain metastasis.
It’s a common question because it’s a common occurrence. But that’s not the way brain metastasis usually presents. So the most common symptom is headaches. If we see headaches that are associated with nausea and let’s suppose somebody who’s on their seventh cycle of the same chemotherapy and all of a sudden, they’re nauseated that’s not right. If somebody wasn’t nauseated for the first six cycles, they shouldn’t really be nauseated for the seventh cycle. That really raises a red flag, especially if their headaches are associated or sometimes people notice that their coordination or their balance is off or they’ve had a fall.
There’s no reason that a 34 year old woman should trip off the curb for no reason. It really raises the red flag. Is there some underlying issue that is need for concern? So I have a very low threshold to image the brain in somebody who has metastatic breast cancer.
Any of those symptoms, headaches in coordination and balance problems, et cetera, certainly any weakness on one side versus the other, and also seizures, which are not so common, but any of those kinds of symptoms should prompt a brain MRI.
You mentioned seizures. How do you know specifically? Cause that’s, in the community that I talked to who have brain metastases, that is certainly a really big worry for them.
Do you know approximately how many? You say they’re not very common.
So when people have looked to see, you know, of the symptoms that were the first symptom of a brain metastasis, but 10% of the time around 10 to 15% of the time, depending on which study you look at, is seizure the first symptom. So it’s not rare, but it’s not the most common, whereas around 70% of people have headaches.
So as far as medication for seizures, it’s not something you would put a patient on prophylactically, you would wait for them to have an actual seizure.
That’s exactly right. So you know, it’s quite reflexive to think that, when you have a patient who has a new brain met on a scan to immediately put them on an anti-seizure medicine, it feels like the right thing to do, but there actually have been clinical trials, randomized clinical trials showing that there isn’t a benefit conferred with that approach. And so the national guidelines, if somebody has not ever had a seizure, at least for breast cancer, brain metastasis is not to routinely give anti-seizure medicine.
There are always exceptions to the rule. And certainly if somebody is going to the operating room and there’s going to be potentially bleeding, oftentimes the surgeons will temporarily put people on a brief course of anti-seizure medicines. Similarly with certain types of radiation, it’s not uncommon if there’s a concern, for a larger lesion to put somebody temporarily, but, you know, in terms of long term indefinite use of anti-seizure medicine, we try to stay away from it, except for patients who have had seizures.
Okay, that makes sense. So for screening or for diagnosis it seems like it’s something dependent. There’s no guidelines for regular screening, even in those who are more likely to develop brain metastasis. Whereas when you have metastatic disease there is the schedule for screening.Can you explain a little bit about why that is?
Yeah, I mean, this is a really important topic. And I think it’s a topic that we just, as a community, have not addressed in terms of clinical data or clinical trials, as well as we could have. We’re trying to do it now. There are actually some trials now, prospective trials, trying to develop evidence to see whether there are benefits to screening, but right now there’s no prospective clinical trial evidence to prove a benefit.
And there’s sort of conflicting evidence if you look backwards in time. So if you look backwards in time, you see of patients who have brain metastasis, could we have made a difference if we did screening on the one hand there’s data, that Dr. Ayal Aizer who is one of the radiation oncologists that I work with, that he generated, where he compared people at our institution who have lung cancer, brain mets, versus those with breast cancer, brain mets, and the differences for lung cancer patients, they usually get screened.
What he found is with patients with lung cancer, their mets are usually diagnosed when they have fewer brain mets on average, the brain Mets are a little bit smaller on average, they tend to need less whole brain radiation. So those are all really good things. And that is in fact what led to the trial that he’s currently running.
But there have been other groups that have looked backwards in time to say, well, if people who had brain mets found because they had a required brain MRI as part of a clinical trial, for example, you know, some other reason they had a brain MRI and they didn’t have any symptoms. And they look to see is survival longer in people who had brain mets found by screening versus those with brain mets found when they had symptoms. And those studies have shown no difference in survival. So that’s why there’s this debate. And if you go backwards in time and medical records, you can’t ask about quality of life and you can’t ask about neurological symptoms or cognitive symptoms because they can’t do that retrospectively back in time.
And so that’s the problem right now. It’s really like a data problem. And so hopefully, you know, there are three trials now going on across the world to try to look at the role of screening MRI. You know, right now we say we don’t do it. And I don’t usually do it because there’s no data, but it’s not that there’s data that it’s not good.It’s that there’s no data. Or no prospective data. I hope that not so long from now, we will have data. We can actually make a data-driven recommendation. That would be optimal, for sure. To have something that guides us rather than making a decision on the lack of data, which is sort of challenging.
I assume there are risk factors for getting brain metastases. Can you speak to that a little bit?
Right. So tumor subtype is one of the risk factors. So if you have triple negative, which is estrogen, progesterone and HER2 negative or HER2 positive, I’m throwing out all these like jargon for subtypes and I just want to preface by saying, if you don’t know what subtype you are, you should ask your doctor and find out because everything in metastatic breast cancer treatment depends on the subtype. It’s something that is a good thing to know for your own care. But the other types of risk factors are things like being young. Young age does seem to increase the risk of brain mets. Having metastasis in the lungs seems to increase the risk of brain mets. And also having inflammatory breast cancer. So there are some of those risk factors. And then finally, for a specific type of cancer in the brain, what I talked about, which was this leptomeningeal disease, a cancer in the spinal fluid lobular breast cancer, which is a type of appearance under the microscope, seems to be more likely to do this.
Dr. Nancy Lin #4 – Treatments for Brain Mets
Well, why don’t we talk a little bit about treatments? So when you get a patient that’s newly diagnosed, what are the considerations and how do you go about treating it? I know this is an extraordinarily complex question, but let’s see if we can break it down and, and talk about how we treat it.
Right. So I think the reason it’s so complex is because we actually have multiple different types of treatments that could be considered. And normally when we think about how we treat cancer in the liver that’s worse, it’s just the medical oncologist trying to decide with the patient should we give drug X or drug Y or drug Z. Although it’s not an easy decision, it’s basically two people, one doctor and one patient talking through the options. What’s really different about the brain metastasis management is it’s oftentimes multiple doctors plus the patient thinking about what’s the right approach, because it may be that radiation is a possibility. It may be that surgery is a possibility. There are even different types of surgery, like regular surgery and this type of treatment called LIT, and there’s different types of radiation. Then there’s chemotherapy and targeted and systemic therapies. So, for any one patient, it may be that all of those things are theoretically possible to do. You have to make a decision together, as to which of those options at this point in time makes the most sense.
So to just give you a couple of very concrete examples, if somebody comes in and they have, let’s say they have a new seizure and they go to the emergency room and they have one very large lesion in the brain. Usually we would recommend that person have surgery first. That person usually would get some radiation to the margins around the surgery, after they recover from surgery.
Then after that, there’s some systemic therapy given. That’s like three different types of doctors to treat that one patient. If you have somebody who’s already gotten radiation, maybe she’s not a candidate for surgery. And now has several new brain metastases such that the radiation option would normally be whole brain radiation, but that person, you know, is very concerned about the side effects of whole brain radiation.
They want to ask if there is some chemotherapy or targeted therapy option? Well, then the radiation oncologist and the patient and the medical oncologist have to weigh well, what is that systemic option? What is the likelihood it’s going to work? What’s the risk if you don’t, if it doesn’t work. So these decisions become quite complicated and they really require that there’s a functional team of people who are going to work together.
It’s also one of these kinds of scenarios where often there’s not necessarily one right answer. It depends a lot on what’s important to the patient. So, if what’s important to the patient is avoiding whole brain radiation at all costs, there might be a different answer than if what’s most important to the patient is I want as long a period of time before I have to deal with anything else going on in my brain.
Those are really important discussions that we have with patients about what is their most important goal, because we might have different recommendations, but depending on what the patient’s most important goal is.
Yeah, that’s complicated. So it sounds like what you’re saying is that it’s first and foremost, really important to have a team that is working together in a comprehensive manner to collectively decide along with the patient about what is the best approach for treating their particular brain mets.
That’s exactly right. I think this is one of the things that I hope that this initiative will help people find, because I think it is hard as a patient to find the right team. And yet that’s one of the most important things that really affect the quality of someone’s care.
Yeah, I agree. It’s really important. And it can be very difficult as a patient if you don’t have that, because that leaves the burden of coordinating care to you rather than a team that’s already established. So that can be very difficult. With your role as a medical oncologist, you focus on the drug side of the treatment, although you’re involved in collaborating with the team, you’re making decisions about treatment. And so I wanted you to talk about the drugs that are available to treat the brain. If you could also discuss how the blood brain barrier affects the drugs that are available to use, that would be great.
So the blood-brain barrier is something that we’ve evolved to basically keep toxins out of our brains. And in the normal brain, there are these barriers or junctions that are very tight and they really keep out a lot. What happens though, is that in brain metastasis, those barriers get broken down because the tumor sort of breaks through those barriers.
And so as it turns out many drugs that don’t get into the normal brain all that well, actually get in decently enough in brain metastasis that we can see some activity. So one of the things that has set back the field for a long time, is making the assumption that if something doesn’t cross the normal blood brain barrier, it can’t possibly work.
And we now have many examples that that’s not true. So ultimately what we have to do is just test the drug on people who have brain metastases and see if it works. But there are some treatments that work and I’ve listed a few of them here focusing on HER2 first. So for HER2, you know, the drug that probably comes to mind most often is a medicine called to Tucatinib, which is an oral pill.
It targets HER2 kind of from the inside out, whereas Herceptin targets HER2 from the outside in. Tucatinib is typically combined with an oral chemotherapy called Capecitabine, along with IV Herceptin. This combination of three medicines has been shown to be effective in patients with brain metastasis. And this has been shown in a randomized trial where it was shown to be better than just Herceptin plus chemotherapy. So it wasn’t a randomized trial against nothing. It was a randomized trial against a normal, HER2 chemotherapy combination and showed actual extension of survival in patients with brain metastasis and is FDA approved for this use. There are other compounds though that have activity defined as if you treat people with brain metastasis.
Some of those patients will have tumor shrinkage in the brain. And some of those patients will have extended survival with the medications. And so these include medicines like Neratinib, which is an oral pill, usually paired with Zeloda chemotherapy. T-DM1, otherwise known as Kadcyla, which is an IV medicine.
We don’t use Lapatanib so much anymore because we have Tucatinib and Neratinib, but it is around and in some countries where the other drugs are not available, it’s still used. We recently showed that by increasing the dose of Herceptin, just regular IV Herceptin, that we might see some additional activity. This is only a phase two trial. So I would not consider it the usual go-to, but it’s something that could be considered. There is actually also a phase two trial that has been presented for people with leptomeningeal disease, so cancer in the spinal fluid that you can actually safely give Herceptin or Trastuzumab directly into the spinal fluid.
That’s what intrathecal means or intraventricular through a special type of port that goes into the spinal fluid. It also has some activity and then, stay tuned, there’s a lot of questions about whether Enhertu has activity in the brain and there will be additional data presented this December at San Antonio.
So I think that’ll be interesting to see. There are some chemotherapies that work in the brain and so we can pair them with just regular IV Herceptin, and sometimes they do work. So for HER2, this is kind of the working list. And then there are on top of this, which I haven’t shown you are quite a number of clinical trials that allow people with brain metastasis. Some of them combine T-DM1 and Tucatinib or T-DM1 and Neratinib or Enhertu and Tucatinib, I mean, there’s all sorts of different combinations and there are new oral medicines that the hope is that they might be better even than Tucatinib or Neratinib. So I think there’s a lot going on there. For patients who have estrogen receptor positive or triple negative breast cancer.
There are drugs that have some reported activity, but the sort of strength of the evidence is not as strong, meaning that, rather than randomized trials or really very tightly controlled phase two trials. They might be more like a hospital team writing in and saying, we treated a certain number of patients with this medicine and look what we found.
So you can believe that there is some activity, but the strength of your certainty about being able to quote a chance of it working is not the same as we have for the HER2 drugs. But with that caveat, you know, there are drugs that work in the brain. And so we’ve seen things like Capecitabine or Xeloda chemotherapy work. On the right is a picture of actually somebody, we treated our institution who had a really dramatic response to her Xeloda.
This is not from radiation therapy. This is just from chemotherapy. Some of the platinum medicines can work. Some of the anthracyclines like Adriamycin or Doxil. And then there’s sort of like a mishmash of other miscellaneous medicines that we have seen some activity with in some patients.
So there are some options for people with estrogen receptor positive or triple negative breast cancer. But I would say that the options are overall a bit more limited. I think this is an area where we very much need better clinical trials.
I agree. When you’re speaking about clinical trials, why is it important for patients to participate or do you think it’s important for patients to participate? Is that something that you encourage your patients to do?
The way that I look at clinical trials is that there are multiple benefits to different types of people. And what I mean by that is that obviously sort of the reason that clinical trials are in place in the big picture is to understand whether medicines or different approaches are effective.
In hopes that if they are, they can be applied to a big population of people. So, whether it’s to try to get an approval for a drug or whether it’s to show a new standard of care, you know, that scientifically the reason a clinical trial is done. From a patient centered perspective, you know, in many cases, not all cases, but in many cases, a clinical trial could represent an interesting or good treatment option. Now, if we knew that the trial treatment was going to be better than all standard therapies, it wouldn’t be a trial anymore. It would just be approved therapy. So I can never promise to patients that the trial treatment is going to help them. But at the same time, I can’t actually promise that a non trial treatment is going to help.
I kind of think of a clinical trial as another option that can be weighed. Just like every option that you weigh you want to say, well, what do you think is your best guess as to whether it’s going to be effective or not? Not that we can be sure. The way that we might think about it is, well, does the target look good? What’s the preliminary data with the drug? Are you the first person in the world to get the drug versus the, you know, 500th person to get the drug? Because there are trials that span the whole continuum. Why do we think this medicine might work in people with brain metastases?
I try to share with my patients my personal feeling of whether I’m excited about a trial or not. I don’t ever make promises because you just can’t promise anything in breast cancer. And you just don’t know, we don’t have a crystal ball, but I think I think of it as really another option. I have a patient who enrolled on the HER2 Climb clinical trial with Tucatinib like four years ago, almost five years ago now. I take care of people who, you know, were on the original Abemaciclib clinical trials, like the phase one clinical trial. And they’re still on treatment now. I mean, it’s this fraction of patients. We have to be realistic, but at the same time, these are people who are alive and still on their trial treatment years later. I take care of somebody who now has been on immunotherapy for triple negative breast cancer with lung metastasis for six years.
She was on this medicine years before there was an FDA approval for any immunotherapy, for breast cancer. These are the kind of situations that give me hope and, you know, again, I, I really try very hard not to over promise, because you really don’t know. And for every person who does amazingly well, there are unfortunately people who don’t. But I think it’s one of the real treasures of working in the environment that I work in to be able to really see the difference that we can make.
Those are phenomenal stories. It’s important to have hope when you are in the situation like myself with brain mets or other patients who come to see you.
The one thing to note with clinical trials is that you’re going to receive, if you don’t go on the clinical trial, you’re going to receive the standard of care. It’s not like you’re going to receive, you know, a placebo or what some people refer to as a sugar pill if there are two arms to the trial. Is that the proper way to say it?
So you’re not going to get a treatment that’s no treatment. So for example, in the HER2 Climb trial, there was a placebo, but it was a placebo for Tucatinib and everyone got Herceptin and everyone got chemotherapy. So sometimes there are placebos, but they’re kind of like that. We don’t really have any trials in metastatic breast cancer that I’m aware of where it’s a treatment versus a placebo only treatment.
The other thing that’s important while talking about clinical trials is that, every drug that you take, that drug was once a clinical trial.
So it’s important. I think, just to recognize that when you’re on a clinical trial, often it’s the most exciting and new drug that could possibly be FDA approved. And what you would take if you didn’t go on clinical trial was once a clinical trial drug. And so it’s kind of a circle.
I think the science has really advanced. When I was a medical student -let’s just take the existing chemotherapies we have off the shelf and just give them the highest dose we possibly can. You know, there’s not a lot of science behind that other than these are the drugs we have. And if a little bit as bad is good, maybe a lot is better. I mean, that was literally, you know, how some clinical trials were done, because we didn’t have anything better. And now there are almost no trials that are just for breast cancer in general.
There are trials for HER2 and there trials for triple negative and trials for estrogen positive. And there’s so much science that goes behind the drugs that are in trials, and there’s a lot required by the FDA before a company’s allowed to test anything in people, you have to come in with a whole package of why scientifically you think your treatment is going to be effective.
Again, many things fail. I’m not saying that they don’t. But I think that the scientific basis behind the treatments that are being tested in the trials is so much stronger today, that it is a different experience going on a trial today than it was 30 years ago.
Oh yeah. That’s really interesting.
It’s not something I was aware of. Well, in speaking of clinical trials and having access to them I think they’re really important to participate in. So how does that work in terms of second opinions, because a lot of people are treated in places where there aren’t clinical trials and, and so do you feel that patients should get second opinions with brain mets?
You know, I think that if someone can do it, and there’s many logistical barriers that we still need to fix, I do think it’s a good idea if it’s possible. I think it’s because even if it’s not just for a clinical trial, it’s also partly for the ability to have an expert multidisciplinary team that can sort of weigh all the options and put them together with the patient. And I think that’s just something that’s really valuable in centers that specialize in people with brain metastasis that is beyond what trials they have on offer.
On top of that, you know, I think the existing way that people find out about trials. Which I know this organization is trying to fix, or at least contribute to an improvement in is fairly haphazard, right? Because, you know, if you go on clinical trials.gov, it has every trial, but it’s hard to really search for the one that fits you.
So it’s very complete, but it’s hard to sort of match with a trial with that website. Any one doctor is going to have a hard time knowing every trial that’s available in the U S like, I don’t know every trial that’s available in the U S. I think an advantage of going to a place that, you know, has a brain mets program, or if not a formal program, people who this is their interest is we all have our friends across the country and their informal networks.
And I know what studies are open at UCLA because I know my friend at UCLA has these studies open and I know it seems kind of crazy in 2021, that this is how we find out about different trials, but it is sort of how we found out about different trials. You know, I’m really hoping that the systematic effort that you’re so involved in is going to help that because I think not only do patients need help, but doctors, we need help as doctors.
And you know, when I see somebody who comes from far away, and is willing to fly anywhere in the country for a trial, I would really like to be able to honestly tell them I looked at all the trials that are available for you in the country. And this is the one I think you should go for. And right now there’s not a mechanism to do that.
There’s a lot of, sort of word of mouth and keeping tabs sort of thing. And again, I’m hoping that this effort that you are such an important part of is gonna make a difference.
Thank you. We will have a search engine or we do have a search engine on the website, and hopefully that process will be a little easier using that search engine.
And, we also have listed the places for second opinions that do have a comprehensive brain metastasis program. And while those are scattered across the US, we also list NCI centers, or where you can find NCI centers which are more likely to be offering clinical trials.
So hopefully if you’re looking for something like that, you can check that out on our website and hopefully it’s useful to doctors too.
So I think that, you know, sometimes patients can get in, you know, some people are very savvy and they’ll get right on the search engine and they’ll find the trials and they’ll sort them themselves. I mean, really, you are like super savvy Lianne. Right. You bring me trials that I might not have seen before and we look at them together. But, but I think the value of the website also is that, you know, if you’re a patient. You can ask your doctor to like add a visit, you know, you could ask your doctor to search it with you and they could give you their thoughts about which trials might be worth traveling for.
And so I think it can also help in a more collaborative fashion as well. Right now, if somebody asks me to do a clinicaltrials.gov search I don’t want to, you know, say bad things about them because the website is very good for many, many things. But if somebody came to me and said, I want to look for all trials for ER, positive metastatic breast cancer. Let’s see what there is on clinicaltrials.gov. It’s really not possible to navigate in a clinic visit. So I think that what you guys are doing is so important because if you get it down to like bite sized pieces, that really are focused on somebody’s specific problem, then it really becomes something that you can use as a tool with your doctors.And I think that that would actually be a great use of the tool.
We hope that patient’s doctors do use it that way together. And the clinical trials.gov has great features, but as someone who has used it, there are just thousands and thousands of trials listed and it can become very difficult looking at.
If you find the trial you want, then it’s great because you can see what the inclusion, you can see the exclusion, you look, you can look at the 174 locations the trial is open at. It works really well, but if you don’t know what you’re looking for, that’s when it becomes challenging.
Dr. Nancy Lin #5 – What is the Prognosis for Brain Mets?
So let’s talk about prognosis. It’s a challenging topic, but it’s important that we address it.
It’s a really challenging topic because it raises questions and thoughts that we don’t often like to think about. and also because there is a lot of variability in breast cancers. You know, if we look at someone with stage four pancreatic cancer there isn’t that much variability, unfortunately, you know?
And so when people are given a prognosis it’s not that different from one person to another. And I think one of the things that gives me hope about breast cancer, but it’s very hard with breast cancer is that there is a lot of variability. And there are people with brain mets who survive 10 years.
I take care of some people who are 10 years out with a diagnosis of brain mets and they’re doing very well. There are people who died within six months of the diagnosis of brain mets. And so when you give an average, you’re averaging those two sets of people and you know, it wasn’t very different to be thinking that you have less than six months versus you have 10 years.
And how do you communicate that with patients and how do you think about it as somebody who’s living with cancer in the brain? I think that’s really hard. The advice I do give to patients when you hear median survival or average survival or prognosis usually when people ask about prognosis, they’re asking about what’s the average survival. That’s how we answer the question. But it’s not a cliff list. So everyone thinks if you’re told six months, or you’ve been told two years, if you’re told whatever time that is, it feels like there’s a cliff and you’re going to get to that point and you’re going to fall off a cliff.
And unfortunately, some people don’t make it to the average. And a decent number of people make it beyond that because the way that we give our numbers is half the people don’t make it to that point and half the people make it beyond. Like 50% of people make it beyond the average that you’re being told. So I think again, that’s one of the tricky parts about breast cancer.
I do think that if you’re ready to hear about prognosis, it’s a good thing to ask your doctor. When you’re planning your life and the things that you want to prioritize and what you want to spend time doing, it is helpful to have some sense of what the range might be. And I think that might be a more useful way to think about it is, you know, what’s not the average, but what’s the range.
What’s the average scenario? What will be the best case scenario? What would be the worst case scenario? Unfortunately, there are people who I take care of and, and the best case scenario is a couple months. There are people who have really bad disease, but they’re also people I take care of where the best case scenario is years. I think if you are somebody who’s ready to hear that information, it’s a good thing to talk with your doctor about. If you don’t feel comfortable talking to your doctor sometimes, you know, you’ll work with a nurse practitioner or physician’s assistant, you could start with them first.
I think that over time, people are ready for different things too.
I agree that it definitely changes with time. Communicating to your doctor, how much information you want in order to be able to prepare or understanding that I’m preparing for this long, but expecting and hoping for this long. I think it’s important for patients to remember that it is an average and that what you just said is so spot on that, you’re averaging together very variable prognosis of life and, I try to tell people just in the end remember that you, you aren’t that statistic really no one is that statistic because it’s an average.
Where we become more accurate is when things really accelerate at the end. So when it comes down to someone having less than three months, are we perfectly accurate? No, of course not. I’m still surprised sometimes with how quickly things can go.
But, usually if somebody has less than three months, that we’re fairly accurate about. If a patient hasn’t brought it up proactively, I’ll start to, when things turn like that, I’m going to start to bring it up proactively. Cause I just think it’s important when people make decisions about next steps to weigh that.
But, you know, the reality is I’m not very good at predicting two years versus five years. Actually not at all. I think we just have to be honest about our limitations, about what we can predict and what we are not so sure about, especially as the treatments keep changing over time. Yeah. That’s something to consider.
From my own perspective, when I entered into the brain mets world, one of the drugs that helped me the most technically didn’t exist. So we were looking at averages without that drug and then for it to enter, it totally changed the game for me personally. And so you never know what’s coming up next and the research is moving in the right direction for those with brain Mets. So that kind of, kind of leads into being hopeful. And while nobody here, we, you, me is telling anybody to be, you know, positive or Pollyanna about this, because it’s very challenging, but there are cases of, I mean, I think it’s important to highlight some cases of hope and you have some of those to share I think.
I do. So I mean, I can tell you a few stories. I’m not going to tell any names. I’m not going to put some dates on it just to keep things confidential, but they are, these are real people. You know, there’s a person that I care for who was diagnosed actually now over 15 years ago with her brain mets and, received radiation treatment as was standard of care. And she’s like one of the lucky ones, like, I can’t explain why she has done the way she is. There’s nothing about her, or that’s different from many other people I take care of other than she has HER2 positive breast cancer, but now all these years later, she’s on Herceptin IV.
You know, and she’s had no progression of her cancer anywhere. It’s not like I had anything to do with it. It’s just we do see these people who have what we call exceptional responses and it doesn’t happen all the time. But it’s not like it’s one in a million either.
So I think for HER2, we are seeing people sometimes who live for years after a diagnosis. But, you know, I think this is where, how things evolve over time is something we can’t predict. So I couldn’t have predicted when she first had brain mets that nothing was going to happen in such a long time.
I wouldn’t have been surprised if something had happened. You know, a year into her brain mets diagnosis that we needed to treat again or wherever it is. So, but you know, again, if you ask pretty much any oncologist who takes care of breast cancer patients as their primary specialty, they’ll be able to name you people who are like this person.
I also know of a person with triple negative breast cancer, who, because she had so much disease actually in her liver and a little bit of disease in her brain. Her doctor decided to treat her with chemotherapy, and then deal with potential radiation to her brain after hopefully her liver responded to her chemo.
And when she had her repeat scans, actually both the cancer in her brain and her liver had gotten better. She actually stayed on that treatment for a period of time. I’m not saying that everybody’s like this, these are exceptional patients, but she had to come off treatment because of problems with her blood counts.
She was off of all treatment for two years, and that’s incredible. So again, these are not common situations, but I think that, and I want to be really careful not to, you know, over promise. But I do know from doing this for a long time, that people surprise me all the time and you Leanne, I mean, I don’t know how much you want to share about your story, but I mean, you know, certainly beyond the average survival and, and we’ve treated you with a variety of regimens, not all of which are necessarily the usual strategy.
I don’t mind sharing at all.
I think the frustrating part has always been like the location, right. Because if you’re, if your brain met had been anywhere else, like you would be even that much better. And, again, when I first met you, when your other doctors first met you, I mean, none of us would have promised that you would get to this point at all, but we would have told you that it’s not impossible that you could get it to get to this point. And then we see other people get to this point and you have, and I think that’s one of the most important parts about the research is like, you know, not to give up on, on patients and I don’t mean this in a way, like when it’s time, I am all for hospice. I’m very honest with patients and I will tell people when I think it’s time. I believe very strongly in honesty. But it’s also true that I think it’s important to share the patients who’ve done far better than we expected because they are not rare.
And because when we see patients like that, we know what’s possible. You can start to see what’s possible and you want it for more people.
Yeah. I mean, when I was first diagnosed, for those who are watching, I was diagnosed with brain mets only. So it was unusual and it was my first site and there was a number of them.
I think it was for those meeting me, you and other oncologists, you know, it didn’t necessarily look good from a standpoint of like she just finished early stages is now progressed to her brain and her brain only. But then here I am five years later. And while I prepared for a year, maybe two, I never let myself stop thinking that longer was possible. And, you know, I’ve fallen into that category of things being lucky or whatever you want to call it. But I think it’s important to remind yourself just that you aren’t a statistic and to take it day by day as best that you can.
I agree. And I think when you ask, when you talk to your doctor about your prognosis or when you go online and you research, which I do think is a good thing to do. I think there’s a lot of information you can get online. I’m not somebody who tells people like don’t go online. but I think that where your doctor can come in is saying for you specifically, what do they think? Because you know, your doctor knows what treatments you’ve gotten before. How many spots are in your brain, where they’re located. What the pace has been. There’s like all these factors that really are not captured in the average, it’s just everybody. When you’re talking about prognosis, I do think it’s important to ask your doctor, like for me specifically, what do you think?
And you know, that you’re not going to be able to have a crystal ball and you know, it’s not going to be perfect. And you might ask for range rather than like, this is the average, but I think it’s totally fair to ask, have you seen people go longer than that? You know, I think that’s a totally fair question. And if you’re ready to hear the answer to that question.
To me it’s so important to have an open dialogue with your doctor throughout all of your metastatic treatment, regardless of whether it’s about prognosis so they know where you’re at and what kind of information you want.