Transcription:

John Leonard, MD (Host):  Welcome to Weill Cornell Medicine CancerCast; conversations about new developments in medicine, cancer care and research. I’m your host, Dr. John Leonard and today, we’ll be talking about brain tumors. My guest today is Dr. Howard Fine. Dr. Fine is Chief of the Division of Neuro-Oncology at Weill Cornell Medicine and New York Presbyterian Hospital. He’s the Founding Director of the Brain Tumor Center and Associate Director for Translational Research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. Dr. Fine is an internationally recognized leader in the field of neuro-oncology with nearly three decades of experience in laboratory and clinical research as well as the patient care for patients with brain tumors. Howard, it’s great to have you here today. Thanks very much for joining us. It’s been nice to interact with you in various venues here at Weill Cornell and New York Presbyterian and it’s good now to learn about your thoughts for our audience on where things stand and where things are moving forward in brain tumors. So, thanks for joining us.

Howard Fine, MD (Guest):  Thanks for having me John. It’s a pleasure.

Host: So, let’s get right into the details of how brain tumors present themselves, how things go for patients. But people are used to hearing about cancers and familiar with cancers being diagnosed in screening tests or sometimes in advanced stage disease depending on the site of the disease with specific symptoms to one area. How do brain tumors most typically, whether it’s a benign and we should say, there are benign and malignant tumors or growths affecting the brain. But how do these typically present to patients given that the unique way that the brain is situated and the role that the brain has in someone’s day to day life?

Dr. Fine:  There are two major categories of brain tumors, primary and secondary. Secondary brain tumors are actually more common are tumors that come from systemic or body tumors. So, someone with a lung cancer or breast cancer or colon cancer, cancer can spread to the brain and affect patients that way. Primary brain tumors are tumors that start out in the brain. They come from the substance of the brain and the two are different as you could imagine, because obviously, if it’s a secondary tumor, patients usually already know they have cancer or a tumor and so it’s another site of metastasis. Primary brain tumor patients are fine but then they present with – come to medical attention because they develop some neurologic symptoms. Very commonly, it may be a seizure, it may be a headache, it may be some neurologic symptom like weakness in one of the extremities or difficulty in speaking or patient’s families may notice some unusual behaviors.

So, as you could imagine, the many functions of what the brain does, any tumor that disrupts that area of the brain could present with a new neurologic symptom associated with that and one thing leads to another and ultimately, the diagnosis, at least the initial diagnosis is made by someone will get a nowadays, most likely an MRI scan of the patient’s brain and a lesion will be seen. And that starts the diagnostic process.

Host:  Are there some scenarios and given that there are some brain masses or tumors that are benign; the one that comes up occasionally in my patients are meningiomas and in some cases, and I’ll ask you to describe what that is as well as any other benign tumors that may come up where a biopsy isn’t necessarily done or needed because they look fairly typical or characteristic so you may watch them. Can you just comment on that before we get into the more malignant tumors?

Dr. Fine:  That is one of the difficulties in talking about brain tumors because beyond the primary and secondary categories that I talked about, even if we go to just primary brain tumors, tumors that start out in the brain, we’re probably talking about anywhere between 20 and 30 different types of tumors and within each of those categories of tumors; there are subtypes that have profound influences on how those tumors may be treated and how they may respond to treatment, their prognosis and so forth. So, we’re really not talking – when we are talking about say breast cancer, although there are several different types of breast cancer; there’s three or four different types. Same thing with lung cancer. Again, we’re talking about many, many, many different types of brain tumors, all of which are hugely different. But you are correct that some of the more common types of brain tumors can behave very benignly, can be found incidentally, a patient bumps their head and goes to the emergency room, they get a scan and we see something on the side of the - on the surface of the brain and those kinds of tumors – some of those tumors can have such a characteristic look on MRI scan that we can be 99. something percent sure that it’s a particular type of tumor, the type of tumor for instance that you just talked about, meningioma is more often than not a benign tumor of the surface or the lining of the brain and in many of those patients, we can be certain of that diagnosis and because generally they are not as I said, malignant, we can just watch them and if they never change with serial MRI scans, we often don’t need to do anything.

Unfortunately, as I said before, even within that group of meningiomas; there are rare types of meningiomas that can behave much more aggressively and need to be taken out surgically and sometimes even have additional therapies and there’s even rare malignant meningiomas. So, again, it’s a complex area. But you are certainly right. There are certain tumors like meningiomas, tumors of the pituitary gland which is a gland in the middle of the brain that kind of is the master hormonal gland that look so characteristic and are generally so benign that sometimes we’ll just follow them with serial MRI scans and in some patients, we’ll never need treatment.

Host:  What are risk factors for brain tumors? And I assume it depends a little bit on the type but, certainly things that come up that I would ask you, age comes up in many cancers and then perhaps if you could mention some of – since we are talking about risk factors in a second, things that people worry about, like I’m sure the whole cell phone issue comes up a lot with people asking about that. But any other environmental things that come to mind or we can rule out perhaps in brain tumor risk factors?

Dr. Fine:  Yeah, that’s a great question and people have wondered that for a long time, when the whole cell phone story broke about 20 years ago, Congress actually gave us and a group of epidemiologic investigators from the National Cancer Institute and from some of the big brain tumor centers across the country a huge sum of money to do an environmental occupational epidemiologic study to identify environmental and occupational risk factors for all kinds of brain tumors and the upshot of that basically ten to fifteen year study with thousands of patients is we identified no risk factors. We ruled out a number of risk factors such as cell phones, so cell phones do not predispose you to any type of brain tumors but there really has never been identified a risk factor with the exception of some very rare types of situations. So, for instance, If you have been exposed to radiation to the brain in the past, you have an elevated risk particularly of those meningiomas, particularly the rare type of meningioma, the malignant meningioma and you have a slightly increased risk of a more common type of brain tumor known as a glioma.

But most patients who get brain tumors don’t have that risk of having had cranial radiation. So, the bottom line is that we do not really understand the reasons that the vast majority of patients that get brain tumors get brain tumors. One thing we know is they don’t run in families so as opposed to prostate cancer; breast cancer that tend to have the familial disposition; that’s not true for brain tumors so I can always reassure my patients that the likelihood of their family members or their children having these tumors is extraordinarily low since they are relatively uncommon or rare tumors. But we really don’t understand what causes them at this point.

Host:  So, are pretty much all patients with the brain tumor perhaps with some exceptions based on the imaging so, as you mentioned, they come to light with a symptom, they may get an MRI scan; is pretty much everyone going to get either a biopsy or a surgical resection or some combination of both? Is that pretty much for everyone a central part of the story, a surgical procedure to both diagnose and potentially treat their tumor?

Dr. Fine:  I think that’s fair to say. As you pointed out, and as we briefly discussed, there are certain types of tumors where we’re so certain that we know what we’re looking at and that they could be benign enough that they may not need treatment. There’s a small subset of patients that we offer an approach we call wait and watch which is exactly what it sounds like which is we’ll just – the patients aren’t having symptoms from the tumor; we don’t think they are tumors that would probably need to be treated right away. So, we’ll get serial MRI scans and in some of those situations, again depending which tumor we’re talking about; some of those patients can be followed for decades and never need any kind of surgical or other type of therapeutic intervention. But that’s an uncommon situation. And the vast majority of patients as you point out, will ultimately need some kind of surgical procedure for at the very least to make a tissue diagnosis and often more often than not, our larger surgical procedure to take out as much of the tumor as possible is part of the first step in therapy.

Host:  So, one of the things I’ve learned from you and the occasional patients that we’ve shared is the importance of a multidisciplinary kind of what’s termed tumor board where a patient presents, maybe in the clinic, maybe in the hospital and you have your involvement as the medical oncologist, the neurosurgeon, the radiation oncologist, the pathologist, the imaging physician, perhaps others as well. I mean I think this is a reflection of kind of the multidisciplinary care which is essential for this group of patients particularly given the uncommon nature of brain tumors and obviously the seriousness of them. And it seems to me like – a place like Weill Cornell and New York Presbyterian is very able to put that together well as opposed to the pattern of someone going and seeing a neurosurgeon, having a procedure then later going to see the radiation oncologist and then having them do their thing and then later seeing the medical oncologist. So, it seems like having a very coordinated multidisciplinary assessment and plan formulated is really a huge part of all of this. So, I wonder if you could just kind of give your thoughts on that and kind of how that typically works for your patients who go through this sort of program?

Dr. Fine:  Yeah, no, you are 100% right. I mean I think more and more so, almost all cancers require expertise from multiple disciplines, but I would venture to say that brain tumors, for many of the reasons you articulated are even more so. So, I mean from the initial diagnosis. So, a person as we talked about already, has some neurologic symptom, someone gets an MRI scan. We see a shadow in the brain and that starts the process. And the process at that point, often starts out with very much more advanced next kind of generation imaging. So, not just the standard MRI scans. MRI scans are not created equal and there are all kinds of specialized MRI scans which with all kinds of different bells and whistles, both hardware and software that give us additional information of what we were looking at to help us make decisions about whether we do need to do surgery and what kind of surgery. There are all different kinds of surgical approaches that could be taken and what part of the tumor can and cannot be taken out. There’s nuclear medicine expertise to help with that imaging.

And then before surgery, we often have patients go through extensive neurocognitive testing to find out the key – what deficits they may or may not already have. There are ways of doing interventions where we give medicines in selected arteries to shut areas of the brain down temporarily for just a minute or two using drugs to see what would be the effects in surgery if we remove that part of the brain that has the tumor in. And so, all this preoperative types of testing that as I said, are involved. Nuclear medicine people, radiology, neurologists, neurophysiologists. Not to mention the neurosurgeons. Then the patient goes to surgery. We often do surgery with patients awake and they are not in any pain. The brain has no pain fibers but we do that so the patient can be moving or speaking if we’re operating in the language area of the brain so we can make sure we are not hurting things.

And we have electrophysiologists in the operating room who are stimulating different parts of the brain to tell the surgeons yes, I can touch or take out that area, no I can’t touch that area. Then the patient – when they recover from the surgery have to go to special neuro-intensive care units which are not available in most standard hospitals around the country. Then there’s the extensive rehabilitation, speech rehabilitation, cognitive rehab, physical and occupational rehab. And then again, we get back into the imaging and then there’s often need for radiation therapy. And the standard radiation oncologist is not the standard brain tumor radiation oncologist. It’s special training to know what to do – how to radiate brains. There’s all different types of radiation from radiation that the radiation oncologist actually can put radioactive seeds into the tumor at the time of surgery to giving special types of focused radiation called gamma knife or stereotactic radiosurgery to whole brain, whole spinal radiation. So, that’s a whole area of expertise.

As I mentioned, obviously neuro-oncologists like myself who are trained specifically to just take care of these types of tumors. We have special neurologists, epilepsy neurologists because these patients as you can imagine often have significant seizure problems and we rely heavily on our seizure specialists to help us manage those. So, yes, and that’s just a touch and you could imagine many of these patients have significant social issues at home so, psychosocial support, neurocognitive training and rehab and support. So, it really does demand – oh and I didn’t even mention the neuro-pathologist. In the old days, we just looked under – the pathologists just looked under the microscope and said this is this tumor, this is that tumor. But one of the many ways that neuro-oncology has changed dramatically, literally in the last three to four years is we’re getting rid of standard pathology and going much more towards molecular and genetic pathology. So, increasingly so, these tumors are being diagnosed based on their genetic profile. So, the neuro-pathologists are now becoming molecular pathologists as well as neuro-oncologists and of course they are vital because we have to know what type of tumor, we’re treating to know how best to treat it.

So, it really does require a huge team and all these people I just mentioned, all they do is take care – at a place like Weill Cornell; all they do is take care of patients with brain tumors. So, we don’t have, as I said, general radiation oncologists. We don’t have general pathologists. We don’t have general oncologists taking care of patients. Our whole team is devoted, and their entire careers are devoted to nothing but brain tumors.

Host:  So, that’s really impressive and I think it highlights the need for really specialized care and expert care in diseases like this. As you’ve also pointed out, there are still a lot of challenges in brain tumor care and outcomes for patients and while there has been progress; there’s still, for many patients, outcomes are not – often they are not as good as we would like. What are some of the things that make a difference for patients in a broad sense and I get that there are many different types? Also why has it been so hard to make more progress? And we can say that about many cancers, but it seems like brain tumors present a particular challenge or some particular challenges in improving outcomes. Your thoughts on that.

Dr. Fine:  So, again, I want to reiterate – I know I have said this a number of times but it’s one of the major take home points talking about brain tumors. Again, the idea that there are many different types of brain tumors and relative to long term outcome and prognosis and how effective our therapies are; that’s critical because there are tumors that we cure. Most of the meningiomas that we talked about. It’s also important to say that one of the most common tumors that children get are brain tumors and there are a number of curable, even highly malignant brain tumors in children that are curable. One of the most common tumors – brain tumors in children are called medulloblastomas and we cure approximately 60 to 70% of our children with that disease. So, there are successes. But that does mean that 30 to 40% of our children are not cured.

We’ve made advances in certain types of the most common type of adult brain tumor called glioma. There’s many different types of gliomas. There are some gliomas such as a glioma called an oligodendroglioma that we’ve extended survival from about three years to now over 20 years. and we expect that when those patients relapse say after 20 years, we’ll have even better therapies for them. But it is true that some of our most common and malignant tumors that generally fall into that category of glioma; we have not made the kinds of progress we’ve wanted and, in some cases, very little progress over the last three decades. And why that is, as I said, is a complicated issue not the least of all is because of the location. These are tumors obviously, in the most important part of the body, the brain and these are tumors – one of the unique things about most types of brain tumors including these gliomas compared to systemic cancers; most systemic cancers kill their patients by metastasizing, by spreading to other areas of the body. Interestingly enough, as deadly as malignant brain tumors can be, they do not metastasize. They kill patients by invading into the local surrounding brain tissue. Almost like sending roots into the brain.

And the point is, as you can imagine, you can’t dig out those roots surgically. And if you are going to try to cure the tumor, you have to get at those far extending tumor cells, those roots into the brain but that also means there’s a lot of intervening normal brain tissue that’s going to have to be treated too. And when you have prostate cancer; you can take out the prostate. When you have breast cancer, you can do a mastectomy and remove the breast. Not to say that those don’t have side effects both emotional and physical but if it’s needed to be done to save the patient’s life; the patient is willing to do that. You cannot take out someone’s brain. You cannot take out a large part of someone’s brain and leave the person in any kind of state that they, their family or we as physicians would consider to be acceptable.

And so one of the many difficult parts about treating brain tumors is the eloquent sensitivity and the necessity of the normal tissue that encompasses and surrounds these tumors. I should also say, one other, I think important thing as far as difficulty in treating these patients relative to chemotherapy and drug therapy is as many of your listeners may know, the brain is in this protected vault. It’s surrounded by something we call the blood brain barrier. So, normally, when you take drugs, when we give drugs, the blood vessels in out body are leaky so if you have a lung cancer, the chemotherapy leaks out of the blood vessels very easily into the lung, into the tumor to treat it. The brain have developed this – nature has developed this thing called the blood brain barrier to protect our most important organ from all the toxic things we put into our system and the blood brain barrier prevents a lot of molecules that are in our bloodstream from getting into the brain. And since chemotherapy and traditional drug therapy are seen by nature as kind of toxic drugs; most chemotherapies don’t pass the blood brain barrier.

So, even if we can develop effective therapies, many of those therapies don’t get to where the tumor is. So, that’s another major, major issue relative to developing effective therapies for brain tumors.

Host:  So, I think people are familiar and you alluded to the different types of surgical procedures and radiation procedures but a big part of this approach and probably the future, as far as making progress lies with medications. And I know there are some chemotherapeutic drugs that are used as brain tumor treatments, some new things that are either available or being studied. Give us a sense of kind of the medical or systemic treatments that perhaps won’t have the same sort of local affects on brain tissue as surgery for example.

Dr. Fine:  Well as I said, one of the major challenges in this field is not just finding drugs that are active against the tumor but drugs that are active against the tumor that will get into the brain and be able to get to the tumor. You can have a great bullet but if you don’t have a gun that can get the bullet to the bad guy, then it doesn’t do very much. But there are even traditional chemotherapies that because of their physical properties do have the ability to leak through the blood brain barrier and get to the tumor. So, there are some effective chemotherapies already. But just like in systemic tumors; we are increasingly going towards more sophisticated medications to try to treat these tumors, medications that are often under the umbrella of precision or targeted medicines. So, medicines that target the specific genetic mutations that we find in these tumors. Again, the challenge is not just to find the medicines that are effective against those genetic mutations but that have the ability to get to the tumor across the blood brain barrier.

Similarly, with all the excitement of immunotherapy, we would like to be able to bring that type of therapeutic strategy to bare on brain tumors. But again, the unique physiology, the unique anatomy of the brain and the spine, the central nervous system is a challenge because it turns out, that the brain and the spine hold this place that we call an immune privilege site and in other words, the standard immune system in our body doesn’t see the brain in the same way that it sees the rest of the body. Matter of fact, we don’t even have lymph nodes and regular lymphoid tissues within the brain. And so, all the rules for modulating the immune system to fight tumors in the body, are totally different in the brain and we’re only beginning to understand them and unfortunately, to that point, most of the immune therapies that have been successful for so many systemic cancers right now have not been successful for brain tumors probably as much for the reasons that I just talked about.

So, again, we’re very excited about the potential of immune therapy in the future but we still – we have additional hurdles that our systemic oncologists don’t have to deal with.

Host:  So, in addition to taking care of patients in the clinic, I know you run a translational research laboratory where you are developing new therapies and using new technologies. I’ve heard you present very eloquently on the mini brain type of program as part of the strategy to develop new treatments. Can you give us a sense of kind of what you’re excited about and what your laboratory and translational program are working on to try to solve some of these problems and bring new treatments to our patients?

Dr. Fine:  Sure. About 15 years ago, after having been in the field for about 15 years, it was becoming increasingly clear to me that the things that we – I was seeing in the clinic with my patients were not what was – did not really bare much resemblance of what we were studying in the laboratory and when I say us, I mean the field as a whole. So, the things that we were modeling as brain tumors, in our case, our major interest is in these tumors called gliomas. The glioma models we were using in the laboratory, whether they be cell models in petri dishes or whether they be animal models; they looked nothing like our patients as far as how they behaved and at a molecular and genetic level.

So, we became increasingly interested over a decade ago in developing model systems that we could study in the laboratory that looked more like our patients because we believe that if you can’t model what is happening clinically in the laboratory; how are you going to develop drugs. Because if you are screening drugs in the laboratory and what you’re screening against has nothing to do with what the patient has; what’s the likelihood of coming up with an effective therapy for that patient?

So, about ten years ago, we were one of the first groups to discover that these gliomas, these brain tumors actually start from a mother tumor cell that we call stem cells so a brain tumor glioma stem cell that most of the tumor cells that constitute the tumor actually don’t have the ability to grow and make new tumor cells, that there is only a small subpopulation of these tumor stem cells that are responsible for the growth of the tumor. So, we were one of the first groups to isolate and show how you can grow these glioma stem cells in the laboratory and in animal models of tumors and that instantly made the model systems much more clinically relevant than they used to be but still the problem was although we’ve spent a decade studying these glioma stem cells in the laboratory and learning their biology; the bottom line is we were still growing them on petri dishes, plastic or in the brains of mice which are not human brains.

And increasingly so, it was clear as I explained before, that not only do brain tumors affect the normal brain, but the normal brain affects how the tumor behaves, it’s in the biology of the tumor. And we really decided that if we were going to really be able to model how tumors behave in our patients, we had to be able to model how those tumor cells interacted with normal brain in the laboratory. And so, we came up with this at the time was thought to be a rather audacious idea of could we build a model of a patient’s brain tumor in a model of the patient’s normal brain in a petri dish?

And we’ve effectively done that. We were fortunate enough based on the work that we did, the preliminary work to win an NIH Director Pioneer Award and through generous funding through that and other grants, we’ve been able to build primitive human brains that are equal to about the 20 to 25 week old human fetal brain that have all the genetics of the patient’s own normal brain and show that we could take the tumor stem cells from the patient’s own tumor and retro engineer them into the patient’s own mini brain, in the laboratory and recapitulate the growth of that tumor in the patient’s own mini brain in the laboratory. And we’ve gone on to show that that at a molecular, genetic and in a drug sensitivity way really more closely recapitulates what’s happening in the patient than any other model system we’ve seen to date.

What’s nice also is that that system is scalable so we can make hundreds of CNN called the mini brains for each patient and screen hundreds to thousands of different drugs or different types of radiation against those mini brains and find the ones that look like they are going to be most effective for that particular patient’s tumor. Because all these tumors are different from one patient to another. And so how do you identify what’s ultimately going to be most effective for that particular patient and we’re hopeful that this mini brain approach will allow us to do that. We also received incredibly generous funding and a grant from the Star Foundation to make a high throughput drug screening core. So, it’s an automated robotic system that allows us to take these tumor mini brains, patient specific tumor mini brains by the hundreds and screen thousands of drugs against them to identify the one or two drugs or drug combinations that look most effective.

And what we plan to do over the next year is to do a prospective clinical trial where we will make mini brains from each patient’s tumor and then screen thousands of drugs or combinations, find the ones that look most effective, bring that combination of drugs back to the clinic, treat the patient with that combination obviously with the patient’s consent on a clinical trial and ask the question; is this the next generation of being able to predict how to actually get better therapies for patients. So, we’re very, very excited about that approach.

Host:  All right, it sounds to be a fabulous example of the precision oncology strategy which has worked in some areas of cancer and probably in many ways, has been at least before, a very difficult one to do in brain tumors but you’re moving forward in a very important way. So, thanks for really a great discussion. I just want to, before we wrap up, ask you, I think you’ve highlighted some of these issues but what for a patient who is newly diagnosed, I mean I think having access to cutting edge care and a multidisciplinary team is going to be key to have the best outcomes. Any other messages that you would give to patients or their caregivers or families if they’ve been diagnosed with a brain tumor as far as what they should do to optimize their chances for a good outcome.

Dr. Fine:  Yeah, I think what you brought out is the number one. Make sure you go to a center that has expertise specifically in treating brain tumors. There are a number of them but there are also many, many centers that don’t have that expertise. That’s been shown to make a difference. Also, don’t be afraid to ask for a second opinion. We don’t have the answers for all these tumors but there’s a lot of good ideas out there. Getting seconds and if you are inclined, third opinions I think are incredibly important. And finally, have hope that even the most malignant – like I said, I’ve been doing this for 30 years, but I can honestly say just in the last three or four years do I really see where this field has the real chance to make a huge impact in the very near future. And so, as much as everyone wants to and understandably will look at Google when they get a diagnosis; please appreciate that that’s history. That’s where we were. That’s not where we are at and that’s certainly not where we’re going. So, I think there’s still great reasons for hope out there should you be diagnosed with one of these tumors.

Host:  Well thank you Dr. Howard Fine for joining us today. This has been a great discussion. I want to also thank our audience and invite you to download, subscribe, rate and review CancerCast on Apple Podcasts, Google Play Music, or online at www.weillcornell.org. We also encourage you to write to us at This email address is being protected from spambots. You need JavaScript enabled to view it. with questions, comments and topics you would like to see us cover more in depth in the future. That’s it for CancerCast; conversations about new developments in medicine, cancer care and research. I’[m Dr. John Leonard. Thanks for tuning in.