Standard of care and novel therapies in the treatment of brain metastases

Podcast Transcript

Dr. Alex Rae-Grant:  Neuro Pathways, a Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology and neurosurgery. Welcome to another episode of Neuro Pathways. I'm your host Alex Rae-Grant, neurologist in Cleveland Clinics Neurological Institute. In an effort to explore the latest advances in neurological practice, today, we're talking with doctors, Gene Barnett and Manmeet Ahluwalia about the standard of care and novel therapies in the treatment of brain metastases. Dr. Barnett is the director of Cleveland Clinic's Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center and a neurosurgeon in Cleveland Clinic's Neurological Institute. Dr. Ahluwalia is a medical oncologist and associate director and head of operations for the Brain Tumor and Neuro-Oncology Center in Cleveland Clinic's Neurological Institute. Gentlemen, welcome to Neuro Pathways.

Dr. Manmeet Ahluwalia:  Oh, thank you for having me, Alex.

Dr. Gene Barnett:  Thanks Alex.

Dr. Alex Rae-Grant:  I'd love for our listeners to get to know you both better. Tell us a little about yourself, where you came from, where did you train, and when did you begin your career at the Cleveland Clinic? Gene, do you want to start off?

Dr. Gene Barnett:  Sure. I have spent most of my life in Northeast Ohio, both in terms of training and career. I went to Case Western for undergrad as well as a medical school and then joined the clinic back in 1980 for a residency and then after a brief foray in Boston and Edinburgh, Scotland have been here the rest of my career. So in all, this is my 39th year at the clinic.

Dr. Manmeet Ahluwalia: My journey started in medical school in New Delhi, India. After which I did a research fellowship at University of Toronto and then came over to Cleveland actually in 2003 when I started my residency in internal medicine at Fairview Hospital, which is one of the Cleveland Clinic Community Centers. I then left for my fellowship to Roswell Park Cancer Institute between 2006 and 2009 and the last 10 years or so, I've been at the Cleveland Clinic in the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center. I have been working with Dr. Barnett developing clinical trials and offering the best treatment options for our patients with brain tumors.

Dr. Alex Rae-Grant:  So Dr. Barnett, you've been at the Cleveland Clinic for a little while and have been involved in the treatment of brain metastasis throughout your tenure. What do you want clinicians to be aware of in terms of signs and symptoms of brain metastasis?

Dr. Gene Barnett:  Well, first, I think that clinicians need to be aware of how incredibly common brain metastases are in patients who have common systemic cancers such as lung, breast, melanoma and so on. So much so that oftentimes screening MRIs are now being done at the initial diagnosis of the cancer. In many cases, these tumors are without symptoms. It can only really be picked up on these screening exams. For those who do have symptoms, progressive neurologic deficit or seizures are probably the most common. It's rare that a headache actually is the premiere symptom.

Dr. Alex Rae-Grant:  Once we make this diagnosis. What are the traditional surgical approaches for treating patients with brain metastasis?

Dr. Gene Barnett:  Well, historically, the favorite approach was to do open surgery followed by whole-brain radiation. Over time, it's been found that whole-brain radiation has undesirable effects both in terms of memory as well as general cognition. And so with the development of stereotactic radiosurgery for which we use something called the Gamma Knife here, that we have an excellent alternative to both surgery and whole-brain radiation with a single treatment that provides both targeted treatment of the tumor while sparing the cognitive and memory functions.

Dr. Alex Rae-Grant:  So with all the new and emerging therapies that are coming, can you describe particularly the role of laser interstitial thermal therapy in brain metastasis?

Dr. Gene Barnett:  Well, whereas radiosurgery, stereotactic radiosurgery is very effective in many patients with metastatic brain tumors, there is that percentage of patients who fail either due to a progression of the tumor or due to local radiation injury called radiation necrosis. In those cases, laser interstitial thermal therapy or stereotactic laser ablation is an excellent option that provides a very good control and resolution of radiation necrosis. And when combined with multi-session radiosurgery produces excellent long-term control of recurrent brain metastases. There is a movement towards considering this in certain radiosurgery-resistant metastases such as triple negative breast, BRAF wild type melanoma and colon tumors, but that is not mainstream as yet.

Dr. Alex Rae-Grant:  Gene, can you elaborate a bit more about the Cleveland Clinic's radiosurgery program?

Dr. Gene Barnett:  So I, and we have been doing stereotactic radiosurgery for brain tumors since 1997. We have the oldest program in Ohio, one of the largest programs actually in the country having treated well over 6,000 patients with Gamma Knife stereotactic radiosurgery. Last year, we treated over 460 patients, most of which had brain metastases and we're one of two sites that are recognized by the manufacturer to give new practitioners to Gamma Knife training for surgeons, radiation oncologists, and physicists.

Dr. Alex Rae-Grant:  Dr. Ahluwalia, can you discuss what traditionally has been the role of chemotherapy in treating patients with brain metastasis?

Dr. Manmeet Ahluwalia: Yeah. As Dr. Barnett alluded to, traditionally, the major focus of treatment of patients with brain metastasis used to be either surgery, whole-brain radiation, more recently radiosurgery or interstitial thermal therapy now. The challenge for us was the chemotherapy, which worked very well in systemic cancers, did not work as well in the brain. And there were a number of reasons for that.

The traditional chemotherapy drugs that we use do not cross the blood-brain barrier as effectively. There are protein binding issues. There are issues of drug efflux pumps that exist on the blood brain barrier. So with all these things combined, the traditional chemotherapies that we used in our patients when we used them to treat brain metastases, the response rates, that means the shrinkage of the tumor only occurred in less than 5% of our patients. So traditionally, the role of chemotherapy was limited in these patients and was generally relegated to when the surgical or the radiosurgery or whole-brain radiation based approach has failed in these patients.

Dr. Alex Rae-Grant:  How has that changed in the last decade or so?

Dr. Manmeet Ahluwalia: In the last decade, there has been immense research done in therapeutics for cancer. What we found out is there are two different avenues that we are using on top of these traditional cytotoxic-based chemotherapies. These approaches either are novel targeted therapy based approaches, which basically are drugs that target these particular pathways which are genetically altered in a patient's tumor that is actually driving the cancer. The other approaches are immunotherapy-based approaches which boost patient's immune system to go and combat the cancer.

Dr. Alex Rae-Grant:  So what do you see on the horizon is novel therapy particularly for the patients with brain metastasis?

Dr. Manmeet Ahluwalia: We are very excited about these novel treatment options for our patients. And as I said before, they are under two buckets. One is the novel targeted therapy based approaches. So I'll take an example of lung cancer. As Dr. Barnett alluded to, it's one of the most common cancer that goes to the brain. And in most large cities it is responsible for around 50% of patients with brain metastasis since lung cancer is so common and goes to the brain so often. So in lung cancer, what we found out in the last decade that it's just not one disease, it's a smattering of different diseases which have different genetic alterations which may be driving subset of these tumors. So an example of that is EGFR pathway for example. This is altered in 15% of the Caucasian patients that we see in clinic but can be altered in 30 to 50% of Asian patients that we see in clinic. 

So now there are drugs which work very well against these tumors, but some of the newer generation drugs actually have excellent blood-brain barrier penetration. That means as compared to the traditional chemotherapies, these drugs actually go to the brain. So with traditional chemotherapy that I mentioned, the response rates were less than 5% but with some of these newer generation drugs, which target EGFR pathway, for example, the response rates are in the ballpark of 50 to 70%, so definitely much more exciting and promising approaches for our patients. The other approaches are immunotherapy-based approaches. A number of our patients have cancer that may not be driven by oncogenic-driven pathway that is actionable. That means we don't have a targeted therapy against the gene mutation or there may not be a gene mutation driving the cancer particularly.

So here, immunotherapy is often used and with some of these immunotherapy drugs which targeted the anti-PD1 pathway drugs like nivolumab drugs like pembrolizumab, we have seen response rates of 30% so definitely better than the 5% that we saw with chemotherapy. Sometimes when we combine these immunotherapies, the response rates can go up to even 40, 50%. The most exciting part about the immunotherapy is that when we get these responses, that's when the tumor shrink. These responses are durable that the shrinkage can go on for months to years. That's the whole premise of immunotherapy in these patients.

Dr. Alex Rae-Grant:  Can I hear you guys talk a bit about the team approach that you take to manage these patients and work on their best outcomes and involving them in research?

Dr. Gene Barnett:  We have a multidisciplinary brain tumor board that is held twice a week where those of us who participate in the diagnosis and management of brain tumors from all the different specialties get together and discuss many of these cases and really provide a team approach for individualized care for these patients. Also, we have a multidisciplinary clinic five days a week, every week day where we have all the specialties represented. And so we concur beside each other at any given time regarding a patient who happens to see us in clinic and get an opinion from multiple specialties on the fly.

Dr. Manmeet Ahluwalia:  I agree completely with Dr. Barnett and I think what it does is it gives us an opportunity to have this team-based approach to provide the best individualized treatments for our patients. I think we are in some ways in an inflection point in patients with brain metastasis because as he alluded to, we've had a very strong radiosurgery program over the years. We have avenues like LITT where we can even work in those patients where radiosurgery doesn't work very well. But we now have these exciting new novel therapies like immunotherapies and targeted therapies. So what we do is when we discuss these patients in our brain tumor board or in the clinic, when we are talking to each other, we are now focusing on what are the best ways to combine these approaches. For example, radiosurgery can relatively easily be combined with most of our targeted therapies or immunotherapies. So what we have done in terms of, particularly in clinical trials, so for example, we have a clinical trial of this drug called osimertinib, which is a targeted therapy that works extremely well with EGFR-directed brain metastases. We have a trial where we are combining radiosurgery with osimertinib.

This is based off an experience where we looked at 350 patients with EGFR-mutated tumors where we found that when you had combined radiosurgery with the first generation drugs, which targeted the EGFR pathway, we got the best outcomes compared to those patients where we give the drug first and then gave radiation at salvage. So our new study is looking at these combinatorial approaches where we are looking at safety and as well as the effectiveness of these combination-based approaches because we want our patients to get more durable responses. So radiosurgery, for example, can work in the brain very well, 80 to 90% for local control, even at a year out. But one of the challenges with radiosurgery is it doesn't target the microscopic disease because you are only focusing the radiosurgery at these lesions that you can see actively on the brain MRI. But when you can combine it with these targeted therapies, they can stop these small microscopic disease from turning into macroscopic disease. So I think a big focus of our efforts here at the Cleveland Clinic working with some of the top centers in the country is to look at these combinatorial-based approaches for the future.

Dr. Gene Barnett:  I believe there has been some evidence already that the combined approach is superior to either one alone.

Dr. Manmeet Ahluwalia: Absolutely. You're spot on. We and others have published on this extensively. We've had papers where we have looked at immunotherapy combined with radiosurgery being superior to what we had seen with either radiosurgery or looking at what we get with immunotherapy alone. We've also had papers coming out of our center looking at HER2-directed therapies in breast cancer where the combinatorial approaches of these new targeted agents worked extremely well with radiosurgery-based approaches.

Dr. Alex Rae-Grant:  So any other major takeaways that you'd like to bring to us today?

Dr. Gene Barnett:  I think the major takeaway is that brain metastasis used to be a death sentence, and these days the vast majority of people have high quality, long lives with good tumor control with the techniques that we have available.

Dr. Manmeet Ahluwalia:   I agree completely with Dr. Barnett. I think we are very excited about the promise of these new combinatorial radiosurgery-based approaches, these novel therapies and immunotherapies, and one takeaway that I would have for physicians is if you have a patient with brain metastasis, refer them to a brain tumor center of excellence where the neurosurgeons, radiation oncologist, medical neuro-oncologist work together in a team-based approach to provide the best individualized care for the patients.

Dr. Alex Rae-Grant:  Well, thank you Gene and Manmeet. It was very nice chatting with you and thanks for your time and efforts for the patients.

Dr. Gene Barnett:  Our pleasure.

Dr. Manmeet Ahluwalia: Thank you for having us.

Dr. Alex Rae-Grant:  This concludes this episode of our Neuro Pathways podcast. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast. Subscribe to the Neuro Pathways podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. And don't forget you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website, consultqd.clevelandclinic.org/neuro or follow us on Twitter at CleClinicMD, all one word, that's @C-L-E clinic M-D on Twitter. Thank you for listening. Please join us again soon.