Hello and welcome. My name is Dr. Andrew Fabiano. I'm a neurosurgeon at Roswell Park Comprehensive Cancer Center in Buffalo, New York and I'm going to be speaking to you today on the topic of brain metastases. This is part of the Brain Metastases 2.0 Breakfast Seminar and specifically I'm going to be speaking to you today about stereotactic radiosurgery. This is an area of great interest to me and I feel like sometimes brain metastases don't get their due might be seen as kind of a mundane part of neurosurgery but actually the management and management strategies used to treat brain metastases have a dramatic difference for our patients and affect their ability to function, receive treatment for their primary disease and directly affect their overall survival. I just want to start off today is by saying you know we're on a web-based format because of the COVID-19 pandemic. I hope everyone is safe, their loved ones are safe and a special thank you. Thank you to all the neurosurgeons, neurosurgeon MPs, neurosurgery PAs and all the medical professionals out there who are taking care of patients during this stressful time. Thank you so much. I have research support for a glioblastoma study. It's not relevant to this talk. So I'd like to start off reviewing a case. It's a 36 year old with headaches and vomiting. She has no weakness or sensory disturbance. The patient has a history of ovarian cancer that was controlled and a subtle left drift. This is her brain MRI. You can see she has two pretty large brain metastases. They're both right adjacent to the motor cortex. Certainly on the left it extends into the primary sensory cortex in important areas and there is some surrounding vasogenic edema. So when you measure these lesions out they're both 28 millimeters so getting close to that traditional three centimeter cut off. And so typically I ask at this point how people would proceed in their practice and there is some usual variability between double craniotomy, stereotactic radiosurgery or whole brain radiation therapy. And so what we ended up doing in this patient was treating her with fractionated radiosurgery. It's actually the first case of fractionated radiosurgery at our institution and she received 18 gray over 5 fractions. Nowadays we might give these lesions something like 24 gray over 3 fractions. But what we see is over a period of months these metastases abated and shrunk down. The edema went down. By three months she was off of steroids and at six months there was no sign of the tumors. So stereotactic radiosurgery basics. NCCN guidelines include stereotactic radiosurgery. It's the preferred treatment for limited brain disease. It's a treatment option for advanced disease. You are able to treat surgical cavities with stereotactic radiosurgery and it's been successful for treating a spectrum of solid tumor types. So certain tumor types like melanoma or renal cell carcinoma, which in the past have been thought to be relatively radio resistance, you know there's a lot of good data to show that stereotactic radiosurgery works well for these tumor types. So traditionally for SR there were these axioms that you only treat up to five total lesions. You only treat up to a size of three centimeters. And as we'll see this is really an antiquated way of looking at brain metastases and you want to have a better understanding of the tumor you're dealing with, the patient you're dealing with, and how in order to provide the best possible care. So really rather than a size approach you want to take a volumetric approach. So it's the volume of tumors being treated not the number of tumors being treated. The volume of radiation dose is what's going to most directly impact the radiation dose to the surrounding peritumoral normal brain and so that's what matters not the total number of tumors being treated. And we looked specifically at this at our Institute and what we looked at was we went back and measured for a whole host of tumors what the radiation dose was that was received by the normal brain. So when we looked at this the number of tumors, so whether we were treating one, two, three, four, eight tumors did not correlate to the radiation dose to the normal brain. However the volume of tumor that was treated did directly relate to the radiation dose received by the normal brain. And you can get a sense of if you have four one millimeter tumors it's actually a pretty small amount of radiation that's delivered in order to treat them versus if you have the patient like we previously described who has two large tumors near three centimeters it's actually a much larger radiation dose that's delivered and there's a larger radiation dose to the surrounding normal brain and thus the volume of tumor that's treated not the number of tumors is what's important. You can just look at these scattered plots if you look at the number of tumors treated relative to the radiation dose received by the brain there's not a real correlation but if you look at the volume of tumors treated you can see that as the volume of tumor treated goes up the amount of brain volume receiving a radiation dose goes up. And so again multiple small metastases are safer than a few large metastases and really though the total volume of tumor being treated is the variable you want to look at when making a determination and is there too much tumor here that I need to consider whole brain radiation therapy versus just having a cutoff oh there's six tumors it goes to whole brain. Now if they're small tumors in most cases they can still be treated by stereotactic radiosurgery. So tumor size again volume is more important than size and when you get into larger metastases stereotactic fractionated stereotactic radiosurgery is a consideration. You know the three centimeter cutoff is still a good kind of generic marker to use and as you approach three centimeters again depending on its location in the brain how sensitive that area of the brain is you can use that to start to consider well maybe fractionated stereotactic radiosurgery plan is better. Oftentimes as we get into larger tumors we'll actually plan it out in advance on to determine if we're going to go with one three five fractions. But again I think the important thing to remember is it's not a hard cutoff. So if you measure it out a certain distance and say up it's 3.1 centimeters can't have stereotactic radiosurgery that's not the case. What it really is is you have to look at how suitable is this patient for surgery what's their overall prognosis what's the location in the brain if they do experience edema how likely is it to cause a seizure or deficit and it's you know that type of multifactorial approach that helps you make the right decision. So fractionated SR this is now a stereotactic radiosurgery that's done in multiple fraction for metastases it's usually three fractions sometimes five fractions that's typically done with a mask for fixation. So patients who traditionally have a frame you know the frame it is uncomfortable going on despite our best efforts and however once the frame is on patients can last you know typically much longer. Whereas once the when you're using a mask typically the limit of the amount of time for a treatment you want to have is around 45 minutes or so. After that patients become uncomfortable they can start moving around and if they move then you have to re-co-register them and it can make the treatment more challenging. So typically when fractionating treatments the treatment will be fractionated into you know three sessions about 45 minutes each. Again often a eight gray over three sessions for a total of 24 gray might be a dose that's used for metastatic lesions and this can be used both for a large tumor or if there's a high quantity of tumor you don't think that that particular patient can stand a two or three hour session in a frame you might break it up and do you know seven one day seven the next seven next to treat 21 small tumors in you know the right scenario with a fractionated treatment. So here's a case of a 78 year old lady she had non small cell lung cancer she had poor lung function and was on oxygen at rest. She occasionally felt dizzy but it wasn't clear if that dizziness was even related in any way to her metastatic disease. She lived alone independently and she was still going to the store and church on a regular basis so she was very functional despite what her brain MRI showed. And what you can see here is she had a sizable right temporal lesion there was some hemorrhage in there there's a fair amount of surrounding edema but it really wasn't causing her a major functional deficit. So again you have your different choices of treatment and in her you know her lung function was not good and she was doing well and my goal was to try to keep her going along well for as long as possible you know her disease was you know had already gone beyond first couple rounds of standard treatment and so her long-term prognosis was guarded and so I felt fractionated stereotactic radiosurgery was the best treatment for her. And what you can see here is we gave her 24 gray over three fractions the blue line in the anterior temporal lobe there was a previous treatment that she had undergone and you can get a sense for the conformal treatment plan. And so she was kept on steroid medications for about a month after Gamma Knife or after the stereotactic radiosurgery. The you can see here her three-month post-operative SR treatment the tumor is shrunk there's still some edema there that's edema off steroids but functionally she didn't have any deficit so she was able to continue on like that on her anti-epileptics. Next technique that we use is what we refer to as adaptive stereotactic radiosurgery. I have a picture here of my partner Dharendra Prasad who's a radiation oncologist who I work very closely with and we do our stereotactic radiosurgery treatments together and this is you know one of his he's certainly an idea of his that we've evolved to use quite frequently. And what this involves is a fractionated stereotactic radiosurgery given over a greater interval so over one to two weeks and we do a new plan in each session and what that allows is by giving a lower dose but enough dose to start shrinking the tumor you can use success you know use a smaller plan with each treatment so you are reducing the overall radiation volume and radiation dose to the peritumoral normal brain. And here's an example this was a 63 year old he had a newly diagnosed lung carcinoma he had a pleural effusion he was on oxygen at rest he had had a MI and cardiac stenting within the past year he had nystagmus dysmetria and a right drift although he was standing up walking around using a cane for balance living independently and he was a very poor surgical candidate and so given his poor surgical candidacy let's take a look at his MRI here he had a fair-sized cerebellar tumor as well as a left-sided tumor in the primary sensory cortex. And so the options were, you know, craniotomy in both locations, whole brain radiation therapy, some form of stereotactic radiosurgery. Certainly you could argue these brain tumors, you know, despite his status as a poor surgical candidate to optimize them as best as possible, but you also have to remember a newly diagnosed tumor, if there's any issues or complications related to his surgery, it's also going to delay treatment of his primary disease. So he had an adaptive stereotactic radiosurgical approach. You can see his initial treatment plan, and he was treated with 12 gray to the marginal dose of 12 gray. He was brought back two weeks later, and what you see is the tumor does shrink down in response to that dose. The blue line represents the initial marginal dose line. The tumor is now smaller, and we created a new plan and gave it an additional dose to a much smaller volume and then brought him back one week later. And then you can see the two previously treatment plans, the tumor shriveled down to even a smaller number of tumor. We now can create, again, create a new plan and treat that remaining tumor. And in this way, rather than three treatments to that largest volume, it's successively smaller tumor treatment volumes in an attempt to limit the radiation dose to the peritumoral normal brain. And then you can see his scan of the date of his first stereotactic radiosurgery treatment, and two months post that treatment, and the tumor has shrunk considerably. There is minimal surrounding edema, and he was at that point already started on treatment of his primary disease. Location. Location, again, is another important factor. I always point out the optic nerve dose typically want to limit to eight gray. Cerebellar and medial temporal lobes are areas that seem to be particularly sensitive to multiple treatments. There's something in those areas that they are more at risk for an adverse radiation effect, significant edematous reaction, and brain stem tumors can be treated. So just because a brain patient has a brain stem tumor, that doesn't mean that they need whole brain radiation therapy. As you'll see, you can give stereotactic radiosurgical treatment to brain stem tumors. And this is just an example of a 52-year-old. He had a lesion in his brain stem, and typically we'll give those either 12 gray or 14 gray marginal dose. We'll treat them to a much lower isodose and make sure that there's a good gradient index so that the surrounding normal brain tissue isn't receiving as high of a dose. And this is treating brain stem metastases with stereotactic radiosurgery is something that we do routinely in our practice. So surgical cavities, there's strong evidence to support stereotactic radiosurgery for resection cavities. You want to include a very thin rim at the edge of the cavity. Typically we treat three weeks post-operatively. I will point out that there are groups who are doing neoadjuvant stereotactic radiosurgery for brain tumors, and that also is an option. Typically when you plan out these surgical cavities, you plan to do a lower isodose line than typical metastases. Dosing is based on the cavity size, often 16 or 18 gray. You have to remember what you're treating, much of it is fluid or air. So most of that radiation dose is not going into tissue that can potentially react. So even though when you're first treating these surgical cavities it might seem like a very large volume that you're treating, the consistency of the tissue is not like treating actual brain tissue of that volume or treating tumor tissue to that volume because the radiation doesn't have the same effect on air or fluid. This is a 51 year old with a histamine of melanoma. He had some new lung nodules on his CAT scan of his gestatum and pelvis. On further questioning he reported that he seemed more emotional, forgetful, didn't have the same motivation or concentration that he felt he normally had. His partner reported that as well, and he had a mild left pronator. What you can see is a tumor in the right frontal lobe with significant surrounding edema. And so how would you treat this? Stereotactic radiosurgery, targeted therapy, combination. So just to prove that you do open surgery not just stereotactic radiosurgery, he underwent a right frontal craniotomy. What you see inside that cavity are some blood products about on the day of gamma knife. This is a gamma knife targeting scan. He received 16 gray to the 55% isodose line and you can see it as we plan it out we include just a very thin rim of that surrounding tissue outside of the surgical cavity. And at seven months post-stereotactic radiosurgery is no sign of any tumor both in our area of surgery and other areas of the brain. Interestingly at nine months post-stereotactic radiosurgery, his partner reported he had an increased temper and you can see this lesion in the area of previous treatment. Seems to be just adjacent to our surgical cavity treatment. You can see at seven months there was a normal MRI so it grew, whatever this is, grew pretty rapidly. And it has a little bit of a fuzzy indistinct border to the area of enhancement. So I felt this was adverse radiation effect. He was treated with of course a corticosteroids because his symptoms were not that bad and they abated with corticosteroids. We were then able to watch him expectantly and at 12 months that area of inflammation had resolved. So adverse radiation effect, it's frequently referred to as radiation necrosis. It's really a misnomer. The pathophysiology of the process is a vasculitis. And so you get vasculitis of abnormal blood vessels and you do end up with a fibrinoid necrosis of the blood vessels and coagulative necrosis of the surrounding normal brain. But really this abnormal vasculitis in response to the radiation is at the heart of what is occurring. When patients have adverse radiation effect. And you can see pathologically you get a hyalinization of blood vessels surrounding fibrinoid necrosis. There's gliosis around it and there is a recognizable pattern that occurs. Now when you go and surgically resect these post-stereotactic When you go and surgically resect these post-stereotactic radiosurgery metastases, oftentimes there will be tumor cells interspersed within a specimen that's mainly adverse radiation effect necrotic material. It's unclear if those are active tumor cells. They have been treated with gamma knife radiosurgery. Presumably if they're just scattered and they're much less than what you would expect at a time of tumor, there's no test currently to tell if they're active tumor cells or tumors that are dying off as part of the radiosurgical process. Certainly there are times though when you find just clear tumor cells or pure adverse radiation effect that you can make a distinguishing factor between the two processes. However in most cases it's usually a mixture of tumor cells and necrotic material. Adverse radiation effect typically occurs nine to twelve months post stereotactic radiosurgery. A three month peak is observed in dual treatment cases. So if a patient is treated with stereotactic radiosurgery to a lesion, at some point later, say six months later, there's a tumor nodule adjacent to the previous treatment that gets treated. That overlapping of treatment zones in the peritumoral normal brain can lead to an adverse radiation effect reaction quicker than what typically occurs after a single treatment when it's nine to twelve months. And what you see is enhancement in a rapid growth pattern in edema. There is not a non-invasive test to differentiate between adverse radiation effect and recurrent tumor. There's no imaging study that can tell you for sure what it is. ASL, PWI, these tests are getting better but there still is not a definitive test. And what this chart just shows is varied sensitivity and specificity for all these different imaging tests. Again there's no slam dunk. And you can see in the other image is an example of a patient who had a head and neck cancer. His initial radiation field caught a bit of his medial temporal lobe when the tumor spread to that area and he received the stereotactic radiosurgery. Three months later that medial temporal lobe showed this florid enhancement and edema. That area was resected. It came back as pure adverse radiation effect necrotic material. And before surgery it was, you know, pet avid. And so the idea that just because it's hot on pet means it's tumor is not true. So the best method is actually to line up all the scans at luck. And if you look at the behavior of the lesion over time oftentimes you can get a very good sense of what it is. And you look at it also in relationship to when the treatments have occurred. A recurrent tumor you'd expect to grow in more of a logarithmic steady state growth pattern. Adverse radiation effect often will be quiescent and then grow very quickly. Its enhancement may have more indistinct borders. It typically will occur in that 9 to 12 month, 14 month time period after a single treatment. It'll occur three months if there's two treatments that overlap. And so by lining it all up looking at the behavior over time that oftentimes will give you a very good understanding of whether this is recurrent tumor or adverse radiation effect. Treatment of ARE. If asymptomatic you just observe and you can follow it closely with serial imaging over time. And I do that quite frequently. You can use a short course of corticosteroids. You don't want to use corticosteroids as a long-term treatment plan for patients with adverse radiation effect. They have significant side effects as we all know. They now impair many targeted therapies. And so you know long-term steroid treatments often cause as many or more problems as the brain lesions themselves. And that's precisely why if a patient's symptomatic I would advocate to do a craniotomy sooner rather than later. Once this lesion declares itself as being symptomatic creating a problem for the patient you can try a round of corticosteroids to see if it abates on its own in a short order. If not and it persists rather than continuing corticosteroids I would recommend a craniotomy. And what happens is if you don't follow that plan and you maintain them on corticosteroids you end up three or four months down the road. They've run into significant side effects from their corticosteroids. Their primary disease may have advanced more and then you're taking a patient to the operating room whose performance status is worse than if you had just taken them and addressed that problem up front. Those patients who are poor surgical candidates bevacizumab is a good treatment option. We've had good success in our practice treating adverse radiation effect with bevacizumab and radiotherapy. Repeat radiation is actually an option in this setting as well. So thank you very much. Feel free to email me if you have any questions. This is a topic that is really of major interest to me so I'm always happy to hear from anyone else who shares that interest. Again thank you to everyone out there for all your efforts to treat patients during this time period. I hope you're all doing well. That's actually a picture I took of the lower Niagara River. I guess one silver lining to the current situation. My daughters and I have been out walking in parks a lot more. So sending my best wishes to everyone out there and please don't hesitate to reach out if there's any questions or information I can provide related to this topic.

brain metastases

stereotactic radiosurgery

treatment options

NCCN guidelines

volumetric approach

COVID-19 pandemic