You always will be called the devil if you don't follow the dogmas. So you should first of all, I'm talking to the young people, you guys are all old people. The young guys don't follow the dogmas. Everything this guy said here, it's true. Everybody's here saying things that are not true. And you should take the truth that they told you and just stand on the shoulders of each one of these guys and just try to see way ahead of what they can see now. And I think a good example of this is Dr. Lexell. I think you heard the name here two or three times already. Why did you hear his name is because he was not full of dogmas. He came up with a completely new thing. One of the sayings that Dr. Lexell used to teach is if you see something once, it's interesting. If you see it twice, it's true. Publish. And let the people that don't have good ideas try to follow it and see if it's true or not. So that's a truth that probably we should follow to be able to develop things. I was asked to talk about something that people here are a bit against, at least the neurosurgeons. The radiation oncologists I think would be on my side, but they are less aggressive than the neurosurgeons. So they will not protect me and I'll probably be lynched here. Well, I have the disclosures you see here. I work with everybody. I don't have any dogma against any one of these instruments. They're all excellent. Some advantages, some disadvantages, but they all do the job you need to do. The concepts of fractionation and radiosurgery, I'll discuss those with you. Single versus fractions. When should you do this in a rational way? It will be in these applications here because they are the most common. I'll go quite fast through them to be able to say all this. Well, Dr. Jouberg was a hard-headed guy. He was a dogmatic man. And you didn't hear his name here today. He passed. He was one of the great radiosurgeons of all times. He was trained by Dr. Lexell. He came and developed a new instrument with a proton beam. He developed a way of calculating doses that we all used previously. And now he was abandoned from the history. He is not even in the society. Nobody talks about this man anymore. It's a shame. He was always insisting in precision and accuracy. I heard that from Dr. Friedman here today. And I learned that from him as well. He had a very good saying at some point. That the one that develops it, this is Dr. Friedman I heard from him, the one that develops it is very careful about it and does it with a lot of care. The second person that does it doesn't have the same care. The third does all the mistakes that the first didn't do. So it's a reality of what we see. Well, at that time, this man was already doing intensity modulation, shape beam radiosurgery, circular collimator, hemi-beam, and two Brazilians were slaves there. A single fraction radiosurgery, five fractions for billing purposes radiosurgery. I think it goes beyond billing. I think if you diminish the fractions of radiation, you do affect vessels way more than you would affect the whole fractionation scheme. Every time you want to affect blood vessels, if you decrease the fractions, you probably get some better results. And I'll discuss that with you a little bit later. So any stereotactic radiotherapy really is what we call the multiple fractions. Devices were developed, you know, best dose distribution, precise, fast delivery. This, the new gamma knife, the Perfection, really tried to embody all that. And more than that, it embodied the saying that it's harder to make the mistake if you are the third guy in the line. There's a lot of saying about that. Why I'm saying that? Because I'm paraphrasing now Dr. Smith that talked before me. I have done 179, published in the literature, have done more than 300 now, radiosurgery with a linear accelerator for trigeminal neuralgia. Well, I used to work in an institution that had a school of physics. The physics people there, they're outstanding. So I was well protected from getting a mistake done. What Dr. Smith showed in Phoenix, I reviewed the case and I said to the guy, pay for it, to the hospital, but you should pay because this is, you can't win this. There are other cases also in the United States that I reviewed because the third guy was not as careful with it. Well, triangulation from the operating room brought the linear accelerator and the linear accelerator now becomes a stereotactic frame, the room. But this stereotactic frame needs more than pins. Put a pin is quite easy. It's not good for the patient, but it's easy. Here you need x-rays, you need the CT scan done at the moment of the procedure, and you need also the reflexive markers. So you are using three techniques to do a frameless stereotaxis of a trigeminal neuralgia. So you check it three times instead of two. And you need that precision also to treat the tumor like this. And what do you do when you have a tumor like this? It was well discussed by Dr. Shulman here, the professor. He discussed with you that you should remove this tissue here so you can not give 64 gray here, 70 gray given in fractions, 64 gray to the middle of the brain stem. Can you do that? This is a question I leave to the radiation oncologist. Well, that's just to illustrate what I said in the beginning. You cannot close your eyes. You just always open your eyes ahead and try to do things innovative. In 1996, we started to have a device that started to do fractions, started to do fraction radius surgery in 93, actually a little earlier. But at UCLA, we got the device then. And it turns out to be 40% of everything we did there. So it's not that we believe only on this. Actually we believe more in single dose. As an example of what happens when you do a single dose, if you immediately after you treat, this is a low grade astrocytoma here in a young girl that we treated. When you give a dose to the gray matter, you have increasing glucose utilization in the next 48 hours, explaining the seizures that you can have after you treat an arteriovenous malformation. Therefore, you should protect the patient with anticonvulsants if the patient has a history of seizure. Demyelination and edema, breakdown of blood brain barrier. So you got the gadolinium there is extravasating, and you got the edema. And then you have the follow up a little later. You have the neuronal death, and you had complete resolution of all. That problem you had before, and you basically are getting a ischemic lesion that is the classical lesion of Dr. Lexell, and this is a classical lesion of edema knife when they were not using a second check. You end up getting an internal capsule if you don't use at least two techniques to check everything you do, MRI and CT scan. If you are doing zero to five fractions, you are treating what's oxic, excuse me gray. If you are increasing the dose to 12 gray, you start to treat hypoxic cells, and you get a little bit more of self-death. Now when you get to the 12 gray, you're getting the vascular damage. That's why when you have 12 gray, you have about 30% obliteration of arteriovenous malformation. You have a 30% obliteration of hearing because you take the labyrinthine artery in other structures as well. So you need to be concerned when you have the 12 gray radiation. If you look at the alphabet, this is the best we have to calculate things. So let's use this Dr. Weir's graph. You see the two alphabet ratio of two. Let's call it the brain. If you are giving out 18 gray, that is for AVMs and for metastasis, a good dose, a lot of people use this or more. You are in effect in fractions of radiation of two gray, you're giving 90 gray. This is a whopping dose if you are fractionating. Now if you are giving your 12 gray in an acoustic neuroma, actually you're giving 45 gray. This is a very acceptable dose to the brain. And if you're using, if you're giving your 8 gray here and you extrapolate, you're actually giving a turn of 20 gray in fractions. So this is very safe. That's why you do that to the optic nerve. Well you should take advantage of all these depending on what you are treating. We will call hypo-fractionation up to five, single, and then full fractionations if we go more. And there it is, the 8 gray. You can destroy if you want. You can manipulate if you want. Radiation is extremely powerful physical way of dealing with lesions in the brain and elsewhere. So you need to know how to manipulate it well for different purpose. For instance, to increase tyrosine hydroxylase in the substantial nigra with a three millimeter collimator precisely place the lesion there. These are tests we are doing to see the precision of our device before we start treating trigeminal neurology and other applications that needs precision. The penumbra dose of less than 40 gray leads to this growth factor increase in this area. JFP increases there as well. Well what happened, I'll pass through now the clinical applications in a very fast way. I don't need to review the literature because each one of these applications were very well reviewed already. So if you irradiate a nerve, there's a peripheral nerve of a pig with a dose of 90 gray, basically that's what you get. You get a demyelination. Well you see that's not a complete demyelination. So you have still fibers working there. That's why when you treat a trigeminal neurology, putting your target right in the middle of the nerve, you are not going to have complete numbness. You may have a little bit decreased. The patient may not complain about it. Mind you that we saw today here by Dr. Schlesinger that all this is moving. So if you are putting a target here and you think you are precise without movement, this is moving and you are probably moving here and that's why you don't have immediate pain relief. Maybe a little later, a little later, it varies. You have a mean pain relief in turn of a month, a month and a half, two months in the literature. Now if you take this target and put right in the entry zone, now you are getting not only Schwann cells but you are getting oligodendroglia now. That's another type of myelin that's way more responsive to radiation and that's why you should have a little bit more numbness and also a little bit better results. More so if you believe that the blood vessel beating here is causing a very unique demyelinization that causes the shock of the trigeminal neurology. Our clinical data on this, on the 79 patients already commented, what we did is this here we are treating in our initial phase with a 5-millimeter collimator, 70 gray. We did this in the early 90s and you progress to bring the 30 percent isodose line to the brain stem and then the 50 percent isodose line to brain stem using 90 gray. You notice here that we improved the results as we moved closer to the entry zone but we did increase the numbness. So we feel that indeed you can take a little bit of the myelin in this area and have a better results in the patients, mid-age of the patients 74 years old. So this is not young patients. And with this we developed the technology of being able to treat pain, dermatomal pain, itching, and other problems that are intractable by medication and even help patients with cancer pain in the dermatome. Currently single-dose radiosurgery works very well in a hypothalamic harmartoma. You can control seizures in a very good class with a dose that's not very high. However, if you try to get the 18 gray, you do have a lot of edema here, as was already discussed. A lot of visual field defects and steroids in a large group of patients, 53 percent, 61 percent with the high and low dose, this is the result of the randomized trial. Therefore when you increase the volume of your treatment, this is an 8 cc volume here in the hippocampus, you have to take another strategies of how to treat this and this needs to be developed. It's not developed yet. Shall we use hypofractions here? Full fractionation already was shown that didn't work in the literature in the early 30s, but shall we revisit that with better technology? So we need to look into this and develop a better way of treating these patients. Now when you increase the volume, this is from Dr. Joberg, this is his graph, then he was already talking about the sensitive areas, and this graph has been used throughout the world, it's just not much common these days. But if you arrive to the 12 gray, we start not to have results in the vasculature. This is done for AVMs. If you have a small AVM, it's a no-brainer, you're going to treat with a high dose, and you're going to have a good result. And this was thoroughly discussed. Well, what about if you have a large AVM and you fail? Well, now you have an AVM that is in a very sensitive area. It's in the motor area. And you have a big challenge here. What to do with this? We decided that we would work with it in a period of about eight years. We had experience working in Sweden that if we fractionated this with a specific dose of radiation, in eight years we will have a result. So we chose not to do the stage. Stage can be very successful. Jason showed it very well here, that you can do this. But you can also fail on this if you do it the wrong way. And you bleed. You can have more hemorrhage here. Interesting, I was in the AVM symposium in Nancy this year. And they were telling there that you should treat the venous portion first. So it's a new paradigm that people are starting to talk with, including Jean-Régis from Marseille starting to talk about treating the venous area first. It goes against everything the neurosurgeons know. Because you know if you close the vein, you're going to blow up the AVM. So we choose to do it in fractions, homogeneous fractions. So we get the whole lesion slowly and progressively going away. So we see a lesion like this. Now I call attention for this blood vessels here. These are very small little blood vessels. These are the ones that respond to radiation. When you look at the fistula, the large blood vessels, they don't respond even to single dose very well. So this is a patient that we retreated with 18 gray later on. Because we had a one year response on this. Very fast, we got to this. We got to this. And then we retreated it here later on. And we reported then that you should hypofractionate. You decrease the volume to 1 4th almost. And then you can treat this. You turn a lesion that is not treated by single dose into a lesion that's treated by single dose. And you are not increasing the risk of bleeding during the waiting period. So you will look in the literature what we could come up in terms of what's the best dose. This is the dose we use. And we do take about eight years to get this 83%. And this is data from Linval in Sweden, in Umeå, with a 4% complication rate. With the same bleeding rate of the natural history of the disease, in turn of 2.5 a year. We have done this here. We have done this as well in the report that we did. And we think we can increase a little bit. We're calling this the red zone because Dr. Andrews from Jefferson University, he has already done this with a 14% complication rate. So where are we on this is very hard to push. Well, do you abandon completely the 12 gray? No, I don't have courage to give more than 12 gray or fractionate a scheme that I don't know very well in a patient that has a brainstem AVM like this. So it does respond to 12 gray. So there's a proof the vasculature do respond to 12 gray. Why I don't go below that, because Dr. Gelberg, who I work with, he treated large numbers of patients with 11 gray and 10 gray. And those patients are reviewed in Germany by Dr. Majorn that showed that it was a disaster. The patients did much worse when you get a dose below that. But this opened up other opportunities, for instance, to treat an arteriovenous malformation located in the shoulder of a young, beautiful lady that had a lot of pain. She had the pain completely controlled. And the AVM almost completely disappeared. There was a little bit of venous drainage is the report of the neuroradiologist. Well, you saw that if you want to destroy blood vessels, single dose is the best way. Hypofractions is the second way, if you want to decrease a little bit your risk. What about the meningiomas? What did we do with them? Well, we classified them. If they are in the optic nerve extending to the brainstem, just increase the classification. And this, in yellow, are the ones that are candidates to stereotactic radiotherapy. Example of this, a tumor in the tuberculum sella, a patient operated on in the neighbor hospital in Los Angeles. And she lost the vision in an eye and half of her vision in the other eye. So I was seeing the patient with just this amount of vision. And we treated with stereotactic radiotherapy, full course, 50-40 gray. And here we have improvement, 15 years, 8 years follow-up. She is now more than 15 years follow-up at this point. This also opens the opportunity to treat the optic sheet meningioma. And Dr. Andrews was first publishing this very nicely. These patients were awaited to lose the vision and then have a nucleation or removal of this whole nerve. And now we can preserve their vision. Tumors involving cavernous sinus and involving the optic nerve, we reported on them, 97% control rate, excellent results, biopsy through the foramen ovalis, so you can confirm if you want. Sometimes you need, depending on the history, you need a biopsy, even though it looks like a meningioma. And meningiomas with single dose, meningiomas with fractionated, you see that it's extremely effective with fractionation. Those are growing tumors that respond to fraction of radiation. If you do single dose, you may miss some of the tumor. Mainly, this is old data. We didn't have the same imaging technology we have today. Well, what about hypofractionation? I have adventured in some of this. Hypofractionation for acoustic neuromas and hypofractionation for meningiomas. You see very clearly that there is some normal brain here receiving my tolerable hypofractionation. And you see that I had a problem with this patient. He became hemiparietic. Obviously, he was uncle of one of the doctors that worked with us, and that was not a good thing to deal with. He got better, though. Now, then I make a statement there that I think meningiomas, you do very well with fractions. If you can do single dose, you do single dose. Fractions of radiation will involve the nerve, and you're going to help the patient. Surgery is the best way to deal with a meningioma, in my opinion, if you can operate the patient without deficits. You're not allowed to make deficits in anybody these days. 16-year follow-up of pituitary adenoma was growing. Radiosurgery starting at UCLA, we treat the patient, and then patient had a son after that and moved to Virginia. I don't know how she's doing at this point. Now, what about tumors involving the nerve, really? Here, this is our old man that didn't want surgery. And then we just fractionated the whole thing with a low dose, not much risk here, and we clean the nerve. My opinion, this patient should be operated on. He is here having his vision being threatened, and I think you should just operate on those patients. You have high control with fractionation, mainly if the tumor is a non-secreting tumor. If it is a secreting tumor, surgery first, surgery second, and then secreting with very high dose radiation, if you can do that without the risk. What about craniopharyngiomas? I want to make a point on the cyst. The cyst responds to fractions of radiation, a cyst that's completely involved in the optic nerve. If you do fractions of radiation tolerable to the optic nerve, and I would not recommend the five fractions or the six fraction of the hypofractionation, because I don't think we know enough about that, and the deficit's too severe. If you get a blind person, you don't want to tell anybody you did that. So you do here 50-40 gray tolerable in the nerve. This cyst will not respond immediately. Actually, it will grow through the radiation. So it's recommended that you have a myo-reservoir, and you image the patient throughout the treatment, and you drain the patient if needed. But in four months, the cysts start to decrease. So it is a good treatment. It's a non-invasive treatment if the patient can't tolerate without a myo-reservoir. Example here, a patient with a craniopharyngioma operated on, a cyst starts to grow. Because the patient had a transfenoidal, we could put a stereotactic needle drain. The cysts is there here. We irradiated this with single dose in 1996. Followed the patient for nine years. Nine years down the road, his cyst grows again. So now here, we treated stereotactic radiotherapy at this time, and we are following it as it grows. Well, acoustic neuromas. John Adler from Stanford, he convinced me that we should do hypofractionation. So what's the scheme, John? John, it's seven times three. I treat three patients with seven times three. I got edema. You put the patient's steroids. I never had that much problems with the 12 gray radiation. I say, John, I'm not going to do this. So let's do five fractions. I then tried 5-fraxane. I had the same problem with it, abandoned it. And then John published about six months later, three patients getting blind, losing hearing, because he was recommending for patients that had hearing. So for us to have hearing, we would go to the full fractionation scheme. I think that's why Dr. Friedman called me the devil. But there are other devils in the literature saying that that works. So I'm not alone on that one. So intact hearing, he is a patient treated with intact hearing. Trigeminal, facial, and hearing preservation. It's very high. It's at the 90% level there. So it's pretty good hearing preservation in our data. The response is pretty similar to what you have with 12 gray. You actually have, in the same time frame, you get the ghost tumor. And then you're going to get it to decrease in size. Dr. Andrews showed that the better hearing preservation. This is not my error here. This is we went to the water computer and kind of messed up. Don't think that I'm not careful with my slides. I am. Another data, the literature from Germany showing the same thing, 94%, five years follow up. So yeah, fractions do work for acoustic neuromas. It's practical. No, it's not practical for the patient. And many patients do prefer to have the single dose radio surgery. Well, this is what you want. This is a comparison, SF36, the quality of life in patients in Los Angeles versus acoustic neuroma. They all have the same quality of life. That's what you want to do for your patients. These two guys here were dating when this guy had the tumor. And I offered him money to buy a ring to marry with him, with her. And she did. He did and reproduced these two beautiful kids here. And this is his tumor 17 years later. So the family is doing well. Now he drives a truck. So if you have a tumor involved, this is a low-grade astrocytoma here involving the hypothalamic area and the optic nerve. And full fractionation, it's a good thing to do. We know it works. Radiation oncologists have a lot of experience with it. Now, glioblastoma multiforme, we really stopped treating this in 1998 when we reported a paper that a single dose didn't work. Well, am I right or am I wrong? Well, I shouldn't be dogmatic. And there are people there in the literature doing this. I think with hypofractions, with fractions, you need to try. But what you're doing is you're just changing the patterns of failure. This is not a local tumor. You may increase a little bit of survival, but you're not going to really make a dent in this very difficult disease. Metastasis, we are doing hypofractionation metastasis. This is 1993. We were doing this in New Mill, and we compared data from UCLA. At that time, we were doing a very high dose in the metastasis here, 70% of those lines. You see the volume. They were doing their 600 centigrade, 6 gray, 2 to 3 fractions, low dose, large volumes. Obviously, this one was better result than this one. But they had the response there, and at that time, we reported that it worked. Well, it's showing up in the literature now. Now that technology allows to do hypofractionation, then you start to see that maybe there is some advantages in cases where the volume is actually bigger here. It's missing the volume here. This is in turn a 21 here versus 15 in the radiosurgery. And you still have a better result in the fractionation. And this was statistically significant in the literature. This is the group with Dr. Valerie at St. Petrie. And also here, we are still looking into diffractionation versus the single dose here. The target volume is usually much larger in the cases that have fractions. So therefore, you will have results that are probably better still with diffractionation, which is challenging for the single dose radiation. But in my opinion, the large metastasis should be operated on. And I would much better to treat the tumor bad than to treat a large tumor in someone's brain and having to put them in steroids for a long time. Other applications with fractionation in general exist. This patient had failure of radiation therapy, was bleeding through the nose all the time, a young man. And here, you do SRT, stereotactic radiotherapy, with resolution in about 10 months. Other very difficult problem, here is a rhabdo. Patient would be enucleated, very young boy, treated. And it's very fast response, April, June, five years follow up. So multi-fraction radiosurgery or stereotactic radiotherapy has a very important role on the management of intra and extracranial diseases. And in extracranial diseases is really the applications increase not only in the spine that you hear tomorrow, but also in the whole body. The choice depends on the location and histology. And I think I hope I could convey to you where I think that you should abandon the single dose of radiation. Thank you.

radiation treatments

effectiveness

innovative thinking

fractionation

radiosurgery

trigeminal neuralgia

glioblastoma multiforme