For the younger people in the audience, if you don't know, the secret of success is to surround yourself with people smarter than you are. And I've been very successful at that. Jason Sheehan was one of them who did some work with us here. And I was pleased to hear that now he's surrounded himself with people smarter than he is, like David Schlesinger, who just gave probably, I agree, the most impressive discussion of medical physics that actually somebody could understand, in my experience in radiosurgery. So we're going to talk about one of the major indications that emerged for the role of radiosurgery. And that began with the first patients actually treated in 1969 in Sweden, but has continued to progress across the United States and the world, where we now have over 100,000 patients with this relatively rare problem that is a condition that is thought to maybe be one per 100,000 people. Maybe in today's era where imaging is showing things earlier, maybe one to 50,000. But it was interesting that this particular tumor, which was sort of considered in neurosurgery one of the great technical tour de forces to be able to achieve removal without significant collateral damage for patients, and yet a technology such as this has come to largely be a primary management of this problem. And interestingly to me anyway, when raised in the field of neurosurgery, whenever these patients were diagnosed, the immediate answer was they need to have surgery, you need to take it out. And then after the development of radiosurgery as an alternative strategy, now what we find is that many people are saying, well, maybe we should just watch them. You don't need to do anything. Maybe if it shows signs of growth over time, you can do something about it. But the reality is that looking at combined data, the average doubling time is about 2.3 years. The concept that a benign tumor just grows to a certain point and never grows again really doesn't fit any other known tumor model that we have. And we know that if we delay intervention, that actually our ability to save hearing worsens. In looking at the literature, at least 40% of patients will undergo some form of intervention within a few years. And once intervention happens, our hearing preservation rates get worse. Now actually the first thing that was desired to be solved by radiosurgery wasn't hearing. And I actually thought that was a reasonably even thought process. The real goal was to save the facial nerve so that many fewer patients ended up with significant facial palsies after surgical removal. Our own feeling is that observation, since this is a minimally invasive outpatient procedure, observation really doesn't make a lot of sense unless your patient has significant comorbidities, is elderly, or is going to have some other thing that gets them long before their acoustic neuroma. So here's a patient who had an acoustic neuroma suspected on the basis of vestibular dysfunction, episodes of dizziness. So they did an original scan. No contrast was given. Hard to see. Two years later, still symptoms. New scan shows a small tumor. 2013, tumor's growing. Why would you not do anything about this particular management? 2015, still bigger. 2016, still bigger. And by this time, the tumor is now very easily seen and continue to grow. So we don't think that observation really makes a lot of sense in this particular problem. The goals of what we're doing, of course, is to stop tumor growth. So that's different than the before and after picture. Now you see it. Now you don't. It's now you see it. Now you still see it. But it's not growing, or over time, it's actually going to shrink. And we wanted to eliminate high surgical risks, maintain neurofunction, and hopefully improve symptoms, if possible. At our center, we've now treated over 1,800 patients over 30 years. Most of these occurring or diagnosed in the sort of middle-aged group. In the earlier years, more of these patients had had prior resection. And that's not so true at the present time. And of course, most have hearing loss and other symptoms. The procedure is done, as David says, by putting on a stereotactic guiding device under local anesthesia, and then coupling this with some form of high-definition imaging, which allows us to make a 3D map of what the tumor looks like. And the paradigm of what we're doing with bradysurgery is largely the parallel to what happened in imaging. When I started training in 1975, the first EMI CT scanner arrived the same day that I did. And I quickly realized that the paradigm was a major shift. And of course, now we have very high-definition, high-quality imaging, and we needed therapeutic tools to be able to match that. So we're doing these complex 3D planning to be able to make the glove fit the hand of the tumor. Initially, we thought that probably the tumor controlling dose for this tumor was higher than it is. And clearly, within the first 10 years of treatment, there was a dose de-escalation strategy, trying to optimize what was needed for tumor control, prevention of growth, while at the same time maintaining cranial nerve function. And that has reached a level so that we now know, giving a minimum margin dose to this tumor of 12 to 13 gray, we can achieve tumor control in the vast majority of patients, and even safe hearing at their existing level in about two-thirds of patients, which is clearly better, as we'll show you, with smaller tumors. The goal of how this works is complex in some ways, but it is related to the energy deposited within the tumor, which leads to not only DNA damage, but also a cytokine release and a free radical release, which leads to tissue damage. And that damage is not something where the tumor vaporizes, but instead slowly responds because the cell cycle of these tumors is relatively slow. The cell doesn't know it's dying until it tries to go through cell division, then goes through an apoptotic phase, and the tumor begins to shrink over the course of time. The secondary effect is by damaging the blood vessels within the tumor, receiving a high dose, leading to sort of an endothelial proliferation within the tumor, starving the tumor of necessary food and oxygen. Now some of these tumors will show, over the course of time, a temporary slight enlargement. This in the early years had great consternation develop in our colleagues, who say, well, you treated this and it failed. But reality is this effect is sort of six months to one year effect that begins to show shrinkage of tumors if simply followed over the course of time, but you need to be aware of this. And we've looked at our center, again, by surrounding myself with a lot of smarter people looking at our database. I strongly suggest that you maintain a very strong database or use one of the existing database structures to follow your patients over the course of time. The difference in what's being done now is that the patient feels nothing, the doctor sees nothing, but you've got to wait over the course of months and years to see what the long-term clinical response is. And so it's critical, as opposed to treatment with cancer patients, where the patient's going to be dead within a year. In many cases, nowadays for a tumor like this, this patient may live for 75 or 80 years beyond this time, and we need to see what long-term tumor growth control is. So we found several features in our own program which suggested we could do a better job with hearing. Younger age, it's always good to be young. We could restrict dose within the structure where hearing processing begins, the cochlea, and that's easier in smaller tumors, and it's also better in patients with good long-term hearing. And among the many things that we looked at in microsurgical removal of these patients, the actual risk of developing these types of long-term complications after radiosurgery are, in fact, extremely, extremely rare. So you can't read all of this, so I'm just going to interpret it. These are studies that we published showing basically that it's better in younger patients to be treated sooner, and treatment of larger tumors can be considered. The criteria that we use primarily is that the patient does not have symptomatic mass effect, that is, significant headache, significant vestibulopathy causing ataxia, imbalance, those kinds of things, in which case partial surgical removal may, in fact, be the right thing. Other centers, this group in Marseilles, looked at comparisons between surgical removal in a comparable group compared to those who underwent radiosurgery, and, in fact, the complication rate is extremely low. You can see that if you had an acoustic neuroma in France, you get a long time off from work if you had surgery four months off before you get back to work, and a full one-third of the patients never got back to work to begin with. So that's the kind of thing we wanted to eliminate with radiosurgery, and similarly for the other types of symptoms associated with this tumor, imbalance, coordination, ataxia, tinnitus, that risk is significantly better in the patients who undergo radiosurgery compared to microsurgery. Now for surgeons in the group, one of the considerations has been is that many patients and outcomes get tarred with the same brush, and the sense of surgeons actually thinking, well, all radiation is the same, even though you just heard it's not, and all radiation delivery techniques are the same, which, in fact, they're not. But the issue is you fail and the tumor grows, is it going to be harder to remove? There is no good consensus on that, but as a general rule of feeling is that most centers who have to do this, which is less than 3% of patients, that there is no real greater difficulty in doing this. Now what about the advantage of doing this in stages or fractions over the course of time? In fact, the wider delivery of radiation to larger fields, in my view, does not make any sense when you can do this very reliable in a single session, and as a general concept, the need to stage or do fractions in the treatment of tumors has got nothing to do with radiobiology because, actually, the radiobiological effectiveness is actually reduced by fractionation in benign tumors who have very low proliferation indices. It has only to do with the technology, so if you're not able to give a very conformal treatment to a very small tumor volume, then to maintain safety, you may have to divide this into multiple sessions to be able to deliver the dose, which, in fact, actually reduces the radiobiological effectiveness of this. We've used this technology over the years because of the accuracy and the ability to deliver conformal plans and believing that the radiobiological effectiveness in a single treatment is actually much higher. The current risk of a facial neuropathy, which was, again, the first goal to solve because of the high risk of that in surgical procedures, is now less than 1%, and hearing preservation rates continue. Some of the things we actually looked at in response to concerns or criticism raised by colleagues over the course of time was this particular thing, which we found interesting, which was that patients were being told that your tumor has cysts or little bubbles of fluid in it, and your tumor is not going to respond to radiosurgery. We actually looked at our program because that wasn't our experience, and you see this particular tumor with a cystic change and a carotid change, and then 33 months later it's actually shown dramatic regression, and we could sort of re-look at our patients retrospectively for those patients who had no cystic changes, these large macrocystic changes and microcystic changes, and, in fact, the chances of significant volume regression over the course of time could clearly be related to that, and the ones with the macrocystic change actually were the ones most likely to show dramatic changes. What about repeating it in the cases of failure? And a failure we ended up defining is sustained tumor growth over the course of years with new neurologic symptoms. So the actual need to do that has been extremely low, less than 2% to 3% of patients over the course of time, and in this report from our center, out of six patients out of 1,300 that were treated, they achieved tumor control as well. For larger tumors, we said we would consider surgical removal as a first step, or partial surgical removal, again, saving cranial nerves and doing radius surgery, but for those patients with larger tumors, it is possible to consider this is a patient with brainstem compression from this relatively larger tumor, and we see over the course of time significant regression of this. So, again, evidence by imaging of pressure against, that's how they grow, there's no place for them to grow but up against the brain. That's not the issue. The issue is what is the patient's clinical neurology as to the decision of what you can do. Now, the great elephant in the closet has always been, okay, well, if you do this, and the patients are told this on a regular basis, if you do radiation, first of all, it's not going to work. Secondly, even if it does work for a while, you're going to die of cancer. And, of course, that's a very scary thing to be told by your doctor, even if your doctor may be a little bit disingenuous in his reason for actually giving you that particular warning. While this is a not theoretical risk, it is potential. We think the estimated actual documentation of such cases fitting the Kahan criteria of radiation-related tumors puts this into a situation where you should probably tell a patient that risk is in the range of 1 in 1,000, probably from a clinical detection standpoint, much greater than 1 in 10,000, even 1 in 100,000 risk. This is a single session, at least how it's done in many cases, not done with multiple fractions to larger volumes, which, in fact, may increase the risk of that particular problem. So this is just a list of studies that have been published. You can't read all of this, but simply we've looked at things related to hearing prediction, long-term follow-up, and even in NF2 types of cases where it's done, and all of those you can find in the literature search. So we can summarize this, that facial neuropathy risk is remained and actually largely solved in the vast majority of patients. For tumors that are large enough to push upward against the fifth nerve, then there is a 3% risk of trigeminal symptoms. Hearing preservation, 75%, even better in the smaller tumors detected earlier. And the long-term outcome study for that is freedom from the need for additional treatment at 20 years, and there is virtually zero data out there related at least to the surgical literature relative to the tumor control rate after surgical removal at 10 and 20 years, I can tell you. It's better with grade one hearing, that is the patients with the very best hearing, and we could take patients with no symptomatic hearing loss. That normal hearing in both ears, group A, and we could look at this versus patients who have some hearing loss, and the probability of maintaining high-level hearing is much better in the patients who actually have no symptoms. Another reason why we think that delaying intervention in a patient with a newly diagnosed acoustic neuroma doesn't make any sense. We actually have the other ear in a patient to serve as a control group, and we could look at features such as what is the pure tone average on the audiogram, and we could actually find that the patients who had more than 10 decibel difference between the left and right ear in their pure tone average actually had worse outcomes in terms of hearing as well. So normal hearing, 80% of patients with some change in hearing less than a 10, greater than 10 decibel difference in this pure tone average, the risks really go, the success really goes way down in terms of controlling a tumor. We believe doing it early makes sense, and we found in our data that earlier treatment in fact is associated with better long-term hearing preservations and treatment later on. So in this analysis of hearing preservation, which again became a secondary but more and more important goal with the earlier diagnosis of this benign tumor, the lack of subjective hearing loss, less than 10 decibel difference, and performing it within the first two years after diagnosis was statistically associated with much better hearing. So if you look at current microsurgical aspects of outcomes, and this was actually modified from work presented at a meeting some years ago in Sydney, we now know that there are 100,000 patients, as we started out with, who have had acoustic neuroma radiosurgery. And if you look at the outcomes in comparison to microsurgical outcomes, we could sort of extrapolate this to the fact that we've reduced deaths by 1,400, eliminated 2,400 clots or strokes, 10,000 CSF leaks, 17,000 patients without facial palsies compared to surgery, and 36,000 patients who have had hearing preservation in this problem. So this type of technology is one of the game changers in the field of medicine, radiation as well as surgery. The message is still getting out in some ways because paradigm shifts are actually quite difficult for any specialty. And this is one example of where these technologies have made a big difference in clinical outcomes. Thank you very much. We're pretty close to time. Yeah. Yeah. Yes, I think the question is, is the imaging appearance of what is maybe interpreted as necrosis in a tumor effect, the planning. The important aspects of this are that you have a very 3T conformal part. You have the actual center of the tumor where that may be seen on an imaging standpoint. And I'm not as quite clear in my own mind that we can use imaging to actually define histologic change within a tumor. This is getting a very high dose and theoretically, although I'm no ready biologist nor radiation physicist, that area representing perhaps more hypoxic portion of the tumor is in fact getting a very large dose, 70%. If we look at actually the development of the loss of that contrast in the tumor and serial follow-up after radius surgery, we see that that black area that occurs in the middle of the tumor actually corresponds to about 70% of the edge dose, of the maximum dose, sorry, that delivered there and is also highly predictive of delayed shrinkage of the tumor over the course of time. So we're actually very happy to see that it doesn't have any effect on tumor control. What we found is actually this microcystic changes within tumors or macrocystic changes is actually a good thing to see because we can now tell patients that actually predicts that the tumor is going to shrink in a much higher percentage of cases over time.

success

radiosurgery

acoustic neuromas

hearing preservation

facial nerve function

complications