Thank you, good morning, thank you having me here. I have no disclosure. I was asked to discuss about multidisciplinary collaboration between radiation oncologists and neurosurgeons. It's a very difficult issue to touch and there are a lot of different issues in each different institution. I like to ask what is a collaboration? It varies a lot when I go to different institutions. Many people ask me, do you put the frame on? Yes, I do. Does the neurosurgeon draw it? Do you draw the normal tissues? Who prescribes it? These are all the questions, practical questions. So where is the collaboration? Those are actually the questions, but I don't know how you would have to function. And I can tell you what we have done and how this more in-depth collaboration led us to this level. And when it comes to oncological combined modality treatment, we say pre-op treatment, pre-op radiation, post-op radiation, and so on and so forth, neoadjuvant therapy is sequential, but we also use concurrent chemo radiation. These are all called multi-modality treatment and these are collaborations. So I don't know how this will turn out in the future, but let's look at what can be done. And radiosurgery is the same. Combined modality surgical and radiosurgical and chemotherapeutic treatments, it can be all concurrent and sequential and any collaboration can occur. And the other big issue in this setting is that what is radiosurgery and what is SBRT? Or there are many different words available, SABR and whatever things, but the only two words that's recognized by the major societies are radiosurgery and SBRT, not SABR. Everybody's using SABR, but SBRT has been approved by ASTRA and AANS too. So we have to all think about it. Some people think single dose is radiosurgery, multiple fraction up to five fraction, which is defined by the insurance company, is SBRT. Those are the examples. Let's look at the question. Someone had brain lesion, three centimeter metastasis, five grade gamma knife. I was actually very surprised to see this patient. Was this radiosurgery or radiation therapy? These are the questions. Also related to collaboration issues. Lung lesions, three centimeter, 12 grade times four. Is this radiosurgery or SBRT or SRT these days, right? So we do not have any questions. I'm not going to dwell on this anymore. So this is sort of my personal journey of developing spine radiosurgery. I put this slide because this is resident talk. I conceived this idea in 1989 looking at this paper. This is used in the paper, 1982, by a Swedish physicist, Brahmi. He drew OAR in the middle of the target, and he drew donut-shaped target here. He did not have any data there at all, but he suggested this. By opening the radiation source here and blocking the middle and arcing it, then you will get this type of a dose distribution. This is not good. However, he said, by some way, by some way, if you can, actually he used the wedge at that time, at that time, 1982. By some way, if you can deliver high dose here, lower dose here, and arc it, you will most likely get this type of treatment. So when I heard, saw this in 1989, that's the time I heard radiosurgery, the terminology first time. I didn't know what it was. So I spoke to my mentors, and probably, we can probably do this with radiosurgery, and no one listened to me. And I did not have any knowledge or experience how to prove it. I had no resources. But I spoke to a fellow neurosurgeon who is at El Paso, Texas now, and he said, oh, probably we can do it. Let's think about it. That's it. And then I was able to start preclinical work in 1996, and I got experience from brain radiosurgeries and studied translational research. When it comes to radiosurgery, you would like to put this target, whatever in this isodose curve area, like a drop of water on the pond. This is just like radiosurgery, and you have to think about two things. Biological effects, which we call rapid dose fall-off, which requires accuracy targeting and precision. And then we are waiting for these biological effects occurring. So biology and physics should be always considered together for radiosurgery, like any other radiation therapy. So spine radiosurgery, this concept was built on the lessons of brain radiosurgery, lung cancer, brain stem metastasis. It can be very well cleared with even 16 gray after two months without any sign of complication in the brain stem or adjacent tissues, whereas a lower panel lung cancer, 18 gray, was delivered, but after six months, you get anticipated radial necrosis. But sometimes you can have marginal recurrence because of this rapid dose fall-off. This was taken out. You see necrosis and viable tumor. So accuracy targeting, accurate delineation of the tumor also is extremely important. And this is an AVM in the left temporal area. This patient presented with headache, and this patient had radiosurgery at some other institution, not by me. And the patient had somehow complete resolution of headache. Headache disappeared. After two years, follow-up MRI scan showed a necrotic cavity, necrosis occurring just here, just above that. This AVM was still present. So what happened? Mistargeting. This type of, even this gross mistargeting occurs in the community setting. That's why many people are saying that good team and vigilance, all these things are very, very important. So these are the lessons we got from brain radiosurgeries. Then what is the second stage collaboration? I called it preclinical studies. Our collaboration actually started from there. It's not who's drawing or something. Collaboration with the physicists and radiosurgery radiation oncologists. I can say radiosurgeons, regardless of oncologist or neurosurgeon. Radiosurgery radiation oncologists and radiosurgery neurosurgeons. So we sat down together and talking about this. With physicists, we had to talk about technical issues and radiosurgeons imaging studies. How can we visualize it for the tumor and for the treatment and so on and so forth? And how can we develop this translational strategy? We also have to think about biology. What kind of core tolerance and dose modeling and these things should be thought out to start all these things. And at the same time, we are dealing with really radiation delivery issues. So technologists, therapists, and nurses, all these things should be laid out very correctly from the start. So we questioned a lot of things. As I said, physics questions, biology questions, clinical questions. And we laid out all those things all together. It's not just my brain only, neurosurgeon, physicists, everyone there. And we questioned and we tried to answer all these questions step by step. So during the time, the main issue that requires for radiosurgery is immobilization, positioning. The only thing at the time, you know, a long time ago available was frame-based stereotaxis. You know, this halo and stuff. And then now, everyone is trying to talk about at least or move to so-called frameless toxicity not only to the brain but also to the body sites including the spines. So our catchword is invasive procedure to minimally or even non-invasive procedure. That's the catchword in surgical society and oncological or radiosurgical societies. And the other technical development was so-called image-guided non-invasive localization. We talk about 3D, 6D fusion, and so on and so forth. Those became also available. At the time, again, in mid-1990s, intensity modulation concept came in and became also available too. We did a lot of preclinical studies and simulations here. How many beams are necessary? Do we need 20 beams or 7 beams, 11 beams? Now we all know that we need about 10, 9, 10 beams, but we didn't know at that time. So we did a lot of simulations to see how this radiation beams will pass through. And what about the beam size, beamlet size? Now we call micromultilift collimator and so on and so forth. So we tested 10 millimeter, 5 millimeter, 2.5, which is the main beamlets these days. So we studied all these. Finally, we were able to do this in 2001 based on this, again, thinking about this diagram, we were able to make the same type of treatment with the intensity modulated radiosurgery. So with that, our neurosurgeons became more convinced, oh, we can do it. Then how can we move it to the patient? This was the first patient I have ever treated with a spine radiosurgery. I tried to find this slide yesterday. This was a recurrent osteosarcoma. It's March 2001. I clearly remember that day in the evening. This patient had multiple surgeries. I think she had about four surgeries here and chemos and external beams before and everything done now stuck. There's nothing else to do. You see the tumor in the spinal canal here and in the axial section. Her main problem is pain. What is your pain score 1 to 10? Her answer was 50. She does not want to go down to even 49. So we offered radiosurgery. Look at this radiosurgery. It was very low at the time. And we gave 12 gray. This is the only result that she can die before. So after two weeks, she reported the pain 5 over 10. She now can survive. She walked in to the clinic, actually. And six months, we had MRI scan. Again, the tumor disappeared and necrotizing on this axial image. So we got very convinced. We were really convinced. So next step, third stage collaboration was not just our radiosurgeons, but non-radiosurgeon, radiation oncologists, and neurosurgeons, our immediate colleagues in the department. They still did not believe it. Our immediate colleagues did not believe it because they are saying, oh, there's external beam radiation therapy. Will that really work? That's the question. The dose is limited due to the spinal cord tolerance. Is that enough for tumor control? And why not fractionate? This is all single dose. And many people, especially neurosurgeons, asked me, scalpel concept, we can cut like this with knife. Can you do it with radiosurgery? Of course not. And then there is a big issue here, commercial aid, gamma knife. Gamma knife is not radiosurgery. It's equipment. It's equipment, right? You are not saying Da Vinci surgery. You say robotic surgery. I don't know why radiosurgery became gamma knife radiosurgery. And a good name. And the cyber knife, the same. You see billboard all the time here, cyber knife radiosurgery. People come to me and say, did you cyber knife it? That became a verb now, right? And in our town at that time, another word, other hospital, big hospital said omni beam. They are doing omni beam. And then in the society, we have Saber, SVRT, as I said, the official name, but many, many others' names fly. So we had to go over that. We have to say, oh, this is the same or not, so on and so forth. So that's the next collaboration. Because of this collaboration, we felt that we have to show the accuracy first. That's the first step. So this is 2001, not now, 2001. On our hand calculation, our precision and accuracy was 1.36 millimeters. Actually, my hand calculation was 1.5. And you will see many publications using phantoms. They don't move. This is in the patient. In the patient, we were able to achieve 1.36 millimeters. And those follow from 90% to 50% was 5 millimeters. Now it became 3 millimeters, but at that time, it was 5 millimeters. It was very hard to publish, actually. It took two years to publish. Now I'd like to discuss this target volume delineation issues. This was all discussed at the time in depth. Now everybody's talking about GTV by our training. This is GTV, of course. How can you define GTV here in this spine? I don't really buy it. This spine is one compact bone marrow, open bone marrow. GTV is gross tumor, right? How can you define GTV within the bone marrow? Do you say GTV for leukemias? No. Multiple myelomas? No. So I couldn't buy it, even in the metastatic disease. And then we call CTV, CTV which we think there is a disease or potential disease, which I can sort of understand. And then we give PTV because of the uncertainties. So you have uncertainty in this paraspinal area in terms of delivering it, but you do not have any uncertainty to the spinal cord, right? So we have to really think about this critically. And the PRV, this is a spinal cord. And then people give PRV, which is spinal canal. That's how people usually do, even now. But we defined only, oh, this will cause dosimetric consequences, obviously. So we defined only two volumes, target volume, spine target volume and spinal cord, OAR. So those were defined using MRI scans, not the spinal connect. So we quickly formulated three different scenarios. Most common spine metastasis like this, we treat like this, and I'm not going to explain too much. We saw this. If there is some more extension posteriorly, you can either treat more generously like a dotted line or like a donut. Sometimes you see only involvement only in the posterior element. We treat like this. And that became our standard approach. And then there was a necessity to form a spine tumor board and clinical trials. So a spinal tumor board, obviously radiological oncology, radiosurgeons obviously, neurosurgeon, radiation oncologist, and radiologist, pathology, and so on and so forth. So how can we overcome the existing data of external beam radiation treatment or surgeries or dogmas? How can we make the basis of paradigm shift? Those were all the questions we asked and tried to answer. And we also discussed a lot about design of clinical trial. What will be the endpoint? Someone said local control of the vertebral body. How can you define it in the bone? You can't, right? Local control of epidural tumors? Yes, MRI scan and imaging studies. And of course, neuro exam is extremely important here. So we talked about all those to formulate the prospective clinical studies. So we, I proudly say, showed two prospective studies done in our institution. The first one was efficacy study for solitary spine metastasis, just like solitary brain metastasis. And we escalated the dose actually every two grades, 10 to 18 gray. And then the endpoint is pain control, pain control, because these patients all present with pain. So we became to know that as long as you go to 14 gray or higher, you will have very consistent pain control. 14 gray more for multiple myelomas, 16 gray for more for other epithelial tumors. And when we reached that 14 gray, we became very confident that we can target the spinal cord compressions. So we started another study from 14 gray. Endpoint is tumor control, epidural decompression, neurological improvement. And we became to know that if you achieve 18 gray or higher, you will get very consistent epidural tumor response. So I will show you all those. During all the course, we kept track of spinal cord tolerance. So this is the phase two result. This patient has solitary spine metastasis, treated dose escalation at that time. You see rapid pain relief occurs within about 14 days. You see the pain decreasing as early as 24 hours. This is now very well known. And durable pain relief of that treated spine, 84 percent. Now everyone is reporting 84, 90, 95 percent range. Again, this was very difficult to publish. I could not publish it at the time. So with that, we moved to treat the spinal cord compression. The one example here, breast cancer, spinal cord circumferentially squeezed and compressed. December 2004, 16 gray at that time. This is again dose escalation mode. And January 29, 2005, this was all decompressed. There still is something remaining. This was Jazz, Jazz trainer. She was, she's still very active even now. When I show this to everyone, everyone asks like this, oh Sam, you are prescribing to 90 percent here and your dose tolerance, I will show you later, is 50 percent to the spinal cord. You are limited with this dose and you are underdosing this tumor. So in fact, this publication was sent to some high profile journals. One reviewer, I'll just tell you to the resident, one reviewer said just one sentence, this is not ethical. There was the comment. That's reality here. So anyways, to answer that question, now with this, we are going back to third stage collaboration. Now, many people are saying that there is randomized class one evidence that surgery is the gold standard for treating spinal cord compression. It's well known. I'm not going to go in detail, but I want to tell you one thing. Endpoint was four steps, even with aid, walker. So in the clinic, okay, move one more step. That made it four steps, ambulatory. Many patients, these patients were ambulatory to start with. I'm not arguing about the role of surgery, but we have to look at very carefully and we can challenge it after 10 years, right? So our hypothesis is this. You have epidural tumor here, you're covering, let's say with 90% spinal cord tolerance should be respected underdosed here. Then can radio surgery reduce this epidural tumor and decompress the spinal cord? So we give radio surgery and follow up and tumor control is the endpoint. Tumor control is epidural tumor control, epidural decompression and neurological improvement. We treat this entire, again, entire bone and epidural tumor and including paraspinal tumor when there is a paraspinal tumor. And this is a result. There was, in all comers, all comers means that there are different extent of epidural compressions, right? In all comers, 65% volume reduction occurred. So epidural decompression occurs. And at the level of the most significant epidural compression, the epidural tumor size decreased from 0.84 to this. And fecal sac area increased statistically significant. This shows, this is the evidence that decompression occurs. So we are calling it decompressive radio surgery as Peter showed this morning. And fecal sac patency increased from 55% to 77% in all comers. When you look at neurological outcome of these patients, it's also very encouraging and promising. Let's look at Patchell's phase 3 study of this arm, surgery plus radiation. And let's look at our phase 2 study here. Overall ambulatory rate was 84%. Our overall intact rate, because some cervical cord patients are, they are ambulatory, but they have weakness of the arms, you know, symptoms of the arms. So we say neurologically intact rate is 81%. Ambulatory patients keeping their ambulation is 94% here. An intact patient being intact, remaining intact was 88%. Non-ambulatory patient becoming ambulatory was 62%. It's not 90%, 62%. Deficit patient becoming intact is 59%. I'm not comparing apples and oranges here, but the number do not look so much different, right? And you are paying this much extensive surgery and TLSO abrase for six months, or for cervical spines, your occiput and cervical spine is fixed. You cannot bend your neck so much well. And same C3 metastasis can be treated very easily with radio surgery with similar neurological outcomes. So because of this, we developed our own grading system. Many people will use MRI scan to predict the patient's neurological status. You can't. MRI cannot use it, cannot be used to predict that. So we developed two grading systems together, dual grading system, radiographic and neurological. A is no abnormality, B is very minor neurological abnormality, and C is, we call it functional paralysis, muscle strength of four or five. They are still ambulatory. They still have useful function. D is less than three over five. E is paralysis. This is very well established. I'm not going to go too much in detail. Grade zero is bone metastasis only. Grade one is epidural fat involvement. The thick or sag is not touched. Grade two is impingement of thick or sag. Spinal cord is still okay. And grade three is spinal cord abutted or impinged. Grade four is so-called partial block on myelogram. Grade five is complete block. In CAUDA level, less than 50% canal compromise is called grade two. More than 50% compromise is grade five, grade four. And then we combined these two together with neurological. For example, grade 2A, grade 3B, or something like that. And we used them. So proposed treatment for canal compromise now is this. For surgery, anyone who has significant neurological deficit, less than three over five, who became non-ambulatory basically, compression fracture with a bony retropulsion, or a bony retropulsion, and spine instability. These are surgical entities. For radio surgery, any type of spinal cord compressions with ambulatory status or better, four over five, we did not use imaging as a upper guideline to use radio surgery. This is one example. Renal cell carcinoma, this is grade 4B. There is a very small CSF seen here. 4B, 18 gray. In three months, became grade 2A, neurologically intact. So that's one example. I did not discuss about kyphoplasty is not recommended for this type of situation. So we had cases, the epidural compression even pushed further back, causing more spinal cord compressions. So kyphoplasty is not recommended for those patients. So next step was fifth stage collaboration. I was going to take it to RTOG. RTOG is to spread this technology, this treatment to the community level, not just, you know, high level university hospitals, but community hospitals. There was a totally different ballgame with QAs and collaboration with other community practicing doctors. So we developed this phase two and phase three study. Phase two study was published. Phase three now is ongoing with a solitary spine metastasis, two contiguous, or three detached solitary spine metastasis. Or more recently, MRI is used. So MRI may show a lot of small diseases here. When you have very small one, they are also eligible and acceptable. You can target these gross lesions up to three. Well, throughout, I'll finish within two minutes. Throughout, we had to pay attention to the clinical biology of radiosurgery, not only looking at the mechanism of radiosurgical cell kill, but also how we can predict this normal tissue effects and prevent or mitigate the radiation damage. As I showed you, we reported partial volume spinal cord tolerance. Partial volume, what it means is the spinal cord circumference is here. Only partially there is a high dose distribution. That's 10% to 10 gray. Spinal cord defined as six millimeters above and below the target. And we chose this percent volume reporting. I know we like to see absolute volume dose, but look at this. This is same level of different patients, same level. Someone has this thick spinal cord. Someone has this thin spinal cord. 0.35 cc of this patient and this patient the same? I don't think so. I don't know. I don't think so. And position is different. Some people have more anterior and posterior. It's not in the middle. So we felt that relative percent dose might be more appropriate for this type of patients. And you see 0.35 was recalculated looking back at 10% range. That's how it was reported. And we also did, during the course, this experiment using radiosurgical dose 23 to 33 gray to the rats and gave, we were looking for some agents that can mitigate the radiation effects. And ramipril ACE inhibitor was given to the to these rats. You see the hair loss here. After 30 gray, everyone gets paralyzed. This is normal control and this 30 gray you see telangiectasia and the UC actually diameter a little smaller than this one. And ramipril, this is a little magnified, ramipril at least got rid of this telangiectasia grossly. And we looked at many different aspects of it. HE stain looks so fast. Blue stain to look at the demyelinization and ramipril restores it. And somehow anti-VEGF stain was very positive in radiation group. And ramipril also improved it. I still am thinking what this means. I don't really understand right now, but this is not the time to discuss about the mechanistic issues. I'd like to show this one as my last slide. In these rats, paralysis occurred 100% of these rats. Ramipril treatment decreased it to 60%. So there is a role that we can probably reduce the rate of paralysis or delay the time of developing paralysis with ramipril. This was significant in these animals, but this was in the paralysis inducing those intentionally. And so my final conclusion is ideal collaboration model. Radiosurgery is not just a frame, drawing, or planning. It's not who draws, who is here, or who said so or something. It is really mutual understanding and learning of the basic concepts of everything and considering the practicalities. No ego, no turf issues. And I propose to have reciprocal interdisciplinary training with a good leadership and collaborators together with the constructive critics and rotation, mutual rotations. Thank you.

multidisciplinary collaboration

radiation oncologists

neurosurgeons

spine metastasis

treatment planning

radiation therapy

spine radiosurgery