Transcript
Bogdan: Hello, everyone, and welcome to a new Novalis Circle webinar. My name is Bogdan Valcu. I'm the director of Novalis Circle. Today I have with me Professor Alongi from Verona. And he'll be discussing a topic pertaining to spine radiosurgery. Before we get going, just a few housekeeping items. I'd like you to remember to use Google Chrome or Safari in order to log into the webinar and have full video access. And as always, we'll take questions via the chat option on the right. And at the end of the lecture, we will answer your questions. And if you'd like to follow us on social media, you could do that as well. The topic for today covers utilization of Brainlab technology for spine radiosurgery treatments. Professor Alongi will start with a review of the current state of the art for treatments in the spine metastases space. He will review the role of conventional treatments versus radiosurgery and SBRT treatments. And he'll review his clinical utilization of our spine radiosurgery product.
Professor Alongi is the chair at radiation oncology at Sacro Cuore-Don Calabria Cancer Center in Negrar, Verona, Italy. He's also an associate professor at University of Brescia. And we had the pleasure to work with him over the years as he began utilizing our spine SRS product. Clinically, he was actually the first user in the European community to implement the product clinically and he now has quite a wealth of clinical experience with the technology. As always, we do provide credits for our webinars. If you're interested in obtaining CAMPEP, MDCB, and ASRT credits, please watch the full webinar. And upon completion, send us an email at info@novaliscircle.org and we will let you know how you can obtain the credits. And don't forget to sign up for our upcoming webinars. The next one will also focus on spine treatments with the group from Thomas Jefferson and that will be on June 10th. So, I'd like to introduce you, Professor Alongi.
Professor Alongi: Thank you. Thank you, Bogdan, for this opportunity. Thanks to Brainlab for the possibility to share our experience and our view regarding automated spine SRS treatment and the benefit of modern software tools. This is my agenda. I will discuss about the emerging role of SRS and SBRT in the setting of spinal metastases. I will describe the target definition approach of SRS and SBRT for spinal lesions. And I will discuss the benefit of modern software tools for spine SRS. And at the end, I will share with you our clinical experience utilizing Elements Spine SRS in this setting of spinal metastases.
So, regarding the emerging role of SRS and SBRT. I'd like to start with this concept regarding the incidence of the phenomenon of spinal metastases. We can say that approximately one third of cancer patient can develop spinal metastases. And 70% of the metastases are properly involving the vertebral column. Back pain is the most common initial symptom. And we know that if these sites are untreated, spinal metastases can cause vertebral body fracture, radiculopathy, and debilitating complication up to epidural spinal compression. We know that the role of historical conventional radiotherapy is well clear. The most commonly used regimen is 30 gray in 10 fraction. We know also that single-dose treatment are usually prefer in patient with limited life expectancies, or poor performance status, or in case of waiting list in the radiation therapy centers. In this table you can see the experience regarding conventional radiotherapy. We know from this data that there are no clear differences in term of approach. The regimen of single dose seems to be not inferior compared to the conventional fractionation in 5 or 10 sessions. What we can see about the limits of conventional radiotherapy. It is well-known that complete response rate seems to be really low. We are approximately between 0% and 20%, partial response, approximately 60%, and the cumulative local control of these cases is less than 50%.
What about radiation therapy? Modern radiation therapy is in the midst of a lot of changes in term of technology, in term of expertise. We know that irrespective of the machine that you have, now we are able to focus very high doses to small volumes. So, starting from this assumption, we know that also from radiobiological point of view, we have new knowledge because we know that if we prescribe very high dose per fraction, we can include, we can take into account new phenomenon including endothelium damage of the vessels, also ischemic and immunological components of cell killing, not accounting for alpha/beta. So, starting from this background, we can say that a lot of new indication regarding ablative doses are emerging. And in the last 10 year, as you know, the world of radiational oncology was changed by the possibility to treat oligometastatic and oligoprogressive patient with curative doses. And specifically in 2020, we can say that there is not an exhaustive terminology to define oligometastases. We could have different declination. We could have synchronous oligometastases, metachronous oligometastases, oligorecurrent, oligoprogression,. In all of these situation, ablative doses can be delivered safely with the intent not only of the palliation, but also to add something to control the disease. Obviously, the lasting point is to increase survival.
This data, very important because, as you know, recently, Palma and colleague published the paper of SABR-COMET. SABR-COMET was an important Phase II trial in which was shown that SABR, compared to standard of care, compared to control could be able to increase survival if we treat up to five lesion in terms of oligometastatic disease. And this paper, this data were confirming this second printed paper in which the advantage in term of survival was concrete with longer follow-up. So we can say that now, compared to control arm that could be represented by standard systemic treatment, the addition of selective radiation therapy to selected sites could be a way to change the disease and to change the behavior of the disease in most of the cases impacting on survival.
What we can say about the emerging role specifically of SRS and SBRT in spinal metastases. For sure, we can say that spine SBRT has been quickly adopt in radiation therapy community. We have available retrospective and prospective evidence growing in this setting. And for sure, we can say that the indication in the setting is increasing a lot, not only for palliation but, as I said, also to try to improve the control of disease. Regarding data, for sure, stereotactic body radiation therapy in de novo spinal metastases is able to increase local control. We have data of local control of 90% at one year, complete pain control in more than 50%. And the toxicity profile seems to be really low because vertebral compression fracture is less than 10%. And myelopathy is approximately close to 0. This paper is an important paper because was shown in "Green Journal" recently with this randomized Phase II trial, that SBRT seems to be not inferior when compared to three-dimensional conformal radiotherapy to treat spinal lesion. And it was the first step to evaluate the role of spine SBRT as a potential application in de novo metastases. Here you can see a table with the synthesis of some of the most important experiences regarding the prospective study in this setting. And we can say, for sure, that local control ranged between 84% and 96%. Very high rate level. And this is another important review published on Journal Oncology in 2020 in which was defined the role of stereotactic ablative radiotherapy for the management of spinal metastases because it could be able to obtain very high local control rate at one year, between 80% and 90% in de novo setting, but also in 80% in postoperative setting, and greater than 65% in the reirradiation setting. And it is very important because, as you know, the scenario of the potential indication of SBRT is larger than expected based on this data.
Here you can see the NCC guidelines. This is one of the last version. You can see that the possibility to use SBRT for treatment in de novo metastases but also retreatment is include. So something is changing also in clinical practice because the emerging data are in favor of this application and guidelines are including even more this kind of possibility. Here you can see the data of retrospective and some prospective trials and study regarding spine SBRT in reirradiation, it is another very intriguing application. And as you can see here, local control rate seems to be very high, in some cases more than 90%. SABR, in fact, in reirradiation is intriguing because it may be able to reduce the maximum small volume dose to the spinal cord and is able to allow the delivery of a comparatively higher dose to much of the progressing tumor reducing the risk of myelopathy.
This is another very interesting paper. This is a paper from dosemetric point of view published by Furuya and colleague this year. This is a feasibility evaluation of large tumors in multiple vertebra undergoing reirradiation. And there was a dosimetric challenge between different techniques. Obviously, for spine SBRT is crucial to concentrate the prescribed dose on the target and simultaneously maintain spinal cord irradiation at acceptable level in term of constraints. And in their analysis, you can see that IMRT and volumetric techniques are viable option for multiple large vertebral SBRT, while CyberKnife plans could not achieve the constraints. And this discrepancy may be related to the treatment duration that can be effective, that can influence obviously some aspects including the dosimetric application of the treatment.
This slide regards postoperative SBRT. This is another very interesting approach because from the data that we have local failure rates are 79.3, 96 at 1 and 4 years after postoperative external beam radiation therapy. So starting from this data, the role of SBRT may be intriguing. And in some paper, including that one, the "Red Journal" in 2016, they had also reported a crude local control of 88.6, very high-level considering this multidisciplinary approach including such. Here, you can see this is a journal, Neuro Spine 2017. A consensus and predominant practice regarding the definition of the volumes of the organ at risk for postoperative spine SBRT. So it's important to focus on the fact that now we have some guidelines, we have some article, and we could have some data that can allow us to face, at first, this kind of situation. Here you can see suggestion regarding fractionation schedules and spinal constraints in postoperative SBRT spinal application. And here you can see some data in detail. We have retrospective and some prospective data regarding local control rates that are variable between 65% and approximately 91%. So also here, intriguing data regarding the role of SBRT also in postoperative setting. This slide, only to say that before to select the patient, we can consider some classification including spinal instability score and NOMS in order to approach the right situation in a personalized way.
The second point that I show you briefly with you is the target definition that is another important, challenging situation for radiation oncologist if they are not used to treat this patient with SBRT. This paper, I think it is a milestone because it was published in 2012 by Cox and colleague. It is a real consensus guideline regarding the target volume definition in spinal stereotactic radiosurgery. I recommend to read it because it is really clear and you can see that considering the site of involvement of the vertebra, this vertebra could be divided in sub segment. And there is a clear recommendation of how you have to include or to exclude some part of the vertebra. However, even if we have this kind of guideline, this paper is clear, published by my friends, 'Dino De Bari and colleague in "Green Journal" in 2017. It is an important paper because it was shown, ESTRO FALCON program you know is a program in which a lot of colleagues are involved to contour some sites including vertebrae in this case. And there was a high variability in target definition for spine SRS. So even if we have learning guidelines available, the variability remain high. And of obviously, it could be a limit regarding the precision [SP] of the treatment. It is important to have also in the target definition, the availability of different kind of images, for sure, MRI, but if you have PET/CT images are important thanks to the fusion of the easy [inaudible 00:17:44.866] you can improve the quality of the target definition, for sure.
As you know, there are other guidelines. It was published by Dunne and colleague in "Green Journal" last year. It is international consensus recommendation of target definition, not only for spinal disease, but also for the pelvis, the first part of sacrum. As for you can see here, you can find some recommendation of how to approach also some extremities in some part of the column that were not included in the previous one. And here, you can see the data of Katsoulakis regarding obviously the impact in term of dose prescription for SRS and SBRT. And as you can see, we have a large variability in terms of the number of session, but also in terms of fractions. Resuming, we can say that obviously single fraction is able to achieve the highest local control with a range between 80% and 95%, but we have robust data that are not in favor regarding the safety because we could have also higher fractual rate between 36% and 39%. While in multi-fraction approach, we could have a little bit less in terms of local control, but we can reduce up to 8% to 15% the rate of compression fracture.
Another important thing is to maintain constraints obviously for the safety of the treatment. The QUANTEC DMax limit recommended this, 15 gray in single fraction or 20 in 3 fractions. Here you can see how to define a spinal cord and to maintain distance between the vertebral body and spinal cord in order to have the reduction of the dose thanks to the delivery of SBRT. Even if in this other paper by Katsoulakis and colleague in "Red Journal" in 2007, you can see that it's possible to maintain a Dmax limit of 14 grays, that it seems to be related to less than 1% rate of myelopathy. So it seems to be safe to maintain within this dose, maximum dose. Here, you can see the evolving role of stereotactic body therapy in the management of metastases. You can see here the dose and the constraints that are usually applied in detail. This paper is obviously available, Clinical in 2020 "Neurosurgical," published by Moraes and colleagues. And it is important also to follow this patient, how to approach the follow-up. For sure, conventional T1 and T2 magnetic resonance imaging is recommended with 1 to 2 millimeters of slice thickness performed at every 2, 3 months after SABR for the first year or the first 18 months, and every 3, 6 months thereafter.
The following point that I will share with you is the benefit of the use of modern software tools for spinal SRS. As Bogdan said, we had the pleasure to be the first center in Europe, for sure, the first in Italy to test in particular Elements Spine SRS. We started in 2018, and obviously, Elements Spine is a solution capable to obtain an optimal multi-images alignment, especially between CT and MRI or PET and/or MRI and simulation CT. This system is easy and you can obtain easily an autosegmentation delineating the targets and the sector that are crucial for your plan. And obviously, SBRT planning was designed to obtain incredibly sharp dose gradient that I will show you in detail in some cases that are follow. Here you can see the first phase that is the deformable registration between CT and MRI. We are able to correct postural setup errors during the positioning of the various exam focused on the column. Here you can see the autocontouring of the system that is able to generate from GTV on MRI and CT images, the CTV. Here you can see, in fact, an example of autocontouring of CTV with bone substructure involved starting from the delineated GTV. I described before the Cox paper regarding the consensus of how to define this volume. Brainlab Element Spine is able to use these guidelines, and to autogenerate in a few seconds what you need for the definition of your volumes. Here you can see the planning optimization in detail. The system is really easy-to-use because we have the constraints and you can see clearly with the colors red or green if you have the SPECT of your constraints. Here you can see the evaluation of the plan. And you can see the dose distribution in this case. And this is the approval. As you can see, most of the spinal canal is out and the spinal cord, for sure, is outside the prescription doses that is what we need to achieve.
I'd like also to share with you this experience. It was presented at the ESTRO by some colleagues from Canada. And it was very important because they did what we did in our...the pattern. They considered the best approach of their department before to have this system. So RapidArc was their best practice before. And after the introduction of Novalis as the Elements Spine SRS, they tried to compare the two approaches. And as you can see here, they obtained a significant reduction of the volume of the spinal cord receiving 10 gray with the use of Spine SRS Element with a significant difference between Spinal SRS Element system and the previous system that they used that was obviously RapidArc.
The last point to share with you is our clinical experience using Elements Spine SRS. It is a pleasure for us to show you this data. This is the paper published by Niccolò Giaj Levra. That is a colleague in my department, but there was the involvement of most of my colleagues. This paper was published in 2019, really, a few months ago. Is open access, so you can find the details of our procedure and our data, really, in detail without problems. And we treated patient between April 2018 and April 2019. Fifty-four cases of spinal metastases. Here you can see the details of the table of regarding the details of the volumes treated, the fractionation used. You can see from 1 to 3 fraction with radical intent in most of the cases. And as you can see here, in a VAS reduction of back pain was observed in several patients. And I'd like to show that there were not acute or chronic adverse event, more or equal to Grade 3. It is important to share with you the data regarding local control for cancer treatment because at medium follow-up of six months, local control rates at six months and nine months were equal, 86%. Here you can see a typical case with the dose distribution to the vertebral body. And as you can see, those prescription is totally inside the body of the vertebra while the spinal cord is absolutely preserved. Here you can see the details of the treatment. I don't treat in detail, but this data, if you want, are available in our paper. We obviously tried to use the constraint that are available in literature. And we treated this patient with flattening-filter-free 10 MV beams. The prescription was done according to ICRU Report 91. So volumetric dose prescription was 95 to 95 of the PTV. It is important because it is a choice that we decided to do. And here, you can see some of our data updated. Here you can see that the number of patient treated was 57, but the number of lesion treated in this patient were 83. The median lesion per patient was one with a range from one to three. You can see that the primitive tumor site was various, from prostate to gastrointestinal to other sites. Schedule of dose were variable. One session or more fraction, most of them in three. You can see the biological effective dose. And as you can see here, in the last period, we included also a boost, a simultaneous integrated boost. And I show you some cases in the example that I have in my slides.
Here you can see a case of spine Segment D4, the prescription was 21 gray in 3. You can see how the system was able to generate the volume that we then treated starting from the GTV. Here, another case, the vertebra is D9, 21 in 3 without specific problems to maintain the dose under 20 in 3 on the spinal cord. Another example, D9, 24 in 3, but you can see a simultaneous integrated boost, as I said before, in the region of macroscopic visible disease on the GTV, 27 in 3, and the system is able to do this kind of very complex and intriguing approach. Another here, 21 in 3, but you can see how we're able to focus the dose on the simultaneous integrated boost region maintaining the dose to 27 gray in 3. And here, I have a clinical case, a brief clinical case. A male with 75 years old, you can see a PET PSMA with a PSA of 7.84. You can see the lesion in L3. And here you can see the PET CT before and after in the middle of the dose distribution. But it is important to underline how in PET PSMA the SUV was reduced after the treatment. Back pain was the half and PSA was in diminishing without changing in or [inaudible 00:30:08.912]. Another brief case here, you can see the vertebra involvement, PET PSMA with a PSA of 2. And here you can see these intriguing images in which you can see the PET before on the left and after on the right in which we have a significant reduction of SUV from 10.3 to 2.5. Back pain was 0 at the end of the treatment and PSA was close to 0. The dose prescription was 21 in 3. Another case here in which you can see the lesion on MRI, the lesion on PET, the dose distribution. It is L1 spine SRS, 24 in 3 plus SIB with a boost of dose of 27 in 3. And you can see a complete response, impressive, with a back pain that disappeared for the patient. So, you can see it is a classic example of what we can see, not only palliation, not only pain relief, but also reduction or disappearance of the disease in the microscopic site that was evaluated before diagnostic images.
So I can conclude, for sure, spinal SRS and SBRT represents an emerging solution for selective patient, obviously. This techniques allows clinician to improve local control and prevent local progression. We have still now remain to define the standard schedule of those fractionation. And toxicity, however, seems to be really low for these patient. For sure, we can say in our experience that the introduction in clinical practice of Novalis Elements Spine SRS is an easy tool useful for maximizing the feasibility of this approach. And I think that if you have a program to introduce this kind of indication, SBRT or SRS in spine, having Novalis Elements Spine SRS, it could be the solution to start easy and without technical and clinical problems. This is a picture of obviously my staff, of my team. You can see physicists, technician, and doctors because the data that you saw, obviously, I have to thanks to them for these results. Thank you.
Bogdan: Thank you very much, Professor Alongi, for a great presentation. And we have a few questions. So maybe I'll start just with a generic one. And I think this one applied to a lot of people that are interested in starting their own spine radiosurgery program. So maybe you can detail a little bit, when you started your own program, how did you manage the referrals from medical oncology? Were there any lessons learned to convince your fellow physicians to refer into spine radiosurgery program? And what would you share with others who are interested in starting such a program?
Professor Alongi: Yes. Thank you. I don't know if you hear me, yes?
Bogdan: Yes.
Professor Alongi: Yes. Perfect. Optimal question. I think that is important to have a network specifically with neurooncologists, but medical oncologist, surgeon. I think it is important to have these kind of deep relationship in order to manage together these patients. But I think that it's important to demonstrate our powerful effects in term of results and in term of tolerability. Frequently, a lot of colleagues are afraid about...have a lot of concern regarding the side effects related to specific treatment in radiation oncology. Now we are demonstrating our ability to be safer in terms of well-tolerated treatment, also in terms of response because, as you can see, if we are able, during a multidisciplinary dissertation and moments to show how this kind of approach are able to obtain complete response, partial response. And one day use this kind of patient obtaining this kind of wonderful results, I think that this is the best way to convince them about our role.
Bogdan: Okay, Dr. Menid [SP] is asking a question regarding fractionation. So most of the lesions that you treated seemed to have three-fraction treatments. Do you prefer that approach to a single-fraction SRS? And as a sidenote, I guess that he's saying that he does.
Professor Alongi: As professional community knows, I like more to fractionate compared to the single fraction. This is a thing that I approach to the brain in which we prefer three fraction compared to the single one. I think that in this way, we could reduce a little bit the risk of fracture, for example, in the body, or in the structure of the vertebra. And we can obtain the timing results in term of response because the biological equivalent dose if you treat starting from 8 to 9 gray per fraction in 3 fraction.
Bogdan: A question from Andrea Alanccia [SP]. Most of the patients treated with radiosurgery had prostrate cancer as a primary. How many of them were receiving concocted ADT?
Professor Alongi: Yeah, good question. I think that obviously we have to distinguish two entities. The first one is the real oligometastatic patient in which we have from one to three lesion in the bone, in this case. For this kind of patient, I think that we could be able to avoid. At the beginning, they could have androgen deprivation therapy, while in case of oligoprogressive patients, and most of them are oligoprogressive patient, I think that the activity of monotherapy is important. And we can add, with local therapy, a specific control in these types that are not under control after systemic treatment. So, I think that there are these two situation to distinguish.
Bogdan: Okay, Linda Neoli [SP] is asking, how was the dose prescribed? In which level of isodose? Is there any difference in single dose versus multi-fraction? And then linked to this, there's a question regarding reirradiation to the same site, and what was the constraint to the spinal cord then for reirradiation?
Professor Alongi: Okay. The positive thing of this approach is that we can retreat easily. Because as you can see, if we are able, using this kind of system, to avoid high doses to the spinal cord, I think that is more easy to repeat this treatment because we cannot treat the entire vertebrae including the spinal cord. So the possibility to have a margin to treat is higher. And it is important, obviously, to evaluate the timing between the treatment, the side effects of the first treatment in term of the tolerability for the first cause in order to establish if we have space for another retreatment. So the situation is really complex, but is easier than in the past because now we can treat only a part of the vertebra. And we can, for sure, be safe, but also when we are retreating and also prescribing high doses. Is possible to prescribe high doses. This is the most important thing.
Bogdan: Have you treated multi-lesion SBRT patients with our Elements software? So more than one vertebra.
Professor Alongi: Yes, I think that usually you need to have space between one vertebra and the other one. I think that we can consider a lot of situation, but thanks to this tool, you can evaluate your solution also in very complex situations.
Bogdan: A more practical question regarding overall time for planning to treatment. How many days does it usually take for the entire process from imaging to actually treating a patient?
Professor Alongi: Yeah, good question. We are fast because usually, the patient arrived from other region in our center. So we are able to be ready for the treatment within two days. In 24-hour, 48 we are able to have the patient on the couch for the first session of the treatment. Obviously, this is the result of the extreme flexibility of my team and physicists, technician are able to be flexible. This is the most important thing. However, this tool, this software can help to reduce planning, especially in the contouring session and also in the planning because it is really easy to use. You could start from the constraints, and elaboration and optimization is not so complex.
Bogdan: Okay, we have a question regarding the spinal cord compression with soft tissue circling the cord. Do you consider CSF gap to be essential for SBRT use?
Professor Alongi: In our center, we prefer to isolate for SBRT and SRS patient without this condition even if there are data literature in which was shown that we can use also SRS in selective cases of spinal compression. The positive thing is that we are seeing this patient less than in the past because this kind of extreme situation is not so usual, while in the past was really frequent. So the problem now was not present in our clinical practice.
Bogdan: Two questions someone related, what kind of immobilization device do you use for your spine patients, and do you monitor at all for intra-fraction motion and with what?
Professor Alongi: Yes. Regarding mobilization devices, so obviously you can use MAC, but you can use also...work on Pilon [SP]. It depends on the site. It depends on your ability or your frequent usage of one or the other one. And the other question was?
Bogdan: If you track for a intra-fraction motion and with what IGRT system?
Professor Alongi: Yeah. Well, it's really we have a system dedicated. So we can use ExacTrac, that is obviously part of the entire program, or you can use also cone-beam CT, depend on your practice, and your normal program regarding IGRT.
Bogdan: Okay. I think these were the questions. Professor Alongi, I'd like to thank you again for the talk, and thank you all for joining. And have a great week, and we'll see you on the next webinar. Bye.
Professor Alongi: Take care. Thank you.
Professor Alongi is the chair at radiation oncology at Sacro Cuore-Don Calabria Cancer Center in Negrar, Verona, Italy. He's also an associate professor at University of Brescia. And we had the pleasure to work with him over the years as he began utilizing our spine SRS product. Clinically, he was actually the first user in the European community to implement the product clinically and he now has quite a wealth of clinical experience with the technology. As always, we do provide credits for our webinars. If you're interested in obtaining CAMPEP, MDCB, and ASRT credits, please watch the full webinar. And upon completion, send us an email at info@novaliscircle.org and we will let you know how you can obtain the credits. And don't forget to sign up for our upcoming webinars. The next one will also focus on spine treatments with the group from Thomas Jefferson and that will be on June 10th. So, I'd like to introduce you, Professor Alongi.
Professor Alongi: Thank you. Thank you, Bogdan, for this opportunity. Thanks to Brainlab for the possibility to share our experience and our view regarding automated spine SRS treatment and the benefit of modern software tools. This is my agenda. I will discuss about the emerging role of SRS and SBRT in the setting of spinal metastases. I will describe the target definition approach of SRS and SBRT for spinal lesions. And I will discuss the benefit of modern software tools for spine SRS. And at the end, I will share with you our clinical experience utilizing Elements Spine SRS in this setting of spinal metastases.
So, regarding the emerging role of SRS and SBRT. I'd like to start with this concept regarding the incidence of the phenomenon of spinal metastases. We can say that approximately one third of cancer patient can develop spinal metastases. And 70% of the metastases are properly involving the vertebral column. Back pain is the most common initial symptom. And we know that if these sites are untreated, spinal metastases can cause vertebral body fracture, radiculopathy, and debilitating complication up to epidural spinal compression. We know that the role of historical conventional radiotherapy is well clear. The most commonly used regimen is 30 gray in 10 fraction. We know also that single-dose treatment are usually prefer in patient with limited life expectancies, or poor performance status, or in case of waiting list in the radiation therapy centers. In this table you can see the experience regarding conventional radiotherapy. We know from this data that there are no clear differences in term of approach. The regimen of single dose seems to be not inferior compared to the conventional fractionation in 5 or 10 sessions. What we can see about the limits of conventional radiotherapy. It is well-known that complete response rate seems to be really low. We are approximately between 0% and 20%, partial response, approximately 60%, and the cumulative local control of these cases is less than 50%.
What about radiation therapy? Modern radiation therapy is in the midst of a lot of changes in term of technology, in term of expertise. We know that irrespective of the machine that you have, now we are able to focus very high doses to small volumes. So, starting from this assumption, we know that also from radiobiological point of view, we have new knowledge because we know that if we prescribe very high dose per fraction, we can include, we can take into account new phenomenon including endothelium damage of the vessels, also ischemic and immunological components of cell killing, not accounting for alpha/beta. So, starting from this background, we can say that a lot of new indication regarding ablative doses are emerging. And in the last 10 year, as you know, the world of radiational oncology was changed by the possibility to treat oligometastatic and oligoprogressive patient with curative doses. And specifically in 2020, we can say that there is not an exhaustive terminology to define oligometastases. We could have different declination. We could have synchronous oligometastases, metachronous oligometastases, oligorecurrent, oligoprogression,. In all of these situation, ablative doses can be delivered safely with the intent not only of the palliation, but also to add something to control the disease. Obviously, the lasting point is to increase survival.
This data, very important because, as you know, recently, Palma and colleague published the paper of SABR-COMET. SABR-COMET was an important Phase II trial in which was shown that SABR, compared to standard of care, compared to control could be able to increase survival if we treat up to five lesion in terms of oligometastatic disease. And this paper, this data were confirming this second printed paper in which the advantage in term of survival was concrete with longer follow-up. So we can say that now, compared to control arm that could be represented by standard systemic treatment, the addition of selective radiation therapy to selected sites could be a way to change the disease and to change the behavior of the disease in most of the cases impacting on survival.
What we can say about the emerging role specifically of SRS and SBRT in spinal metastases. For sure, we can say that spine SBRT has been quickly adopt in radiation therapy community. We have available retrospective and prospective evidence growing in this setting. And for sure, we can say that the indication in the setting is increasing a lot, not only for palliation but, as I said, also to try to improve the control of disease. Regarding data, for sure, stereotactic body radiation therapy in de novo spinal metastases is able to increase local control. We have data of local control of 90% at one year, complete pain control in more than 50%. And the toxicity profile seems to be really low because vertebral compression fracture is less than 10%. And myelopathy is approximately close to 0. This paper is an important paper because was shown in "Green Journal" recently with this randomized Phase II trial, that SBRT seems to be not inferior when compared to three-dimensional conformal radiotherapy to treat spinal lesion. And it was the first step to evaluate the role of spine SBRT as a potential application in de novo metastases. Here you can see a table with the synthesis of some of the most important experiences regarding the prospective study in this setting. And we can say, for sure, that local control ranged between 84% and 96%. Very high rate level. And this is another important review published on Journal Oncology in 2020 in which was defined the role of stereotactic ablative radiotherapy for the management of spinal metastases because it could be able to obtain very high local control rate at one year, between 80% and 90% in de novo setting, but also in 80% in postoperative setting, and greater than 65% in the reirradiation setting. And it is very important because, as you know, the scenario of the potential indication of SBRT is larger than expected based on this data.
Here you can see the NCC guidelines. This is one of the last version. You can see that the possibility to use SBRT for treatment in de novo metastases but also retreatment is include. So something is changing also in clinical practice because the emerging data are in favor of this application and guidelines are including even more this kind of possibility. Here you can see the data of retrospective and some prospective trials and study regarding spine SBRT in reirradiation, it is another very intriguing application. And as you can see here, local control rate seems to be very high, in some cases more than 90%. SABR, in fact, in reirradiation is intriguing because it may be able to reduce the maximum small volume dose to the spinal cord and is able to allow the delivery of a comparatively higher dose to much of the progressing tumor reducing the risk of myelopathy.
This is another very interesting paper. This is a paper from dosemetric point of view published by Furuya and colleague this year. This is a feasibility evaluation of large tumors in multiple vertebra undergoing reirradiation. And there was a dosimetric challenge between different techniques. Obviously, for spine SBRT is crucial to concentrate the prescribed dose on the target and simultaneously maintain spinal cord irradiation at acceptable level in term of constraints. And in their analysis, you can see that IMRT and volumetric techniques are viable option for multiple large vertebral SBRT, while CyberKnife plans could not achieve the constraints. And this discrepancy may be related to the treatment duration that can be effective, that can influence obviously some aspects including the dosimetric application of the treatment.
This slide regards postoperative SBRT. This is another very interesting approach because from the data that we have local failure rates are 79.3, 96 at 1 and 4 years after postoperative external beam radiation therapy. So starting from this data, the role of SBRT may be intriguing. And in some paper, including that one, the "Red Journal" in 2016, they had also reported a crude local control of 88.6, very high-level considering this multidisciplinary approach including such. Here, you can see this is a journal, Neuro Spine 2017. A consensus and predominant practice regarding the definition of the volumes of the organ at risk for postoperative spine SBRT. So it's important to focus on the fact that now we have some guidelines, we have some article, and we could have some data that can allow us to face, at first, this kind of situation. Here you can see suggestion regarding fractionation schedules and spinal constraints in postoperative SBRT spinal application. And here you can see some data in detail. We have retrospective and some prospective data regarding local control rates that are variable between 65% and approximately 91%. So also here, intriguing data regarding the role of SBRT also in postoperative setting. This slide, only to say that before to select the patient, we can consider some classification including spinal instability score and NOMS in order to approach the right situation in a personalized way.
The second point that I show you briefly with you is the target definition that is another important, challenging situation for radiation oncologist if they are not used to treat this patient with SBRT. This paper, I think it is a milestone because it was published in 2012 by Cox and colleague. It is a real consensus guideline regarding the target volume definition in spinal stereotactic radiosurgery. I recommend to read it because it is really clear and you can see that considering the site of involvement of the vertebra, this vertebra could be divided in sub segment. And there is a clear recommendation of how you have to include or to exclude some part of the vertebra. However, even if we have this kind of guideline, this paper is clear, published by my friends, 'Dino De Bari and colleague in "Green Journal" in 2017. It is an important paper because it was shown, ESTRO FALCON program you know is a program in which a lot of colleagues are involved to contour some sites including vertebrae in this case. And there was a high variability in target definition for spine SRS. So even if we have learning guidelines available, the variability remain high. And of obviously, it could be a limit regarding the precision [SP] of the treatment. It is important to have also in the target definition, the availability of different kind of images, for sure, MRI, but if you have PET/CT images are important thanks to the fusion of the easy [inaudible 00:17:44.866] you can improve the quality of the target definition, for sure.
As you know, there are other guidelines. It was published by Dunne and colleague in "Green Journal" last year. It is international consensus recommendation of target definition, not only for spinal disease, but also for the pelvis, the first part of sacrum. As for you can see here, you can find some recommendation of how to approach also some extremities in some part of the column that were not included in the previous one. And here, you can see the data of Katsoulakis regarding obviously the impact in term of dose prescription for SRS and SBRT. And as you can see, we have a large variability in terms of the number of session, but also in terms of fractions. Resuming, we can say that obviously single fraction is able to achieve the highest local control with a range between 80% and 95%, but we have robust data that are not in favor regarding the safety because we could have also higher fractual rate between 36% and 39%. While in multi-fraction approach, we could have a little bit less in terms of local control, but we can reduce up to 8% to 15% the rate of compression fracture.
Another important thing is to maintain constraints obviously for the safety of the treatment. The QUANTEC DMax limit recommended this, 15 gray in single fraction or 20 in 3 fractions. Here you can see how to define a spinal cord and to maintain distance between the vertebral body and spinal cord in order to have the reduction of the dose thanks to the delivery of SBRT. Even if in this other paper by Katsoulakis and colleague in "Red Journal" in 2007, you can see that it's possible to maintain a Dmax limit of 14 grays, that it seems to be related to less than 1% rate of myelopathy. So it seems to be safe to maintain within this dose, maximum dose. Here, you can see the evolving role of stereotactic body therapy in the management of metastases. You can see here the dose and the constraints that are usually applied in detail. This paper is obviously available, Clinical in 2020 "Neurosurgical," published by Moraes and colleagues. And it is important also to follow this patient, how to approach the follow-up. For sure, conventional T1 and T2 magnetic resonance imaging is recommended with 1 to 2 millimeters of slice thickness performed at every 2, 3 months after SABR for the first year or the first 18 months, and every 3, 6 months thereafter.
The following point that I will share with you is the benefit of the use of modern software tools for spinal SRS. As Bogdan said, we had the pleasure to be the first center in Europe, for sure, the first in Italy to test in particular Elements Spine SRS. We started in 2018, and obviously, Elements Spine is a solution capable to obtain an optimal multi-images alignment, especially between CT and MRI or PET and/or MRI and simulation CT. This system is easy and you can obtain easily an autosegmentation delineating the targets and the sector that are crucial for your plan. And obviously, SBRT planning was designed to obtain incredibly sharp dose gradient that I will show you in detail in some cases that are follow. Here you can see the first phase that is the deformable registration between CT and MRI. We are able to correct postural setup errors during the positioning of the various exam focused on the column. Here you can see the autocontouring of the system that is able to generate from GTV on MRI and CT images, the CTV. Here you can see, in fact, an example of autocontouring of CTV with bone substructure involved starting from the delineated GTV. I described before the Cox paper regarding the consensus of how to define this volume. Brainlab Element Spine is able to use these guidelines, and to autogenerate in a few seconds what you need for the definition of your volumes. Here you can see the planning optimization in detail. The system is really easy-to-use because we have the constraints and you can see clearly with the colors red or green if you have the SPECT of your constraints. Here you can see the evaluation of the plan. And you can see the dose distribution in this case. And this is the approval. As you can see, most of the spinal canal is out and the spinal cord, for sure, is outside the prescription doses that is what we need to achieve.
I'd like also to share with you this experience. It was presented at the ESTRO by some colleagues from Canada. And it was very important because they did what we did in our...the pattern. They considered the best approach of their department before to have this system. So RapidArc was their best practice before. And after the introduction of Novalis as the Elements Spine SRS, they tried to compare the two approaches. And as you can see here, they obtained a significant reduction of the volume of the spinal cord receiving 10 gray with the use of Spine SRS Element with a significant difference between Spinal SRS Element system and the previous system that they used that was obviously RapidArc.
The last point to share with you is our clinical experience using Elements Spine SRS. It is a pleasure for us to show you this data. This is the paper published by Niccolò Giaj Levra. That is a colleague in my department, but there was the involvement of most of my colleagues. This paper was published in 2019, really, a few months ago. Is open access, so you can find the details of our procedure and our data, really, in detail without problems. And we treated patient between April 2018 and April 2019. Fifty-four cases of spinal metastases. Here you can see the details of the table of regarding the details of the volumes treated, the fractionation used. You can see from 1 to 3 fraction with radical intent in most of the cases. And as you can see here, in a VAS reduction of back pain was observed in several patients. And I'd like to show that there were not acute or chronic adverse event, more or equal to Grade 3. It is important to share with you the data regarding local control for cancer treatment because at medium follow-up of six months, local control rates at six months and nine months were equal, 86%. Here you can see a typical case with the dose distribution to the vertebral body. And as you can see, those prescription is totally inside the body of the vertebra while the spinal cord is absolutely preserved. Here you can see the details of the treatment. I don't treat in detail, but this data, if you want, are available in our paper. We obviously tried to use the constraint that are available in literature. And we treated this patient with flattening-filter-free 10 MV beams. The prescription was done according to ICRU Report 91. So volumetric dose prescription was 95 to 95 of the PTV. It is important because it is a choice that we decided to do. And here, you can see some of our data updated. Here you can see that the number of patient treated was 57, but the number of lesion treated in this patient were 83. The median lesion per patient was one with a range from one to three. You can see that the primitive tumor site was various, from prostate to gastrointestinal to other sites. Schedule of dose were variable. One session or more fraction, most of them in three. You can see the biological effective dose. And as you can see here, in the last period, we included also a boost, a simultaneous integrated boost. And I show you some cases in the example that I have in my slides.
Here you can see a case of spine Segment D4, the prescription was 21 gray in 3. You can see how the system was able to generate the volume that we then treated starting from the GTV. Here, another case, the vertebra is D9, 21 in 3 without specific problems to maintain the dose under 20 in 3 on the spinal cord. Another example, D9, 24 in 3, but you can see a simultaneous integrated boost, as I said before, in the region of macroscopic visible disease on the GTV, 27 in 3, and the system is able to do this kind of very complex and intriguing approach. Another here, 21 in 3, but you can see how we're able to focus the dose on the simultaneous integrated boost region maintaining the dose to 27 gray in 3. And here, I have a clinical case, a brief clinical case. A male with 75 years old, you can see a PET PSMA with a PSA of 7.84. You can see the lesion in L3. And here you can see the PET CT before and after in the middle of the dose distribution. But it is important to underline how in PET PSMA the SUV was reduced after the treatment. Back pain was the half and PSA was in diminishing without changing in or [inaudible 00:30:08.912]. Another brief case here, you can see the vertebra involvement, PET PSMA with a PSA of 2. And here you can see these intriguing images in which you can see the PET before on the left and after on the right in which we have a significant reduction of SUV from 10.3 to 2.5. Back pain was 0 at the end of the treatment and PSA was close to 0. The dose prescription was 21 in 3. Another case here in which you can see the lesion on MRI, the lesion on PET, the dose distribution. It is L1 spine SRS, 24 in 3 plus SIB with a boost of dose of 27 in 3. And you can see a complete response, impressive, with a back pain that disappeared for the patient. So, you can see it is a classic example of what we can see, not only palliation, not only pain relief, but also reduction or disappearance of the disease in the microscopic site that was evaluated before diagnostic images.
So I can conclude, for sure, spinal SRS and SBRT represents an emerging solution for selective patient, obviously. This techniques allows clinician to improve local control and prevent local progression. We have still now remain to define the standard schedule of those fractionation. And toxicity, however, seems to be really low for these patient. For sure, we can say in our experience that the introduction in clinical practice of Novalis Elements Spine SRS is an easy tool useful for maximizing the feasibility of this approach. And I think that if you have a program to introduce this kind of indication, SBRT or SRS in spine, having Novalis Elements Spine SRS, it could be the solution to start easy and without technical and clinical problems. This is a picture of obviously my staff, of my team. You can see physicists, technician, and doctors because the data that you saw, obviously, I have to thanks to them for these results. Thank you.
Bogdan: Thank you very much, Professor Alongi, for a great presentation. And we have a few questions. So maybe I'll start just with a generic one. And I think this one applied to a lot of people that are interested in starting their own spine radiosurgery program. So maybe you can detail a little bit, when you started your own program, how did you manage the referrals from medical oncology? Were there any lessons learned to convince your fellow physicians to refer into spine radiosurgery program? And what would you share with others who are interested in starting such a program?
Professor Alongi: Yes. Thank you. I don't know if you hear me, yes?
Bogdan: Yes.
Professor Alongi: Yes. Perfect. Optimal question. I think that is important to have a network specifically with neurooncologists, but medical oncologist, surgeon. I think it is important to have these kind of deep relationship in order to manage together these patients. But I think that it's important to demonstrate our powerful effects in term of results and in term of tolerability. Frequently, a lot of colleagues are afraid about...have a lot of concern regarding the side effects related to specific treatment in radiation oncology. Now we are demonstrating our ability to be safer in terms of well-tolerated treatment, also in terms of response because, as you can see, if we are able, during a multidisciplinary dissertation and moments to show how this kind of approach are able to obtain complete response, partial response. And one day use this kind of patient obtaining this kind of wonderful results, I think that this is the best way to convince them about our role.
Bogdan: Okay, Dr. Menid [SP] is asking a question regarding fractionation. So most of the lesions that you treated seemed to have three-fraction treatments. Do you prefer that approach to a single-fraction SRS? And as a sidenote, I guess that he's saying that he does.
Professor Alongi: As professional community knows, I like more to fractionate compared to the single fraction. This is a thing that I approach to the brain in which we prefer three fraction compared to the single one. I think that in this way, we could reduce a little bit the risk of fracture, for example, in the body, or in the structure of the vertebra. And we can obtain the timing results in term of response because the biological equivalent dose if you treat starting from 8 to 9 gray per fraction in 3 fraction.
Bogdan: A question from Andrea Alanccia [SP]. Most of the patients treated with radiosurgery had prostrate cancer as a primary. How many of them were receiving concocted ADT?
Professor Alongi: Yeah, good question. I think that obviously we have to distinguish two entities. The first one is the real oligometastatic patient in which we have from one to three lesion in the bone, in this case. For this kind of patient, I think that we could be able to avoid. At the beginning, they could have androgen deprivation therapy, while in case of oligoprogressive patients, and most of them are oligoprogressive patient, I think that the activity of monotherapy is important. And we can add, with local therapy, a specific control in these types that are not under control after systemic treatment. So, I think that there are these two situation to distinguish.
Bogdan: Okay, Linda Neoli [SP] is asking, how was the dose prescribed? In which level of isodose? Is there any difference in single dose versus multi-fraction? And then linked to this, there's a question regarding reirradiation to the same site, and what was the constraint to the spinal cord then for reirradiation?
Professor Alongi: Okay. The positive thing of this approach is that we can retreat easily. Because as you can see, if we are able, using this kind of system, to avoid high doses to the spinal cord, I think that is more easy to repeat this treatment because we cannot treat the entire vertebrae including the spinal cord. So the possibility to have a margin to treat is higher. And it is important, obviously, to evaluate the timing between the treatment, the side effects of the first treatment in term of the tolerability for the first cause in order to establish if we have space for another retreatment. So the situation is really complex, but is easier than in the past because now we can treat only a part of the vertebra. And we can, for sure, be safe, but also when we are retreating and also prescribing high doses. Is possible to prescribe high doses. This is the most important thing.
Bogdan: Have you treated multi-lesion SBRT patients with our Elements software? So more than one vertebra.
Professor Alongi: Yes, I think that usually you need to have space between one vertebra and the other one. I think that we can consider a lot of situation, but thanks to this tool, you can evaluate your solution also in very complex situations.
Bogdan: A more practical question regarding overall time for planning to treatment. How many days does it usually take for the entire process from imaging to actually treating a patient?
Professor Alongi: Yeah, good question. We are fast because usually, the patient arrived from other region in our center. So we are able to be ready for the treatment within two days. In 24-hour, 48 we are able to have the patient on the couch for the first session of the treatment. Obviously, this is the result of the extreme flexibility of my team and physicists, technician are able to be flexible. This is the most important thing. However, this tool, this software can help to reduce planning, especially in the contouring session and also in the planning because it is really easy to use. You could start from the constraints, and elaboration and optimization is not so complex.
Bogdan: Okay, we have a question regarding the spinal cord compression with soft tissue circling the cord. Do you consider CSF gap to be essential for SBRT use?
Professor Alongi: In our center, we prefer to isolate for SBRT and SRS patient without this condition even if there are data literature in which was shown that we can use also SRS in selective cases of spinal compression. The positive thing is that we are seeing this patient less than in the past because this kind of extreme situation is not so usual, while in the past was really frequent. So the problem now was not present in our clinical practice.
Bogdan: Two questions someone related, what kind of immobilization device do you use for your spine patients, and do you monitor at all for intra-fraction motion and with what?
Professor Alongi: Yes. Regarding mobilization devices, so obviously you can use MAC, but you can use also...work on Pilon [SP]. It depends on the site. It depends on your ability or your frequent usage of one or the other one. And the other question was?
Bogdan: If you track for a intra-fraction motion and with what IGRT system?
Professor Alongi: Yeah. Well, it's really we have a system dedicated. So we can use ExacTrac, that is obviously part of the entire program, or you can use also cone-beam CT, depend on your practice, and your normal program regarding IGRT.
Bogdan: Okay. I think these were the questions. Professor Alongi, I'd like to thank you again for the talk, and thank you all for joining. And have a great week, and we'll see you on the next webinar. Bye.
Professor Alongi: Take care. Thank you.