RADIOTHERAPY SECTION - TECHNICAL ISSUES WITH STEREOTAXIC RADIOSURGERY by Randall Ten Haken, PhD

SLIDES & TRANSCRIPTS
Tuesday, June 19

RADIOTHERAPY SECTION - TECHNICAL ISSUES WITH STEREOTAXIC RADIOSURGERY

Randall Ten Haken, Ph.D.

Slide 1: Introduction

DR. TEN HAKEN: All right. I know what you are thinking. I have been here for 12 hours now. I have got the most boring title of the whole day, and you are going to hear a lecture by a physicist. The good news is that both Scott and Rick asked me to not talk about physics very much at all and as Rick just said to talk about issues that might be of importance in a multi-institutional trial. So, I am going to do a whirlwind tour of some issues that are going to be of consequence in that type of a setting.

Slide 2: Overview

I am going to go through a brief introduction. I will talk about some of the patient immobilization and setup issues, different methods of dealing with breathing, whether it is possible to do online imaging and tracking and then some of the dosimetry issues that were already alluded to.

Slide 3: Radiotherapy Target Volumes

In radiotherapy if we are uncertain as to the clinical tumor margin or the location of the tumor at the time of treatment we need to treat a volume that is larger than the physical tumor to ensure adequate coverage as the previous speaker just mentioned.

Slide 4: Target Volumes

These are loosely called the GTV, the clinical target volume and the planning target volume which takes into account organ motion. We have to treat something this big to make sure that something this big gets the dose we want.

Slide 5: ?

So, do millimeters matter?

Slide 6: Target Volumes

Well, I am going to do a little bit of physics not too much but a lot of what I really needed to know about physics I should have learned in math class and that is true in this situation, also.

Slide 7: mm Matter?

. These are the only formulas that I am going to show you, but this is an easy one, volume of the sphere and heaven forbid this is differential calculus but it is not that hard. If we look at the fractional change in volume as a function of diameter it is just the differential of this, and we can divide one by the other. If I take delta V and divide by V I can find that the fractional change in volume is three times the fractional change in diameter. So, what does that mean?

Slide 8: mm Matter?

That means that if I add a 1 millimeter margin to a 6 millimeter target this increases the volume by 100%. It means I have to add a millimeter to each side. So, I am increasing the diameter by 2 millimeters and that increases the volume by 100%. If I add a 2 millimeter margin to a 6 millimeter tumor I increase it by 200%. If I put a 3 millimeter margin I increase the volume by 300%. Those margins are all in normal tissue. We are treating more normal tissue by each one of these millimeters that we add to the outside. So, these millimeters do make a difference because we are adding them at the outside of the target volume that we are trying to treat. So, every millimeter we add has a big consequence.

Slide 9: Patient Fixation

First some of the fixation techniques. As the previous speakers were talking about there are a couple of nice devices to try to re-set up the patient, their body habitus at least at the same point each time that we are going to treat them. This is one such study. It uses one device from Germany.

Slide 10: Patient Fixation

They have a sophisticated system that has a body cast and a face cast. It has a device that you can use on the CT scanner and another localization device that has radio-opaque markers they can use at the time of treatment.

Slide 11: Patient Fixation

This is another device, and again this one was evaluated by some people in Germany.

Slide 12: Patient Fixation

It is the device that the previous speaker was just referring to. This is the stereotactic body frame which was developed by Blomgren and Lax at the Karolinska. It has again fiducial markers, it has this thing that you can push down on the abdomen for patient fixation. The point of all these is to show you that there are devices that try to place the patient at the same point each time they are going to be treated and then try to have some assurance that they are not going to move once they are there. This is called immobilization or fixation.

Slide 13: Patient Fixation

Then at least in these people's hands what they would do is use these external markers on the patient and some internal bony structures and then try to treat the soft tissue lesion with some margin and hope that it is in the same place each time they treat it, both at the treatment planning and at the CT simulation. So, we are going to use these external markers that I can see on imaging studies and hope that all of the internal stuff is going to be in the same place by using some sort of immobilization device.

Slide 14: Patient Fixation

The point of this graph is to show that they needed to leave at least a 5-millimeter margin to cover most of these people's tumors and even if they left a 10-millimeter margin which this, you might not be able to see this graph very well - each one of these columns still shows one patient that exceeded the 10-millimeter reference. So, the bottom line for this type of immobilization at least in their conclusion, was that in single cases of soft tissue targets of the planning target volume would not sufficiently cover target deviation without isocenter correction. This indicates to them at least that CT simulation prior to treatment should be performed if you are trying to do more heroic things than on the order of 10-millimeter margin, particularly if you want to do it several times and cover every patient. Now, you just heard a previous speaker say that they can do better in some cases, but this is just using the marker. So, if you are going to try to push on the abdomen to keep them from breathing and try to set them up you still need to leave a bigger margin for multiple fractions.

Slide 15: Dealing with Respiratory Motion

How do we deal with this respiratory motion? As many people have mentioned, the patients breathe. We want them to be breathing when we are done treating them, too. So, this is a good thing. As previous speakers also mentioned, the planning target volume margins that we use are uniform sometimes but usually they are asymmetric. Things move under motion more in one direction than they do in the other. So, there are ways to try to minimize this, using shallow breathing, an abdominal belt or pressure on the abdomen. We can gate the treatments to the breathing cycle, just turn on the accelerator when the patient is at the same point in the breathing cycle or we can try to stop the motion using voluntary breath hold or actively control the breath hold. I am going to go through a few quick examples of each one of these.

Slide 16: Minimize Motion

This, again, by the Swedish group, the diaphragmatic movement as measured by fluoroscopy under free breathing has this range, 15 to 25 millimeters. With this abdominal pressure they were able to reduce it to the 5-to-10-millimeter range, very similar to what the previous speaker just mentioned. So, this type of thing can reduce that margin substantially. It is not zero, but it reduces it.

Slide 17: Shallow Breathing

Another way to do this is with shallow rapid breathing with oxygen. This is by one of the Japanese groups with the abdominal belt which was optional. We see that the breathing motion is less than 10 millimeters in just about all the patients, less than 5 millimeters in some of the patients.
So, we are getting close. We are getting things that are pretty small, but we are not completely eliminating this.

Slide 18: Gating

Gating experience, I am just listing these for the purpose of showing it. The idea is that you try to pick some phase of the breathing cycle and just turn on the accelerator to treat the patient during that part of the breathing cycle. It is up to you to try to pick how much of the breathing cycle you want to use and then you can use the smaller margin. I just wanted to go through this quickly to show that there are a variety of methods going back to 1989, again in Japan for the early experience for this and moving on now to other manufacturers.

Slide 19: Gating

In the Japanese experience for some of these tumors they resulted in a 28 to 85% reduction in the amount of lung that was irradiated in their heavy ion therapy project but they still required a safety margin of 10 to 15 millimeters despite the use of gating to account for the continuous organ motion and unexpected excursions.
So, you have to narrow down the window when you want to treat. If you are only going to treat when the lung tumor is at one spot you are not going to have the beam on very long and it is going to take a long time to treat. So you have to pick some window that you are going to use, and this data describes experience in their hands with their limit. Again, this is a similar number to what we were hearing in the last couple of slides.

Slide 20: ABC

There has been something popular in this country over the last couple of years called active breathing control which was first pioneered at William Beaumont Hospital by John Wong and collaborators.

Slide 21: ABC Device

It looks like this in their hands. It is essentially a pneumotach that is connected to a box that has a valve where the air goes in and out, and it has some sort of a device, a computer that monitors the breathing wave form.

Slide 22: ABC Device

There is another system that we have been using at our institution that is made by Sensor Metrics. It is another similar thing.

Slide 23: ABC Device

This is something that they use for doing lung function testing for athletes and it looks like this. It has again a flow sensor, a mouthpiece that goes into the patient's mouth, which then just opens out to the air. So, you breathe through it normally. There is a little thing in here that detects the flow and provides electrical signals. Then there is a bladder here that can open or close this opening so that you cannot breathe anymore.

Slide 24: Breath Hold at Normal Exhale

So what happens is a form of gating actually. As the valve is opened the patient is breathing. We can look at pressure. We can look at volume. Then we close the valve and turn on the beam for some part of the cycle. We choose whatever part of the breathing cycle that we think is the most reproducible and try to treat the patient at that point. Then we treat for a reasonable amount of time, 10 or 20 seconds, let them breathe and then recapture again at the same point in the breathing cycle and turn the beam on.

Slide 25: ABC

This is a type of reproducibility that you can see using this technique. Here is with normal breathing. We notice that we see artifacts in CT scans where the diaphragm shows up on some slices and then disappears again. Other things are moving around. These are two CT scans that were separated by 30 minutes in time which look for all practical purposes to be nearly identical. So, the short-term reproducibility of this is quite good.

Slide 26: ABC

In their hands for two CT scans separated by 30 minutes they were seeing these types of reproducibility on the order of 2 to 4 millimeters.

Slide 27: On-line

We have been doing an online study where we have been looking at using the ABC device in a treatment room we have equipped with diagnostic x-ray tubes that are mounted on the walls of the room and a detector which you can use to see inside the patient fairly well.

Slide 28: Image Alignment

Then we can do an online analysis where we compare the DRR to the images that we get at the time of treatment and in this case we are looking at the position of the diaphragm.

Slide 29: ABC Reproducibility

In our hands again we get numbers that are quite small for the standard deviation of these patients during one treatment, and they again are averaging on the order of 2 millimeters or so. Even between one treatment and the next the margin increases slightly. As this patient is being treated over the course of many weeks, the diaphragmatic position is not completely reproducible vis-a-vis the part of the respiratory cycle and we see that we need to increase this margin. But what is even a little bit more alarming is that these maximal excursions are almost on the same order of magnitude as the free breathing which to us it is quite stable during one treatment, but to use it over a long period of time you need to do some sort of online imaging to re-establish patient position.

Slide 30: Online Radiographic Localization

So, this brings us naturally to online radiographic localization. If we are going to try to use some device that to try to suspend ventilation or do something heroic like this, are we able then to see anything on a daily basis? Well, there are obstacles. There is difficulty in landmark visualization, the ability of quantitative analysis tools, speed in doing this, the speed of making a correction once you see that something is wrong. But we have one advantage over diagnostic procedures that we were talking about today, and that is that we have prior information. We know there is something there and we know approximately where it is. We don't have to go look for it and screen the whole lung to find out where it is. We know that somebody else told us there is a nodule there or we implanted a radio-opaque marker someplace or there is something that we know about, and so we can use this to our advantage to look in the right spot.

Slide 31: Soft Tissue Imaging

In preparation for this meeting we did a couple of measurements this weekend and I must admit that I was completely floored when people started talking about how small these things are. I was even more floored when I started doing some measurements. We wanted to see if we could see some of these little soft tissues on a megavoltage x-ray film. Remember we are using 6 or 10 MV photons to treat these patients and we want to see if we can see a soft tissue mass on some sort of a port film, and so I have got some balls here. This is a 9.5 millimeter plastic ball. This little guy here is a 3 millimeter Teflon ball, and when you say 3 millimeters in diameter, it sounds big, but when you look at a circle there is not a lot of mass there. These are small things which again floors me when I hear the discussions today when taking out big chunks of tissue and there are still having problems with controlling these things. So, these are small.

Slide 32: Soft Tissue Imaging

So, can we see them? I don't know if we can with the lights up like this, but this is the way that the x-ray film turned out. If we enhance it a little bit yes we can see them, but I know where they are. With prior knowledge I know where we placed them on the surface of the phantom. I know we placed them in this region here, and maybe you can start to get an inkling of where they are. I will help you out a little bit. Again, I don't know if you are going to be able to see this with the lights up, but this is in this region. There is one. The largest ball is here. The second largest ball is here. The third largest ball is here, and you can start to imagine the last one.

Slide 33: Soft Tissue Imaging

So, this is a blown-up area of that image. This is the 9.5-millimeter ball. This is the 8-millimeter one. This is the 6.5-millimeter one, and I can imagine something might be there for the little guy.

Slide 34: Soft Tissue Imaging

We can do some enhancement, histogram equalization of things in that region and we can start to see these things a little bit better but yes, at least from a physics standpoint these things could be visible in megavoltage x-rays if we knew where to look and we could see them on a daily basis.

Slide 35: Soft Tissue Imaging

We can also see them on electronic portal imagers. This is not a complete state of the art portal imager, but we can see an electronic portal imager, meaning we can get a digital online image which we can manipulate to make a decision about how to reposition the patient.

Slide 36: Direct Online Imaging

Okay, those are points inside the patient that I am trying to see on flat films to try to align the patient. If I do an orthogonal set of films then I can do triangulation and do a 3D correction of the patient position, but I still cannot see the whole soft tissue mass. So the next thing is doing something maybe more heroic, placing a CT scanner in close proximity to the treatment unit or trying to use the treatment beam itself or some diagnostic beam to do online imaging. Now, this is something that not very many places are doing but I am trying to give you a flavor of the variety of things that could be available at certain institutions to attack this problem.

Slide 37: Tumor Tracking

These types of things are clear. The leaders in this field have been several groups in Japan and I am going to show you a few things from their work.

Slide 38: Tumor Tracking

In this institution they actually have a treatment room that has a CT scanner and a simulator. This is a source of diagnostic x-rays that rotates on a C arm around the patient and megavoltage treatment unit that are all in the same room. They have a couch that moves on a rail system and rotates from one machine to the other. So, this patient can be inserted into the CT scanner to do a CT scan, rotated, put underneath the simulator to watch under fluoroscopy to see how much things move up and down with breathing, rotated around in the other direction and inserted into the treatment unit and be treated. This is truly a heroic effort to localize things, to do soft tissue, online soft tissue localization.

Slide 39: Tumor Tracking

Another group is this group in Tokyo which is doing online megavoltage CT. They are using the treatment beam itself to do computer tomography and try to get an idea of where the sections of the patient are at the time of treatment. This would look something like this.

Slide 40: Tumor Tracking

This is a planning scan where they are going to try to treat this lesion with some sort of a margin and this is an image that they would get at the time of the treatment using the megavoltage source of treatment. So, you can see that they are off a little bit, more than they wanted to be. So, they move the beam over to where they want to be and try to continue the treatment.

Slide 41: Tumor Tracking

They also have a nice little system where they can have a monitor for the therapist to watch so that they can project the beam edge that is detected by a detector onto the scan that they had previously and try to make sure that things are in. I will give you a little visual cue to see that things are in the right place.

Slide 42: Tumor Tracking

The most heroic effort I think is probably being done here in Sapporo where they are actually doing real-time tumor tracking.

Slide 43: Target Motion

This is done by means of some x-ray tubes which are mounted in the floor and some image intensifiers which are mounted in the ceiling of a patient so that no matter what position this gantry is at a couple of these can see through the patient if they have diagnostic x-rays that are on at the same time.

Slide 44: Tumor Tracking

They would implant, for instance, a fiducial marker or something close to the inside of the patient and then gate the radiation by that image that is coming out of the beam. Not just by a scan that is connected to the patient or something with their breathing but actually looking at the image that is transmitted through the patient, turn on the beam when everything is in the right spot. So, when things are in the right position they turn the beam on.

Slide 45: Tumor Tracking

When they are not in the right position they turn the beam off, and they can move. This is a 10-millimeter circular aperture and this is placed on a radiographic film. This is what it looks like with breathing motion. This is what it looks like if they don't take into account the slight time delay between trying to decide whether things are in the right place and turning on the beam. So, there is a little delay. If they take that delay into account they can get a very tight distribution, and you will have to believe me when I say that this is on the order of 10 millimeters. It is the same size as the aperture.

Slide 46: Lung Dosimetry

Okay, almost there. So, what the previous slide should have showed you is that there are lots of techniques to try to localize patients and each one of those techniques will determine how big of a margin you need to leave around the tissue to treat it. The other major issue is lung dosimetry, and I am going to show you a couple of titles of papers and discuss the major issue associated with this without trying to get into too much physics. This has to do with the dose calculations and the way radiation interacts in tissue.

Slide 47: Lung Dosimetry

These are a tumor volume inside of a lung phantom. This is a mock-up. So, they put a soft tissue mass, a piece of plastic with an ion chamber inside of a phantom that has air or a lung-like material surrounded by other normal tissue and are looking at the dose distribution. If the patient were made completely of water this would all be fairly uniform. It is not. The patient is not made out of water. So, a couple of things happen, and one of the big things that happens is that the beam spreads out at the edges.
Another thing that happens is that the dose in the center of the field is not what you would expect, and I am going to talk a little bit about why that is true.

Slide 48: Lung Dosimetry

There are better ways of doing the dose calculation, and this is one of the early papers that talked about doing this. There is something called Monte Carlo calculations of dose which actually track each one of the photons through the patient, use some physics, look up tables to decide what type of interaction it had and deposit the dose.

Slide 49: Lung Dosimetry

They are sort of the most accurate dose calculations that we have today, and they are here compared to some measurements. I apologize for the fuzzy graphs. The message to get out of this is that these are all three different dose calculations of what the dose would be for this four-by-four centimeter field in this air volume between normal tissue, air and lung. This is as we go deep into the phantom. As I go crosswise across the beam you notice this is spread out, and again, I get three different predictions depending upon what the dose calculation model is of what the dose would be in profile at this spot. This is clearly a problem in terms of recording what the dose would be.

Slide 50: Single Beam Dose

Finally, Bob just lent me these slides which I think very nicely illustrate the dose buildup and build-down effect. If we have a beam that is coming into the patient phantom, and here we have a nodule, if we assume that this patient is all made out of water, the dose builds up the normal way. This is called the depth dose, and it falls off as a function of depth, and this gives a very nice rounded edge. If we have now a lung that starts about here and goes to about here with this nodule in the center of it, the dose falls off and builds up again inside of this little solid tissue, falls off again and then builds up again when it gets back into the normal tissue. This is for two different beam energies. This is for a high-energy beam where the effects are worse and for a low-energy beam where the effects are better.

Slide 51: Lung Geometry

They also did some measurements in a phantom trying to mock-up some of these small tumors.

Slide 52: Tumor

So, they have a small tumor inside of this essentially water phantom that is going to have some cylinders which will have air-like or tissue-like materials and they did some Monte Carlo calculations of that situation, and this is what you would normally get from a planning system for a homogeneous medium. As Bob mentioned to you they are prescribing to this outside of the circle and with little margin at all. In this case they would think that the 75% isodose line covers this, and things are fairly uniform.
They did this for higher energy x-rays just to magnify the effect.

Slide 53: Tumor

If we actually look at this now surrounded by lung a couple of things happen. First of all we notice that the dose in the center is not what it was before. It is not 1000. It is a little bit less. The dose at the periphery is not 1000. It is a little bit less now, and there is, also, a higher dose in the center, and so this demonstrates the two effects that are going on. You are going to hear people talk about heterogeneity corrections and dose calculations. There are two things going on. One is this beam that is going through the air. It is not attenuated as much as it would have been in water. So, in one circumstance we are getting photons that reach this target volume that normally wouldn't have. The other effect is the way photons deposit their dose in tissues. The photons interact. They set in motion electrons. Those electrons deposit the dose and if this is all surrounded by water and this is a broad beam there are just as many electrons coming into this point as there are going out of that point, and we have what is called electronic equilibrium. If we surround this with lung-like material, these electrons go whizzing away, deposit their dose some other place, and there is not a compensatory effect of coming back in, and so this is spread out. The dose is spread out at the margin. I just have a couple more.

Slide 54: Tumor

This is almost the second to last slide. This is just to demonstrate that again this is much worse for 15 MV photons than it is for the 6 MV photons. In this case I think you said that only the 50% isodose line was covering as opposed to what they would have hoped originally.

Slide 55: Summary

Okay, so, in summary it was sort of a long whirlwind tour to show you I think there are two primary concerns from a physics standpoint from multi-institutional trials and QA of those trials. First of all, the differing immobilization techniques, online imaging capabilities and methods of dealing with breathing lead to a range of margins that individual institutions should use to treat these lesions. The second thing is that the differing methods to compute the dosimetric effects of tissue and homogeneities can lead to disparities in the reported dose and, also, what you are really doing in reality to what you thought you might be doing.