RADIOTHERAPY SECTION - STEREOTAXIC RADIATION THERAPY by Robert Timmerman, MD

SLIDES & TRANSCRIPTS
Tuesday, June 19

RADIOTHERAPY SECTION - STEREOTAXIC RADIATION THERAPY

Robert Timmerman, MD

Slide 1: Stereotactic Irradiation

DR. TIMMERMAN: I want to thank Scott Saxman and Richard Cumberlin for inviting me. I have to confess from the onset that I am an imposter. My clinical focus is actually in brain tumors, but I am lately treating a lot of lung cancer and would like to make it a new focus for myself as well. When we got the stereotactic equipment there was nobody at our center that really was pushing to do it and since I was a junior member I got elected, but it has ended up being an interesting experience which I would like to share with you briefly.

Slide 2: Rationale

The rationale for applying this technology is that basically in the treatment brain metastasis or brain tumors with a gamma knife that experience has been characterized in most circles as favorable. Radiosurgery in the brain appears to durably control brain metastasis from carcinomas and therefore one might rationalize that if it worked in the brain why wouldn't it work in other parts of the body. For those of you who don't know, the elements of radiosurgery is that there is immobilization well beyond what is done in conventional radiation treatments and the targeting is done stereotactically which is different from the skin marks and bony landmarks that correlate to tumor location but don't directly correspond to tumor location that we see in conventional radiotherapy. The accuracy of actually delivering the radiation is much beyond conventional radiotherapy and is in the submillimeter range. Highly conformal dose distributions are used with little or no margin of normal tissue, and instead of fractionating the treatment we give it all at once which results in a different radiobiology.

Slide 3: Hypothesis Testing

The hypothesis that we are testing in our lung cancer experience is a bit sacrilegious among the radiotherapy community and that is the notion that large doses per treatment, that is greater than 10 Gy per treatment would be more biologically effective at eradicating gross tumor lumps than conventionally fractionated radiotherapy. The other corollary to our hypothesis is that while radiotherapists always talk about the dose tolerance of a structure that we would postulate that radiation volume, that is the volume of normal tissues that receives radiation is actually more likely to correlate to toxicity especially in organs that are called parallel functioning such as the lung. That is to say that the top part of the lung is doing more or less the same thing as the bottom part of the lung, whereas in the brain different parts of the brain are clearly doing different things.

Slide 4: Historical Aspects

As a background, the historical aspects of radiotherapy are probably well known to some of you, but it has been around over 100 years now. When radiation was first discovered it was done in a manner akin to surgery, that is all at once and it was found quickly that it was too toxic. It caused ulcerations. It caused fibrosis that did not occur right away. Those toxicities didn't appear sometimes for several months after the treatment but it didn't look good for radiotherapy right from the beginning as a feasible treatment for cancer. Not until the 1920s when the French investigators discovered this notion of fractionation and they found that by giving a little bit every day over many days you could get away with treating the tumor amid a large volume of normal tissues. Interestingly then for the rest of that century radiotherapists embraced this notion of fractionation. Independent of the radiotherapy community in the 1950s a Swedish neurosurgeon went about on his own to do single high-dose treatments. He was a surgeon, so he did it in one treatment and of all places the brain, the least tolerant structure in the body to radiation. This was Lars Leksell, and he invented the concept now called radiosurgery with the gamma knife.

Slide 5: Radiobiology

To bore you a bit with radiobiology but I think this is important, the notion of fractionation follows from these four R's of radiobiology. That is that by fractionating one can take advantage of some differential effects between tumors and normal tissues and as far as the normal tissue is concerned there does exist repair of normal tissue from the damage caused by radiation between fractions and clearly that is good. Also, the normal tissues are able to repopulate between fractions and thereby heal or reform mucosa or whatever it is you are treating and indeed that is good. As far as the tumor is concerned there are different phases of the cell cycle that are more or less sensitive to radiation, and by fractionating you may allow the cells to go through the cycle and be present in a more sensitive phase which is good for killing tumor. Finally, since oxygenated tissue is more radiosensitive we could re-oxygenate tumors as they shrink and get closer to their blood supply, all of which is good.

Slide 6: Radiobiology

What we don't talk about somewhat conveniently in radiobiology is the fact that for every good there is a bad, that is that tumors clearly repair and tumors clearly repopulate and this is probably the major mode of failure for radiotherapy in treating lung cancer. Normal tissues can also become more sensitive throughout the course of a radiotherapy 6-week treatment plan all of which can be bad, and what we are postulating to some degree is that in certain circumstances with certain types of cancers fractionation may actually be more bad than it is good which is counter to the common conception.

Slide 7: Stereotactic Body Radiotherapy

. The history of stereotactic body radiotherapy as opposed to brain radiosurgery is that again it came from Sweden. The same hospital that developed the gamma knife actually developed the first systems for doing body radiosurgery with stereotactic localization. Drs. Lax and Blomgren invented a frame that both immobilized the patient to some degree as well as decreased the major cause of target motion which was respiratory motion. They, also came up with some rather novel dose profile and prescription concepts that mimic to some degree the gamma knife itself. They started treating patients in 1991, and the population that they chose was mostly patients with horribly incurable malignancies, widely metastatic disease, or hepatomas similar to what we now use for testing Phase I chemotherapy agents.

Slide 8: Swedish Experience

They reported it just a year ago, 50 patients with 75 tumors in the chest, abdomen and pelvis. Many of them had been heavily pretreated and look at these doses, 15 to 45 Gy in one to three fractions and so these are massive single fraction doses at the edge of the target., They showed a major response rate in the 60% to 70% range and according to their results only 5% ultimately progressed at least in the time of observation. We acquired this technology in 1997, and initially tried to treat similar patients to what the Swedes did to try to reproduce their results. We came somewhat a little bit lower control rates than what they published, but we soon realized that a lot of the community felt like what we were doing was voodoo. I think that this impression was justifiably because this was all ad hoc retrospective experiences basically stating how wonderful it is.

Slide 9: Study

At the same time Ron McGeary who is our radiotherapist at our VA hospital looked at a large group of patients that were treated for stage I tumors at our VA hospital that were medically inoperable because of co-morbidities and found that over half of those patients in fact died of lung cancer. So, this is a group of patients who cannot have surgery. Many times people think that these patients will die of their COPD, of their heart disease or whatever but most of the time they die of lung cancer. So we decided to embark on a prospective phase I trial followed by a Phase II trial to use this new technology carefully and prudently in this population.

Slide 10: Eligibility

The eligibility was that they all must have tissue confirmation of non-small cell lung cancer. I was interested to discover that almost all of our pathology reports are not very specific about what kind of cancer this is. They are all just saying, "Non-small cell lung cancer." So, we don't have the kind of clarity that people were talking about before in differentiating these lesions. These are all stage I lesions, about evenly divided between T1s and T2s. About 3 out of 22 patients that have currently been enrolled had complications of their biopsies but recovered in all cases. The medical problems were typically emphysema and heart disease like you would expect. Another eligibility requirement was that they fit in our stereotactic frame which is a problem. It was designed in Sweden where people are quite fit. In Indiana we are, I think, 49th in terms of obesity, and so we have many patients who could not fit in the frame and couldn't be treated in this way.

Slide 11: Phase 1

This is a classic Phase I toxicity study. These are unusual in radiotherapy and they are somewhat harder to do than you might think. We do evaluations every 3 months with subjective and objective evaluations. All patients are screened up front with CT scans. They have all been biopsied. We get blood gases and PFTs on everybody. We started to get PET scans on everybody after the New England Journal of Medicine article was published. The dose-limiting toxicity according to the study would be Grade-3 pulmonary, esophageal or cardiac toxicity or any Grade-4 toxicity ascribed to the treatment.

Slide 12: Dose Escalation

We started out at 800 cGy per fraction. We prescribe to the 80% line, and we give three fractions. So, the starting dose was 24 Gy to the PTV which is the target that we give with some margin and I will show you what that is. We have escalated by 200 cGy per fraction in cohorts of three patients, very classic phase I design. We anticipated the dose limiting toxicity would be pneumonitis. We haven't confirmed that yet, but that is what we were expecting to see and of course our studies were looking for it. What is interesting about the study is that with radiotherapy side effects may be subacute or even delayed and so we have had to have observation periods built into the study to try to be able to observe these toxicities before we go ahead to the next dose level.

Slide 13: Treatment Logistics

The logistics are we immobilize the patient, and do a CT scan. We can do MRI scanning but CT scan is what we have been using in most patients. Treatment planning occurs, there are a fair amount of physics involvement. We actually have used seven fields but we have also used arc rotations in some patients. We do intensity modulation. So, this is stereotactic 3D conformal intensity modulated therapy using respiratory inhibitory device. So, this is pretty high-tech stuff. Then we treat the patients over a week and one-half time period, two treatments one week and one on the next week. When we started doing this it took about 60 minutes total for setup and treatment time. With our learning curve improving we are down to about 20 to 30 minutes.

Slide 14: Tumor

Here is how we target the tumors. This is a T2 tumor with what we considered atelectasis going out to the pleural surface. The way we target this is that first we draw what we call the gross tumor volume and then we give a margin around that for motion. The motion that has been documented for this particular system is that there will be an axial excursion of the tumor from treatment to treatment of up to half a centimeter and the biggest motion is up and down in the Z plane, that is, craniocaudal plane. So, we give a 1 centimeter margin in that direction to allow for respiratory motion to not let the target slip out of our fields as we are treating.

Slide 15: Tumor Targets

In 3D this is how it looks. Here is a target, a yellow target and then the dose cloud that is formed by these different beams that converge on the target creates a bigger margin in the Z plane than it does in the X and Y plane.

Slide 16: Seven Beams

Here are the seven beams coming through. Here is this system for decreasing respiratory motion.

Slide 17: Valsalva

We actually valsalva the patient extremely so that their diaphragm physically cannot move very well into the abdomen with a breathing cycle. It is uncomfortable but patients are tolerating it.

Slide 18: Current Status

The current status is we have finished treating 22 patients since February of last year. The first three dose levels were performed lumping T1s and T2s together and then we stratified T1s and T2s, did separate dose escalations. It is sort of an interesting point that we are at right now. We thought we would be done with Phase I by now but we have gone all the way up to 20 Gy per fraction. We are enrolling patients at 20 Gy per fraction for three fractions. That is 60 Gy total in T1 tumors and we are enrolling patients at 1800 cGy per fraction for T2 tumors and we haven't hit the maximum tolerated dose yet.

Slide 19: Dose Limiting Toxicity

Basically what that is saying is that the conventional dose of radiotherapy is 60 Gy in 30 fractions. We are going to be giving that dose in three fractions when we reach the next dose level. We have had two patients with dose limiting toxicity. In the T1 population we had one patient at 16 Gy who had transient grade 3 hypoxemia which we don't really think was from our treatment. He had walked a mile in a rainstorm shortly after the treatment and got a bronchitis, but the criteria was we have to count that as a dose-limiting toxicity. The other patient clearly got toxicity from radiation and this was a very large T2 tumor who at 14 Gy got a fairly severe pneumonitis that was treated with steroids. At both these dose levels the additional patients were treated without further toxicity.

Slide 20: Pulmonary Function Tests

Here is our pulmonary function test both before the treatment and post-treatment, which is done typically at 3 months. What it shows is that there is no change in these parameters. The FEV1's were typically low, about half our patients have under 1.0 FEV1 and in fact in FVC we had a trend toward improvement with the treatment which we don't certainly ascribe to our treatment but I think they get some peace of mind and blow harder.

Slide 21: Observations

Now, these are observations. They are not scientific, but they are observations that I would like to offer. First of all, it appears that the toxicity that we are seeing, not too many patients have had toxicity, but when we see it is happening faster than one might expect. We have seen anybody's decline in PFTs or pneumonitis occur always within 4 weeks of therapy. One of our patients failed at the first dose level. I retreated him, and he got radiation pneumonitis within 2 days of the treatment, which is unusual for radiotherapy. You usually see pneumonitis much later than that. The complete response rate in our study which I will show you some pictures of is really not very high, but the major response rate which is defined as greater than 50% response rate is very high. These tumors shrink rather rapidly but there is always an abnormality left behind that we speculate might be scar tissue with this ablative type therapy. We have had one local failure treated at the first dose level. So, we think we might have under treated him at our starting dose level for the Phase I study. We have had, this is interesting, four other patients failed out of field and my notion was that they would fail in the mediastinum and may be able to be retreated with chemo or radiotherapy, but that has not happened. They have all failed in a pattern that has made them clearly incurable either with contralateral or ipsilateral lung metastases combined with mediastinal adenopathy or even distant metastasis. So, we haven't been able to salvage any of our failures although very few have failed.

Slide 22:

Here is our patient that got the bad pneumonitis, and I show this slide because first of all it was a fairly large tumor. He got pneumonitis. This was scanned at 6 weeks but it actually was apparent on chest x-ray before that. It is a different pattern of pneumonitis than you have probably seen. Usually pneumonitis from radiation has a fairly geometric shape and this is not. The reason is that the radiation fall-off dose is not typical of these geometric treatments that were done using fractionated radiation.

Slide 23: Tumor

Here is a small tumor that is the kind of tumor that this group is interested in. We actually have not had that many of these tumors. I think we have only had three people with tumors under 1 centimeter. They have all completely responded, and we have had no toxicity in this group and so here is a before and after. Notice the scar tissue that is next to the mediastinum before and after. There is increased scar tissue at 9 months, and the volumes that were treated is just a little area around that target that we would treat.

Slide 24: Tumor

Here is a patient with a T2 tumor treated at 1200 cGy per fraction. We did not target this atelectasis, and it looks like we didn't need to because it resolved with the treatment.

Slide 25: Tumor

This, again, is not showing up very well but the reason I am showing this is that this region back here is just a huge bleb and this is typical of the patients with rather lousy lungs that were treated in this protocol. Almost half our patients are on home oxygen. So, this is a frail population that still seems to be tolerating things quite well.

Slide 26: Tumor

Even a 91-year-old treated for a large tumor at a very high dose per fraction for three fractions had no pneumonitis 1 month later.

Slide 27: Tumor

Those are the last slides. A tumor that was treated here in the periphery. At the time we treated it there was no mediastinal adenopathy but at 9 months we have got a good response but new adenopathy in the hilum. She also had a contralateral lung nodule. So, this is kind of an example of how these therapies are inadequate for some patients.

Slide 28: Conclusions

In conclusion, our Phase I study is recruiting surprisingly well. We are at surprisingly high doses. Even in these frail patients we are able to deliver this ablative therapy with reasonable toxicity. We are trying to find the maximum tolerated dose although we may end up just stopping the study pretty soon and just moving on to Phase II because we are already at such high doses. The phase II study could potentially be done on a wider scale but since it is ablative in nature this technique is different from fractionated radiotherapy which is more forgiving. So a phase II study is going to require fairly strong QA requirements in order to be done on a larger scale. Thank you.