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Good morning, everybody. Before I get started, I just want to point out that the definition of SRS used over here is the new, recently ASTRO-endorsed definition that, still technically localized high dose radiation up to 5 fractions. So, over here I'm not talking about a single fraction, stereotactic radiosurgery, you know, we use 3 fractions. This is a report of our phase 1 study to combine this stereotactic radiosurgery called the fractionated stereotactic radiosurgery with a EGFR inhibitor called gefitinib or Iressa in the patient with recurrent astrocytoma, or the GBM.

As we know that the recurrent malignant gliomas, including AA and the GBM, they are uniformly fatal. I don't think anybody has cured anyone with recurrent GBM so far. But, you know, as of today, there is no standard care. And for the patient, if they are fit enough for the surgical resection, surgery plus Carmustine wafers can prolong the survival for about two months. For the majority of the patients, they cannot get surgery done, the radiation therapy remains the main local therapy modality. As a patient in this population received a full dose radiation before and almost all the patient, they tried a different chemotherapy, exhausted all the conventional chemotherapy options. So, it's really a tough situation to treat. Over the years, there are some reports with radiation therapy. Usually, you give a little bit bigger fraction than conventional 1.8 or 2 gray per fraction people call the hypofractionated radiation therapy.

Well, okay. So, the fraction size, over here I gave you a few examples, you know, varying from 3 gray all the way up to 6.2 gray per fraction, and total radiation dose, you know, they end up from 20 gray all the way up to 50 gray. With the small patient numbers, all these studies were retrospective single institution studies. They're called HSRT.

Now, with those treatment regimens, they reported the treatment will tolerate the toxicity, you know, relatively low, but most patient they suffered from disease progression and eventually died from disease progression with the median for survival, you know, from anywhere 7 months all the way to 14 months.

There was RTOG study, a big phase 1 study, to try to define the reirradiation. They used a single-fraction radiosurgery, and see how much more dose the patient can tolerate for the patient. They received the prior four dose radiation with a medium dose of 60 gray. And depending on the lesion size, for the biggest lesion, they treated about 4 centimeter, the maximum tolerated dose was 15 gray as a single fraction with a biological effective dose for the acute side effects around 40 and late side effect BED was around 90 gray.

Now, because the patient exhausted conventional chemotherapy, so people have tried the biological effective agent, so the EGFR inhibitor, the Iressa, has been tried in the preclinical animal model and the serum lines and showed some, you know, tumor activity in the clinic. NCCTG performed a phase 2 study and they published data in the JCO a couple years ago, they used a single agent Iressa 500 milligram per day. Obviously, there was no complete response, 2% of patient got a partial response, about half, 40% of them, got a stable disease. Still not a great single agent, but, you know, showed some anti-tumor activity.

Now, we initiated a trial about three, four years ago. And before, the patient, they really exhausted all the treatments with recurrent astrocytoma, or the GBM, and we combined the fractionated stereotactic radiosurgery with this Iressa. You know, the objective of this protocol was to define the highest SRS dose a patient can tolerate with this agent. This is study schema. Escalating the radiation therapy dose from 18 gray in 3 fractions all the way to 36 gray in 3 fractions.

And all the patient, they took this Iressa 250 milligrams daily, starting 7 days before the radiotherapy and continued for up to 1 year if they don't hit their dose-limiting toxicity low disease progression. And this table shows the BED, we just look at the RTOG study. But if we go to the highest dose of 12 gray times 3 and the BED for the late complications was 180, that's a very strong radiation treatment.

The major inclusion criteria for this study was for the patients with previously, you know, confirmed GBM, anaplastic astrocytoma they recur, but the recurrent tumor cannot be in the brainstem. The largest diameter was 6 centimeters, so it's a little bit bigger than the RTOG single fraction radiosurgery study. Up to three lesions can be treated and the patient got to have a little more organ function and the the patient did not have history of using the EGFR inhibitor in the past.

The study drug would start the drug seven days before the SRS and the patient continue the drug for about one year. Now, the SRS. We used the Novalis BrainLab machine and we used the removable BrainLab mask because we were doing three fractions, you cannot put the head frame on for three times. And then we routinely perform CT simulation, CT with the treatment-planning MRI for the fusion. The target volume was T1 enhancing lesion on the brain MRI plus 2 millimeter margin. And we used dynamic arcing.

Now, there's a dose escalation from 18 gray to 36 gray in 3 fractions. This is one of the examples of the treatment planning. And this is the tumor and with 2 millimeter margin, this purple area. And this brownish area, the 36 gray, that's the prescribed dose. We usually prescribe to 80% to about 95%. So, there is not a whole lot of big hotspot and we achieved really, a rapid dose falloff around the tumor. We used 5 dynamic arcing for this case.

The toxicity definition. We used the CTC version 3.0, we did not use the RTOG definition. We'll discuss it later. The acute toxicity we defined with the toxicity happening within 30 days of SRS, any toxicity happening after that we defined as a late toxicity. Dose-limiting toxicity is defined as any grade 3, 4, or 5 toxicity, hematological or whatever the toxicity was.

We put 15 patients on this study, The median age was 47 years old. The histology, four patients with anaplastic astrocytoma, 11 patient with a GBM. The median time from the prior radiation therapy was 12 months. All the patients received the prior radiation from 54 to 61.2 gray with a median dose of 60 gray. And all the patients but one received the concurrent chemotherapy with the radiation in the past. And all the patients had neoadjuvant chemotherapy. Most of the patient got temozolomide, the other patient got some BCNU, one patient got the PCV.

For the treatment, all the patients on the trial received the prescribed dose of the stereotactic radiosurgery in 3 fractions. And with the median target volume of 41 cc, 12 to 151 cc except the one patient who did not have the dose over three consecutive days but within one week. Everybody took the study drug with median duration 5 months and range from 2 to 12 months. All patients finished the whole year.

Iressa toxicity. Now, there were two patients who had grade III, this patient got a grade II, this patient got a grade III seizure. This patient, three months after SRS, he developed the grand mal seizure. And on the brain MRI, there was a new lesion, 3 cm, developed after SRS outside the PTV. And this new lesion was associated with dramatic vasogenic edema. So, we thought that his seizure was related to the new lesion, not really related to, you know, the treatment.

And another patient develop the seizure grade II, sort of, complex seizure, breakthrough seizure, this patient had a history of that, and she had the seizure about six months after the SRS treatment and then just after seizure medicine, she was stabilized. And she is still alive 38 months after treatment. So, we think that her, you know, seizure problem is really not related to the treatment.

There were five hospitalizations, one patient with diverticulitis, one patient with a DVT, another patient with a skin breakdown, not before the SRS, you know, after SRS, a couple months later he got a biopsy so the area, you know, the scalp did not heal really well. And two patients with a general decline of health situation, most of the patient had in the end.

The study drug related toxicity. We know that there is a history associated with the skin reaction to diarrhea. And most of the patients actually had this but very mild. Eight patients had grade I skin reaction, this shows the grade I skin reaction over here. And two patients had grade II skin reaction. For the diarrhea, four patients had grade I diarrhea and three patients got grade II diarrhea. Two patient with increased liver enzyme, grade I, two patients with decreased platelets, grade II.

Outcome. With the median follow up of 7 months, 13 patients have died. And all the patients but one died from the brain tumors. Median overall survival from study entry was 10.3 months. And overall survival for the whole group from the initial diagnosis was 28.6 months. For the 11 GBM patients, the overall survival or the median overall survival from initial diagnosis was 21 months. The median progression-free survival was 7 months. And 6 months progression-free survival was 63%. One year overall survival, 40%. This is the survival curve from the study entry from the initial diagnosis.

Now, response. I want to point out that we used the conventional MRI. You know, the patient will have an MRI for the treatment planning right before the SRS, then one month after, SRS will follow up, then at three months, then every three months. So, just the contrast in MRI. Now, with the conventional MRI, I think most of you probably treating GBM will know that after this strong radiation treatment, they have the volume change. Well, some investigators just mentioned that a lot of patient got edema even after the moderated dose for the meningioma, but with this strong dose of radiation activity, we'll see a lot of change, even T1 and T2 changes. I'm not sure it's just edema. We call it the treatment effect. I will show you some MRI.

Now, by the conventional MRI, we had, two patients got a partial response, a little bit response, two patients with stable disease, all the other patients got disease progression. We defined a disease progression as that on the T1-enhanced MRI, that area, increased more than 25%. In the end, almost all the patient had that. I'm not sure that's a disease progression but we defined as that. Two patients developed a new lesion outside the SRSPTV.

Now, this is the MRI. On the panel A, the up two rows, these are T1-contrast MRI. Before SRS, this is the lesion, this is where we treat it. One month, not much change. Look at the five months, there is dramatic increase of the T1 enhancement. Whereby look MRI, we say this patient progressed. Between five and six months, the patient resection, then the T1 enhancement stabilized after that.

The T2 enhancement you see over here at five months dramatically increased. Well I'm not sure it's edema, probably there is some edema over there but if you're looking at midnight, there is not much midnight shift or anything like that. And after the surgery and with more time, it gradually subside.

This is another patient, did not have surgery. This is the initial volume we treated. Go to their 6 months and 12 months, you see how much volume, you know, how much increased. Then the patient continued on the treatment because both of these patients were asymptomatic. And up to 18 months, look, the volume comes back, T2, the same thing you cannot see it really. There was a curve here a little bit, they increased, then subside without any treatment just, you know, conventional just washout.

So, we literally...I have a resident, we pull out all the patients MRI, and we import the MRI to the eye plan and we outline the T1 and T2 enhancement on each slide when we calculate the volume change. These are the mean volume of all patient with MRI, look at that, you know, after the treatment, this is the month after the SRS, you see the T1 enhancement increased a lot. And the T2 enhancement primarily, excuse me, increased up to six months then gradually stabilized.

So, almost all the patients after this kind of treatment got a dramatic MRI abnormality. And we have the final way to define if this is progression or just the treatment effect. As a matter of fact, two patients got a surgical resection because of the MRI abnormality and we thought it was a disease progression. Those two patients were not symptomatic, but we did the surgery. Look at this, this A and B from one patient, C and D from another patient, just show the dramatic radio nucleosynthesis. Obviously, those two patient, the MRI changes were not from the disease progression, they were from the treatment effect.

Now, well, with the small patient number but we did look at that within the 6 months of the SRS if the T1 enhancement, the changement, the increase of the volume, increased more than 90% for those patients, actually, they survived longer. Even with the patient they have the dramatic change in more than 150%, the survival was much better. Obviously, we need to validate this with larger patient number.

Now, discussion. From this study, we feel comfortable that 36 gray given in 12 gray fractions over 3 consecutive days is well tolerated with this Iressa 250 milligrams a day. And from this study we learned that a conventional MRI is no good to assess response. In this disease progression, this study, we have to find out the other way. Now, people probably think about functional imaging and we did some of it but it was not required in the study so I'm not reporting it over here. The bottom line is that as far as we are standing now, there is no big help from particularly, MR spectroscopy. So far, you know, people have been, you know, studying this modalities but, you know, so far there is no really big breakthrough.

Another thing I want to point out, that the asymptomatic radio-necrosis should not be graded as dose-limited toxicity in this setting. As we know that this is a recurrent tumor, if the radiation is not strong enough to kill off this piece of tumor, edema will progress and the patient will die. But, you know, Bate radiation got to be strong enough then after that, if we do surgery, you will see dramatic radionucleosis. It's just a matter of how you're gonna tailor that to the patient situation, not make the patient sick. If your radiotherapy makes the patient sick, lower neurological with neurological deficit, that's gonna be dose-limiting toxicity. Otherwise, if the patient is asymptomatic, tumor is small enough, knowing your location, you can really, you know, kill that piece, the tumor will not progress, I think the patient will get benefit from it.

Now, based on this data, we used a 36 gray grade III fraction study safe. We are doing another study, everybody gets 36 gray radiation, we'll combine with a another drug called ZD6474, is a EGFR and FR inhibitor with those escalating this study drug. And I want just show the last slides over here, this is the patient with a recurrent GBM over here. He was on this drug for five weeks, that's the full weeks of the SRS. You can see that the tumor is still here, on the T1 enhanced MRI, but after 3 months, 13 weeks after the study drug, you see the T1 enhancement is gone. So, this drug probably is more promising than the rest. But, you know, people just started this kind of research right now. Thank you.