MD Anderson Cancer Center
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Lisa Garvin: Welcome to Cancer News Line, a podcast series from the University of Texas MD Anderson Cancer Center. Cancer News Line helps you stay current with the news on cancer research, diagnosis, treatment, and prevention providing the latest information on reducing your family's cancer risk. I'm your host, Lisa Garvin. Today we have two guests. One is coming to us by phone from Maryland. Our first guest is Dr. Mark Gilbert. He is a professor of Neuro-Oncology here at MD Anderson. And Dr. Minesh Mehta who is a professor of radiation oncology at the University of Maryland's Greenebaum Cancer Center. The subject of our podcast today is a study that has just been presented to the American Society of Clinical Oncology concerning the angiogenesis inhibitor drug bevacizumab and its role in glioblastoma. Dr. Gilbert is the principle investigator of this study and Dr. Mehta is the co-principal investigator. Dr. Gilbert, some sobering news about the efficacy about bevacizumab in glioblastoma.
Dr. Mark Gilbert: So I think the study was designed to ask the question is the addition of bevacizumab helpful in patients with the new diagnosis of glioblastoma. Bevacizumab has been approved by the FDA in the United States for treating patients with recurrent or regrowing glioblastoma. And so what we were trying to ask is whether there was additional benefit to the use of bevacizumab in the newly diagnosed setting.
Lisa Garvin: So it wasn't really off label but weren't you using in newly diagnosed patients. That was kind off the reservation a little bit as far as the drug's approval.
Dr. Mark Gilbert: So there were physicians who were using bevacizumab in patients with newly diagnosed glioblastoma but again, that had not been tested in a way that would allow one to answer the question is there benefit in the newly diagnosed setting over using it later in the disease trajectory. As an FDA approved agent, physicians do have the option to prescribe drugs for other diseases or for what would seem other indications.
Lisa Garvin: And which is what we call off label use.
Dr. Mark Gilbert: That is correct.
Lisa Garvin: And but isn't it true that bevacizumab also known as Avastin had some -- shown some early promise.
Dr. Mark Gilbert: I think there was some remarkable studies. Bevacizumab was first tested in the mid-2000s, 2003, 2004 in brain tumors with some remarkable response rates. In those studies it was always patients who had recurrent disease. Response rates by imaging of 40 to 50 percent were reported and what appeared to be prolongation of progression free survival. It was very difficult in those studies to really determine whether it actually prolonged survival but clearly there was benefit when one looked at images. When we looked at the requirements for corticosteroids in those patients so that it made it a very convincing story that bevacizumab had activity. Looking at it from the biologic perspective, it turns out that glioblastoma are amongst the most angiogenic or the cancers make the most prominent feature of blood vessels and many of the early studies of angiogenesis in cancer were done in glioblastoma. And so it was a very logical connection to use what appeared to be one of the most effective antiangiogenic agents in this patient population. So it made a very compelling story with testimonies from many patients about how much it improved their quality of life. It reduced their corticosteroid requirement and neurologically, many of them improved with the bevacizumab again leading to the FDA deciding to give it an approval in the recurrence setting.
Lisa Garvin: And so your study, the one that we're discussing today, was actually looking at it as frontline therapy.
Dr. Mark Gilbert: That is correct.
Lisa Garvin: Okay.
Dr. Mark Gilbert: So frontline therapy. To be very carefully distinguished from therapy in the recurrent disease setting.
Lisa Garvin: So tell me how you went about crafting this study. You obviously had a big burning question you wanted to answer.
Dr. Mark Gilbert: Right. So it is been traditional and I think appropriate that in the field of neuro-oncology or brain tumor treatment that we test many of our agents in the recurrent setting. Look for evidence of activity and if there is, we bring them to the frontline setting with the hope and expectation that in the newly diagnosed setting, tumors may be more sensitive to therapy. You may actually see even better responses, more prolongation of survival. So it was very logical to take the bevacizumab which looked very promising in recurrent disease and bring it to the frontline setting. We also recognize that bevacizumab that has a toxicity profile. And that some of the toxicities are somewhat unique. In this setting we do need to worry about things like high blood pressure or hypertension, kidney failure as well as potentially some effects on the patient's quality of life. There have been reports of increasing fatigue and other types of patient functional status affects. So in that context, we thought it was very important that the study not only be randomized so that there'd be an arm -- a group of patients who get the bevacizumab but another group of patients who get a placebo. So that the interpretation not only of the effects of treatment on the tumor but the effects of treatment on the patient could be very carefully compared between the two and that the patients and their treating physicians would not know what therapy the patient was getting.
Lisa Garvin: And Dr. Mehta as a radiation oncologist, drugs for glioblastoma are given along with radiation. Can you talk to us a little bit about chemo radiation?
Dr. Minesh Mehta: Absolutely. So we know that historically the therapies that have worked for patients with glioblastoma include surgery, radiation, and some of the first generation chemotherapeutic agent. But increasingly we're beginning to recognize that the biological diversity of this tumor presents to us a large number of molecular targets. And there are agents that can be used against this molecular target. Many of which works synergistically with radiation therapy. Bevacizumab is one such agent. There are lots of data from the laboratory and other clinical experiences suggesting that there is potential synergy or interaction between radiation and drugs that work against the angiogenic pathways which allow tumors to grow. So combining radiation with such agents with a very natural approach in trying to improve the outcome of patients with glioblastoma.
Lisa Garvin: So typically a chemo radiation for glioblastoma is the drug temozolomide. So what did you do in this instance, you replaced the temozolomide with the bevacizumab?
Dr. Minesh Mehta: No actually we did not do that. The drug temozolomide is another example of synergy between radiation and chemotherapy. This is a drug that unlike most chemotherapy drugs when it's given with radiation for glioblastoma is given every day as a pill. As you are well aware the typical course of chemotherapy is that patients receive chemotherapy generally for a few days every few weeks but not in a continuous manner for the most part. For glioblastoma, the temozolomide is, in fact, given daily with radiation. This is in fact the standard of care. When such an approach is taken the survival of patients with glioblastoma is superior to those treated with radiation therapy alone. So in this trial, we did not want to lose out on the benefit of combining temozolomide with radiation. So what we did for all patients is that everybody received temozolomide with the radiation and subsequently they received it as maintenance therapy. But in addition to that, we added bevacizumab approximately halfway through the course of radiotherapy and then continued it afterwards with temozolomide.
Lisa Garvin: And Dr. Gilbert or Dr. Metha, either one, you managed together quite a number of people. You got almost 700 people in the trial. I would think with glioblastoma that wouldn't be easy especially for newly diagnosed disease.
Dr. Mark Gilbert: So we were quite fortunate. This study was actually a collaboration between three of the large cancer groups. It was led by the Radiation Therapy Oncology Group but we were joined by the Eastern Cooperative Oncology Group and the North Central Cancer Treatment Group. So it was really a national study and the time it took to actually get all the patients onto the study. So we were able to randomize almost 640 patients and it took less than 2 years. So it was a remarkable achievement. And I want to add to that and I want to really acknowledge the collaborative spirit and the level of engagement across both the physician as well as the patient community. It was not an easy study. The patients were required to get treatment every 2 weeks. The patients went into the study knowing that they had a 50 percent chance that they were getting placebo and yet there was tremendous enthusiasm. From the physician standpoint, there was a requirement that every patient provide a block of tumor tissue so that we can do some of the molecular analysis that Dr. Mehta referred to. And that was required before the patient started treatment. So there were a lot of logistical components and they were all successfully achieved. One hundred percent of the patients who were treated on this study, we were able to not only confirm that they had glioblastoma but that we had a usable tumor tissue block for those analyses.
Lisa Garvin: So what was the upshot of the study? Obviously the toxicities were hard to handle but what were the basic results of the study?
Dr. Mark Gilbert: So we analyzed the results and there were -- it was somewhat unique in that there were two primary results. One was looking at overall survival comparing the bevacizumab with the placebo. And the other is looking at progression free survival. And so having two co-primary endpoints, we had to be very aware that there was some statistical modifications that we needed to make. And so we looked at both. As it turned out there was not a statistically significant improvement in survival with the addition of bevacizumab in the newly diagnosed patients. However, we should point out that written into the study was the ability for the patients on placebo to at time of tumor progression to crossover to bevacizumab. So a high percentage of patients at the time of progression, we looked at what treatment they were on and many of the patients who were on the placebo arm actually crossed over and received bevacizumab either alone or in combination with other chemotherapy agents. So the overall survival wasn't different. The progression free survival was different but it did not reach the level of statistical significance that we had set in advance prior to the initiation of the study.
Lisa Garvin: And obviously and Dr. Mehta, I'm pointing this question at you. This must have been disappointing because you probably went into the trial with a lot of optimism.
Dr. Minesh Mehta: Well obviously whenever we put resources into doing a large based free trial for patients with glioblastoma which is a disease that takes quite a toll on patients in terms of life and quality of life, our goal is to impact both. To improve survival and improve the quality of life of our patients. And we were naturally hopeful when we started that we had a lot of basic science supporting this approach and we had data from the trials in recurrent glioblastoma where bevacizumab showed quite a lot of promise. And so we were enthusiastic and optimistic that we would, in fact, have an improvement both in survival and also in the quality of life in the progression and in the symptoms that patients experienced. Unfortunately, we were not able to reach that level of outcome and naturally we are disappointed by that.
Lisa Garvin: By it doesn't really discount Avastin or bevacizumab as an agent in treating glioblastoma, correct?
Dr. Minesh Mehta: I'm glad you asked the question because that is a key distinction to make. It's important to recognize that bevacizumab is an approved therapy for patients with a recurrent glioblastoma. There have been clinical trials that clearly show that patients with a recurrent glioblastoma benefit when they're treated with bevacizumab. And so when we started this trial, one of our concerns was that because the agent has been shown to be active and expective [phonetic] in recurrent glioblastoma, would it be possible that the effect of using the agent later on at the time of recurrence for the patients who did not get it upfront might perhaps takeaway from any of the upfront benefit that patients might receive. It's possible that that's one of the explanations for the results that we saw in this trial.
Lisa Garvin: But it sounds like, obviously and glioblastoma typically is one that really creates its own, you know, blood vessels and its own system to feed itself. Are you finding other agents or are there other agents on the horizon that you might be looking at to stem angiogenesis?
Dr. Minesh Mehta: Certainly many groups including us and others have looked at other anti-angiogenic agents as well. We have completed a trial with another potentially promising anti-angiogenic agent. We don't have the results analyzed for that particular trial so I don't have them with me to review for you. But other groups have looked at some of the other agents. In general we haven't found what we would call a homerun. So we have not yet found an agent that dramatically includes survival in patients with glioblastoma using an anti-angiogenic strategy. That is not to say that anti-angiogenic agents do not work in this disease and that they will not have a future in this disease. We think that angiogenesis is such an important component of the ability of these tumors to grow that in time, we will find that there are potentially subset of patients that benefit. And it's quite likely that we might find that there are agents with greater potency that might prove to be positive in the future.
Lisa Garvin: And I think some of us remember the Judah Folkman and the TIME magazine cover of angiogenesis and the cure for cancer was around the corner. So I guess reality is hitting now, Dr. Gilbert.
Dr. Mark Gilbert: Yeah I think that's correct. I mean there was and still is enthusiasm for approaching anti-angiogenesis as a therapy. I think we're now realizing that angiogenesis alone doesn't fully drive tumors. And in the case of glioblastoma there are certainly situations where prolonged exposure to anti-angiogenic agents appears to change the way the tumors grow. So no longer do they require their own blood vessels but they seem to be able to spread out into the surrounding brain tissue and use the blood supply of the normal brain tissue as a way of them to continue to grow.
Lisa Garvin: How far have we come with glioblastoma? It's still probably like one of the top 5 worst cancers, at least in my book. I mean prognosis is generally poor.
Dr. Mark Gilbert: Right.
Lisa Garvin: Are we seeing any budges in morbidity and mortality with glioblastoma?
Dr. Mark Gilbert: In the 28 years that I've been involved in the field, I've seen a consistent improvement. There has been, I would say, gradual improvement. I think if we look at the modalities of treatment that have been traditionally used for glioblastoma starting with surgery. Surgical techniques have markedly improved. The percentage of patients who are able to undergo a surgical procedure that takes out all visible tumor has increased dramatically. And there are newer technologies that are being developed to even improve that. In fact here at MD Anderson we have the brain suite and that allows our neurosurgeons to look in the middle of the operation using an intraoperative MRI and see if there's tumor left behind. They can go back. There are other techniques that are being evaluated that further improve the surgeon's ability. There's the ability to do an awake craniotomy so that they can figure out what part of the anatomy is eloquent or essential and avoid that in their surgical procedures. In the past those patients would've typically received just a biopsy leaving the bulk of the tumor behind. When you look at radiation and certainly Dr. Mehta is a world renowned authority in this, radiation technologies have improved. There's more precision. There's a better ability to deliver higher doses to the tumor and avoid the normal surrounding brain.
Lisa Garvin: And I'd like to bring Dr. Mehta in on this. What -- are you using IMRT or you using proton? What sort of radiation are you using with glioblastoma?
Dr. Minesh Mehta: At this point actually the first major glioblastoma protocol conducted by our group that permitted the use of IMRT. As you know this technology also known as intensity-modulated radiation therapy is unprecedented in its ability to conform or shape the distribution of the radiation to essentially mimic the shape of the tumor. And thereby reduce the amount of normal tissue that is exposed to radiation. In the past, we did not have sufficient experience with the use of IMRT in a corporative group setting to ensure that we would have sufficient quality and consistency to do this in a large trial of this nature. So this is probably the largest trial of its kind to have allowed IMRT to be done on this particular approach. And we were quite successful when we did the quality assurance to find that the majority of patients were treated with very high standard of quality meeting all the protocol requirements. We did not permit the use of protons on this particular trial because at the time that the trial was written there were a very small number of centers in the country that could treat patients with proton. And we were not geared up to do the quality assurance from a multi-institutional perspective for the proton therapy aspect of it. That has actually now changed. The number of centers with proton therapy has increased and the quality processes are in place so that our future trials will potentially allow the use of proton as we move forward.
Lisa Garvin: So in closing, would you say -- I mean it's kind of a good news bad news but really more good news than bad news. How would you wrap this up in a nice little bow for our listeners, Dr. Gilbert?
Dr. Mark Gilbert: So I think we have achieved our primary goal and that was to carefully evaluate the role of bevacizumab in patients with newly diagnosed glioblastoma. We did it in a way that was comprehensive. We not only evaluated for the primary outcomes of overall survival and progression free survival. We had a whole component that looked at patient outcomes, looking at quality of life and symptom burdened and their neurocognitive function over time which is, in fact, quite informative to the results of the study. We have a bank of tumor tissues which we can now interrogate and start answering some of the questions of whether there is a specific molecular profile that would predict response to bevacizumab in exclusion of the other patients. And maybe going forward, there is a subgroup of patients that we can identify who do truly benefit from the use of bevacizumab as first line therapy reserving bevacizumab for the remainder of the patients as a later or a salvage regimen.
Lisa Garvin: Any finals thoughts from you, Dr. Mehta?
Dr. Minesh Mehta: I think Dr. Gilbert has summarized this very nicely that this was a tour de force. This was a major trial. We could never have completed this without the willing cooperation and participation of so many of our patients and centers. And it's a testimony to our patients that they're willing to put their lives in our hands to try and improve the outcome of the entire population of patients with glioblastoma. We think that it's this kind of support that makes it possible to ask major questions of this nature and move the field forward. So we are highly appreciative of their contribution.
Lisa Garvin: Great, thank you both for being with us today. If you have questions about anything you've heard today on Cancer News Line. Contact MD Anderson at 1-877-MDA-6789 or online at MDAnderson.org/ask. Thank you for listening to this episode of Cancer News Line. Tune in for the next podcast in our series.
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