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Progress and Challenges in Glioblastoma

Insights From:Susan C. Pannullo, MD, Weill Cornell Brain and Spine Center; Steven A. Toms, MD, Geisinger Health System
Published: Tuesday, Feb 09, 2016



Transcript:

Susan C. Pannullo, MD:
There are many barriers to achieving progress in the treatment of glioblastoma. Firstly, the brain is a difficult organ in terms of managing side effects of therapy. For example, something as simple as doing an operation—which in other organs in the body would be a relatively simple task—is extremely complicated in the brain. You can’t take out a large portion of the brain, as you would want to do when treating a malignant brain tumor such as a glioblastoma, because that would produce unacceptable damage to the patient.

In addition, a large operation such as taking out an entire hemisphere of a patient with the glioblastoma, because of the infiltrative nature of these tumors, would not actually accomplish much. The tumor would likely occur again on the other side of the brain opposite the side that was removed in its entirety. So, one of the major challenges for the treatment of glioblastoma has been the inability to do a very big operation—in most situations.

An additional challenge to treating patients with this disease is the fact that the therapies given are actually screened out—for the most part—by the brain. The brain is unique in its capacity to screen out what it perceives as toxins, and this ability is due to it having what’s called the blood-brain barrier. The blood-brain barrier is essentially a mechanism for screening out toxins, which the brain correctly perceives things such as chemotherapy drugs as being. So, it’s doing what it should be doing in terms of protecting the brain; however, in doing that, it develops mechanisms for keeping out treatments that you would want to get in. Because of that, treatments like chemotherapy have to be given in very, very high doses—unacceptable in terms of toxicity to the patient—in order to get enough into the brain to affect change in a tumor that’s occurring in the brain.

In addition, radiation therapy, which is also a very useful technique for many types of cancer, is challenging in glioblastoma because of the toxicity that may not be tolerated by a patient who’s getting treated with radiation. You may be able to give a very high dose of radiation to an organ in the body, but in the brain, this may produce damage to the normal brain structures—inflammation and swelling around the area that was radiated. That, in turn, can cause patients to have cognitive or other problems that are unacceptable in terms of toxicity.

Steven A. Toms, MD: I’ve been in the field of neurosurgical oncology for about 25 years now and glioblastoma is the challenge that brought me into the field of neurosurgery. It’s been a very tough nut to crack in that it’s an incredibly aggressive weed that grows in the brain. In the 25 years I’ve been working on this, there have been very few advances. When I first started as a medical student and resident, average survival was about 9 months—maybe 10 months after diagnosis and patients were treated with surgical resection, radiation, and often nitrosourea, like CCNU (lomustine) or BCNU (carmustine).

Over time, some new therapies have come out, but we’ve been through many, many negative clinical trials with glioblastoma. The biggest advance occurred about a decade ago when Roger Stupp presented what is now known as the Stupp Protocol which combined the oral alkylating agent, temozolomide, or Temodar, along with radiation therapy. Temozolomide had been out for few years and traditionally had been delivered after six weeks of radiation. But Dr. Stoop published in a New England Journal of Medicine article about a decade ago, that adding the two together increased the overall survival from about 12 months to about 14.2 months. That was the biggest advance we had had in the last 25 years in glioblastoma therapy.

Shortly thereafter, bevacizumab, the anti-angiogenesis drug, was introduced. And that was FDA-approved. It was usually used for recurrent glioblastoma, and it did seem to extend the life of a few patients and acted somewhat like a super steroid in reducing the amount of swelling from these very aggressive tumors.

But the biggest advance we’ve had in the last decade—since the Stupp Protocol—has been a trial called the EF-14 trial that just came out, showing an unusual alternating electrical field run by a company called NovoCure, with a device now known as Optune. There was increased survival from about 14 months up to about 17 months after the initiation of therapy. This result was just published in The Journal of the American Medical Association in December of 2015, and I think is one of the biggest recent advances.

We’ve got a number of new items coming down the pike and a lot of interesting new data coming along about immune modulatory therapies that include some cell vaccines, peptide vaccines, and some immune checkpoint modulators like PD-1 inhibitors. And then we’re seeing that a lot of the viral therapy and gene therapy that has been worked on for the last several decades may be working through an immune mechanism as well. So, there’s a lot of promise in the field right now—in a field that had been really quite stagnant in the first 15 to 20 years that I’ve been involved with it.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Susan C. Pannullo, MD:
There are many barriers to achieving progress in the treatment of glioblastoma. Firstly, the brain is a difficult organ in terms of managing side effects of therapy. For example, something as simple as doing an operation—which in other organs in the body would be a relatively simple task—is extremely complicated in the brain. You can’t take out a large portion of the brain, as you would want to do when treating a malignant brain tumor such as a glioblastoma, because that would produce unacceptable damage to the patient.

In addition, a large operation such as taking out an entire hemisphere of a patient with the glioblastoma, because of the infiltrative nature of these tumors, would not actually accomplish much. The tumor would likely occur again on the other side of the brain opposite the side that was removed in its entirety. So, one of the major challenges for the treatment of glioblastoma has been the inability to do a very big operation—in most situations.

An additional challenge to treating patients with this disease is the fact that the therapies given are actually screened out—for the most part—by the brain. The brain is unique in its capacity to screen out what it perceives as toxins, and this ability is due to it having what’s called the blood-brain barrier. The blood-brain barrier is essentially a mechanism for screening out toxins, which the brain correctly perceives things such as chemotherapy drugs as being. So, it’s doing what it should be doing in terms of protecting the brain; however, in doing that, it develops mechanisms for keeping out treatments that you would want to get in. Because of that, treatments like chemotherapy have to be given in very, very high doses—unacceptable in terms of toxicity to the patient—in order to get enough into the brain to affect change in a tumor that’s occurring in the brain.

In addition, radiation therapy, which is also a very useful technique for many types of cancer, is challenging in glioblastoma because of the toxicity that may not be tolerated by a patient who’s getting treated with radiation. You may be able to give a very high dose of radiation to an organ in the body, but in the brain, this may produce damage to the normal brain structures—inflammation and swelling around the area that was radiated. That, in turn, can cause patients to have cognitive or other problems that are unacceptable in terms of toxicity.

Steven A. Toms, MD: I’ve been in the field of neurosurgical oncology for about 25 years now and glioblastoma is the challenge that brought me into the field of neurosurgery. It’s been a very tough nut to crack in that it’s an incredibly aggressive weed that grows in the brain. In the 25 years I’ve been working on this, there have been very few advances. When I first started as a medical student and resident, average survival was about 9 months—maybe 10 months after diagnosis and patients were treated with surgical resection, radiation, and often nitrosourea, like CCNU (lomustine) or BCNU (carmustine).

Over time, some new therapies have come out, but we’ve been through many, many negative clinical trials with glioblastoma. The biggest advance occurred about a decade ago when Roger Stupp presented what is now known as the Stupp Protocol which combined the oral alkylating agent, temozolomide, or Temodar, along with radiation therapy. Temozolomide had been out for few years and traditionally had been delivered after six weeks of radiation. But Dr. Stoop published in a New England Journal of Medicine article about a decade ago, that adding the two together increased the overall survival from about 12 months to about 14.2 months. That was the biggest advance we had had in the last 25 years in glioblastoma therapy.

Shortly thereafter, bevacizumab, the anti-angiogenesis drug, was introduced. And that was FDA-approved. It was usually used for recurrent glioblastoma, and it did seem to extend the life of a few patients and acted somewhat like a super steroid in reducing the amount of swelling from these very aggressive tumors.

But the biggest advance we’ve had in the last decade—since the Stupp Protocol—has been a trial called the EF-14 trial that just came out, showing an unusual alternating electrical field run by a company called NovoCure, with a device now known as Optune. There was increased survival from about 14 months up to about 17 months after the initiation of therapy. This result was just published in The Journal of the American Medical Association in December of 2015, and I think is one of the biggest recent advances.

We’ve got a number of new items coming down the pike and a lot of interesting new data coming along about immune modulatory therapies that include some cell vaccines, peptide vaccines, and some immune checkpoint modulators like PD-1 inhibitors. And then we’re seeing that a lot of the viral therapy and gene therapy that has been worked on for the last several decades may be working through an immune mechanism as well. So, there’s a lot of promise in the field right now—in a field that had been really quite stagnant in the first 15 to 20 years that I’ve been involved with it.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Provider and Caregiver Connection™: Addressing Patient Concerns While Managing GlioblastomaSep 29, 20182.0
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