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Electric Field Therapy in Newly-Diagnosed GBM

Insights From:Susan C. Pannullo, MD, Weill Cornell Brain and Spine Center; Steven A. Toms, MD, Geisinger Health System
Published: Friday, Mar 18, 2016



Transcript:

Susan C. Pannullo, MD:
Optune is a novel therapeutic approach for patients with glioblastoma. Optune was initially FDA approved in 2011 for patients with recurrent glioblastoma, and was most recently approved in October of this past year for patients with newly-diagnosed glioblastoma.

Optune was used following its initial FDA approval in 2011 for recurrent glioblastoma. We often saw patients with recurrent disease who we would counsel regarding this therapeutic approach, and then prescribe the device. Once the device became FDA approved for newly-diagnosed glioblastoma, it took on a role in the discussion regarding therapeutic options in the upfront setting.

We discuss the treatment approach for a patient with a newly-diagnosed glioblastoma and include—since the most recent FDA approval—a review of both the chemoradiation and subsequent maintenance temozolomide that we will be recommending for the patient for their newly-diagnosed glioblastoma. We also discuss the option of using the Optune device once they’ve completed the chemotherapy and radiation phase of their initial treatment.

Steven A. Toms, MD: One of the more exciting developments in the last decade has been the development of tumor-treating fields with a device called, Optune. This was first postulated about 12 to 15 years ago by an Israeli physicist, who postulated that by applying an alternating electrical field between about 100 and 300 millihertz, we could enter interfere with cell division. The strength of this electrical current is about one to three volts per centimeter depth. With this, what we seem to get is an ability of these electrical fields to interfere with the mitotic ability of the cell. It appears to work on a couple different mechanisms, although the basic science and molecular biology of this device are still being worked out.

The leading hypothesis right now is that the electrical fields—and we’ve got two alternating electrical fields that line up the polar dipoles in the cell—all molecules, including proteins in the cell, have an electrical charge on them. Some of these highly charged molecules tend to get lined up in these electrical currents and can’t perform and can’t get to their normal orientation.

When the electrical fields are turned on, these highly charged molecules, such as tubulin, get lined up and can’t polymerize, can’t come together to form the microtubules that are used to pull chromosomes apart during the mitosis portion of the cell division. In addition to interfering with the polymerization of tubulin, there are other highly charged molecules involved in attaching to the chromosomes and segregating them that seem to be involved.

In addition to interfering with the ability of the chromosomes to pull apart properly, the electrical currents seem to interfere with the ability of the cell to divide into two. If you think of the cells as a big balloon that starts to get pinched in the center, these electrical currents concentrate around that pinch point in the center where the cells are about to divide the two daughter cells. If the electrical current drives some of the subcellular organelles to the center of that cleavage point, and presents unequal segregation of the chromosomes and some of the subcellular organs, the cells either arrest in mitosis, or bleb and start to undergo apoptosis—or program cell death.

Those cells that don’t undergo program cell death are often arrested there and bleb, which probably puts some proteins up on the surface that aren’t normally there and become exposed to the immune system. So, it’s a combination of this program cell death or apoptosis from failure of the chromosomes to segregate properly, failure of the subcellular organelles to segregate properly, and an immune-mediated mechanism that seems to lead to the death of cells under tumor treating fields.

After tumor treating fields were postulated and worked out a little bit in the petri dish, an initial study was done in Europe about 10 years ago called the EF-7 study. In that study, which I believe was done in Czechoslovakia, about 20 patients were enrolled, and each of these patients was given the Optune Device, which has a generator and a battery pack that weighs about 6 pounds. It looks like carrying around a laptop over your shoulder or in a backpack. The currents are delivered through some electrodes that are applied to the head. Each of the electrodes is about the size of a man’s palm and they fit on opposite sides of the head—side-to-side and front-and-back. The currents vary between those paired electrodes on the sides, front, and back about every second.

Patients who wore the device in the EF-7 trial—this was mostly in recurrent glioblastoma— seemed to have a prolonged survival and didn’t notice much toxicity. As a result of that, a larger study was designed called the EF-11 trial for recurrent glioblastoma. This study closed back in about 2011 and a total of 216 patients were enrolled, randomized one-to-one of those who got the electrical device—or the Optune Device, to treat the tumor as monotherapy, and those who had already failed radiation chemotherapy and were on to their second- or third-line chemotherapy. The physician involved in the team was allowed to choose what other therapy they liked—whether it’s bevacizumab, CCNU, or any other agent.

Of those 216 patients randomized one-to-one to Optune—or the electrical treating fields, or the chemotherapy, we found near equipoise in that EF-11 trial in that the tumor treating fields seemed to give the patients about equal survival as any of the chemotherapies out there, including bevacizumab, which was used in about half of the patients in the EF-11 trial. Interestingly, there seemed to be a long tail in those patients with the electrical device in that there was a minority of about 5% to 10% of patients who seemed to survive a long period of time. Based on that data and the lack of toxicity from the trial, the FDA approved Optune for monotherapy for recurrent glioblastoma in 2011.

Many people started using the Optune—either alone or in combination with chemotherapy. The company that was involved in that trial did a large patient registry called the PRiDE data set, which also seemed to show very good survival. Some data suggested that the patients who got this device who were bevacizumab-naïve, who hadn’t yet seen the Avastin, tended to do a little bit better. There was some suggestion in this database—and again, it was just a registry—that patients who got the device, plus chemotherapy, seemed to do a little bit better. But that’s certainly not what the FDA approval was given for. But, based on those positive results, both in real patients and the PRiDE database, as well as the F-11 trial, a new trial was designed in upfront glioblastoma called the EF-14 trial.

And what this trial was, was to try and use the Optune device in newly-diagnosed glioblastoma. So, in this trial led by Roger Stupp of the Stupp Protocol, patients were randomized two-to-one to either get the device, or not get the device in addition to the standard therapy for glioblastoma.

The study was designed to enroll 700 patients, randomized 2 patients to 1 for getting the device. Each of the patients would get their biopsy or surgical resection, undergo their radiation and chemotherapy with the temozolomide and 60 gray of radiation, and then right after that was done, within 4 weeks they would get an MRI. As long as there was no progression, they were then randomized to wearing the device at least 75% of the time, or not wearing the device. So, this was not a blinded study; patients obviously got the device or didn’t get the device, and people were not made to wear a sham device. That’s one of the critiques that was studied by some of the folks involved.

The study was powered such that in the intent-to-treat population, we were expecting to see a difference in progression-free survival at 6 months, and it was set up for an interim analysis after the first 315 patients had been monitored for at least 6 months after the device. That interim analysis occurred in November of 2014, and was presented at SNOW about a year and a half ago.

In that interim analysis of the initial 315 patients, what we saw was that progression-free survival extended by about 3 months. In the intent-to-treat population, an overall survival increased by nearly 5 months. Over 48% of the patients who were treated with the Optune device lived at least two years versus only 32% who had gotten the Stupp Protocol alone.

The other thing about this trial is that patients, once they did have some progression, were expected to continue on the device to a second agent. After a second failure or after two years they could go off the device.

Because of the results of this, the monitoring board decided that the study should be shut early after the results were presented at the Society for Neuro-Oncology in 2014, and the study was shut for accrual with total accrual being 697—only three short of the planned 700. But, this was the first clinical trial for glioblastoma that’s ever been shut early because of a positive result.
                                                                                                                                                                                                                                                                                                               
Transcript Edited for Clarity
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Transcript:

Susan C. Pannullo, MD:
Optune is a novel therapeutic approach for patients with glioblastoma. Optune was initially FDA approved in 2011 for patients with recurrent glioblastoma, and was most recently approved in October of this past year for patients with newly-diagnosed glioblastoma.

Optune was used following its initial FDA approval in 2011 for recurrent glioblastoma. We often saw patients with recurrent disease who we would counsel regarding this therapeutic approach, and then prescribe the device. Once the device became FDA approved for newly-diagnosed glioblastoma, it took on a role in the discussion regarding therapeutic options in the upfront setting.

We discuss the treatment approach for a patient with a newly-diagnosed glioblastoma and include—since the most recent FDA approval—a review of both the chemoradiation and subsequent maintenance temozolomide that we will be recommending for the patient for their newly-diagnosed glioblastoma. We also discuss the option of using the Optune device once they’ve completed the chemotherapy and radiation phase of their initial treatment.

Steven A. Toms, MD: One of the more exciting developments in the last decade has been the development of tumor-treating fields with a device called, Optune. This was first postulated about 12 to 15 years ago by an Israeli physicist, who postulated that by applying an alternating electrical field between about 100 and 300 millihertz, we could enter interfere with cell division. The strength of this electrical current is about one to three volts per centimeter depth. With this, what we seem to get is an ability of these electrical fields to interfere with the mitotic ability of the cell. It appears to work on a couple different mechanisms, although the basic science and molecular biology of this device are still being worked out.

The leading hypothesis right now is that the electrical fields—and we’ve got two alternating electrical fields that line up the polar dipoles in the cell—all molecules, including proteins in the cell, have an electrical charge on them. Some of these highly charged molecules tend to get lined up in these electrical currents and can’t perform and can’t get to their normal orientation.

When the electrical fields are turned on, these highly charged molecules, such as tubulin, get lined up and can’t polymerize, can’t come together to form the microtubules that are used to pull chromosomes apart during the mitosis portion of the cell division. In addition to interfering with the polymerization of tubulin, there are other highly charged molecules involved in attaching to the chromosomes and segregating them that seem to be involved.

In addition to interfering with the ability of the chromosomes to pull apart properly, the electrical currents seem to interfere with the ability of the cell to divide into two. If you think of the cells as a big balloon that starts to get pinched in the center, these electrical currents concentrate around that pinch point in the center where the cells are about to divide the two daughter cells. If the electrical current drives some of the subcellular organelles to the center of that cleavage point, and presents unequal segregation of the chromosomes and some of the subcellular organs, the cells either arrest in mitosis, or bleb and start to undergo apoptosis—or program cell death.

Those cells that don’t undergo program cell death are often arrested there and bleb, which probably puts some proteins up on the surface that aren’t normally there and become exposed to the immune system. So, it’s a combination of this program cell death or apoptosis from failure of the chromosomes to segregate properly, failure of the subcellular organelles to segregate properly, and an immune-mediated mechanism that seems to lead to the death of cells under tumor treating fields.

After tumor treating fields were postulated and worked out a little bit in the petri dish, an initial study was done in Europe about 10 years ago called the EF-7 study. In that study, which I believe was done in Czechoslovakia, about 20 patients were enrolled, and each of these patients was given the Optune Device, which has a generator and a battery pack that weighs about 6 pounds. It looks like carrying around a laptop over your shoulder or in a backpack. The currents are delivered through some electrodes that are applied to the head. Each of the electrodes is about the size of a man’s palm and they fit on opposite sides of the head—side-to-side and front-and-back. The currents vary between those paired electrodes on the sides, front, and back about every second.

Patients who wore the device in the EF-7 trial—this was mostly in recurrent glioblastoma— seemed to have a prolonged survival and didn’t notice much toxicity. As a result of that, a larger study was designed called the EF-11 trial for recurrent glioblastoma. This study closed back in about 2011 and a total of 216 patients were enrolled, randomized one-to-one of those who got the electrical device—or the Optune Device, to treat the tumor as monotherapy, and those who had already failed radiation chemotherapy and were on to their second- or third-line chemotherapy. The physician involved in the team was allowed to choose what other therapy they liked—whether it’s bevacizumab, CCNU, or any other agent.

Of those 216 patients randomized one-to-one to Optune—or the electrical treating fields, or the chemotherapy, we found near equipoise in that EF-11 trial in that the tumor treating fields seemed to give the patients about equal survival as any of the chemotherapies out there, including bevacizumab, which was used in about half of the patients in the EF-11 trial. Interestingly, there seemed to be a long tail in those patients with the electrical device in that there was a minority of about 5% to 10% of patients who seemed to survive a long period of time. Based on that data and the lack of toxicity from the trial, the FDA approved Optune for monotherapy for recurrent glioblastoma in 2011.

Many people started using the Optune—either alone or in combination with chemotherapy. The company that was involved in that trial did a large patient registry called the PRiDE data set, which also seemed to show very good survival. Some data suggested that the patients who got this device who were bevacizumab-naïve, who hadn’t yet seen the Avastin, tended to do a little bit better. There was some suggestion in this database—and again, it was just a registry—that patients who got the device, plus chemotherapy, seemed to do a little bit better. But that’s certainly not what the FDA approval was given for. But, based on those positive results, both in real patients and the PRiDE database, as well as the F-11 trial, a new trial was designed in upfront glioblastoma called the EF-14 trial.

And what this trial was, was to try and use the Optune device in newly-diagnosed glioblastoma. So, in this trial led by Roger Stupp of the Stupp Protocol, patients were randomized two-to-one to either get the device, or not get the device in addition to the standard therapy for glioblastoma.

The study was designed to enroll 700 patients, randomized 2 patients to 1 for getting the device. Each of the patients would get their biopsy or surgical resection, undergo their radiation and chemotherapy with the temozolomide and 60 gray of radiation, and then right after that was done, within 4 weeks they would get an MRI. As long as there was no progression, they were then randomized to wearing the device at least 75% of the time, or not wearing the device. So, this was not a blinded study; patients obviously got the device or didn’t get the device, and people were not made to wear a sham device. That’s one of the critiques that was studied by some of the folks involved.

The study was powered such that in the intent-to-treat population, we were expecting to see a difference in progression-free survival at 6 months, and it was set up for an interim analysis after the first 315 patients had been monitored for at least 6 months after the device. That interim analysis occurred in November of 2014, and was presented at SNOW about a year and a half ago.

In that interim analysis of the initial 315 patients, what we saw was that progression-free survival extended by about 3 months. In the intent-to-treat population, an overall survival increased by nearly 5 months. Over 48% of the patients who were treated with the Optune device lived at least two years versus only 32% who had gotten the Stupp Protocol alone.

The other thing about this trial is that patients, once they did have some progression, were expected to continue on the device to a second agent. After a second failure or after two years they could go off the device.

Because of the results of this, the monitoring board decided that the study should be shut early after the results were presented at the Society for Neuro-Oncology in 2014, and the study was shut for accrual with total accrual being 697—only three short of the planned 700. But, this was the first clinical trial for glioblastoma that’s ever been shut early because of a positive result.
                                                                                                                                                                                                                                                                                                               
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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