Neurosurgeons have used a laser probe to open the brain’s protective cover to deliver chemotherapy to patients with a deadly form of brain cancer.
In a pilot study, 14 patients with glioblastoma, the most common and aggressive type of brain cancer, underwent minimally invasive laser surgery to treat a recurrence of their tumors. Heat from the laser is known to kill brain tumor cells but, unexpectedly, the technology can also penetrate the blood-brain barrier.
“The laser treatment kept the blood-brain barrier open for four to six weeks, providing us with a therapeutic window of opportunity to deliver chemotherapy drugs to the patients,”
says co-corresponding author Eric C. Leuthardt, professor of neurosurgery at Washington University in St. Louis.
“This is crucial because most chemotherapy drugs can’t get past the protective barrier, greatly limiting treatment options for patients with brain tumors.
We are closely following patients in the trial. Our early results indicate that the patients are doing much better on average, in terms of survival and clinical outcomes, than what we would expect. We are encouraged but very cautious because additional patients need to be evaluated before we can draw firm conclusions.”
Laser Interstitial Thermal Therapy
Glioblastomas are one of the most difficult cancers to treat. Most patients diagnosed with this type of brain tumor survive just 15 months, according to the American Cancer Society.
The new research is part of a larger phase II clinical trial that will involve 40 patients. Twenty patients were enrolled in the pilot study, 14 of whom were found to be suitable candidates for the minimally invasive laser surgery.
The laser technology, laser interstitial thermal therapy, was approved by the Food and Drug Administration in 2009 as a surgical tool that can be used to treat brain tumors. But the new study marks the first time the laser has been shown to disrupt the blood-brain barrier, which shields the brain from harmful toxins but also inadvertently blocks potentially helpful drugs, such as chemotherapy.
[caption id=“attachment_26145” align=“aligncenter” width=“1713”] Radiographic appearances of post-LITT changes.
(A) A woman with a left thalamic GBM treated with LITT underwent axial and coronal T1-weighted post-contrast enhanced MR images of the brain pre-LITT, during LITT and 48 hours post LITT. (B-I) A woman with a left insula GBM underwent axial T1-weighted post-contrast enhanced (B-E) and axial FLAIR-weighted (F-I) MR images of the brain pre-LITT and within 48 hours post LITT, 2 weeks post LITT, and 4 weeks post LITT. In both cases, the enhancing tumor (solid red arrowheads in A and B) is replaced by a central zone of T1-weighted signal hyperintensity (open red arrowheads in A and D) and a faint, new discontinuous rim of enhancement extending beyond the original tumor associated enhancing rim (solid blue arrowheads in A and D). The rim of contrast enhancement intensifies at 2 weeks post LITT (D) and remains stable at 4 weeks post LITT (E). Perilesional edema evaluated on FLAIR-weighted images is slightly increased between the pre-treatment (F) and immediate post-treatment (G) images, increases to a maximum point on the 2-week post-treatment images (H) and improves slightly by the 4-week images (I). The orange circles denote a representative ROI used to calculate temporal progression of Ktrans after LITT Credit: Eric C. Leuthardt, et al.[/caption]
As part of the trial, a widely used chemotherapy, doxorubicin, was given intravenously to 13 patients in the weeks following the laser surgery. Preliminary data indicate that 12 patients showed no evidence of tumor progression during the short, 10-week time frame of the study.
One patient experienced tumor growth before chemotherapy was delivered; the tumor in another patient progressed after chemotherapy was administered.
Blood-brain Barrier Permeability
The laser surgery was well-tolerated by the patients in the trial. Most patients went home one to two days afterward and none experienced severe complications.
The surgery is performed while a patient lies in an MRI scanner, providing the neurosurgical team with a real-time look at the tumor. Using an incision of only 3 millimeters— about the thickness of two pennies— a neurosurgeon robotically inserts the laser to heat up and kill brain tumor cells at a temperature of about 150 degrees Fahrenheit.
“The laser kills tumor cells, which we anticipated,” Leuthard says, “but, surprisingly, while reviewing MRI scans of our patients, we noticed changes near the former tumor site that looked consistent with the breakdown of the blood-brain barrier.”
He then confirmed and further studied these imaging findings with coauthor Joshua Shimony, associate professor of radiology.
The researchers performed follow-up testing, which showed that the degree of permeability through the blood-brain barrier peaked one to two weeks after surgery but that the barrier remained open for up to six weeks.
New Treatment Avenues?
Other successful attempts to breach the barrier have left it open for only a short time, about 24 hours, not long enough for chemotherapy to be consistently delivered, or have resulted in only modest benefits. In contrast, the new laser technology leaves the barrier open for weeks—long enough for patients to receive multiple treatments with chemotherapy.
And the laser only opens the barrier near the tumor, leaving the protective cover in place in other areas, potentially limiting the harmful effects of chemotherapy drugs in other areas of the brain.
The findings suggest that other exciting approaches such as cancer immunotherapy— which harnesses cells of the immune system to seek out and destroy cancer— also may be useful for patients with glioblastomas. The researchers are planning another clinical trial that combines the laser technology with chemotherapy and immunotherapy as well as trials to test targeted cancer drugs that normally can’t breach the blood-brain barrier.
“We are hopeful this technology opens new avenues to treating these devastating brain tumors that cause great suffering for patients and their families,” Leuthardt says.
Leuthardt EC, Duan C, Kim MJ, Campian JL, Kim AH, Miller-Thomas MM, et al. (2016) Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier PLoS ONE 11(2): e0148613. doi:10.1371/journal.pone.0148613
Top Illustration: Alex Gray, Wellcome Images