Laser breaches blood-brain-barrier to deliver chemo

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Using a laser probe, neurosurgeons at Washington University School of Medicine in St Louis have opened the brain’s protective cover, enabling them to deliver chemotherapy drugs to patients with a form of deadly 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 tumours. Heat from the laser is known to kill brain tumour cells but, unexpectedly, the researchers found that the technology can 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,” said co-corresponding author Dr Eric C Leuthardt, a Washington University professor of neurosurgery who treats patients at Barnes-Jewish Hospital. “This is crucial because most chemotherapy drugs can’t get past the protective barrier, greatly limiting treatment options for patients with brain tumours.”

“We are closely following patients in the trial,” said Leuthardt, who also is a Siteman Cancer Centre member. “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.”

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, a technology that Leuthardt helped pioneer.

The laser technology was approved by the US Food and Drug Administration in 2009 as a surgical tool that can be used to treat brain tumours. But the new research marks the first time the laser has been shown to disrupt the blood-brain barrier, which shields the brain from harmful toxins but inadvertently blocks potentially helpful drugs, such as chemotherapy.

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 tumour progression during the short, 10-week time frame of the study. One patient experienced tumour growth before chemotherapy was delivered; the tumour in another patient progressed after chemotherapy was administered.

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 tumour. Using an incision of only 3 millimetres, a neurosurgeon robotically inserts the laser to heat up and kill brain tumour cells at a temperature of about 150 degrees Fahrenheit.

“The laser kills tumour cells, which we anticipated,” said Leuthardt, who also directs the department of neurosurgery’s Centre for Innovation in Neuroscience and Technology and the Brain Laser Centre. “But, surprisingly, while reviewing MRI scans of our patients, we noticed changes near the former tumour site that looked consistent with the breakdown of the blood-brain barrier.” He then confirmed and further studied these imaging findings with co-author Dr Joshua Shimony, an associate professor of radiology at Washington University.

The researchers, including co-corresponding author Dr David Tran, a neuro-oncologist who is now at the University of Florida, 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.

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 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 tumour, leaving the protective cover in place in other areas of the brain. This has the potential to limit the harmful effects of chemotherapy drugs in other areas of the brain, the researchers said.

The findings also 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 tumours that cause great suffering for patients and their families,” Leuthardt said.

Abstract
Background
Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.
Methods
Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.
Results
In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1–3 weeks before decreasing to baseline by 6 weeks.
Conclusions
The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1–2 weeks after laser ablation and resolving by 4–6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.

University of Washington in St Louis material
PLOS One abstract


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