Biomedical Engineering Reference
In-Depth Information
14
Focused Ultrasound
Applications for Brain Cancer
14.1 Introduction ............................................................................................................................ 241
14.2 Focused Ultrasound in the Brain ......................................................................................... 242
Ultrasound and the Skull Bone • The Skull Window Approach • Focusing through
the Skull • System Design for Transcranial Ultrasound Therapy
14.3 Therapeutic Effects of Ultrasound on the Brain ................................................................ 246
Hyperthermia • Thermal Ablation • Cavitation Effects • Microbubbles and
Liquid Nanodroplets • Blood-Brain Barrier Disruption
14.4 Applications and Clinical Studies ........................................................................................ 249
14.5 Potential Future Treatments ..................................................................................................251
14.6 Needs for Advancement of Transcranial FUS into Routine Clinical Practice...............251
Acknowledgments ...............................................................................................................................251
References .............................................................................................................................................251
Meaghan A. O'Reilly
Sunnybrook Health Sciences Centre
Kullervo Hynynen
Sunnybrook Health Sciences Centre
14.1 Introduction
weight of approximately 500 Da [Pardridge, 2005] from cross-
ing into tissue. Unfortunately, this prevents most potentially
useful therapeutic molecules from having a significant effect
in the brain. In tumor tissue, the BBB can be leaky, but still
prevents adequate drug delivery. One means of circumventing
the BBB is to inject or implant the anticancer agents directly
into the brain tissue and allow them to diffuse through the tis-
sue. This approach, however, requires a surgical window in the
skull. Radiotherapy or brachytherapy present other options for
the treatment of brain tumors, however they require exposing
the patient to ionizing radiation, which can harm the healthy
tissues [DeAngelis, 1989; Leibel et al., 1989; Chang et al., 2009].
Research into focused ultrasound (FUS) in the brain began in
the 1940s when Lynn et al. conducted the first focused ultrasound
experiments in biological tissues [Lynn et al., 1942] and used FUS
to produce neurological effects in laboratory animals [Lynn et al.,
1942; Lynn and Putnam, 1944]. Since the first experiments, much
research has been devoted to translating FUS into a clinical tool
for brain therapy. FUS provides many advantages over traditional
brain cancer treatments. A nonionizing energy source, FUS can
be used to noninvasively produce a range of biological effects.
Focused ultrasound has the potential to revolutionize cancer treat-
ment, not only by noninvasively ablating tumors that are untreat-
able via traditional surgery but by providing new drug delivery
techniques to improve delivery of therapeutic agents. This chapter
will discuss the range of therapeutic effects that ultrasound can
produce in the brain, the difficulties inherent to transcranial FUS,
and how these problems have been addressed to date.
In 2007, the United States' National Cancer Institute reported
that over 126,000 individuals in the United States alone were
affected by primary brain or other central nervous system (CNS)
cancers [Altekruse et al., 2010]. In addition to these numbers,
metastatic brain cancer affects a significant percentage of those
suffering from other primary cancers. Lung and breast cancer
patients are particularly prone to developing brain metasta-
ses, with one study finding that as many as 19% of lung cancer
patients will be diagnosed with brain metastases, and as many
as 5% of breast cancer patients [Barnholtz-Sloan et al., 2004].
Old autopsy data from patients with breast carcinoma suggest
the incidence may be higher, with as many as 30% developing
CNS metastases [Tsukada et al., 1983]. Survival rates are poor
once brain metastases develop, with a reported median survival
of just seven months in patients with good prognosis [Gaspar et
al, 1997]. Thorough reviews on both primary [Behin et al., 2003]
and metastatic [Kamar and Posner, 2010] brain cancer exist that
describe diagnosis and classification of the various tumor types.
Treatment practices vary depending on tumor type and
location. Surgical intervention is an option for some tumors,
but always results in some damage to surrounding structures.
Surgical interventions are highly invasive, and many patients do
not meet inclusion criteria for surgical removal. Chemotherapy
or other anticancer agents can be delivered to the brain, however
these agents have difficulty diffusing into tissue due to the tight
junctions in the cerebral vasculature that form the blood-brain
barrier (BBB). The BBB prevents molecules beyond a molecular
241
