Cancer Answers: Surgical Treatment Options for Brain Tumors, April 6, 2008

Dr. Joseph Piepmeier, Surgical Treatment Options for
Brain Tumors April 6 , 2008Welcome to the Yale Cancer Center Answers with Drs. Ed Chu
and Ken Miller.  I am Bruce Barber.  Dr. Chu is Deputy
Director and Chief of Medical Oncology at Yale Cancer Center and
Dr. Miller is a Medical Oncologist specializing in pain and
palliative care. He also serves as Director of the Connecticut
Challenge Survivorship Clinic.  If you would like to join the
discussion you can contact the doctors directly.  The address
is cancerasnwers@yale.edu and
the phone number is1888-234-4YCC.  This evening, Dr.
Miller speaks with Dr. Joseph Piepmeier.  Dr. Piepmeier is
Nixdorff/German Professor of Neurosurgery at Yale School of
Medicine.Piepmeier
There are basically two types of brain tumors, tumors that arise
within the brain called primary brain tumors,  and secondary
brain tumors which are metastatic lesions or cancers that arise
somewhere else in the body and then deposit tumors in the
brain.Miller
Are all tumors that arise in the brain cancerous, or are some of
them benign? Piepmeier
Most of the patients I see have a malignant disease, but the World
Health Organization calls all gliomas malignant.  This really
is not helpful because gliomas are primarily classified as either
high grade or low-grade lesions, and there is a very different
biology between those two groups.  The high-grade lesions,
unfortunately, are far more common than low-grade tumors, but there
are a variety of benign lesions that arise from the nerves, or the
covering of the brain called meninges, and these are also
classified as brain tumors.Miller
That would be meningioma, and that is usually not a cancer.Piepmeier
Correct.Miller
How common are tumors that arise in the brain, a glioma for
example?Piepmeier
The incidence is probably somewhere between 13,000 and 15,000 cases
in the United States annually, so it is not common as other forms
of cancer.Miller
Do we know why this is? People have been talking about cell phones
for example.Piepmeier
There is no evidence that cell phones have a relationship to the
evolution of these tumors.  The only known causative factor is
exposure to ionized radiation at primarily a young age. Aside from
that there are really no other known causes.  We do know that
all cancers are the result of genetic mutations and there is a lot
of work being done establishing how that2:28into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3relates to the evolution of brain tumors, but in terms of the
causative factor, we do not know.Miller
Are they becoming more common?Piepmeier
As the population ages and with the improved ability to diagnose
and access to imaging, the frequency probably is increasing.Miller
For a patient who has a brain tumor, typically what do they come to
the doctor complaining of, how would they know that there is
something wrong?Piepmeier
The most common symptoms are progressive headaches, new onset of
seizure activity or a progression of a neurologic problem such as
weakness, numbness, memory change or vision change, and this
typically progresses over days to weeks.Miller
Lots of people get headaches, how would these be different than
just the regular headache or a migraine headache which people talk
about a lot.Piepmeier
Sometimes you cannot tell the difference, but what we are noticing
is that these headaches are very different than headaches the
patient may have routinely.  They commonly do not respond to
over the counter medications.  Very classically they are worse
in the morning when the patient awakens and get better during the
day. That constellation of a headache would be sufficient for the
patient to consult with their physician.Miller
So mainly if it persists?Piepmeier Correct.Miller
If a patient goes to the doctor and they have experienced a new
onset of seizures, or this different type of headache, what would
typically happen then?Piepmeier
We would examine the patient to see if there is any neurologic
problem to correlate with the symptoms. If that were the case, this
would lead us to think there may be a structural lesion in the
brain.  Then that would be someone who should proceed to some
diagnostic imaging.Miller
At this point, what is state-of-the-art in terms of imaging, as a
neurosurgeon what would you choose?4:37into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3Piepmeier
The best anatomic detail and resolution is clearly an MRI. The
quality of imaging and the degree of information you can gain from
that sequence of imaging is very important. It is really the gold
standard in terms of evaluating the brain tumor.Miller
You and I were talking before the show about how long we both have
been involved with Yale.  If we went back to the beginning of
your career, what was available, in comparison, for someone with a
brain tumor?  What would have helped you make the diagnosis at
that point?Piepmeier
Fortunately my career started when we had the old ACTA scan, which
was an ancient machine that took black and white Polaroid pictures
of the brain. They were not very informative, but preceding that it
was a matter of examination and arteriography and even
pneumoencephalography, which were very poor surrogates for brain
imaging.Miller
How has that changed your approach in terms of surgery, are more
people operable, less people operable; how do you make that
decision?Piepmeier
Tumor location is the primary indicator as to whether or not this
is something that has to be removed, but there is a lot of
information on additional imaging strategies such as what is called
a functional MRI where you actually map out specific cortical
regions in the brain that activate with certain activities. Then,
based on the knowledge of neuro anatomy, you can anticipate what
the potential neurological problems are that might occur with
surgical removal of the tumor. All of that is incorporated into
making a decision about whether or not the patient will have an
operation.Miller
Let us go back to a functional MRI because I know very little bit
about it.  What does it mean and how do they do a functional
MRI?Piepmeier
Basically this is a technique with an MRI machine where you can
measure increase blood oxygen demand, and when you activate a
certain area of the brain, such as with movement of your hand, that
area of the MRI that is primarily mediating that activity gets an
increased blood supply.  That increased blood supply can be
detected by an MRI, so you can delineate on a specific cortical
region that area of the brain that mediates that function.
Important activity such as motor function, language or even vision,
are things that can be anatomically located within the brain on an
MRI prior to surgery.7:30into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3Miller
It sounds like you can predict before surgery, what impairment the
patient may have with surgery, is that correct?Piepmeier
You can make an estimation, yes.  There is no such thing as
the procedure without risk, but you can minimize that risk by
knowing the anatomy and knowing the localization and infiltrative
nature of the tumor prior to surgery.Miller
You are looking at an MRI scan and you've got someone with new
onset seizures, different headaches and they have a mass in the
brain and you need to find out what it is.  How do you do a
biopsy of a brain tumor?Piepmeier
One of the important factors of the MRI scan is that they are very,
very good at showing us abnormalities, but in general they are not
very good at telling us what the abnormalities are; they are not
specific enough to make a diagnosis with most primary brain
tumors.  In order to render a diagnosis, you need a biopsy
which is a procedure that can be done through a small opening by
passing a probe into the target region and sending that to the
pathologist for an answer.  We do these with what is called
frameless stereotaxis, which means we can actually use facial
features of the patient to render precise localization through a
computer in the operating room that demonstrates a probe going
precisely to the target at the time of surgery. This way, the
surgeon knows he is biopsying the precise area that he wants.Miller
As the surgeon are you guiding the biopsy probes done or is the
computer? How do you do it?Piepmeier
The surgeon is guiding and doing the surgery, but you get
visualization in three dimension of that probe passing through the
imaging study at the time of the operation.Miller
It sounds amazing. Piepmeier
It is a nice way to do surgery and it has a degree of safety
ensured. Miller
When you have made a diagnosis, you then have to discuss about
whether to operate or not. What are the factors that you consider
before you make that final decision?Piepmeier
Risk is the ultimate decision making issue.  In general, it is
fairly well accepted that when reducing the amount of tumor that is
present when a patient has to move on to other forms of treatment,
such as radiation,10:06into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3chemotherapy, that cytoreduction has benefit in terms of
improving the efficiency of those next steps in treatment.Miller
In terms of risk, it would be loss of function, or potentially loss
of life.Piepmeier
It is extraordinarily rare that a patient would die from one of
these operations, but it is the impact on the patient's capacity to
function that is the primary factor that dictates how aggressive
you can be with surgery.Miller
 We have an email from one of our listeners asking about gamma
knife.Piepmeier
Gamma knife is a technology that can highly focus high dose
radiation to discrete targets. It has been a wonderful tool for the
treatment of patients, primarily with metastatic disease. 
Some benign brain tumors were also good candidates for this
treatment, but for the vast majority of patients with gliomas,
these were not well-demarcated focal targets.  They are
diffuse and infiltrative tumors and gamma knife is a wonderful
tool, but not very helpful with the majority of patients with
primary brain tumors or gliomas.Miller
So for those patients you would generally lean towards surgery as
opposed to radiation?Piepmeier
Those patients typically would have surgery and in the high-grade
population, these patients would then move on to external beam
radiation treatment.Miller
We would like to remind you that you can email your questions to us
at cancerasnwers@yale.edu. 
We are going to take a short break for a medical minute. Please
stay tuned to learn more about the treatment of brain tumors with
Dr. Joseph Piepmeier from the Yale Cancer Center. 12:37into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3Miller
Welcome back to Yale Cancer Center Answers.  This is Dr. Ken
Miller.  I am here with Dr. Joseph Piepmeier, who is the
Professor of Neurosurgery at Yale School of Medicine and the Yale
Cancer Center.
 Joe, we are talking about the symptoms of brain tumors and how you
make a diagnosis. We started talking about surgery and
radiation.  If someone has had a resection, if you have
removed a brain tumor, what is the typical recovery like for that
patient?  How long will they be in the hospital and what
happens next?Piepmeier
The patient is usually in the hospital about 3 or 4 days and when
they go home they are typically independent in their activities,
but restricted for a couple of weeks. At that time, we will start
the next steps of treatment.Miller
Let's get right into that.  You have removed the tumor, and
years ago with a lot of other types of tumors, the surgeon would
say I got it all and that is all you need to do.  Is that case
with neurosurgery?Piepmeier
It is not the case with gliomas. We know that these are tumors that
are not well demarcated from the surrounding brain, so the surgical
target is that part of the tumor which is identifiable as solid
tumor tissue. The portion of the tumor that infiltrates into the
brain around that original tumor, is not a surgical target. That is
the portion of the tumor that radiation therapy and chemotherapy
treat.Miller
The patient has recovered and they go to the radiation oncologist,
how do they target the area and what do they do?Piepmeier
Fortunately we work as a collaborative multidisciplinary unit at
our institution and so decisions about the treatment are made in
consultation with a neurosurgeon, a neurooncologist, the radiation
oncologist, the medical oncologist, the neuro pathologist and the
neuro radiologist. All of this material is reviewed on each
patient.  The decision about what type of radiation or what
type of chemotherapy, is basically derived from input from all of
those disciplines, but traditional radiation therapy is given in
daily fractions; typically 5 days a week for up to 6 weeks. 
That dose symmetry planning enables you to focus radiation on the
tumor to try to kill those tumor cells and yet spare injury from
the surrounding brain.Miller
In terms of chemotherapy, is there a role for chemotherapy in
trying to reduce the risk of the cancer coming back?Piepmeier
Absolutely, and the standard of care right now is the drug
temozolomide, which is an oral agent that is taken in low doses
during radiation. Once15:21into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3radiation is completed, it is given in cycles with a higher
dose.  These are a series of pills that patients can
take.  They do not cause the side effects that used to
characterize chemotherapy in the past.  Most of these patients
can take this medicine and go to work.Miller
I was going to ask about that. There is a common misperception
among patients that they will have a lot of side effects and if
they don't, they think it's not effective.Piepmeier
It is very effective and we are seeing some very nice responses to
it, but even more than that, now we are finding that because there
are specific genetic defects that relate to the evolution of these
tumors, these genetic defects turn off the cells ability to stop
proliferation.  We are now able to identify those pathways and
target therapies in directly to address the signaling problems in
those pathways to help control the tumor.Miller
It is essentially targeted therapy, which is being used a lot in
oncology.  I know you are doing work on convention enhanced
delivery chemotherapy, what does that mean?Piepmeier
This is a new technique where you can actually place a small
catheter in the brain and directly infuse the chemotherapy or the
targeted treatment directly in the brain where those infiltrative
tumor cells reside. By selecting an agent to infuse, it attacks
only the tumor cells.  You can selectively control the tumor
and not injure the surrounding brain tissue.Miller
So the tumor cells that are left in that area will actively take up
the chemotherapy.Piepmeier
Correct.Miller
How do you choose drugs that have fewer side effects in terms of
normal tissue? Piepmeier
One of the ways is to try to select a specific target that is
present on the tumor cells and not on the normal brain
tissue.  There is a receptor for epidermal growth factor, a
mutative receptor called EJFRV3, which is present in about half the
malignant primary brain tumors and by targeting that specific
receptor with an antibody, you can actually direct therapy toward
the tumor cells and spare the brain.Miller
If you gave the same drugs intravenously, as we do for treatment of
other types of cancer, would they get into a brain tumor?17:55into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3Piepmeier
To a certain extent they would and intravenous is still a viable
option.  It has the benefit of being distributed to the blood
system, to having access to wide areas.  It is the ability of
that compound to pass from the blood vessel into the brain that
remains to be a challenge. The benefit of the convention delivery
strategy is you obviate that blood brain barrier obstruction by
putting the agent directly into the spot or site where you need
it.Miller
What else is new in terms of cutting edge therapy? Tell me about
using viruses, how would you do that?Piepmeier
This is a very interesting strategy that we have developed in the
neurosurgery laboratories with Tony Vandemore. We have developed a
virus, which is a variant of vesicular stomatitis virus, which has
been developed to directly attack tumor cells and not normal brain
tissue.  This is a replication competent virus, which means
that once it gains access to the tumor cell, it can actually
replicate and go to the next tumor cell. There has been some fairly
remarkable laboratory work both in the Petri dish and in the
research animal, showing that this virus directly attacks the tumor
and does not attack the brain.  It is very exciting work.Miller
The next step is bringing this to people; is there some trepidation
with that, or is there confidence that this really may be a
breakthrough?Piepmeier
I think the strategy may be a breakthrough, whether or not this
virus is the ultimate agent used is unknown.  Our primary
concern is not only its ability to kill the tumor cell, but to
protect the patient, so additional work needs to be done to make
sure this virus, or some variant of this virus, is safe so the
treatment itself does not make the patient sick.Miller
If a patient or a family member is listening to this and wants to
learn more about what is available in terms of clinical trials here
at Yale, how would they get involved?Piepmeier
It is very easy to get involved.  We are certainly on the Yale
Cancer Center website and there is a Yale Brain Tumor Center
website. There is also a phone number, 203-785-2791, where Betsy D'
Andrea, who is the clinical coordinator, will be happy to take
information and make arrangements for the patient to be seen. 
We are dedicated to seeing patients rapidly and typically we can
see new patients within the same week.Miller
At that point they would perhaps be seen by yourself, but also by
the20:44into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3entire team of people and different specialists that you
mentioned before. It sounds like a strategy is mapped out.Piepmeier
That is correct.  We believe that this collaborative
relationship in bringing multiple disciplines to the table for each
patient enhances the quality of healthcare.Miller   We received an email question from a woman in
Southington. She was asking about drugs that are involved with
angiogenesis, which is the development of blood vessels, and how
that property of angiogenesis comes into play with brain tumors and
how you are targeting that?Piepmeier
Angiogenesis is a very robust part of primary malignant brain
tumors and it is a viable target for therapy.  Developing
strategies specifically focused on this are an ongoing
interest.  We have seen some fairly remarkable responses to
the use of the current drug Vevasystemac. It has been recently FDA
approved for the treatment of breast cancer.  It has also been
used to treat primary malignant brain tumors and we see this as a
significant benefit in some patients in terms of controlling their
tumor.Miller
It is a fascinating thing that some of the drugs that are approved
for one indication such as for breast cancer, can have activity in
tumors that are very, very different.Piepmeier
Absolutely and that is one of the reasons why, especially with many
solid tumors, advances in one area can be adopted in other
disciplines and other types of cancer.Miller
People talk about the concept of bench to bedside, what does that
mean in terms of Yale and brain tumor research?Piepmeier
 That is a very active process at our institution and we have
dedicated science and research personnel that are actively working
on these problems, not only in our own department of neurosurgery,
but also in the Department of Biomedical Engineering and the other
disciplines within the hospital.  We have a new research
project that will be starting this spring, which will be dedicated
toward adapting convention-enhanced delivery of targeted therapies
that attack cancers stem cells.  We feel that these are likely
the most resistant form of cancer within primary malignant brain
tumors, and if we can target those cells specifically, we are going
to be much more effective in terms of treatment.23:24into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3Miller
 It is an important term you just brought up. What are cancer stem
cells and how are they different than the cancer itself?Piepmeier
The identification of the stem cells is probably the most important
discovery in the history of medicine.  These are cells that
reside within the adult human brain that maintain the capacity to
produce other more mature forms of cells.  We also think that
these plurry potential cells are the cells of origin for brain
tumors. The ability for these cells to migrate within the brain and
to go to different regions, also characterizes the same
problems that we see with primary brain tumors.  New evidence
shows that of all the forms of therapy we use, the most resistant
cells appeared to be a subpopulation of cancer stem cells. 
Our strategy is, if that really is the cause of resistance, then we
need to focus on that subpopulation within the cancer. We are
dedicating an entire research project to this.Miller
I shouldn't say easier, but the slightly easier cells to get rid of
are the more mature tumor cells that were used to seeing.  You
are saying that there is actually a population of cells that are
more primordial, more primitive than that?Piepmeier
That is a very important concept that is relatively new. 
There are a number of ways to try to identify what a stem cell is
within a brain tumor and that still remains to be defined. 
Apparently, there are several different markers that can be used,
but I think the research data is pretty clear that if you take that
population of cells out of a malignant tumor and study those in a
laboratory, they have much more aggressive behavior than the other
more mature cells that were within the tumor.Miller
So in a sense the goal of treating someone with a brain tumor is
with surgery to remove the bulk of the tumor, and then the second
goal is to remove any other mature tumor cells. What you are really
saying is probably the toughest goal right now is getting rid of
the stem cells.Piepmeier
That appears to be the case.Miller
Anything else you want to share with us in terms of advances in
surgery, surgical techniques or advances in research that you are
excited about?Piepmeier
One of the important things about the new Smilow Cancer Hospital at
Yale is that we are going to incorporate a high intensity MRI unit
within the operating room. This will enable us to do more precise,
detailed surgery and more aggressive surgery in the treatment of a
variety of disorders including brain tumors. The other thing that
we have, along with26:20 into mp3file 
http://www.yalecancercenter.org/podcast/Answers_Apr-6-08.mp3the multidisciplinary approach, is that the nurse coordinator,
Betsy D' Andrea has a patient, family support group that meets
monthly. We feel this is also a very valuable asset in terms of
patients and families dealing with cancer, especially cancer in the
brain.Miller
 I want to thank you Dr. Joseph Piepmeier for joining us.Piepmeier
 It was great, thank you.Miller 
 It has been wonderful hosting you on Yale Cancer Center Answers
today. Until next week, this is Dr. Ken Miller at Yale Cancer
Center wishing you a safe and healthy week.If you have questions, comments, or would like to subscribe
to our podcast, go toyalecancercenter.org where you will also find transcripts of
past broadcasts in writtenform.  Next week, we will learn about the treatment of
childhood cancer with Dr. GaryKupfer