Cancer Answers: New Hope for Patients with CNS Tumors, April 26, 2009

Dr. Jill Lacy, New Hope for Patients with CNS
Tumors
 April 26, 2009Welcome to Yale Cancer Center Answers with Dr. Ed Chu and
Francine Foss, I am Bruce Barber.  Dr. Chu is Deputy Director
and Chief of Medical Oncology at Yale Cancer Center and he is an
internationally recognized expert on colorectal cancer.  Dr.
Foss is a Professor of Medical Oncology and Dermatology and she is
an expert in the treatment of lymphomas.  If you would like to
join the discussion, you can contact the doctors directly. 
The address is canceranswers@yale.edu and
the phone number is 1888-234-4YCC.  This evening we welcome
Dr. Jill Lacy.  Dr. Lacy is an Associate Professor of Medical
Oncology at Yale Cancer Center specializing in the treatment of
brain and spinal cord tumors.Chu
 Jill, let's start off by discussing what tumors of the central
nervous system are.Lacy
Well, the definition of a tumor of the central nervous system is an
abnormal growth of cells within the brain or the spinal cord, or
within the tissues that cover the brain.  Basically, there are
two types of brain tumors that we talk about, primary brain tumors
and metastatic brain tumors.Foss
What is a metastatic brain tumor?Lacy
That's a tumor that begins as a cancer elsewhere in the body,
outside of the brain, and then spreads to the brain where it can
grow either as a solitary single tumor mass, or in some cases as
multiple small discrete tumor masses within the brain.  For
example, lung, breast, kidney, and melanoma are the cancers that
frequently metastasize to the brain, and lung and breast are the
most common types of metastatic brain tumors.Foss
How common is brain cancer and at what age do patients generally
come down with brain tumors?Lacy
Metastatic brain tumors are quite common.  There are about
150,000 new cases of metastatic brain tumors diagnosed each
year.  Turning to primary brain tumors, these are tumors that
arise in brain tissue and grow within the central nervous
system.  They can diffusely infiltrate the brain and spinal
cord, but they rarely spread or metastasize outside of the CNS to
other sites in the body.  What can be a little confusing for
patients, and even in some cases for physicians, is that there are
many different types of primary brain tumors.  There are at
least 15 by the current classification system and they all have a
somewhat different biology, natural history, prognosis, and
treatment.  Some of these primary brain tumors are truly
benign and others are malignant.2:40 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Apr-26-09.mp3Chu
 What would be the primary CNS tumor that we should be most aware
of, especially for the adult population, which type?Lacy
Well let's backtrack a little bit.  Brain tumors are
classified by pathologists based on the type of cell from which
they arise.  The most common type of primary brain tumor is
called a glioma.  A glioma is a brain tumor that arises from
glial cells, and these are the cells in the brain that form that
kind of spongy material that supports the brain nerve cells or
neurons, and more than half of primary brain tumors are
gliomas.  There are actually several different subtypes of
gliomas, and they run the spectrum from being indolent low-grade
benign tumors to very malignant, highly aggressive tumors. 
The most common type of brain tumor overall is the highly malignant
variant of glioma called glioblastoma multiforme.Chu
 Are there any risk factors that have been identified, say for this
most aggressive form of brain cancer, glioblastoma multiforme, that
is also known as GBM?Lacy
Who gets brain tumors? What are the risk factors? There have been a
number of studies looking at potential environmental factors that
can cause brain tumors.  In fact, there have been hundreds if
not thousands of these studies looking at things like
petrochemicals, dietary components, power lines, cell phones, and
none of these studies have really shown any substantive link to the
development of brain tumors, which is somewhat reassuring. 
The only clearly defined risk factor for primary brain tumors is
ionizing radiation, or x-rays, and this link comes primarily from
treatment of children with leukemia who get brain radiation to
prevent relapse in the brain. We know from that data that radiating
the brain is associated with about a ten fold increased risk for a
benign type of tumor called meningioma, and about a sixth fold
increase in risk of gliomas, which sometimes can be
malignant.  Given the link with x-rays, there is some concern
about unnecessary radiation of the brain, and this concern has been
raised, for example, with dental x-rays.  Now, dental x-rays
involve a very low dose of radiation and so far there is no clear
link to brain tumors with judicious use of dental x-rays in the
general population.Foss
What are signs and symptoms of a brain tumor?Lacy
There are patients who present with focal neurologic symptoms,
headaches, or seizures.  The focal neurologic symptoms can be
quite varied depending on the location of the tumor within the
brain.  For example, a patient may present with several weeks
of right-sided weakness, reflecting a tumor in the left side of the
brain, they may present with difficulty speaking, which is
reflective of a tumor in the language center of the brain, or with
visual abnormalities, reflective of a tumor in the vision center or
occipital lobes of the brain. 6:13 into mp3 file 
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 Typically, these focal neurological symptoms are progressive over
weeks or months.  They usually are not sudden in onset and in
fact we are often taught in medical school that the sudden onset of
focal neurologic symptoms, in general, is indicative of a stroke
rather than a brain tumor.Foss
You talked about headaches.  Can you reassure our listeners a
little bit about headaches, because we all have them so when do we
worry about a headache as potentially being a brain tumor?Lacy
Good question.  About half of the patients who are ultimately
diagnosed with a brain tumor will complain of headache.  There
is no clear pattern of headache associated with brain tumors. 
They can be mild or severe.  In some cases they are quite
severe and associated with nausea and vomiting, which can be
indicative of an increase in pressure in the brain from the mass of
the tumor.  Now headaches are obviously very common and we all
experience them often on a regular basis, and the overwhelming
majority of people who experience headaches obviously do not have
brain tumors.  But, if you are experiencing headaches for the
first time, headaches that are more severe than the usual pattern
or increase in severity and frequency, it's always wise to check in
with your health care provider.Chu
 So say if the headaches are different than normal, or any of the
other symptoms that you had mentioned should arise, who should they
go to? Should an individual see their primary care physician?
Should they see the neurologist? Should they come and see you, the
medical oncologist? And then what needs to be done
subsequently?Lacy
Seeing your primary care provider is often the first place to
start, and then they can refer you on if it's necessary.Foss
What is the treatment for brain tumors?  You have talked about
a number of different types, and I am sure there is a whole bunch
of different ways of approaching them, but can you give us just a
general overview of the treatment approach?Lacy
Treatment of brain tumors is very interdisciplinary and involves
primarily three modalities; surgery to remove the tumor or get a
biopsy, radiation therapy either as the primary treatment or as an
adjuvant to surgery, and chemotherapy or drugs are used to treat
brain tumors.  The primary treatment generally is considered
surgical resection, and for benign tumors that often is curative,
for malignant tumors it will relieve mass effect and symptoms and
has been associated with a better survival.  However, not all
brain tumors can be removed surgically. If they are located deep in
the brain, if they are located in a critical site within the brain,
or if9:02 into mp3 file 
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 the tumor is very extensive, it's not possible to remove the tumor
surgically.  The alternative in that case would be either
radiation or something called radiosurgery.Foss
You talk about brain tumors as being solitary lesions, and we use
the word metastasized for other kinds of cancers.  Could you
clarify for our listeners, do brain tumors spread to other parts of
the brain and do they spread outside of the brain?Lacy
This relates in part to a question that patients often ask when
they are first diagnosed with a brain tumor, is this tumor
malignant? Is it cancerous, or is it benign? Because outside of the
brain that's obviously a very important distinction. Malignant
tumors in the brain are aggressive and they can diffusely
infiltrate the brain and even the spinal cord and they grow
rapidly. They are life threatening and in most cases eventually
they will recur and are often fatal. Interestingly, they rarely
metastasize outside of the brain and the spinal cord, outside of
the CNS.  Benign tumors by contrast grow very slowly. 
They can be present for years with no growth.  They tend to be
well demarcated within the brain, they don't diffusely infiltrate
the brain and they often are associated with a very long natural
history and may not need treatment. 
 Where it can be confusing in the brain when we are dealing with
primary brain tumors is that benign tumors can present with the
same types of symptoms that malignant tumors present with and
patients often are living with significant neurologic deficits from
benign tumors.  Benign tumors are also treated with the same
modalities that we use to treat malignant tumors; surgery,
radiation, and less often drugs. Benign tumors, if progressive, can
in some cases rarely be fatal.  The other issue is that benign
tumors sometimes have the potential to become malignant, and by
that I mean that they can recur after they have been treated, they
can recur multiple times, and in some cases they can actually
transform and become a malignant or aggressive tumor.  The
distinction between benign and malignant tumors in the brain can
sometimes be a challenge both for the patients and the
physicians.Chu
 The help to distinguish between benign and malignant, can that be
done solely on imaging such as a CT or an MRI, or does a more
invasive procedure need to be done?Lacy
The way we define a tumor in terms of the subtype and whether it's
malignant or benign is done using two modalities.  The first
is imaging, brain imaging, and most patients who are diagnosed with
a brain tumor will get a CAT scan or an MRI scan that will show the
tumor within the brain.  Now, if they have had a CAT scan they
should get an MRI scan because it's a much more sensitive
test.  It also gives us a lot of information about the type of
tumor that we are dealing with based on these characteristics; does
it take up the dye that's injected when the study is done and are
there multiple lesions? Often times, from the MRI scan alone,12:22 into mp3 file 
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 we have a pretty good idea as to whether we are dealing with a
benign tumor or a malignant tumor.  Ultimately, of course, we
want to get tissue to look at under the microscope and the
pathologists can usually tell us whether we are dealing with a
benign tumor or a malignant tumor.Chu
 I have heard this expressed by some patients that they get
extremely claustrophobic in tight quarters, and as I understand it,
with MRI sometimes it's pretty tight quarters.  What would you
do in a situation where you have a patient who gets very fidgety
and anxious at even the thought of undergoing an MRI?Lacy
That's an important practical issue for the patients.  MRI
scans are absolutely critical to the management of brain tumors, so
we really want to get an MRI instead of a CAT scan, which is easier
for patients.  There are open MRI scanners, but they are not
quite as good in terms of the information that we get.  We try
to get patients through it; sometimes they do require a sedative to
help with the procedure.Foss
Is there any role for PET scanning in the diagnosis or management
of brain tumors?Lacy
Yes, PET scanning is one of the emerging diagnostic tools that we
are using to help us define the biology of the tumor and help us
determine if the tumor has recurred.  A PET scan is a
metabolic scan, it shows how metabolically active tissues in the
brain are and we know that malignant tumors are very metabolically
active; they are quite hot on PET.  Benign tumors tend to be
much less metabolically active, and in fact, cold.  It's still
somewhat of a research tool, and we are still learning how best to
use and apply PET scanning in evaluating and managing brain
tumors.Chu
 Jill, at Yale Cancer Center you are part of a team that works very
closely together when evaluating patients with brain tumors. 
Can you tell us a little bit more about that?Lacy
As I mentioned earlier, the management and treatment of brain
tumors is very much interdisciplinary.  It involves a
neurosurgeon to get the biopsy or remove the tumor, a radiation
oncologist to utilize radiation therapy as a treatment modality, an
oncologist, either a medical oncologist or neurooncologist, who
oversees administration of medications and chemotherapy, and a
neurologist to manage seizures and other neurologic problems. 
Behind the scenes there is a neuroradiologist who is critical in
interpreting the MRI scans, and the neuropathologist who we
absolutely rely on for the diagnosis.  It is a team and
because of the complexity of treating brain tumors, and the number
of specialists involved, there is benefit in being treated by a
team of doctors that work very closely together.15:19 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Apr-26-09.mp3Foss             
 Thank you very much Jill. We would like to get into more detail
about the types of treatment for brain cancer after our
break.  You are listening to Yale Cancer Center Answers, and
we are here discussing the treatment of brain tumors with Dr. Jill
Lacy.Foss
Welcome back to Yale Cancer Center Answers.  This is Dr.
Francine Foss and I am joined by my co-host Dr. Ed Chu and Dr. Jill
Lacy, a medical oncologist at Yale Cancer Center.  Jill, in
the first part of our discussion we talked extensively about the
diagnosis of primary brain cancers, but sometimes when you think a
patient has a primary brain tumor, you find out after biopsying
that it is a different cancer, a cancer that spread from another
part of the body.  How often does that happen?Lacy
As we had discussed earlier metastatic brain tumors are actually
far more common than primary brain tumors.  In most cases,
patients with metastatic brain tumors already have a diagnosis of
cancer outside of the brain, breast cancer or lung cancer, and so
when they develop symptoms and have a scan and we see spots in the
brain that are consistent with metastasis, we usually are fairly
comfortable that that's the diagnosis and we don't have to get a
biopsy.  In some cases, however, patients with metastatic
brain tumors will present for the first time, without a diagnosis
of cancer, with neurologic symptoms and we will have a scan. 
There may be a lesion there and in some cases it may be difficult
to distinguish a metastatic tumor from a primary brain tumor. In
that case, of course, one must get a biopsy to make the
diagnosis.Foss
 In terms of thinking about the primary therapy, we talked about
surgery as playing a17:59 into mp3 file 
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 major role, can you tell us a little bit about the types of
surgery that are done and if there are any alternatives to
surgery?Lacy
Conventional surgery to remove a brain tumor involves a craniotomy,
which means that the surgeon will remove a small piece of the
skull, expose the brain and the tumor, and carefully dissect the
tumor away from normal brain and basically cut it out, if you
will.  Now, as I had mentioned earlier, there are some
situations where the tumor cannot be removed surgically because
it's either too deep within the brain and inaccessible, or it's
located in a very critical area of the brain such as the speech
center, and if one were to remove it, it would leave the patient
with significant neurologic impairment.  An alternative to
surgery is something called radiosurgery, commonly referred to as
Gamma Knife or CyberKnife. So what is radiosurgery? Radiosurgery is
actually not surgery at all.  It's a very specialized type of
radiation where the radiosurgery device, say the Gamma Knife,
delivers a very high dose of very focused radiation to a small area
of the brain to the small tumor.  The benefit of this is that
you can deliver a high dose that's very focused without a lot of a
scatter of radiation to normal brain tissue. Radiosurgery can
ablate a tumor in basically the same way that removing the tumor
surgically can accomplish; which is why it's often referred to as
radiosurgery.  It's quite a sophisticated technical
procedure.  It's usually done in one sitting with one
treatment.  It requires very sophisticated computer assisted
technology to localize the tumor very precisely and usually
involves putting on what is called a head frame or halo that is
pinned to the scalp.  Radiosurgery does involve an experienced
team of physicians, once again a neurosurgeon, radiation
oncologist, and radiation physicists, and it's important that this
procedure be done in the context of a radiosurgery team.  Just
as an aside, I would mention that we have a very robust and busy
Gamma Knife Center here at Yale.  It's one of the ten busiest
Gamma Knife Centers in North America and is staffed by a very
terrific team of physicians.Chu
 Say once surgery of the primary tumor is performed, is there any
role for any type of follow-up therapy afterwards; such as either
chemotherapy or perhaps radiation therapy?Lacy
Yes.  We talked about the important role of surgery, and in
the case of benign tumors, surgery is often curative and there is
no need for any additional treatments.  However, with
malignant tumors surgery is important.  It relives mass effect
and symptoms and debulks the brain, but in most cases malignant
brain tumors will grow back, and they actually will grow back quite
quickly.  So there is a need for what we call adjuvant
therapies after surgery, and I think the treatment of the most
malignant brain tumor, glioblastoma, illustrates how we use those
adjuvant therapies.  For glioblastoma we like to remove the
tumor if we can, ideally, in its entirety, which is called a
complete or gross total resection.  We know that patients who
are able to undergo a complete resection actually do better and
have a better prognosis.  But21:57 into mp3 file 
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 even in patients where all of the tumor that we can see is
removed, glioblastoma always recurs and it recurs quickly. We have
learned that administering radiation treatments after surgery
significantly improves the outcome for these patients.  So, if
you do not do radiation, the tumor usually is back within three
months, with radiation treatments often it's a year or more before
the tumor recurs.  Radiation treatments for malignant gliomas,
including glioblastoma, use conventional radiation.  Its small
doses fractionated over usually five weeks, so the patient will
come in every day, Monday through Friday, for radiation
treatment.  The radiation oncologist will treat the area of
the original tumor, plus some surrounding brain, to try to kill any
cells that have infiltrated into adjacent normal brain. Where does
chemotherapy fit into all of this? This has been a recent advance
in the treatment of glioblastomas.  We learned a few years ago
that administering chemotherapy, along with the radiation and after
the radiation, significantly improves the outcomes for
patients.  The chemotherapy drug that we use is a drug called
temozolomide, or Temodar.  This was specifically developed to
treat brain tumors.  It's actually taken as a pill, and it has
very few side effects.  It's taken once a day throughout the
radiation and then once radiation is finished, patients will
continue on Temodar for at least six months to usually a
year.What does Temodar accomplish? It's actually quite
striking.  The main benefit of Temodar is that it
significantly increases the percentage of patients that are alive
at late time points.  So, for example, at two years 25% of the
patients who get Temodar will be alive, compared to 10% of those
who do not get Temodar.  At five years its even more striking;
10% of patients who get Temodar are still alive whereas only 2% or
less, who do not get Temodar, are surviving at five years. 
Temodar has had a very positive significant impact on the natural
history of glioblastoma, and frankly, has been the biggest
breakthrough in the treatment of this deadly disease over the last
several decades.Chu
 I am just curious, say for instance, in patients who might not be
able to undergo surgery, but who receive radiosurgery, the Gamma
Knife, CyberKnife procedure, is there any role for follow-up,
either chemotherapy or whole brain radiation therapy after that
radiosurgery has been done?Lacy
It depends a little on the specifics and the type of brain tumor
that we are dealing with.  Radiosurgery is most commonly used
to treat brain metastasis and benign tumors.  We use
conventional regional radiation to treat malignant tumors. 
Invariably there will be follow-up after radiosurgery, and serial
MRI scans to assess the response to ensure that there is not a
recurrence.Foss
You talked about 25% of patients doing well a couple of years
later.  I am wondering, do most of those other patients
relapse with their brain tumors, and if they do, what kinds of
therapies do you use at that point?25:19 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Apr-26-09.mp3Lacy             
 Malignant glioma is the most common brain tumor.  In most
cases it will at some point recur and when they recur, up to this
point, we have not had highly effective therapies and rarely are
recurrent gliomas ever cured.  It's a very challenging area
for us and certainly there is a real compelling need for new and
better therapies to either prevent recurrence or to effectively
treat recurrence when it happens.  What has been exciting is
that there have been some advances in the field that are related to
the use of so called "targeted therapies" to treat brain tumors, so
these are drugs that are developed specifically to target cancers,
and in the treatment of brain tumors, many of these drugs look
quite promising.  One example is Avastin or bevacizumab. 
This is a targeted therapy that works by preventing blood vessel
formation and it affects the blood supply to tumors.  You may
have heard about this drug in the media, it's got a lot of
attention because it's quite costly.  It's already approved by
the FDA for use in breast cancer, lung cancer, and colon cancer,
where it's used in combination with chemotherapy.  In treating
malignant brain tumors, Avastin, as it turns out, is very active,
even in the absence of combining it with chemotherapy.  It can
dramatically reduce the swelling around the tumor, the mass effects
of the tumors, the symptoms from the tumor, and in some cases
shrink the tumor.  Avastin, as it turns out, right now is
probably the most effective treatment that we have for recurrent
malignant gliomas.  It's not yet FDA approved, but hopefully
that will be coming soon.Chu
 Do you use that, as you say, as a single agent where it has
activity, or do you typically combine it with standard
chemotherapy?Lacy
It can be used either way.  It does have activity alone in
brain tumors, which is in contrast to its use in say colon cancer,
breast cancer, and lung cancer.Foss
Are there other options for patients with brain tumors? Are there
other new drugs that are being developed?Lacy
Yes definitely.  There are a number of very exciting and
promising drugs in development, in clinical trials.  Many of
these are the so called targeted therapies as I just alluded to. In
addition to Avastin there are small molecule inhibitors of
angiogenesis, these are often taken as pills and are being
developed and are showing considerable promise in the treatment of
brain tumors.Chu
 Is there any research going on at Yale Cancer Center with respect
to developing new approaches to treat this disease?Lacy
Yes definitely, we have a very active clinical research program at
Yale, largely focused on the treatment of glioblastoma, the most
malignant form of glioma.  So for example, we have28:19 into mp3 file 
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 a very interesting vaccine trial.  In this trial, patients
with glioblastoma will get standard of care radiation, Temodar, and
in addition will get monthly injections of a vaccine.  The
idea here is to boost an immune response to the tumor and use the
immune system to hopefully prevent the tumor from coming back. The
preliminary data with this vaccine is really quite exciting.Chu
 It's amazing how time flies.  Jill, we would love to have you
back and hear more about this vaccine trial.  You have been
listening to Yale Cancer Center Answers.  I would like to
thank our guest Dr. Jill Lacy for joining us this evening. 
Until next time, I am Ed Chu from Yale Cancer Center wishing you a
safe and healthy week.If you have questions or would like to share your comments,
go to yalecancercenter.org where you can also subscribe to our
podcast and find written transcripts of past program.  I am
Bruce Barber and you are listening to the WNPR Health Forum from
Connecticut Public Radio.