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PLEXIFORM NEUROFIBROMAS
Roger Packer, M.D.
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I would like to give an update on both the studies optic glioma and plexiform neurofibromas
with some new information that we are a little bit excited about. I also want to suggest a
certain direction which we are pursuing for plexiform neurofibromas.
- Optic Glioma:
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I am primarily a pediatric neurologist who works at the Children's National Medical Center
in Washington D.C. For the children we see with NF-1, approximately 20% will have or will
develop optic nerve gliomas.
One of the major challenges that we as physicians and you as families have been battling
with over the past few years are in a child with neurofibromatosis (NF) who are at risk for
an optic nerve glioma is how to predict which child will develop the tumor and which child
will require treatment. This whole issue is going through a lot of transition and a lot of
thinking, some of which is pushed by science, some pushed by insurance companies who do not
want to pay for surveillance scanning and other things.
At least five years ago I would have told you that most medical centers that have
Neurofibromatosis Clinics, just as the one in Washington D.C., where I am and the one I
left in Philadelphia, routinely did surveillance testing when they saw a child initially
diagnosed with Neurofibromatosis Type I (NF- 1) whether or not the child had a family
history of NF- 1. Because the child was young and very difficult to evaluate, we would
do an MRI scan. We would know then whether a child did or did not have enlarged optic
tumor or had a tumor deeper into an area of the brain, called the chiasm.
This was despite the 1987 NIH Consensus Conference panel that did not recommend
surveillance testing unless there were clinical symptoms. It was our feeling, and the
feeling of a lot of different doctors, that it was very difficult to clinically diagnose
optic nerve or chiasmatic involvement in a very young child. For that reason we do the testing.
There have been some very interesting studies done recently questioning whether that
testing is appropriate.
We have always thought that if a child had a tumor or did develop a tumor later in life, if we
had looked early, we would find the tumor. There is some information to suggest that children
may not be born with these tumors but may truly develop these tumors years later. One study
suggested that children who had negative scans initially did develop tumors over time.
Now the good news about having an optic nerve tumor or tumor chiasm in children with NF is
that the majority of those tumors will not grow and will not require treatment. I think we have
known that for the past five to ten years. I think these studies are just catching up with
clinical judgment. We have known since the late '70s and early ‘80s that maybe up to 4/5 of all
patients who have optic nerve gliomas or at least enlargements of the optic nerve that look as
if gliomas will not require treatment.
But that still means that 20% who will have optic gliomas, will develop either increasing
cosmetic problems of the optic nerve enlarging (the eye becoming more extruded, called
"proptosis") or actually losing vision. One of the challenges has always been to predict which
child would get into trouble.
We still do not have good clinical ways to know which child will get into trouble if they
have a known tumor. We are still basing all of our therapies on determining if there is
any progressive visual loss, progressive neurologic problems, or progressive tumor growth.
We are now working with a genetic testing laboratory that is marketing the test for
the NF-1.
Essentially, 13 different truncated mutations have been found on this NF-l gene, and these
are the abnormalities genetic testing tries to evaluate in patients with NF-1. Because the gene
is so long, there can be mutations all along this gene. One of the things that has come out
recently is that, for the rare occurrence of myelogenous leukemia in children with NF-I, a
certain pattern along this genetic mutation predisposes them to this condition. If they have
a certain mutation, they are more likely to develop acute myelogenous leukemia.
We have been able recently to convince the company who does the testing to allow us to
test up to 35 children who have known NF-1 and known optic nerve gliomas to determine if they
have a specific pattern of these 13 mutations so that we would not have to do tests like MRIs
to screen these children.
We could do a blood test to screen these children. If the child's mutation pattern is
different from others with NF-1 who don't have tumors, the laboratory can compare many
other NF-1 patients who do not have optic nerve gliomas. A blood sample of about 5 to 10 CCS
of blood is required. Currently we have 10 samples. We are looking for another 30 to 25
patients over the next six months from our population of children that we follow.
The other thing the study might tell us is that if there is a certain pattern within that
genetic grouping of children, we can know which children will get a progressive problem
and which will not.
We were going to look very quickly at this focus population. So I hope that about six
months to a year from now we will be able to update you on that result. We will have either
a positive result that will lead us to a larger study or nationwide study, or insignificant
results. We will also receive responses from those who think that maybe we should not
pilot this kind of genetic information -- that is the predisposition of the developments
in the optic nerve gliomas.
The second issue I would like to just share with you a little bit of information on the
clinical protocol that I have been running for about six or seven years ... for children who
do have optic nerve and chiasmatic glioma. We have been using a two-drug regimen called
carboplatinum and vincristine for any newly diagnosed low-grade glioma in a child less than
five years old. This study required that the tumor be biopsied to be sure it was a low-grade
glioma of the optic nerve or the optic chiasm. The chiasm is the region behind the eye, the
optic nerve. Because in the vast majority of children with NF-1 who have an optic glioma, it will
be a low-grade glioma. Children with NF-1 were the only children who could be entered on
the study without diagnosis excised tissue.
The treatment was a fairly aggressive 10 weeks of continuous treatment with one drug
called vincristine which was given weekly. The other drug called carboplatinum was given
one day a week for four weeks in a row. Then there was a two week break period and then
the drugs were repeated. For those children who had some response to this treatment, we would
go on with more of this drug combination for up to approximately one year. This chemotherapy
is considered minor chemotherapy and is not terribly toxic. There may be some lowering of blood
counts and some hair loss. But overall it is rarely a life-threatening type of therapy, as long
as we monitor the children appropriately.
And I will tell you at the end this will soon be part of a nationwide study. We, in
Washington and with the eight other institutions around the country as collaborators, were
looking at children who had progressive gliomas. Of the 79 children, we have now treated,
15 of them had NF. And we followed many more children who have potential optic nerve gliomas
with NF than those without. But most of them do not require treatment.
Now why did we want to do this kind of treatment? Because the knee-jerk type of treatment
for chiasmatic glioma until now has been to give radiation. Irradiating the brain in a very
young child's brain, was not very appealing to most people. It provoked worry about the
long-term effects that radiation might have on cognition, the possibility that radiation
would cause secondary tumors in children with NF and the long-term effects on the blood
vessels if radiation is given to the brain. It can cause strokes and other difficulties.
That was the rationale of why we wanted to do that study.
The children with NF tended to present primarily with decreased vision plus proptosis
which is a bulging eye. Optic gliomas were picked up on screening tests that showed decreased
vision. For children treated, this is the "actuarial progression free-survival curve." At three
to four years, the percentage of children who are doing well on the study is 70%. This means
that the tumor is under control or it shrunk. Seventy percent of all children who entered
this study at three to four years remained on the study. They never had to go to radiation or
surgery or anything else. Tumors were controlled without needing any other type of therapy.
That would include the one year of treatment plus two years of follow-up. That is very
reassuring to us. So the children with NF, by and large, do well with this.
Even though we treated primarily children who had chismatic tumor, children with NF-1
whom had brain tumors did just as well as those who did not have NF and chiasmatic tumors. So
I think this is applicable to other sites that they have to treat.
One of the interesting factors for kids, for your own children with NF we would need to
keep in mind is the purpose or objective of these kinds of studies. There are now other
studies around the country that I have some discomfort with which are using more aggressive
chemotherapy's. The investigators say that they can shrink the tumor better, and thus the
outcome will be better. Now a lot of the new protocols are trying to use drugs that are
more potentially toxic but trying to get better shrinkage rates.
In our four year study, 70% of children are doing well on therapy. We were able to show
shrinkage in approximately 60% of children. Only three children in this series had early
progression (during therapy) which includes the optic pathway had tumors that grew during
therapy. The majority have either tumors that shrunk to some degree or were stable.
Now one other. observation is that children who were younger did just as well as older
children in this study. There have been some studies that suggest that younger children
do not do well in chemotherapy or with surgery and need to go to radiation early. That was
not our finding. If the children were young, one or two years of age when they needed
treatment, they did just as well as a child who was five. I think this is very important
when we are using a therapy to try to avoid other kinds of complications.
One child who had a fairly large tumor that was biopsied because it looked like a
different kind of tumor. No tumor was left after chemotherapy. This is exciting because
this child has not needed radiation and is doing well three years later. The majority of
children in our study had done this well.
You have to keep in mind with these very small slow-growing tumors is that we have now
been able to show that shrinkage means better long-term control. Those children who have had
50% reductions or greater have not done any better in the long-term than those children who
have just had stable disease. We think that as long as we can get some control, it does not
really matter that we can make the tumor go away. We do not have any evidence that we have
to make it go away. We just want to stop it from growing, which is another very important
issue when we talk about plexiform neurofibroma.
One thing that we are interested in is that we see the older children (greater than seven)
are not doing as well. Maybe we are getting to them a little bit later. The majority, 70%,
are still doing well. Soon our study is going to be a nationwide study that will look at
this drug regimen, an intravenous regimen, that is given once a week in the office. It does
not require hospitalization. It will compare results to a different regimen used at the
University of California at San Francisco.
We will try to determine which regimen is the best. Even that other regimen is considered
to be sort of mild or weak chemotherapy that should keep children out of the hospital. Our
take home message for this study, so far, is not that this is the best drug regimen, but
that with relatively well-tolerated chemotherapy we can get away with delaying the need for
radiation, and delaying the need for extremely aggressive surgery in children with large
neurofibromas and large tumors that are growing. We will try to determine if there are better
regimens over time. My concern is always not to make things too aggressive so we will hurt
more children than we could help.
As we enter this important era of treating charismatic gliomas, some of these drugs have
what we cab "mutagenic potential," meaning they have the tendency to potentially turn on
cancers. Now none of the drugs that we have used in out combination are mutagens or drugs
that cause cancer at the doses we are using.
As we are getting to (inaudible) regimens more aggressive, we will be potentially using
these drugs, we may cause a low-grade to mutate into a higher-grade tumor, which may not help
the child but may hurt the child. So for this nationwide study, although we are randomizing
between two arms, since the San Francisco study has a potential mutagen in their combination
drug, we will not use that on children with NF.
The children in our study will continue to receive the carboplatinum/vincristine regimen
because we are afraid of the long-term effects, not only on the intracranial tumor, but also on
their blood and everything else. We know that they are predisposed to developing cancer.
- Plexiform Neurofibroma:
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We know that plexiform neurofibroma is a big and extremely important issue. You would
think that given all the experience we now have with children with optic nerve gliomas that we
would have been able to watch what happened to their plexiform neurofibromas while we were
treating their optic nerve gliomas.
An interesting phenomenon that I do not think I can really understand is that the
majority of children with the optic nerve glioma that required treatment and did not
have growing plexiform neurofibromas. It may be they just expressed their disease differently.
You get either optic glioma or plexiform neurofibromas. Over time, you may develop something
else. So we do not have that information.
There has been reluctance to treat these very slow-growing tumors with any kind of tumor
therapy especially even this kind of therapy. By and large, we have looked at different tissue
cultures for these kinds of plexiform neurofibromas. I think many of you might have a plexiform
neurofibroma or know a patient who has one. You know that the small ones are nuisance, but the
big ones can be disfiguring, can be very damaging. They can be paralyzing. They can be life-
threatening. It depends where they are. Sometimes surgery is not an option for how extensive
they are and how vascular they are. Radiation really has not worked well with them. Other drug
trials, like Dr. Riccardi's drug trial with antihistamines, although it relieved some of the
itching, did not shrink the tumors.
Approximately three years ago with co-workers, Dr. Phillips and his cohorts at Children's
Hospital of Philadelphia began a study to start looking at two drugs, Alpha interferon (ph.) and
Cis-retonac (ph.) acid. One, The Alpha-interferon, having a lot of variety of different
properties, is thought to be possibly an anti-angiogenesis (or an anti-blood vessel growth
factor). The retinoic acid being something called more of a maturation agent making the tumor
stop growing and maturing it to where they would not grow. The mature nervous system does not
grow.
The study was halted a few months ago, or slowed down, because we were a little bit more
willing to put patients who had large tumors that the families told us were growing on the study.
We have had quite a few patients on these studies whose tumors have not grown while they have
been on the study. We had not documented the tumor growth in all patients. The Army, which
has continued to fund this study, has suggested that we have to show either by X-ray or by
absolute measurements that things are getting bigger before we can enter another patient on the
study.
These tumors or these growths are so funny in so many different shapes that it is hard to
do it with just measurements. We are usually dependent on MRIs or CT scans to do the measurements.
This study is still open and will continue to be open for a little while longer. The
two things that we do not know. (1) the final results from the study, (2) how many patients had
shrinkage. We know that some patients clearly had some degree of control in that their itching
stopped and the tumor stopped growing.
In the next six months, we are going to be looking at two probable approaches. One is to
potentially mix the Alpha interferon, which is a subcutaneous, like the Insulin shot type of
treatment, with the cis-reto-nic acid to see if we get more control. The other that we will be
participating in as soon as it gets through the FDA is a study using Thalidomide. In the '60s and
the '70s, Thalidomide was used in pregnant women because it is an excellent anti-nauseating
agent. It is an excellent agent that calms people and an excellent anti-anxiety agent. However, it
was found too late that in pregnant women this cause abnormalities in the fetus of children,
especially limb abnormalities -- missing fingers, missing arms, and missing legs. Thalidomide still
is actually a very safe drug unless you are pregnant. It has been used for many years around the
world for leprosy because it seems to control the itching and some of the growth. It is still used
as a sedative by some people around the world and as an anti-anxiety agent. One of the reasons
thalidomide seems to work on leprosy is that, at least in the experiments, it causes tumors to stop
growing new blood vessels. It is an anti-angiogenesis factor. Similar, I think Dr. Martuza
talked to you about a whole host of new anti-blood vessel drugs. Thalidomide seems to be a very
good one. There are a lot of reasons to believe that this may be a reasonable approach for
children with (inaudibility) and ultimately for adults with NF. If you do not have blood vessels
that are growing, your tumor cannot grow. That study will be ran through Washington and in
collaboration with Cleveland Clinic and probably two other centers around the country. As soon
as we get the final okay from the government, we will make a decision as to which institution we
will offer the Thalidomide or the cis-retonic acid and the Alpha interferon studies. I think that we
might also have to do a little bit of funding, although the drug company has agreed to fund the
study at this point.
One potential treatment that I do think will be coming soon is a new generation of what are
called "maturation agents". I just ran a international program with about 430 people from around
the world talking about new means of treatment for childhood brain tumors. There is a
tremendous amount of interest for these new drugs. They do not kill the tumor and are not really
anti-cancer drugs. They make the tumors get so mature that the cells cannot divide any more.
Potentially this is a very useful approach for Neurofibromatosis where you are very worried about
using mutagenic drugs. Using something that can mature the cell so it becomes so mature that it
does not divide any more might be one of the successful treatments for this disease. One of these
drugs called phenyl acetate. Presently I am working on the study at the National Cancer Institute,
Building l0, which I think has potential applications for the plexiform neurofibromas. We are still
working on the best dosage. I would expect in the next year or two some kind of human trial will
be set up (already set up with Dr. Adamson).
I do not have the Information which I would like to tell you that we have the cure for
plexiform neurofibromas or that we have drugs to shrink them. But we do have some data that
some of these drugs have at least temporary benefit. They do not seem to have hurt the
patients at all. I think we are going to get much improved drugs as time goes on and we get into this
program.
- Questions:
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Q: I saw the protocol and the informed consent from the original study that you all had
and I was somewhat concerned about the informed consent for the families. It
seemed very confusing because the one document solicited consent for two
completely separate studies. I am also concerned about the informed consent in
light of the genetic aspect to this optic glioma study. Is there a separate informed
consent document for genetic aspect of the study?
A: We have now separated the consent forms for plexiform neurofibromas and optic nerve
gliomas. Families who would now be entered on that study would get one or the other
form depending on what condition we are treating. For the genetic testing, it has been
decided, because all we are doing is asking for blood, that this could be very short one-
page consent forms.
The form lays out to the families that we are just asking for is a 10 CCs, two
tablespoons of blood for this testing and there should be no harm. Then we would inform
them of the results and analysis of the study following the close of the study which could
be months to years afterward.
We have simplified the consent form. We have been criticized for other consent forms
as well as the NF one, which are difficult to read. Part of the problem is that when you
use these new drugs, the FDA mandates to the drug company before they give it to us, we
list every side effect possible and probably list them twice. That means we are writing 10-
pages consent forms! When I started working in this field 10, 12, years ago, I never saw a
consent form that was more than two pages. We live in a medical/legal era especially
when we use drugs that have never been tested in children. We have to cover everything.
It is unfortunate because nobody reads them any more. They either trust you and they
sign it. Or they do not trust you and they do not sign it.
Q: Is the blood that you are going to be taking only from children who you are going to
be actually following? The reason I am asking is that my 21 year old daughter had
an optic glioma removed when she was two.
A: Ultimately, the answer is "no". It becomes an issue on the study because we will have to
include a lot of different patients. What I did not feel comfortable with, because it was
very exploratory, was to start calling families and then say come on in and give us blood.
What we have said, since we do see most of these children within a year -- most of them
within six months, will receive all of these when they come in. And we have to draw
blood to monitor blood levels for other things when we draw their blood at that time.
And we have not really advertised this project nationally. But if anybody in this room
has a patient, it does not have to be a child, who has confirmed neurofibromatosis Type 1
and has had an optic nerve or chiasmatic glioma, we would be more than happy to enter
them on the study. The sooner we hit our 30 patients the sooner the company will analyze
the information and tell us if we should be going to a nationwide study. So it is not
exclusionary, except I did not want to inconvenience people. So we did not advertise.
Q: I had a stromal tumor removed from the small intestine in November, 1995. The
interesting thing was it took about three to four weeks for me to get results back as
to whether or not it was malignant or whether or not it was NF. And the it was sort
of uncertain. That is where it still stands. (May, 1996) I have not been told
specifically whether it is malignant or not malignant -- except that it is probably not
NF.
A: You raised two important points. One, that patients with Neurofibromatosis are at higher
risk for having a lot of different kinds of tumors, tumors that arise in people without NF.
So many of the tumors, like an optic nerve glioma or chiasmatic glioma, look the same
under the microscope whether the patient has NF or not.
So you cannot look under the microscope and say, "this is NF or it is not NF." As far
as malignant and benign, those are tough concepts in that things on TV fall into two
categories: malignant and benign. In the real world, there is a whole spectrum in
gradation. We ... do our best estimates looking under the microscope. But you know
that some things that look benign may act aggressively and some things that look
aggressive may not grow very quickly. There is a whole host of genetic markers that
people are using to try to determine those things. But for some tumors, especially those
that look "strandy," it can be difficult because there can be variations. So I do not have an
answer for you except that I do not think that the people are incapable of diagnosing
things but it may be one of these things that is very difficult to put a sign on.
Q: Just so that I have the definition correct and somebody else too, what is stromal?
A: Stromal is the underlying, underpinnings of a structure. I mean, you know, it is sort of the
thing that runs through that keeps everything together. I think that is what they are saying
when they are saying stromal.
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