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Today I’m going to be talking, very briefly, about ultrasound,
MRI guided focused ultrasound, as well as some other things in the future,
that would point the way to new therapies for fibroids. And I think one
of the important things that focused ultrasound provides for us, is that
it is a fibroid specific therapy and we’ll talk about that in a
minute.
As gynecologists we are well aware that fibroids come in many different
sizes and shapes and in fact, we often forget to stop to think about
them. And on the uterus on the left you can see two different subserosal
fibroids coming, one anteriorly, one posteriorly, and on the right we
have what appears to be a relatively small uterus with a very large stalk
and a very large pedunculated fibroid, and I think we don’t understand
the biologic basis of the diversity. What makes one fibroid appear to
be like it does on the right, and makes each of these appear differently.
And also there’s clinical differences in terms of which women have bleeding,
which women have significant size of a fibroid without bleeding symptoms, and
as we go to less and less invasive therapies in the future, that these differences
will be important.
There are problems using thermally ablative therapy and unless you have
a way to gauge the temperature of your target tissue you can err in two
different ways. If you don’t heat or freeze enough, you may not
kill the cells, and your efficacy may be limited. If instead you go in
the other direction and raise or lower the temperature too far you can
destroy normal tissue and therefore have your safety compromised. And
so, without some kind of monitoring, thermal ablative therapies can either
have limited efficacy or compromised safety.
This is a diagram of myolysis where bipolar needles are used to destroy
a subserosal fibroid. This technique was used but really hasn’t
caught on, in part because of concerns about damage to normal tissue
that after this procedure there were reports of adhesions. And, again,
without a way to gauge therapy it’s hard to know when you have
successfully completed your intervention.
There have been efforts with previous thermally ablative therapies to
gauge temperature using MRI monitoring and this is a slide from Dr. Gedroyc
at St. Mary’s in London where he’s using fibroid laser ablation.
What you can see in the picture on the left are laser fibers that are
placed percutaneously into a fibroid accessible by the anterior abdominal
wall. And as the laser fibers then transmit energy and heat the fibroid
you can gauge the therapy. So this technique did have the advantage of
having some thermal feedback, but it still required probe placement and
really restricted the kinds of fibroids that you could treat with this
method to ones where they were accessible from the interior abdominal
wall.
With focused ultrasound we have the potential of having a non-invasive
therapy. I think gynecologists are very familiar with diagnostic ultrasound
where you have a flat transducer. The waves go out, hit the target and
bounce back, so that you can either see the picture of the uterine myoma,
or the fetal head, and be able to use it for diagnostic purposes. There
actually is quite a history of using therapeutic ultrasound, where multiple
waves of ultrasound converge in a particular volume or spot and at this
point in time you have a large amount of energy so that you can destroy
tissue. This dates back, actually, to the 1930’s or 40’s,
but the control was always the issue. There were many animal experiments
where focused ultrasound energy was used to destroy tissue, but to be
able to target and correctly control it, limited its clinical applicability.
There are two acronyms that are often used for this technology: one is
FUS or focused ultrasound surgery, and the second is HIFU high intensity
focused ultrasound. For all practical clinical purposes they are the
same.
The way to carry out this therapy is very much like you would with myolysis
or a laser ablation. You start by ablating a small target tissue and
then you are able to sum up many sonications to cover your treatment
area.
There was also some in-vitro evidence that focused ultrasound would
be useful for the clinical treatment of uterine leiomyomas. This comes
from the group at the University of Seattle that used a model where they
used the echo rat cells and a nude mouse and what they were able to
do was either to do a high intensity focused ultrasound treatment or
a sham treatment in an opposite group of animals and to show that they
were very successful at treating this model system leaving the possibility
of clinical treatment of these neoplasms in women.
Although for gynecologists, they’re more comfortable, in general,
using ultrasound for monitoring because of ease of use. But I think that
for the technology, as it exists today MRI gives you something that you
can’t see with ultrasound monitoring. That we know about the T1
and T2 modes of MR imaging and for focused ultrasound, I call it the
four T’s. The advantages are that MRI gives us much more exquisite
targeting, it lets us see both the target fibroid, and the tissues you
don’t want to target, such as sacral nerves or bowl or bladder,
much better than we can see on ultrasound. As we talked about before,
it gives us temperature feedback and this is available to us in real
time so that between sonications energy parameters can be changed to
optimize this, and it also allows a test sonication. You can send out
a low energy pulse and be certain that all of your parameters are aligned
as you think they are, but the temperature doesn’t rise above the
area where tissue destruction occurs. So you can see the beam, but it
doesn’t destroy tissue. Finally by using gadolinium, which is the
standard contrast medium for MR imaging, you can have therapeutic verification
at the end of the treatment. Gadolinium is given as a vascular injection
so you can see the area of the tumor where the blood supply is cut off.
And I’ll show some illustrations of each of these from here.
So, for those of you not used to looking at MR images: this bigger image
is a sagittal image. You can see the sacrum in the back and all of the
anatomic landmarks are clearly seen. You can see the pubic bone, you
can see the bladder that has a bit of urine in it, and you can see the
outline of the uterus and the myoma. And also, like I said, you can see
sacral nerves coming behind, and in many other images, you can see bowel
easily.
And so, this is an image of therapeutic verifications with gadolinium.
On the left you can see a uterus that has a single dominant fibroid in
it, this is before the gadolinium is administered but after treatment,
and on the right you can see that the white area is where the gadolinium
has gone into the vessels and shows vascular perfusion and this very
large area encompassing almost all of the treated fibroid shows that
the sonications were able to coagulate this area and destroy the blood
supply.
When we first set out to do our clinical trial, I was anticipating clinical
outcomes very similar to that seen in uterine artery embolization, and
so in fact I had planned to admit every patient to make sure that they
went home with narcotics and we found out that you got a very different
clinical treatment than you do with uterine artery embolization.
This was our first group of patients where they were treated ether prior
to hysterectomy or the sub group that was treated in Israel, were treated
and allowed to proceed without hysterectomy. We checked their pain level
on a three-point scale with three being severe and zero being none before
their procedure, in the middle of the procedure and when they were in
the recovery room.
And we found that at most pain went up slightly above a mild level of
pain and that at the time they were in recovery room their pain was not
statistically different than prior to treatment Although their discomfort
was modestly elevated this was statistically significant.
Patients are treated with intravenous conscious sedation for several
reasons. First of all, it helps them maintain the position they need
to be in, women are positioned prone so that their abdomen is over the
transducer, which is in the table of the Focused Ultrasound apparatus.
The other thing is that we want women to be able to give us feedback
and we’ll talk a little bit later about why this could be very
important. If she is at all uncomfortable we would like her to be able
to tell us.
With this initial group of patients we were also trying to make sure we did
not miss complications so we saw everyone within 72 hours. Interestingly, we
found only 10% of women were taking any pain medication. And this involved
over the count of medication such as ibuprofen and acetaminophen and very few
of the women were taking narcotics at that time.
We were also able to document that we were indeed destroying the tissue.
This is one thing that we really don’t even know about uterine
artery embolization to date. Although most of the early treatments were
planned to be followed by hysterectomy there is a good pathologic data
to tell us is the fibroid itself destroyed? Is there necrosis
of normal endometrium. With this technique we were able to find that
the treated volume was nicely anatomically correlated with the area that
we treated. The non-perfused volume or the area where the gadolinium
did not go was actually significantly bigger than the treatment volume
and at least half of the women in this series underwent a hysterectomy
within thirty days of the procedure. And the non-perfused volume better
approximated the pathologic necrosis than the treatment volume. So it
does appear that we get some extension of treatment in uterine fibroids.
And I think that this is helpful, first of all, in decreasing the time
of treatments so that not every square centimeter of the fibroid needs
to be treated to ensure the treatment effect. The other thing is that
it allows us to maintain a margin of safety at the periphery, which I
think is also beneficial.
This is a photograph from our paper in the American Journal of OBGYN.
This is the sonicated fibroid, this is actually a fibroid that underwent
degeneration prior to treatment and, this is another advantage of this
technique of MRI guided focused ultrasound, is that there is a pre-operative
MRI. This, first of all, lets us know that this fibroid is degenerated
before we start, so if we had targeted this one we couldn’t claim
complete ablation of it because, we knew that it was necrosed before
we started. The other potential benefit MR gives us is that it can allow
us to choose not to treat women that have suspicious lesions. There’s
always a concern with any alternative to hysterectomy that we could unintentionally
treat a sarcoma rather than a myoma. And while we can’t rule out
that possibility with this technique, I think the literature documents
that the next best thing to having pathology is having an MR image. And
that there are classic signs that make lesions suspicious for malignancy
and in fact, some of those women that we have screened for protocols
have been referred to surgery and indeed had a malignancy. So, although
this may happen with treated women in the future, we have not seen it
to date.
So this is the treated fibroid. You can actually see that the area that
was targeted was a wedge shaped treatment area. This protocol was not
aimed at complete treatment but was really looking for verification of
treatment. But what you see is that instead of just getting the gadolinium
to not be infused in this area we see a big extension, almost a tri-lobed
area where gadolinium appeared not to infuse into the fibroid. And this
is the gross histology of the targeted area and the histology is well
showing that when we believed by imaging we had destroyed the tissue
that that indeed was the case.
There were very few adverse events in the earliest study. There were
a few skin burns and there were some women with increased bleeding, again,
this was hard to know whether this was the treatment or the disease itself.
We had only one woman stay overnight in the hospital and that was for
nausea. And there was one area where the serosa was sonicated. And, that
in retrospect we were able to go back and examine the films. And the
reason for this non-targeted sonication is that as the treatment continued,
the bladder filled and moved the target and so in subsequent treatment
protocols we have used a Foley catheter to minimize this as an issue.
For our pivotal study we used the uterine-fibroid quality of life questionnaire
and this is something that many people in the field are not yet familiar
with. It's a scale that tries to measure the quality of life both bleeding
and bulk related symptoms and it has been validated in a number of populations.
What you see are normal women in pink and uterine fibroid women in blue-green.
There are two subscales of symptom severity scales, so that women with
fibroids have approximately double the number of symptoms, about a level
of forty, compared to about a level of twenty. And then there are subscales
for quality of life where the relationship is different but there's clear
differentiation between the two groups.
We found in our pivotal study that approximately a quarter of women
met the improvement in symptom severity score at six months that we had
designated for success, that we had gauged a ten point improvement, or
half of the distance between the typical fibroid patient and the typical
normal patient for this treatment.
We also found that women return to work much more quickly and had decreased
disability. There was a control-arm to this study which has not yet been
reported in the literature, and we found that women missed, in the thirty
days following focused ultrasound, only approximately one and a half
days, compared to almost twenty for women undergoing hysterectomy. You
see the same general pattern in days from normal activities to days in
bed. And we also looked at medical resources and they were decreased
compared to the use of resources compared in hysterectomy.
Again, in this series of women we had an excellent safety profile. There
were no deaths, no emergent procedures, life threatening events. And
in fact the most serious event we saw was a woman with a sacral neuropathy.
Again, this is what changed our treatment planning, regarding sedation
and patient feedback, this is a woman who was very motivated to undergo
treatment, and had significant sciatic pain throughout the procedure,
which she did not let the treating physician know about. In retrospect,
we could see by looking at the images, that the sacral nerve was not
heated. However, the sacral bone was, and because bone is such a good
transmitter of energy there was some transient nerve damage. Since that
time, over 500 women have been treated with the modified protocol, and
a similar event has not been seen.
We found with our pivotal study that a sizable number of women went
on to have additional treatment in the first year of treatment, almost
twenty percent. I think that this is not surprising given the selection
criteria, where the main uterine volume of the treated women was approximately
a thousand cc’s, and the average treatment was under two hundred
cc’s. I think that this suggests we have to further refine our
assessment of treatment and optimization of treatment candidates. We
did find out however, that the subgroup of women that continued on to
twelve months, and did not undergo additional treatment seem to have
stabilization of their disease. Again, starting from a symptom severity
score of about sixty and going down to the mid-thirties. Again, comparing
this to approximately twenty in normal women.
This is a composite group of patients who were treated under a variety
of different protocols. What we're finding is that over all of the protocols,
again, women start with an average symptom severity level of about sixty
on a hundred-point scale. Initial improvement appears to occur fairly
promptly in the first three months, and then for women who have adequate
treatments, there appears to be stabilization. We've got women, currently,
who have been followed out barely beyond two years to give us information
about this.
I think as I say from the title, I think our goal is understanding predictors
of long-term efficacy. I think that when we continue to treat people
and have high enough numbers, we'll find that both imaging characteristics
and patient characteristics will be helpful in optimizing treatment.
There's also some data from my colleagues both at Saint Mary's and at
Sheba who have used GNRH agonists and the advantage of this modality
of treatment before focused ultrasound is that they have been able to
more efficaciously treat women with large uterine volumes. You see a
similar pattern with a score beginning about sixty going down to, approximately,
20 at the time of treatment. Then you actually see the GRNH agonist wearing
off, and then some consolidation of treatment and the two different lines
probably reflect the learning curve and the red lines are the first fifteen
patients and then the subsequent number. This may be an important part
of our therapeutic options for focused ultrasound in the future.
So, I think that focused ultrasound is an important technique for the
future, and will allow us to specifically target certain fibroids and
this has been one of the early challenges with this technique is knowing
which fibroid to treat. If you had a woman with this uterus and her primary
complaint was bleeding, some people would go in and say, "Well,
there's two hysteroscopically resectable small submucosal fibroids. Let's
go ahead and see if we can remove these and decrease her bleeding".
But I think we don’t know enough about the relationship between
imaging characteristics and genotype and phenotype to really say that
may be ablating this fibroid, behind the cavity, maybe more important
than removing these two or alternatively, this anterior one maybe important.
I think that we need further understanding of the genetics and the biology,
to really be able to help us move forward in the future.
I think, again, as we go to fibroid specific therapies, understanding
which fibroids are most important biologically and genetically is vital.
This is another spot where we have a lot of interest, although genome-wide
scans have been done for many complexes diseases including asthma and
hypertension, to date it has not been employed for uterine fibroids.
There is a big genome wide screen, as you probably know about, going
on for endometriosis as well and the goal for these kinds of studies
is to use sibling pair analysis. In the case fibroids - a pair of sisters,
both of whom have fibroids, and this allows you to look throughout all
of the chromosomes to look for shared regions of DNA. And this is likely
to turn out to have new genes that may be important for the future, and
it's also likely to show different results in different populations.
One of the goals of our finding genes for fibroid study is to get a
wide geographic and racial diversity of patients in our study. Because
of the Internet and FedEx we've been able to do so. We would love to
have groups in Israel participate with us, because we believe that the
genes that cause Israeli women to develop fibroids may be very different
than the genes that are predominant in Boston or Alabama or South America.
This technique also represents a good deal of collaboration both at
my home institution, between the departments of gynecology, radiology,
physics and pathology.
Plus, this has been a world wide collaborative effort. The major groups
that were involved in the pivotal trial, includes Saint Mary's in London,
Sheba Medical Center, Charite and Hadassah and if these lists are incomplete,
I apologize, there are many, many people involved in these efforts.
And then, with newer sites in the US: the Mayo clinic and John Hopkins’s
have been vital. I thank you for your attention and your invitation.
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