[MUSIC] The topic of the talk that I will be giving
is on the management of oligometastatic prostate cancer,
and I'll be discussing
everything from imaging to therapy.
I will say before I begin that as a radiation oncologist,
I've been at UCSF for many years now.
When I first came to UCSF,
we actually didn't see
oligometastatic prostate cancer as an entity.
I saw localized prostate cancer and
I saw widely metastatic prostate cancer.
Over the course of the last few years,
from the advent of PET imaging as Dr. Lopez described,
I would say now about a third of
my patients have oligometastatic disease and so
this entity is very much increasing in prevalence.
Here are my disclosures.
None are actually directly relevant today.
But I want to begin with a question and
that is what is oligometastatic disease?
It's actually defined as the
intermediate state of cancer spread
between localized disease and widespread metastasis.
There's no actual magic number
to the number of metastasis.
You need to have to qualify as oligometastatic disease.
The word oligo means limited,
and typically we say it's about
1-5 metastasis that constitutes oligometastatic disease.
Why do we put
so much weight on the definition
of oligometastatic disease?
The answer is because we fundamentally believe that there
are patients with oligometastatic
disease that are curable.
What that means is that they get
some comprehensive form of treatment and then 5,
10 years later they don't have any evidence of disease.
That probably ends up being just a minority of
cases but it is possible to cure some of these patients,
probably a small percentage.
That's why we focus on this disease space.
Just following up on Dr. Hopes's talk.
Why has the oligometastatic space increased?
The answer is because of the advent of PET imaging.
I show you plots on the usage of PSMA PET.
When PET scans became available
first at Melbourne in Australia,
at the Peter McCollum cancer center,
and then secondly at UCSF.
What you can see is that starting about 5-7 years ago,
centers that had access to this technology like ours,
started seeing an uptake
in the utilization substantially.
Now because of work led by Tom Pope and
Peter Carol and collaborators at UCLA,
PSMA PET is now FDA-approved for use in prostate cancer,
and Axumin PET or fluciclovine,
which Dr. Hope mentioned
previously is also an FDA-approved as well.
PET imaging actually has
created the space of oligometastatic prostate cancer.
As Dr. Hope mentioned,
PSMA PET identifies oligometastatic disease
that little PSA recurrences.
This is our UCSF experience
where we took our first 125 patients,
where PSA recurrences after prostatectomy.
I think the point to bring up is that 38 percent of
these patients had a spot of
prostate cancer found outside the pelvis.
We don't usually radiate outside of the pelvis,
and therefore, not surprisingly,
30 percent of these patients had to
spot outside of a standard radiation field,
so surely this is changing our practice.
From what Dr. Hope presented,
and what I just spotlighted,
I think the first conclusion we can
make is that the increasing use of
advanced PET imaging has led to
an increased detection of oligometastatic disease.
This brings us to our next question, which is,
what is the best treatment approach
for oligometastatic disease?
I want to actually slow down a little bit and go back to
the biology of metastatic prostate cancer.
This was a study done a number of years
ago where researchers were able
to access autopsy samples from
prostate cancer patients who had very generously donated
their samples and these researchers
have basically been able to get a sample of
every piece of cancer in a patient's body
and had been able to do
deep genomic sequencing to study those cancers.
The reason why deep genomic sequencing
is useful as a tool
is that it picks up all the mutations
in a particular cancer,
and what that allows you to do is,
it allows you to track which cancers
came from which other spots in the body.
You can make maps of spot 1 came from spot 2,
spot 2 came from spot 3, and so forth.
Based on this, what the authors
concluded is that both the primary tumor,
which was the original tumor in the prostate,
as well as areas of
metastatic disease in the areas
in the bone or lymph nodes or in the liver,
can seed or can spawn off new metastasis.
Actually, the principal mode of spread is
metastasis to metastasis,
and therefore to cure oligometastatic disease,
one might need to address
both the primary cancer and also the metastasis as well.
This leads us to a three-pronged approach for
managing oligometastatic prostate cancer.
The first is treatments directed at the prostate itself,
and that could be either surgery or radiation.
The second is metastasis-directed therapy
where we use radiation to
treat areas of metastasis or in the case of,
let's say, public lymph nodes,
those can be taken out surgically.
The third treatment approach is systemic therapy,
meaning in our case,
next-generation Andrew and signaling inhibitors.
I'm going to go through these each point by point
but in the context of prostate-directed therapy,
there was a trial called the Stampede Trial,
which I'll show you the results from,
which was a randomized phase III trial
of radiation versus
no radiation in men with
newly diagnosed metastatic prostate cancer
was over 2,000 patients,
40 percent of which had a "low metastatic burden" that
might be more congruent with the oligometastatic state.
This is data from the STAMPEDE study.
On the top, you can see
curves for what we call overall survival,
which is whether patients lived or they didn't live.
On these curves, basically,
the higher the curve or the
closer the curve is to the top of the graph,
the better patients did.
What you can see is that in men
with low metastatic burden,
patients who got radiation to
the prostate shown in blue did
better than patients who did not get
radiation to the prostate shown in red,
but that in patients with high metastatic burden,
there really appears to be
no significant advantage of radiating the prostate.
The same can be said for failure of free survival,
which is how long the patients did before,
let's say the PSA started rising and so forth.
This trial, which basically was a large randomized trial,
actually changed our practice because
now we routinely recommend
either radiation or surgery to the prostate
for patients with limited metastatic prostate cancer,
recognizing that there may be a survival benefit.
The next pillar of treatment I want to talk
about is metastasis-directed therapy.
In that space, I want to actually point to
two randomized trials: the
STOMP trial and the ORIOLE trial.
Both these studies were smaller studies
that randomized patients with
limited metastatic disease to
radiation to the metastasis
or no radiation to the metastasis.
I'm going to highlight one of them today,
just in the interest of time the ORIOLE trial.
Again, this was a study in a little bit over
50 patients that randomized about a third
of the patients to observation and two-thirds of
the patients to stereotactic ablative radiation therapy,
also known as SBRT or SABR saver,
to the sites of metastatic disease.
Again, on these curves,
the higher the curve is or the closer
the curve the line is to the top of the screen,
the better the patients did,
and so blue did better than red here.
Blue are the patients who
got radiation to their metastasis,
red is patients who did not.
I think this is really
important because this actually has led us to
now starting to offer radiation to
the metastasis for patients
with limited metastatic disease.
I want to point out that the majority of patients who get
the radiation may not necessarily be cured,
but at the same time that the premise
of radiation is perhaps we can either
delay initiation of hormone therapy
or for patients who are on hormone therapy,
extended duration of response to that agent.
Now what was interesting about
this trial was that patients were
defined as having oligometastatic disease
based on conventional imaging,
meaning CT scan or bone scan.
But they also ended up getting PSMA PET scans.
Now sometimes for patients,
their results from the PSMA PET scanner are
the same as for a CT scan and bone scan,
but sometimes they're different.
There were actually some patients where let's say on
the left here they were found to have two spots of
cancer based on a CT scan,
but then on PSMA PET,
they had three spots.
But on this particular trial,
they were treated based on the CT scan
and not on the PET scan and
this allowed us basically
to come up with two populations of patients.
One that basically had what we call total consolidation,
meaning all the spots seen on
PSMA PET were radiated versus those
that had subtotal consolidation where
the spots on CT scan were radiated,
but there happened to be an extra spot seen on PSMA PET.
What you can see based on the ORIOLE study
is that patients who
received SBRT had variable coverage
of PSMA-detected spots,
but basically, I think
the main take-home point is that patients who had
all their spots seen on PSMA PET
radiated do better than patients who
only had some of the spots radiated.
That's the difference between blue and red again,
blue is better than red in this case.
This suggests that not only should we be radiating
metastatic disease in patients with limited metastasis,
but if we do, we should try to treat
all the areas of disease that we can see.
Then the last point I want to bring up is
Systemic Consolidative Therapy which
is basically in this case,
I'm going to talk about using
more powerful hormone therapies
than standard first-line androgen deprivation therapy.
The data from that is from the management of what
I term to be high-risk prostate cancer,
which is non-metastatic prostate cancer patients,
but they're non-metastatic because
likely they didn't have PSMA PET.
Again, I'm going to point you to
the STAMPEDE trial and this
is a data that was presented a year ago by one
of my friends that got retired out of
the United Kingdom and this again was a large trial that
randomized patients with
high-risk non-metastatic prostate cancer
to either androgen deprivation therapy shown
in the black line or
androgen deprivation therapy with
the addition of androgen and signaling inhibitors,
abiraterone, and enzalutamide.
What you can see here is that
actually patients who received
the more powerful hormone blockade actually did better
than patients who received standard hormone therapy.
I want to point out that these patients, again,
were non-metastatic by conventional imaging
with CT scan and bone scan,
but they were likely oligometastatic,
they just didn't have a PSMA PET.
This suggests that there's a subset
of patients that maybe we
want to consider intensification of systemic therapy for.
Now, I've shown you data for
why we should treat the prostate,
why we should think about treating the sites of
limited metastasis and that maybe we should
also think about intensifying systemic therapy.
But I also want to point out
that all patients are different.
I'm going to tell you a tale of two patients.
They actually had similar
presentations but different outcomes.
The first patient was a patient who had surgery for
his prostate cancer in 2007 and then
he ended up having a PSA recurrence that was treated with
salvaged radiation therapy and
a short course of hormone therapy in 2013.
This was done at another center.
But then in 2017,
he presented with oligometastatic disease
in the left pubic ramus which is
a bone of the pelvis with
a slowly rising PSA and at that point in time he saw me.
This was a picture of his PET scan and in red,
you can see the area of
the oligometastasis is the spot in his pelvis.
What happened was that when I saw him in 2017,
I was able to obtain a CT scan from
outside hospital that was performed in 2013.
What you can see here is that the spot of cancer
that I saw in 2017 was actually there in 2013.
In the intervening period from 2013 to 2017,
he actually had no treatment and so this patient had
a single detectable site of
metastasis despite almost no treatment over four years.
He had no emergence of
additional metastasis during this period.
I ended up radiating the spot and now we are
five years later he hasn't
had any treatments since that radiation.
His PSA is undetectable
and I'm keeping my fingers crossed.
Perhaps he is cured
but right now things are looking very good for
him after being treated with
just a single course of radiation.
Now I have Patient 2 to show you here who
actually had a very similar presentation as well.
Also was after he had surgery, also recurred,
also was treated with salvage radiation
and short-term androgen deprivation therapy,
and also you can see he had
a very similar appearance of
a metastasis actually in the same bone,
on the left pubic ramus.
I radiated this spot in
January of 2017 and literally in February of 2017,
his PSA rose and he had three other
spots pop up in the pelvis.
Again, what I will say is that one of
the most difficult aspects of treating
oligometastatic prostate cancer is, right now,
we don't have a great sense of who is going to
respond very well to
the radiation for a very long period,
and who will progress through the radiation.
Again, it's not really an issue of where we
radiate in terms of
the cancer progressing and it's where we don't radiate.
It's almost certain that sometimes
it's like cancer pops up elsewhere.
Again, this brings me to the point that
not all oligometastatic disease is the
same and so Patient 1 that I talked about,
the disease we saw was
all the disease that was probably there in his body.
We radiated this, we got rid of the tip of the iceberg,
he did well and for these patients,
we should think about intensification of
what I turned to be a local therapy, radiation,
or surgery for the primary and for the metastasis.
The Patient 2 I showed you,
maybe I got rid of the tip of the iceberg,
but then everything else popped to
the surface and so for Patient 2 maybe we should think
about intensification of
systemic therapy with hormone therapy.
As many of our previous speakers have mentioned,
our mission here at UCSF is to improve patient care,
either coming up with new therapies or
also trying to come up with
better biomarkers to identify
patients that may or may not
respond to particular therapies.
Working with investigators from
both the ORIOLE and the [inaudible] ,
the two studies of radiation to
the sites of metastasis that I mentioned to you,
we went back and did
genomic sequencing on cancer samples from those patients.
What we found was that metastasis-directed therapy,
meaning radiation to metastasis
may work better in patients
without "high-risk" mutations in their cancers.
I'm sorry, there's a typo here.
The high-risk mutations are defined
as somatic mutations in ATM,
BRCA 1/2, RB1, or P53.
Again, patients who had
these mutations shown in blue did worse than patients
who did not have these mutations
shown in red when treated with
radiation to the sites of metastatic disease.
In conclusion, oligometastatic disease is
increasingly diagnosed due to
advances in molecular imaging.
Treatment intensification approaches involve
local therapy to the primary tumor,
metastasis-directed therapy,
an intensification of systemic therapy.
Ultimately, we need randomized clinical trials
to determine the importance of each.
We already have a large randomized trial that tells us
that we should radiate the
primary tumor meaning the prostate,
in the context of oligometastatic disease.
There are ongoing studies
regarding other forms of treatment intensification.
But ultimately better predictors of less
aggressive versus more
aggressive oligometastatic disease are
needed and that's what we'll probably spend
a lot of effort trying to predict.
I'd like to acknowledge
all the collaborators here at UCSF.
We have a wonderful team
of clinicians and researchers here.
Thank you. [MUSIC]