[MUSIC] I am going to spend the next few minutes
just giving a bit of an overview in terms of
where prostate cancer is by
the numbers and give up some of the basics.
Some of the nuts and bolts in terms
of considerations that you
need to think about before even getting
into the questions of treatment decision-making.
Starting with the basics, what is prostate cancer?
Cancer is a term we use for an abnormal growth of
cells anywhere in the body and typically a lot of
our focus is on cells with the potential to spread,
to metastasize to other parts of the body.
This is actually becoming a pretty important question
in prostate cancer because there are those of us that
are starting to ask
the question whether we should even be using
the word cancer for some of
the lower-grade prostate cancers.
Prostate cancer, of course,
is a cancer that starts in the prostate,
which is the organ sitting between
the bladder and the urethra in front of the rectum.
This is a side view and the diagram here,
it's a reproductive organ
whose purpose is to make some of the fluid that's
surrounding the sperm and to help push seminal fluid
forward at the moment of
ejaculation so it does reproductive organ.
Prostate cancer cells spread to other parts of the body.
Most typically the bones are still
prostate cancer cells and this is
an important concept that sometimes does cause confusion.
It is not bone cancer is still
prostate cancer and still
typically responds to treatment.
You're going to hear more about some of
the risk factors for prostate cancer this afternoon.
But as with any cancer,
prostate cancer reflects a combination of genetics,
genes that you're born with,
that you inherited from your parents,
and a host of environmental factors
that we're still sorting out.
There are many that way in here.
Dietary factors, smoking, chronic stresses, exercise.
Some of these environmental factors
are controlled, but many are not.
We know that there's a substantial proportion of
cancers that we ultimately just
say are bad luck. They are stochastic.
They come from radon in the soil,
cosmic ray is things that we really have no control over.
Prostate cancer is extremely common.
It is by far the most common cancer that men get in
the US over a quarter million diagnoses a year.
It's the second most common cause of
cancer death among men
in this country and has been for many years.
Over the years and the decades prostate cancer
is the brown line here,
the second one from the top.
Prostate cancer mortality rates,
death rates have fallen very
substantially since we started screening with PSA,
prostate-specific antigen in the early 1990s,
the mortality rate has fallen nearly 50 percent
over the 20 years after PSA clinical practice.
It's the steepest decline we've seen for
any cancer with the exception of lung cancer.
We know the lung cancer decline is largely attributable
to smoking cessation efforts and
less cigarettes around the country.
What drives the prostate cancer drop
is a little bit more controversial,
but a lot of it is clearly
directly attributable to use of
the PSA test in primary care and
earlier identification of high-risk cancers.
It is important to point out though,
just to emphasize the points that Dr.
Washington was making in his talk,
that the racial disparity has really not
gotten much better, if any,
over the same time period since the 1990s,
we've seen a similar drop in
mortality for white and black men.
But the delta, the space between these two,
has not gotten any narrower.
This is on the right here is a look at the rate ratio.
In other words, the multiple of
mortality faced by black men compared to white men.
It has hovered consistently
over two-and-a-half-fold mortality
facing African American men.
The greatest disparity is actually in younger men.
Men in their 40s and 50s,
not many men die of prostate cancer this young.
But those that do, there's 3 and
4 fold excess mortality for black men.
Now the reason prostate cancer has been
such a controversial screening question
all these years really relates
to the exceptional variation in prognosis in risk
reflected in this collection of lesions that we
all brand with this prostate cancer label.
This is a terrific cartoon from
a paper written a number
of years ago now by Laura estrogen,
who is a breast surgeon at UCSF,
and Ian Thompson, urologist at UT Southwestern,
thinking about screening for any cancer.
The idea is if we screen at periodic intervals,
this can be PSA testing for prostate cancer.
Colonoscopy is for colon mammography for breast cancer.
Doesn't really matter. The idea
is if you get to the far right here,
you've died of something else.
In the US that's almost always cardiac disease it's
the most common cause of death
for men with prostate cancer,
just like it is for men without prostate cancer.
If you get to the top of the graph,
you'd actually died of the cancer.
We know that even with PSA testing,
there are many cancers we never find.
These are the so-called autopsy tumors.
We don't diagnose them and this is a good thing.
They cause absolutely no symptoms or threat to life.
Then there are cancers that we can find,
we can supposedly sure
them while they're in the prostate.
But how do we never found them?
The men would have died of something else,
never knowing he had the prostate cancer.
This is called overdiagnosis.
These are tumors that we do not need to
find and we can only do harm by treating them.
Then there are the rabbits, the ones that we can find
when they are in the prostate,
we can cure these.
If we do not cure these, these would
spread to cause metastasis,
progression, and ultimately mortality.
We believe that it is the chase and
treatment of the rabbits that has
driven a lot of that drop in mortality.
Then there are the ones that
fortunately in the case of
prostate cancer are quite uncommon.
So-called integral tumors, ones where
the men who have PSC 0.71 year,
then 0.8, and then 2.1.
By the time we
diagnose the prostate cancer, it's too late.
It's just exploded in a six-month, one-year period.
This is very uncommon for
prostate cancer. Other cancers do this.
This is why we cannot screen for pancreatic cancer,
for example, but the so-called birds are very uncommon.
The snails we don't really care about.
The whole question is the rabbits versus the turtles and
how many turtles we've switched
in the course of chasing the rabbits.
Just to emphasize this point about the snails,
about the autopsy tumors,
this is a look at the prevalence of
prostate cancer when we do
autopsies tremendous who die of
other causes and look hard enough,
we find prostate cancer very commonly.
I would start over here on the left.
These are men in their 30s who die in
car crashes or accidents, etc.
We can find prostate cancer cells already in their 30s.
In over 15 percent
of white men and over 30 percent of black men.
By the time you get to your 70s,
these numbers are 40 and 50 percent.
This is almost a feature of normal aging.
If you live long enough,
almost every man will get
a couple of cancer cells and the prostate.
Labeling this cancer, giving them
a cancer diagnosis when we find a low-risk tumor
may really not be appropriate in
2022. Which ones do need treatment?
As I said, most men diagnosed with prostate cancer,
most of the ones we find are
the turtles rather than the rabbits.
Most men diagnosed would never know they had
it if we had not found it the reason to screen.
The reason we look is to find the aggressive ones.
As I said before, most men with
prostate cancer die of other causes.
However, the aggressive ones can be
lethal and we need to find them before this happens.
We have a very good sense in 2022 of how to
risk stratify and how to
target treatments according to risk.
We know that men with low-risk disease should be
managed almost exclusively with active surveillance,
meaning following the cancers carefully with
treatment brought to bear only if
the cancer shows signs of getting worse.
Those which are slightly higher risk,
maybe amenable to focal therapy treating
the tumor and leaving the rest of the prostate alone.
Those at intermediate to
high risk do well with whole gland treatment,
surgery, or radiation therapy,
or sometimes a combination.
Those with high-risk disease often do best
with multi-modal treatment, meaning,
in some cases, surgery followed by
radiation or radiation with aggressive hormonal therapy.
Then some cancers we find too late.
We find that they are already metastatic and
these were men who will start with systemic therapy,
hormonal therapy in many cases,
augmented by chemotherapy or other novel treatments.
You're going to hear talks
over the morning and afternoon,
really drilling down into each of these alternatives.
We have not done a great job across
the country over the years in targeting
the treatments appropriately to the men
who are most likely to benefit from them.
This is a look from a large registry called
Capture, which tracked practices,
but 45 urology practices around the country,
which we ran out of UCSF for
many years and throughout the 1990s and 2000s.
If you look at the left here, these are low-risk tumors.
Up until the end of the 2000s,
we treated almost every low-risk prostate cancer.
We could find only 10 percent or
fewer of men actually got
active surveillance or watchful waiting.
The beginning of the last decade,
this number went up pretty rapidly to about 40 percent.
In the meantime, we
were under-treating high-risk disease.
The proportion of men who were getting
only hormonal therapy for
high-risk localized prostate cancer without an attempt to
cure peaked at around 50 percent and has now fallen.
We're getting better. We're treating
less low-risk disease and treating
more high-risk diseases, which is appropriate.
Now 40 percent was still too low,
even though we showed rapid progress.
More recent analyses from other datasets,
this is from the aqua registry,
which tracks now 350
urology practices around the country.
The rate of active surveillance for
low-risk disease has risen much further.
We're now up to 60 percent.
Still not where we need to be,
which should be around 80 or 90,
but it is progress.
However, there is massive variation.
This is a look at individual urology practices.
An individual urologist showing
the proportion of men with
low-risk disease who get active surveillance.
And the bottom line here is that
your likelihood of getting active surveillance if you
knock on a urologist store with
a diagnosis of low-risk prostate cancer
ranges from 0 percent to
100 percent depending on
whose door you happen to knock on.
Now, this is a massive problem.
It is hardly unique to prostate cancer or to urology.
This is called the small area of
variations problem and we see it
everywhere in medicine we have the courage to
pick up the rock and look and see what's under there.
But the only way we can solve it and fix
the problem is to start to shed light on it.
Let's talk a little bit more about what we mean
when we say low-risk versus high-risk disease.
There's a number of factors that drive this distinction.
The first of which is, again the PSA tests,
the same blood tests that we use to
screen for prostate cancer.
Prostate-specific antigen.
It's a protein that circulates in the blood.
It's produced by the prostate.
We can pick it up with a simple blood test.
Historically, we used to call it a normal PSA,
less than four, that has really fallen out of favor.
The median PSA for the population is around 0.7.
For men in late 40s,
this drifts up slowly,
0.8 for men as early 50s.
By the time we get to 60, the median is around 1.0.
But 90 percent of all prostate cancer deaths happen in
men who have a PSA above two at age 60.
Now, once you've got the diagnosis,
PSA is still valuable,
and the higher the PSA,
the higher risk for cancer we'd like to see it under 10,
even better if it's under six,
but it's important to recognize that PSAs,
prostate-specific antigen, is not
prostate cancer specific antigen.
Anything that happens to the prostate as you get
older will drive up the PSA.
The most common thing that happens to the prostate
as you get older is it grows.
You get BPH, or benign prostatic hyperplasia.
This is what typically causes men to have
obstructive voiding symptoms as they get older,
slow stream, having to get
up at night to pee, the thing.
Extremely common, even more common
the prostate cancer and does not raise the risk
of prostate cancer in any way
except to the extent that it causes the PSA to go up.
We now have this concept of PSA density,
which is the PSA divided by the volume of the prostate.
We measure that by ultrasound or MRI.
Acknowledging that the bigger the prostate,
the more we can write off the PSA
to the size of the prostate.
We like to see this density under around 0.15.
Now what about the Gleason score?
This is one of the most important drivers
of prostate cancer risk.
This is how the cells look under the microscope.
The pathologists get biopsy tissue,
they say it is or cancer or not.
If there is cancer, does it look aggressive?
They assign patterns.
Gleason pattern 3 is low grade,
pattern 4 is intermediate,
and pattern 5 is high-grade.
These are now lumped into Gleason grade groups which are
a little bit easier to understand in many cases.
If the cancer is all low grade,
this is what we call a grade group 1.
Grade group 1s never ever
metastasize if it is purely a grade group 1.
These are the ones that we're starting to
question whether we should even
label cancer because they never spread.
Grade group 2s are mostly low grade pattern
3 with a little bit of pattern
4 which is intermediate grade,.
Grade group 3s have more intermediate grade
than low-grade or plus 3.
If it's all intermediate grade,
that's a grade group 4.
When we see the highest grade pattern,
then we call it grade group 5.
Now there are other details that matter here.
We take a 12-14 core biopsy
plus if there are lesions on MRI or ultrasound,
we will sample those as well.
The more cores we see involved,
the more aggressive the tumor,
but details really matter here.
Small amount of high-grade cancers often a bigger
problem than many cores of low grade cancer.
It's important to have the pathology read by
an expert of subspecialists because the details,
even if what is pattern 4 really matter.
There are some subtypes of pattern
4 that you'll see on the pathology reports in
terms like fused gland and poorly formed glands
that are much less concerning than other types,
which we refer to as
expansile cribriform or large cribriform.
It's really essential to have pathology re-reviewed by
genital urinary pathologists subspecialists
as we have at UCSF and many other medical centers.
We look at stage. It's not necessarily
the most important factor in localized prostate cancer.
This is the prostate cancer palpable.
Can we feel it on
a digital rectal exam or is there an indication on
MRI or ultrasound that the tumor
has pushed outside the capsule of the prostate.
That's what we call at T3. Then if
the cancer has spread to other parts of the body,
we call that N1 if it's in the nodes or
M1 if it has gotten out into the bones or other organs.
Then we draw these altogether
to do what we call risk stratification.
This integrates all these
different risk factors to try to
get a sense of whether the cancer will
spread to other parts of the body or not.
There are lots of different ways to do this.
The NCCN risk groups are the most commonly used.
This has become pretty cumbersome quite
honestly and doesn't necessarily do the best job
stratifying men in terms of
likelihood of cancer will eventually progress,
but you'll see these terms
used in clinical notes quite frequently.
At UCSF 17 years ago now we publish the CAPRA score,
which uses the same parameters
to come up with a 0-10 score,
which actually works much better to
stratify men across the spectrum of risk.
You get up to four points for PSA,
up to three for the Gleason score,
one each for the stage,
the number of cores involved and age.
This does a very good job
predicting what will happen over the years.
This is what we call a Kaplan-Meier plot.
The idea here is every time there's a step off,
a patient has an event.
In this case, it's actually dying of prostate cancer.
Men with low risk disease out to
16 years plus really nobody dies with cancer.
Whereas those with high-risk disease,
it's nearly half by 10 years if you
have multiple bad risk factors.
Briefly, what else do we need to think
about additional imaging is important.
We have become strong advocates for
multi parametric MRI when it is
done at a center of excellence like UCSF.
In terms of staging the cancer
to look and see if it has spread,
PSMA PET has really become our gold standard.
As Eric mentioned, this is a test
which Tom hope here and colleagues at
UCLA really drove forward to
clinical practice the United States
and it's now broadly available.
This is rapidly replacing bone scan and
CT as our means of
looking for cancer in other parts of the body,
but you really only need a PSMA Pet if you have
risk factors for cancer that has spread.
What about genomic and genetic testing?
These terms can be confusing.
Genomic testing means looking at
the gene expression in the cancer itself.
We're often using these for men where we were on
the fence in terms of whether to go
forward with treatment or not.
What we use most commonly here is called a cipher.
It looks at 22 genes in the cancer and helps us get
a bit of a sharper crystal ball picture in terms
of what may happen over the next 5-10 years.
Genetic testing means looking at the DNA
you're born with to get a sense
of whether there are genes that actually
drove the cancer development in first-place.
In some cases, these can change how we manage you,
but it's also very important information
for family members.
The recommendations in terms of who
should get genetic testing
are getting broader every year.
We're doing more and more of this.
Final point I want to make is that you'll
screening has been controversial over many years,
but we're finally coming to
a consensus in terms of how to do this properly.
We now have led at UCSF after
an excellent conversation with
our primary care leadership here,
a program that really emphasizes
smarter screening and treatment.
This is baked into our primary
care electronic medical record system
now that we really should be offering screening
to healthy men who have a good life expectancy,
that subsequent testing really should be
tailored based on what that baseline PSA is,
especially when it's done at a young age and
tailored further based on
risk factors like race, family history.
We manage almost all low-risk disease
here with active surveillance.
We use markers quite extensively actually to help
make decisions about who should get
a biopsy and who should get treated.
Finally, I would just say stay positive on all this.
It's really important to remember
prostate cancer is slow moving.
In the vast majority of cases,
five-year survival is basically
100 percent even for high-risk cancers.
Even metastatic cancers grow much more slowly
in most cases than many other cancers.
The treatments are improving all the time.
You're going to hear about all the incredibly
exciting and very rapidly moving innovations
management of high risk and advanced prostate cancer.
We can manage many of the side effects as well.
In most cases you have time to collect opinions and
to make decisions that make the most sense for
you and your families, and friends.
[MUSIC]