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Program Supplement
INTERVIEW WITH DR EDWARD MESSING
DR NEIL LOVE: While
the emergence of PSA screening has resulted in far fewer patients
presenting with positive lymph nodes, the ECOG randomized trial
of androgen deprivation in this subset by Edward Messing et al and
mentioned by Dr Soloway, is frequently cited in the debate on the
pros and cons of early endocrine therapy. The Journal of Urology
paper by Walsh, which did not support immediate treatment, included
a follow-up commentary by Dr Messing, who discusses his current
approach to these patients in a non-protocol setting.
DR EDWARD MESSING: Unquestionably, those patients
who have positive lymph nodes on their prostatectomy, regardless
of the state of the primary tumor, I advise to strongly consider
early endocrine treatment and I quote my study to say it. I do tell
them it was a small study. I do tell them that there are critiques
of it, and I also say that we did not treat the patients who were
not treated; you know the deferred group until they had metastasis.
It's certainly possible that had we treated them earlier, they may
have done just as well. But that group, I unequivocally recommend
that they go on hormonal therapy.
DR LOVE: And what
specific hormonal therapy?
DR MESSING: I usually use LHRH
agonists. I leave it up to them whether it's Lupron or Zoladex.
I usually use anti-androgens for a brief period of time. The charge
to patients for the full dose of Casodex, where if potency is an
issue where it is in some men or at least libido anyway, is an issue,
I'll try to get them on that and I have some patients like that.
Those men I'll give breast irradiation to in advance and then put
them on that. But usually LHRH agonists because I say that's where
the data are.
DR LOVE: When you
use Casodex in that situation, what dose?
DR MESSING: I've done 150 milligrams.
DR LOVE: What do
you think is happening in the community in that regard in those
kinds of patients?
DR MESSING: Surprisingly, fewer than I would
have thought with my paper. I certainly have had several guys in
the community, even at conferences, present cases and then ask me
what I would do. I say, well you know what I do based on the study.
Then I throw out, but maybe if we treated them when their PSA became
detectable it would be OK. They say well that's what they prefer
doing and I say, that's fine. So I think fewer than should based
on the data in the community.
Possibly part of that is because of Pat's critique of my study,
making it carry less weight, and possibly it's just a general reticence
to acknowledge that you weren't cured. I think one of the problems
with urologists as opposed to, I guess Bernie Fisher needs to be
credited with this, but as opposed to breast surgeons or maybe colon
surgeons, is that urologists tend to think that their treatment
has to be curative to be worth doing.
And yet, for say testes cancer which is a much less common cancer,
I think that all urologists understand that if it weren't for Larry
Einhorn and the like, their success rate wouldn't be so great.
So I'm confused about that, but I think that most urologists, and
we had a conference about it back at our institution with people
of the community there, looked at prostatectomy as either it was
going to work or wasn't worth doing. I think that attitude is probably
wrong. It's a lower morbidity procedure than it was a decade ago.
It's still a major operation and bad things can happen, but the
numbers of bad things happening are much, much fewer nowadays. And
it might be worth considering again in conjunction with additional
treatments, and particularly for the bad risk patient it should
be understood that it maybe should be looked at that way. I mean,
breast surgeons have known that for a long time, colorectal surgeons
have known that for a long time, but urologists have not looked
at their surgical treatments that way.
DR LOVE: I think
also they try to make it more palatable to a patient. Breast surgeons,
colon surgeons, general surgeons say this is kind of preventative,
maybe you won't need it, but this is a little bit extra insurance.
DR MESSING: Right. Right.
DR LOVE: That way
it doesn't seem like it's such a dire situation.
DR MESSING: Right. Right. I think urologists
don't have their mind set that way, and I think that's probably
wrong. They look upon additional treatment, same as with adjuvant
radiation, as being a defeatist policy, and that's probably a wrong
approach.
DR LOVE: I thought
it was interesting in listening to your lecture that you just came
right out and said something that I can almost never get people
to say. When I asked you what you would do if you were the patient,
you made the statement that if you were in the situation of having
positive nodes you would take early endocrine therapy.
DR MESSING: I would, and I'm as concerned about
potency as the next guy is. But yes, I would without question. And
I would not have done it before I did my study. I mean it would've
been exactly the opposite.
DR LOVE: It's interesting.
I wonder sometimes whether if we say there was a survival advantage
in this study but maybe the study was small or maybe we could have
done the same thing. It's kind of putting a reverse spin on what
I think the patient is most concerned about, which is dying of prostate
cancer.
DR MESSING: Right. I'm seriously convinced. Before
I ever published that, they wanted me to publish this thing, you
know when we had the surrogate endpoints and I said, come on. I
mean, it would be just be like the RTOG and maybe you think those
are meaningful but I never did. I said we need to wait until there's
a survival difference and then we need to prove that it isn't an
artifact, and we did everything we possibly could to slam through
that data and prove that there was something different in the groups.
And Pat knew that, I sent that to him way before we ever published
it. Because, I knew, and I said, look we have this study coming
out that's going be really meaningful. Do you have any thoughts
on why we are different?
DR LOVE: You talked
about waiting until there's a survival difference, but I guess really
the issue is waiting until there were enough deaths that you can
determine one way or the other. That get's into, for example the
Casodex study, and there are not being deaths at this point, not
enough deaths.
DR MESSING: Although the data on the watchful
waiting group is impressive. I was actually much more impressed
by that - a quarter of the people or a little higher have already
had bone mets within two years. These people had an aggressive disease
and it was across the board that Casodex worked. It was impressive
to me too, that in every single group whether it was preventing
bone mets, it was all preventing bone mets, but whatever treatment
you had, it caused a 40-50 percent reduction. The numbers were pretty
superimposable, it went down from 25 percent to 15 percent, and
in that group it went down from 9percent to 6percent.
DR LOVE: Do you think
this data is something that a community urologist should know about
at this point?
DR MESSING: Yeah, I think they should. I would
argue that in the high-risk patient, the one that doesn't have 85
or 90 percent chance of being disease-free ten years from now and
really being cured by the surgery. But someone who has a 50 percent
chance of failing within a few years, and you know that already
by pathologic markers - volume of disease, Gleason grade and the
like - that those people, if they're not going to be on a study,
would've really considered this treatment. I would think that the
person who has a high Gleason grade tumor with positive margins
and a large volume disease, where you know from the report by Pound
and so on, that they have a very high chance of PSA failures within
two years, that their course is pretty obvious and that treating
them would be worthwhile. Sure, so I think for a high-risk group
that it's not unreasonable to treat.
DR LOVE: So getting
back to your positive lymph node patient. For example, do you discuss
as an option with that patient taking 150 milligrams of Casodex?
DR MESSING: Yeah, I do. I say that right now
there's no reason to expect that it's any different in terms of
efficacy based on some of the other studies. It has probably a lower
side effect profile on libido and potency, which may not return
any way because this is early after the prostatectomy. I mean libido
will return but potency may not. And I say that it may be reasonable
to do that, but it does require breast irradiation first and it
does require making sure you can pay for this because the other
medicines are more readily paid for.
DR LOVE: Let's get
to the other scenario that you talked about, the man who has positive
margins, 50 percent chance of developing progression, what options
do you discuss with that man and what do you recommend usually?
DR MESSING: With that sort of person with negative
nodes I would talk about three alternatives. One is being observed
until the PSA turns positive, and then treating. The second would
be radiation therapy to the prostatic bed and the third would be
hormonal therapy. If it's a low-grade tumor, I'll probably push
him more towards external beam radiation, with the "chance
of truly curing you" with local modalities and saving hormonal
therapies until later on. If it's a high-grade tumor, I'll explain
that it's probably unlikely that radiation alone based on what we
know is going to hold this, not so much that it may not work locally
but there's probably disease elsewhere as well when it's this extensive.
Those people I'll push more towards hormonal if they are willing
to do it. But I will say that there is no real data on this, and
it is extrapolating what we know from other studies to do it. But
those people I'll probably push towards hormonal therapy.
DR LOVE: Any that
you do both on?
DR MESSING: No, the radiation therapists on occasion
have, with I think, bad data all together, but I normally do not.
I do say that some people will do that, but that level of a kitchen
sink approach is not substantiated. It may be the right thing to
do for them, but we just don't know. So, I do bring it up as being
a possibility, but I say we really don't know what we're doing when
we're doing that.
DR LOVE: And in those
men that you do suggest hormonal therapy. What's specific hormonal
therapy do you talk to them about?
DR MESSING: It depends on whether potency or
libido is an issue. If libido is an issue, I usually ask them to
consider anti androgens, Casodex almost exclusively. If it's not
an issue, then I usually talk about more standard chemical castration.
I rarely, now a days, unless there's a very usual circumstance do
I talk about orchiectomy.
DR LOVE: Generally
speaking, do most of these men accept treatment or decide to take
that treatment?
DR MESSING: Yes, most do, but not all. One of
the issues about the medical therapies are that you sort of say,
that while we think this is for the rest of your life, we don't
know that. With the medical therapies, if there are side effects,
we can stop and start it again, without seeing penalty for resisting
cells, although we don't know that for sure. But with the medical
therapies, there may be some chance of stopping it in the future
and never needing it again. I think those are both attractive possibilities
to patients, maybe completely false hopes, but I do bring that up
as a rationale for picking non-permanent castration.
DR LOVE: Thinking
it through from your own point of view, what do you think you would
do in that situation?
DR MESSING: I think I'd probably would take an
LHRH agonist or if I thought that someone would preserve my nerves
that control erections, I would take Casodex. It would depend on
my read of those levels of side effects and the likelihood of regaining
potency after the surgery.
DR LOVE: You mentioned
the radiation therapy, is there a very standardized approach to
what that is?
DR MESSING: There's data from the old DES literature
that you could reduce the incidence of gynecomastia with a 1000
rads, I guess that's 10 centigray now, or whatever it is, in a day.
So it's a single treatment of the equivalent of a 1000 rads.
DR LOVE: I don't
know how many men you've had on 150 milligrams of Casodex that you
did that with?
DR MESSING: I had people on the study, and I
didn't do it with them. I probably have fifteen or twenty men on
that now for various indications, certainly not all node-positive
disease, but for various indications I've done that and very few
have gynecomastia. It's not supposed to work on everyone. I've heard
people give examples where that hasn't happened, where they've not
benefited by it, but I've not seen that yet.
DR LOVE: Let's bring
the risk to progression down a little bit lower to let's say 25percent.
DR MESSING: I certainly offer hormonal therapy.
I basically tell these people that there's an option if there are
positive margins particularly that I would probably treat with radiation
and only use hormonal therapy if that failed. And that the option
of waiting and seeing if you fail, there's a three-quarter chance
you won't fail, maybe we should just wait and treat you later on.
There are no randomized studies done on early versus late radiation.
If you administer it earlier it looks like people do better, but
of course a large percentage of those people never needed the treatment
to begin with, so that's why the data looks so good. I think you'd
have to do a controlled study seeing that. There is a controlled
study that's accrued which was surgery plus or minus radiation for
positive-margin disease but the data on survival aren't in yet.
DR LOVE: Now you
talk about treating men in all these scenarios when the PSA becomes
detectable. Can you talk a little bit about specifically what level
would you start treating it.
DR MESSING: Oh, I think there are data, certainly
for radiation literature that you need to treat before the PSA reaches
1 and that the success rate is lower if you wait until after that,
after prostatectomy. I usually will offer to a patient treatment
once I'm convinced that the detection of PSA is real and that it's
rising at a rate that you can measure. It doesn't have to be a doubling
time of less than a year, but it is certainly rising at a rate that
you can measure over a period of six months and it's gone from .06
to .07 or some such number.
DR LOVE: Do you think
that's pretty standard in the community?
DR MESSING: I think so, but I don't really know.
I mean I think people have different thresholds. Clearly one of
the issues is how people's side effects are doing from surgery.
I'd be much more reluctant to radiate someone who is incontinent
then I would someone who isn't because there is almost no chance
of regaining continence once you radiate an incontinent man. So
I would tend to allow that to be part of the picture, but if everything
was equal, if the side effects were approximately equal, I think
that people have different thresholds. I have certainly seen people
who've just been followed, which hasn't made a lot of sense to me,
and then recommended radiation when it's 2 or 3. But I think there
are several articles that indicate that if you radiate after the
PSA is above 1 it is worse than if you radiate before it.
I think only for the very bad risk patients, the node-positive
disease or the very high-grade disease where the likelihood of systemic
disease is so high, is hormonal therapy used preferentially to radiation
in a post-prostatectomy failure.
DR LOVE: What is
the typical clinical scenario where you are seeing detectable PSA
or rising PSAs where hormonal therapy is used. Is that usually post
radiation therapy?
DR MESSING: Certainly post radiation it is used.
I think again, it's primarily for the high-grade disease. People
who are likely to fail systemically where you really think you're
going to prevent metastases, or delay metastases are the people
where they are used. So the node-positive patient, the patient with
Gleason 7 or above are the ones were there's much more willingness
to use hormonal therapy.
DR LOVE: For PSA
elevations?
DR MESSING: For PSA failures, biochemical failures
only. I don't always use it in radiation failures either for a couple
of reasons. First, the definition of PSA failure after radiation
therapy is fairly obscure unless you have also had prostatectomy
first, so it's a peculiar thing.
Second of all, I am actually doing a study. I am the PI on it,
it's for an anti PSA immunity and so I would try to push people
into that study because I want to know if it works. All people get
hormonal therapy there for a brief time and then people get this
anti PSA immunity using ex-vivo education of these dendritic cells,
and so on. And not anti PSA, anti acid phosphatase immunity. Whether
it will do any good or not, I don't know.
But the third reason I would try not to do that except in the real
failures, is that again you don't know if it's doing any good. The
only way you have to follow people is by PSA, and I think getting
some handle on the rate of rise of PSA is important.
The fourth was at the brachytherapy group, which is a big group
of people we see now. A certain proportion get this bump in PSA
a year to two years out that apparently has nothing to do with outcome.
You don't know what to do with that, and I don't want to confuse
things by giving hormonal therapy there.
DR LOVE: What would
you say is a typical clinical scenario of a man who eventually is
going to end up with gross metastatic disease. If you were to describe
a typical time course, in terms of what happens and what treatments
that man is going to receive, what would it be?
DR MESSING: Well it depends on their initial
disease and when they failed. Obviously the person who fails within
a couple of years with a PSA failure after prostatectomy, who has
high-grade disease usually within three years of failure and has
signs of metastatic disease, that group of people I would put on
hormonal therapy as soon as they failed. Especially, if I had not
done it earlier. I think the group of people who are recurring quite
a bit later, 4-5 or 6-7 years down the road, I would talk about
radiation assuming there are no metastases and delay hormonal therapy.
Because it's often, based on data from Hopkins, another 5-8 years
before they get metastases. And then it's another 5 years before
those metastases are lethal. So, you're talking about a 10-13 year
picture down the road, and I think if there's a chance of curing
them with radiation first, I would try to do that. So their time
of failure, their initial histology and so on are very important
in predicting, and PSA recurrence, doubling time, or whatever.
DR LOVE: Of the men
that you see who actually develop gross metastatic disease, how
many have you actually started treatment, prior to that, when their
PSAs were elevated?
DR MESSING: Only a couple.
DR LOVE: Hmm.
DR MESSING: Most have not. Most I have delayed
treatment until they developed it and the question, of course, would
have been, had I started it earlier would it have made a difference?
It is relatively rare that people have bad prognostic indicators
who I've treated right away, and it hasn't seem to do some good.
Most of the patients I've waited and those people who've developed
mets, then I've treated. One could argue from that experience why
don't I treat a lot more people earlier and my answer in converse
is, I really don't have enough good data on that. And anecdotes
tend to be things one tries to shy away from.
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