a United States Army Medical Department continuing
education program,
effectiveness of radiotherapy
with jimmy a light.
Lieutenant Colonel,
United States Army Medical Corps Assistant
chief organ transplant service,
walter reed Army Medical center Washington D.C.
Based on based on work by hume and several of his
colleagues at the Medical College of Virginia.
In the middle and late 60s.
Many transplant centers around the world have used
a radiation therapy in one form or another
as an adjunctive measure in the treatment of ala graft
rejection.
I think we've had the impression for some time that
radiation therapy has been effective in
helping to reverse acute rejection episodes
that have not resolved with standards federal pulse
therapy.
But this kind of impression is almost impossible to
document in any objective manner.
And there's a despite
your own impressions and other scattered reports
of which you have not been very many.
Now the role of radiation therapy and
reversing acute rejection then I don't particularly want to
address at all.
But the question I do want to specifically address is whether a
graft or radiation in the immediate post transplant
period is beneficial because this I think
this has real importance because if it is effective then all
patients who are subject to Allah graft
rejection are at risk for rejection
namely hap low non identical
uh H.
L.
A non identical and cadaver transplants should probably
all be irradiated in the post transplant period.
But if in fact it doesn't really help then
the 600 to 900 hours that are used in that time
are wasted If in fact it might be
useful later on to help reverse acute rejection episodes.
To say nothing of the any other side effects that might
occur in the future years on the
ovary,
or perhaps on the testes from the scatter.
So from the beginning of our program,
again,
dating back to 1970
we've administered 100 and 50 are on alternate
days,
beginning on the first or second,
post transplant date.
All cadaver recipients total
dose was 609 100 are based on
again,
hume's.
Uh And in several of his colleagues work
in animals in the sixties.
Two years ago,
we looked at our series of 18 living
related half low mismatched transplants
and found that almost all these patients required a radiation
therapy sometime in the first one or two months after
transplant for either recurrent acute rejection
episodes or for rejection episodes that failed to
resolve with standard pulse therapy and in
the slides that you'll see where I'm calling this
therapeutic radiation At this
time.
Then,
two years ago,
I elected to begin routine postoperative radiation
therapy just as we were doing for the cadavers for
all these haplotype mismatch patients,
we gave them the same treatment and we subsequently
treated 14 patients in this manner,
calling it prophylactic radiation.
Now these two groups are the ones I wish to compare then
and give you the basis for this report.
I hate to talk down my own stuff.
But uh when you think about a series of
33 patients followed for a couple of years that
are done in a retrospective,
uncontrolled,
non randomized manner.
I'm not sure you can answer any questions at all uh
from this kind of information but I think
the uh I'll present it and you can decide
first slide please.
I think we needed.
You need to approach the problem by asking a series
of questions and the questions are quickly.
Does it prevent acute alla graft rejection
or does it affect the severity?
Will it decrease the incidence or severity of
later rejection episodes?
Now we're talking about immediate prophylactic
post transplantation or radiation therapy.
Does it alter the long term success rate?
Uh Does it lower the pulse requirement.
Does it decrease immuno suppression requirements?
Or does it change long term mortality or the
incidence of severe infection presumably from
immuno suppression?
Well then to try to answer these questions,
then we have these two groups of patients,
uh one of which received prophylactic
radiation,
14 patients,
the other of which received comprised all the
remaining patients who are not H.
L.
A.
Identical.
So in other words,
we have 33 patients who are half low identical.
Either parent child or sibling
transplants.
All living related again.
Uh and of these uh situations
then 14 obviously of the
received immediate post transplant radiation,
only 12 of 19 required therapeutic radiation
over?
Uh later on
I'm sorry,
scratch that,
please.
Uh That has nothing to do with what I'm saying.
What I'm trying to do here is compare the
database and I'm saying that parent
child ratio and a sibling ratio is essentially the
same in these two groups.
Trying to offer you the thesis that these groups do.
In fact compare and that the data I'm presenting is
valid.
The ages are similar as you see.
Uh this is percent reactive antibody.
Uh and there's not significant incidents
in either series of these patients.
The weeks on dialysis for people who believe that that
affects transplant success are greater in the
prophylactic group,
something around a year,
half year in the therapeutic radiation group,
sex differentiation.
A little difference.
I don't know exactly what that means.
If anything.
There was as I remember one scattered reports
that uh transplantation across sex lines
was a little less uh
was Had a higher incidence
of graft non six.
It wasn't as successful if you transplanted across sex lines
as uh otherwise I don't know that that's ever been
documented that I just tossed it in
consideration.
One thing that's important.
The primary diseases are similar in both groups.
So that recurrent disease should not be a consideration.
And as I said,
all donor recipient pairs are happy so identical
living related.
Okay,
the first question then is,
does prophylactic postoperative radiation
prevent acute graft rejection.
We define this as occurring within 21
days.
Uh for arbitrary reasons.
And as you see,
only half the patients who received prophylactic therapy
rejected.
Whereas uh something nearer two thirds of the
patients had acute rejection episodes
uh in the early post transplant
period.
Now,
the interesting thing,
I think that modifies my early enthusiasm
for the treatment then was that
44 of the seven patients who did
not have acute rejection in this group
subsequently had rejection episodes and have
gone on to something that may resemble
chronic rejection.
And I'll show you that data later.
Whereas none of these seven
patients who had no acute rejection
had chronic rejection or a significant rejection later
on.
So the total number of patients that have had rejection at
some point uh after
transplantation is uh perhaps a little higher in the
prophylactic radiation group than the other.
The next question is,
does prophylactic radiation therapy delay the
onset of acute rejection or affected severity?
The answer is it does not delay it.
The means are basically the same with similar ranges
and the answer about affecting its severity will go
to in a second while uh after we've talked
about how you engage whether rejection episode is
severe or not,
I don't know that you can but this
maybe then the closest thing to
doing that.
It's an index proposed by Mayor and the Green
Journal American Journal of Medicine.
Uh this past spring
1970 for and this
index merely does these things that
compares the Peka Creatinine
during rejection to its previous baseline and
creates that ratio and then multiplies it
uh times all the below
factors,
which means obviously that this
creatinine rises heavily weighted just as
we all would wait it uh in our own sort
of empirical way.
But anyway the some of the other factors are the sum of the previous
baseline apron and milligrams per
kilogram plus the previous baseline
predniSONE milligrams per kilogram plus the number of
predniSONE bolus doses in milligrams per kilogram that were
given over the five day period.
And then you add in the new predniSONE maintenance and the new ways of
maintenance and any radiation therapy
uh in terms of hundreds of rads,
if you use that.
The thing,
that's the thing that is not taken into
account by this uh
indexes the duration of the rejection
episode which I think has been pointed out and
again by dr human colleagues uh in the
sixties as being one of the critical factors in
determining long term graph success in their
setting in their patients with their treatment at that time in
any way.
But that fact is not considered and uh
therefore I'm not sure you know if it's totally valid.
But it when I looked at all our rejection episodes,
it turns out that it fits very nicely with my clinical
memory of and the flow sheet data that's going on at the
time.
So anyway grading that and we'll go back to the
previous slide and say does it affect its
severity and the answer may be
yes it does.
Maybe it does now severity of course
increases as the number increases and
a a pretty good rejection episode is about
100.
Uh So the mean plus or minus the standard
uh air is
79 the prophylactic group and
100 and 37 in the radiated group.
With a fairly wide scatter of results.
Now I'll present this afternoon some data
on adverse effects of contrast media.
And I would say that this value here is probably skewed
upwards by uh I think some
intermixed contrast media toxicity with acute
rejection because we simply haven't seen rejections of this
magnitude since we stopped doing uh
contrast studies.
So then the next question I think logically follows.
Does it alter the incidents or affect the severity of
subsequent rejection episodes?
I think we can reasonably say it hasn't done much for the first
one.
So the number of patients with acute rejections in that
will be considered are obviously seven.
From these data from the previous slide.
And a number of patients of that group who have had
subsequent rejection episodes are three quarters of
the patients in the
therapeutic group uh
and all the patients in the
uh
prophylactic group.
But this this asterisk indicates a finding on the bottom which you've
probably already noticed.
And it says that four of these patients didn't
actually have later rejection episodes.
But for patients who didn't have acute rejection
episodes had later once.
So we still wind up with seven as you remember from the
earlier slide they undergo about the same number of
rejection episodes.
Uh 12.
And it figures out to be about 1.7 per each patient.
Now this is in a three month period,
post transplantation.
Uh again an arbitrary figure
that may be short and I think we'll look at the data again
later on over a longer time and see if this kind
of thing holds up.
But it's about 1.7 um
rejection episodes per patient experiencing it
in each group time of occurrence is scattered
over the period of observation.
The rejection severity is almost exactly the same
with more skewing towards the upper end in the
prophylactic group.
Again,
hard to say that it's done anything for us now.
Does prophylactic radiation therapy improve overall
graph success or decrease mortality?
I think here the problem is uh
it's hard to assess again.
Here we have 12 or 14 who are still
functioning,
but the period of time is only 3 to 30
months.
Uh with the mean time of around a
year here we have 14 of 19
functioning,
suggesting that prophylactic therapy in fact who helped.
But the period of observation is considerably longer,
with the meantime being on the order of 30 months.
So I think that's apples and oranges
and hard to say chronic
rejection about the same in both groups.
Uh But in fact,
this number is a little smaller.
And this number is a little bigger,
Most likely deaths from sepsis.
Uh about the same serious infection.
About the same.
This number should be three,
not four.
Uh so in that setting it
looks like about the same thing and again,
but the numbers are all small and all we need is one or two on either
side and it means nothing.
But it doesn't seem to have had any real
uh great
effect.
I guess we could say now quickly onto the
remainder of things.
Does it decrease steroid requirements?
I'm almost ashamed to show this slide after listening to dr turK
a program for steroid
therapy and the post transplant period.
Um I don't know why we use so much.
All I can say is that I guess that's why we always have.
We just always have.
And uh that's the way the program started and when I came into
it and the succeeding succeeding people that have come,
we just sort of continued the early uh
early program regimens.
But anyway,
let's look at it and see what we're saying.
We're saying the number of steroid pulse is required in this
three month period that we're observing them.
It's just about exactly the same.
Eight plus or minus two.
This is a one standard error of the main 9.5
plus or minus 1.4.
The mean steroid dose,
the mean federal dose,
this is the oral dose that does not count.
It is not counting those pulse therapies as a whopping
2.4 mg per kilogram per
day at one month.
The same in both groups.
No,
I beg your pardon.
Yes,
that's that's correct.
But I didn't say it quite right.
Let me rephrase it again.
The mean medical dose administered over the period of one
month.
This is all the medal they got orally in the first month
of time.
And that's what this average comes out to be about 2.5 mg per
kilogram at the 30 day mark.
Uh This number should be 78 that's the
oral dose each patient was on in the mean
oral dose.
So that's roughly 80 mg per
patient per day at
one month at 30 days.
Post transplant at three months.
Uh Typographical error.
Three months.
Post transplant.
The mean oral dose is
34 mg here.
32 mg there at 12 months.
The mean daily oral dose is 15
mg here,
18 mg there.
If we look at the number we've converted to alternate day therapy
who are eligible for consideration.
Having reached that period,
none of the patients treated with prophylactic radiation
have been converted all today steroids at three months.
Whereas uh not quite half those
treated therapeutically,
were able to be on alternate day therapy at that
time at 12 months.
Uh three of five patients reaching that period of
time.
We received prophylactic radiation or on alternate day
therapy about the same percentage as those who were treated
therapeutically.
So in the long haul it looks as the,
uh,
the number on all day
therapy may sort out to be about the same.
I think another question obviously is does it have any effect
on kidney function at any point in time?
And the answer is it doesn't seem to,
uh,
I doubt that although statistical manipulations have not
been applied to this data,
I think looking at it is enough to say that there probably
isn't any consistent significant difference at any point
in time after transplant and either of these groups,
uh,
which have undergone the same number of rejection episodes of
the same kinds of severity.
Furthermore,
what,
what's the story on the number of rats we've delivered to
these people.
And have we perhaps have we done any harm?
I don't think we can answer the question whether we've done any
harm or not.
Uh,
there's some errors on this slide as well.
Uh,
but what I'd like to just show you in a period
of when we should consider how much money we're spending
for various and sundry things and and whether treatments of certain
kinds are necessary.
This probably is appropriate as well.
In the group who received prophylactic radiation
therapy,
14 of them received nearly 14,000
rads.
This is the mean dose.
But if we subtract the amount we administered
prophylactically.
And then say,
well,
how much did you give therapeutically,
then it turns out to be about 5000 rads.
And if we divided by the number of patients we administered it to,
we come up with a mean dose of about 600 rads.
Or a treatment for one or 1.5 good
rejection episodes.
This should be 12.
Obviously when that's divided in the 7800,
it comes out 6
650.
And so these numbers are very much the same.
In essence suggests that we've wasted 8000 r
this slide is very busy.
All I was trying to show from this uh is whether
or not we were adversely affect adversely affecting
the white count at any point in time in the early
post transplant period.
Following therapeutic or following prophylactic
radiation therapy.
Since our Sarandos is
based on the peripheral white count
if it's depressed artificially by some other means
it might conceivably adversely
affect uh
long term function If you believe
that low in urine doses or noam Yuran
doses predisposed to chronic graft rejection.
Suffice it to say from all of this,
the Mun doses are fantastically large.
Again,
compared to dr turk a program in
both series,
there is some tendency towards Luca pena at four
weeks.
Unfortunately just didn't go any further than that with a data
collection.
Uh But on the other hand,
these patients have received a slightly larger dose of m Iran
in the preceding week or two,
I don't know how that's going to sort out
later on the three months and one
year for patients who have reached those
points,
the M Iran doses are basically the same.
So I think in conclusion it's
uh as you see
before you,
it's hard to prove that radiation therapy
uh used prophylactically in the early post
transplant period and patients who are at
risk for rejection episodes.
Uh It's hard to prove that it helps that setting at
all.
Does it alter the severity of that first rejection
episode?
Perhaps does it alter
the incidents or affect the severity of subsequent rejection
episodes by having used this additional immunosuppressive
agent in the early post transplant period?
I think the answer to that is clearly no,
thank you very much
effectiveness of radiotherapy
with jimmy a Light Lieutenant Colonel,
United States Army Medical Corps,
assistant Chief Organ transplant service,
walter reed Army Medical Center Washington D.
C.
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division,
Academy of Health Sciences,
United States Army Fort SAm Houston
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