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. Was produced through the mobile facilities of the Television division, Academy of Health Sciences, United States Army Fort SAm Houston texas