Ray Garry, MD - A Trial of a Trial of Endometrial Resection
Endometriosis Foundation of America
Medical Conference 2019
From Biomarkers to Precision Surgery
March 8-9, 2019 - Lenox Hill Hospital, NYC
It's a great honor to be here and to share these thoughts with you. I'm sure everyone in this room subscribes to the concept of evidence-based medicine. Perhaps we don't all agree with what is evidence and what evidence are we going to believe, and more importantly, is that going to make any difference to what we actually do. I like everybody else have been profoundly influenced by a few people in my life and in my career. These are the two guys who've transformed my own life. One of them we know extremely well in this room, Harry, and the other probably less well known to most of you is a colleague called Iain Chalmers, Sir Iain Chalmers, and I'll discuss his work in a moment.
Obviously, I met Harry in 1990 when he did his first hysterectomy in England, in fact in Europe, and we immediately formed a bond both professionally and socially. Harry is an extremely effective teacher and persuader. I love this photograph of some of the team at a workshop we had and look at the interest, almost adoration of the participants in the Cadaver Workshop. This is where Harry was at his best. We worked together on producing this book, and I must say that was the beginning of the end for me in professional terms because I went to his unit and stayed with Liz and Harry and followed his work for some days. I was keen to get all the data about hysterectomies. He kept doing these stupid operations, endometriosis, and I knew all about endometriosis. All we had to do is buzz the little lesions, take out the normal looking uteruses sometimes or the ovaries, and leave that pesty difficult stuff behind. We used to call it burned out or fibrotic lesions that didn't need any treatment.
I watched him one day chuck away at this for hours and [inaudible 00:02:39] watching, and I said, "Why have you done this, Harry?" He said, "Well, actually, go to the path lab," and there were 19 little pots. I recall it very clearly. Every one of these little pots, every one of these tiny little bits of useless fibrotic material that I thought actually contained endometriosis. My comment was, "Ah." I then realized that I had to start all over again and learn this surgery, this terribly difficult surgery, and start all over again. So, he had this very profound effect on me.
But Iain, the other guy in those photographs, Iain Chalmers, he was the guy ... he and I were new doctors together for a while, and whilst I was doing what most junior doctors do, going around, trying to get experience in cases and doing stuff, Iain was always saying, "Why are you doing that? What's the evidence for this? You know how often doctors have been wrong in things." Iain went on to found the Cochrane collaboration and really develop the concept across medicine of evidence-based medicine.
He pointed out that women's health is perhaps been a victim of bad medical understanding ever since its foundation. Here is Hippocrates here, and who could be more famous, more important in medicine than the founder of the thing. He had this philosophical concept of the four humors, and of course women with menorrhagia, they had blood, they were hot and moist, and therefore what had to happen? You had to get rid of this excess humor. So you had to bleed them. So the thought of treating heavy periods by repeated sampling of blood lasted for 2000 years. Every respectable physician throughout the world believed and followed this. So the motto of this is it doesn't matter how important people are, it doesn't matter how emphatic they are or where they're coming from, they've got to be right. This was certainly not the right thing.
Iain introduced me to the work of Archie Cochrane. Now, I know a lot of people think, particularly in surgical disciplines, that it's difficult or impossible to do proper studies. But Cochrane's view, on which the Cochrane Foundation is based, is that you can only really determine what is true and false by doing randomized controlled trials. Now, this concept I bought into in a big way. I did a lot of contributions to Cochrane reviews, I did nine actually. Then I also did a lot of randomized trials, a lot of the little simple ones of the very early things, learning the basic techniques of doing trials and finished up doing this extremely large trial, a randomized trial comparing abdominal hysterectomy, vaginal hysterectomy with laparoscopic hysterectomy though too, and it was 1,380 patients into two parallel trials.
This trial was basically very successful. It showed what we wanted to do, that laparoscopic hysterectomy was more effective than abdominal hysterectomy in terms of pain, in terms of length of stay, in terms of quality of life. So it was good. What it also showed, which ... so a lot of people took notice of this bit of the trial. What it also showed is that vaginal hysterectomy was better than laparoscopic hysterectomy when you could do a vaginal hysterectomy. A lot of people didn't take any notice of that bit of the trial because it didn't fit with something rather. But anyway, those things remained true.
This wasn't as well received as I hoped this trial would be because I feel the messenger was shot because there were actually in the laparoscopic arms six ureteric injuries, and because that suggested, at least at the time, that this was a dangerous procedure, a lot of people took exception to the conclusions. The reality is that these were beginners' efforts. This was what's happening across the field in the UK and it needed improvements in techniques and technology. Anyway, that was that.
I eventually started to do studies in endometriosis and we did quite a long-term study of 218 over two to five years and showed what we would hope to show that there was an improvement in all forms of pain management with our treatments. So this was good. Then maybe in the first or certainly early on, we started to introduce quality of life indicators to measure their response to surgery. The situation obviously is the term people don't die of endometriosis, so what we're doing is to try and improve their quality of life. So these are perhaps the better markets, and we did this study, which was okay.
Basically, I yearned and longed to do this study, it was my final randomized trial before I retired. I was trying to put into this all this other experience, and this was a laparoscopic excision of endometriosis, a randomized blinded placebo-controlled trial. Now these are, for anybody who's tried this in a surgical discipline, are really rather difficult to do and there is a whole load of things. We have to design the trial. I've learned a lot about trial design. Obviously, you've got to have the ethics approved and I won't go into that unless somebody wants to ask about it.
Equipoise, this is one of the hardest things in a surgical discipline because you have to genuinely not know the answer before you start. You have to say, "Well, it might not be correct." To get somebody who's really good at something to then say, "Well, I'm not sure it works," and then it's also a difficulty when dealing with patients to say, "Well, I'm going to give you this option or that option and I don't know which is right," and they don't have much faith in you if you don't know what you're doing. So it's really a very difficult thing to do.
Then you've got to choose the right endpoints, and this is where so many trials are a load of rubbish because if you've got a commercial or a biased interest if you choose the right endpoint, you will always get a positive answer. So it's not worth the [inaudible 00:10:08], but if I was going to sell robotic machines to do hysterectomies, I would always compare it with the length of stay of abdominal hysterectomy, or something like that. You know the answer, but it doesn't mean that this is a good idea. So you've got to choose the endpoints very carefully and you've got to choose the power of this study, you've got to know roughly how many patients you need to prove what you want to prove. You've got to adhere to this idea, you analyze the results in the way you intended, even if you don't finish up treating this, and this is all just to avoid bias. Almost, well, many, many studies, particularly in a surgical thing, are biased. Anyway, here we go.
This is the trial we set out. It was a randomized blinded controlled trial to compare the effectiveness of excision of endometriosis against placebo. Sorry, I'm pressing the wrong button. Okay. What we did, each patient had two procedures separated by six months, had baseline investigation, six months investigations, and a year assessment. The patient either had definitive surgery at the first visit, and we did everything we could at that surgery, and then reviewed them six months later to measure what was left and to assess the symptoms, or we did a diagnostic and staging procedure, waited six months, and then took away the materials. That was our delayed surgical group.
Now, these are I think self-evident, I'm not going to go into that really. Now, we went to extraordinary levels to make sure the patients and the attendance were blinded. Obviously, the surgeon couldn't be blinded, he had to know what he was going to do, but we prevented anybody else from knowing, particularly including the patient. So the first thing is we had an off-site generation of the randomization. This is very important. If you have two patients coming in for the day and there's one fat one who's had previous myocardial infarction and this other lovely slim person, then you say, "Well, I'll do my pet treatment on that one and I'll do the other treatment on this one," consciously or subconsciously, it squares the pitch completely. So you have to generate the thing off-site and we do that computer.
We have to use the same portals and the same approach to everybody, and we even went and sneakily put some of the patient's blood on the dressings of the portals just so they weren't aware. The operating records were retained in a special file in the OR, and only a simple note that they were part of the trial was sent down to the ward. The operating surgeon did ward rounds and said, "Good morning and how are you," but took no part in any management decision. The award medical staff and the nursing staff had no idea which procedure was undertaken. The patient gave their own analgesia, they had PCA, so they chose how much analgesia they had and the patient alone selected the time of discharge. This produced the perhaps expected sort of mad things. Some patients had no treatment, gave themselves loads and loads of opiates and stayed in the hospital for days and days, and one very frightening patient who had the most extensive excision that we did in the series hardly had any analgesia and went home the same day. So, the patient response was obviously quite interesting.
Actually, I forgot to say, these blobs, I chose the color of this as you do when you're doing a talk, and I thought, "I quite like the color of this," and then these blobs came up and, "It looks terrible," and then I thought, "No, actually, this talk is about a messy end point to what was started out as a good thing." So this is the good bit. These are the results that we published and I'm not going into this very much. Basically, we show that immediate surgery produced a much greater relief of symptoms than the placebo. Really nice, a lot of naughts and clinical significance. So that was good.
There were 12 people in the series who wanted the pregnancy. Six people after the operation had it and none of the patients who prior to surgery got pregnant. So we're happy that we made the thing. So this was a pain. If we looked at pain scores in both groups before and then 12 months after, there's a satisfactory response, and there was no longterm problem about whether the patient's had primary or delayed surgery. So we concluded that laparoscopic excision was more effective than placebo in reducing pain and improving quality of life. Hurrah! That's what we wrote up. That was the job done.
But this relied on a simple idea of medicine, that you make a diagnosis, and we've heard how difficult that is, we do the treatment and we've certainly continued to hear how difficult this is, but then we expect a cure, and we've purported this very much as this sort of study. But the problem with having too much time on your hands when you retire is that you can look back at these things in more detail and a less driven way, and I call this now the messy bit of this trial because it went back to the results and looked at and found some interesting or different things. Perhaps not surprisingly, there was no difference in the groups of analgesia required between those who had major surgery and those who had a diagnostic procedure.
Analgesic use was the same. Perhaps not surprising because the entry is the most painful bit of it, anyway, that was what we found. Similarly, no difference in length of stay, no difference in length of medication and treatments. So there was no difference in this study between. These facts are all well known, the severity of pain was not correlated with the severity of the disease. There was a pain without endometriosis in some patients and endometriosis without pain in others. So this is all, again, well known.
Now, what's the matter with this slide? If we looked at six months, we get in the delayed group, we get some improvement in the symptoms. Now, this is not surprising. The placebo effect is well known, and so this was an improvement in the placebo. But this was a surprise. This was the people who had an immediate operation and they were better. Their pain score was better at six months than it was. But after a further six months, when they had no further treatment, their pain score got better, better. This was true whether we looked at pain for nonmenstrual pain, whether we looked for pain with dyspareunia, whether we looked for pain with dyschesia. Of all the measurements we took, the only one that did what it was supposed to do was this particular quality of life measure EuroQol 5D where the delayed surgery stayed the same while there was an improvement in the immediate surgery. But at the end of the day, they caught up again.
So what does this mean? Even, this is more quality of life, this is short form 12, similar changes, short from a mental component, similar to whether you had the operation or not, and even sexual activity. How can this be that both of them had an improvement from baseline, whether they had the surgery or not, there was a further improvement after six months. How can we summarize all this?
Well, we can say that in the delayed surgery group, about a third of the patients reported a positive placebo response. That is in keeping with lots and lots of other studies about this. But in the immediate group of surgery, between six months and a year, more than half of the patients reported further improvement. Now, making decisions without adequate information.
My great country at the moment seems to be in the first known democracy to have willingly voted itself to be poorer and less effective. We're plotting on it a massively brilliant way at the moment, but part of the problem was that we didn't have enough information to make a proper decision. The same is true about all of these qualities of life and pain and all its ways that we try and assess things. What do we do? We've got a whole load of tick boxes or a whole load of lines to put what you feel. Now that presupposes that all these things are constant whereas the reality is how much pain you have or whether you feel depressed or not, depends as much of what the traffic was like on the way into the hospital that day or whether you had a row with your husband or whatever. Many things can alter the way and we all know, if you buy something off the internet, within a day, they will be asking you, "How was our service?" and you have to put somewhere down and then they'll quote a satisfaction level and things.
This is doing stuff, making judgments, and I think because we so effectively prevented the patients from knowing what would happen, they didn't know how properly to respond. They didn't want to say they were completely better in case they hadn't had the operation, and they didn't want to say they were terrifically better when they had nothing happen. So it really brings into question the validity of some of these tools that we've been using. The placebo effect is very well known and it's quite real and it's important. Most clinicians don't care whether it's a placebo effect or a real effect. If the patient feels better and has a real benefit, then that's fine. But what I think we did with this blinding thing is we took away all the contextual clues, the verbal clues, the emotions, and so we removed some of the drivers that gave us an assessment.
So the power of proper blinding, we have both a positive placebo relief and this thing which I haven't seen described, perhaps people who know more about these things than I do have known about this negative placebo effect, which obviously exerts something on our outcome. Okay. Moving away from the assessment.
We had the opportunity to study a patient six months after their first treatment, and we looked very carefully at this and we found that only 31% of them had no evidence of any disease after our surgery. 25% of them had some evidence of that wasn't normal but on biopsy, we didn't find endometriosis. 44%, we had a biopsy-proven disease.
Now, I'm sure David and Harry would probably say this is entirely due to the fact we were rubbish surgeons and we didn't get rid of it all. I think there is clearly an element in that. Clearly, some of this will be inadequate surgery, but I don't believe all of it is, and I will give you some more evidence in a moment. We also have the opportunity of watching over six months what happened to the group who didn't have surgery. What we found is that 45% of them up scored and in three of them, they upstaged in the sixth month. So some of them were progressing the disease quite rapidly. A third of them were unchanged and then over 20% of them were better, they downstaged. This is a dynamic situation we like to assume this is a fixed thing, we know what we're dealing with, but in fact, it changes over time, or it appears to change over time.
So some specific cases just to illustrate this, because these individual cases get lost when you summate things. So one patient had a stage two disease at first excisional surgery. Six months later, she had a stage four surgery with bilateral endometrioma. So these are definitely calm and this definitely got worse within the six months. We had thought we'd excised it all in the first. So at very least, this is a rapidly progressive disease and we couldn't have missed all of that on examination.
This is another patient who normal examination, and with very meticulous protocol, it seemed normal on pelvic examination. Six months later, there was a large extrinsic mass which was very easy to feel pressing on the rectum and vagina and producing a symptomatic stricture. We could possibly have missed it on the first, but I think that's very unlikely given our thing, and so we're suggesting this is a very rapid progression in this particular case.
Here's another one, is a lady who's had a lot of treatments elsewhere. She had four laser laparoscopies and multiple medical treatments. She came to us with stage two disease on the right-hand side, which was easily treated. Six months after, she said she'd had a wonderful response for two months, and then it got really quite bad despite union dyschesia. Then four months later at her followup, she found to have a full-thickness vaginal lesion on the left side of the cervix while the original lesion had been on the right side. So again, we're suggesting that in some cases there can be extremely rapid progress.
So the dynamics of the disease, recurrence of new disease in different sites and second inspection suggested a very rapid development and progression, but the disease may be due to the development of new disease. This I'm pretty sure is true, new Disease and not always the result of inadequate excision. Now, we could get confused by patient's response too. Initial stage two, six months later, she reported improvement in the symptoms, so she hadn't had her surgery and she felt better. She then had the definitive surgery. Six months later, she said she had no improvement, and four months after she got fed up with us, went somewhere else, and because of worsening dysmenorrhea, they not following the protocols, just took the uterus out and found no evidence clinically or histologically of any endometriosis. So the patient got better when she didn't have an operation and didn't get better when she had the operation and then had an operation and didn't have the disease. So the complexities of dealing with individuals as opposed to trying to generalize into a great thing, and so there, rather you can read these things yourself. There are other cases.
My messy conclusions, instead of this lovely thing that we do, excision and it just goes away and it's fine, is that our assessment tools probably aren't perfect, however hard we try, and these were the best-validated tools on the market at the time. Pain isn't correlated with severe lesions. Not all pain is caused by endometriotic lesions. We had a 32% positive response, 53% negative placebo response, 20% of our patients didn't respond at all. We noticed rapid recurrence and/or progression. A new disease was seen and we're suggesting not to all persistent symptoms were due to inadequate excision.
So, this leaves us with the conclusion that there are three people in this equation. There is the disease, well, three things, the patient and the surgeon, and they all vary enormously and they don't stay. Let's say the disease has a different dynamic, sometimes it's static, sometimes it gets better, sometimes it rapidly gets worse. There is an invasive component. So the disease is a variable phenomenon and not just endometriosis. The patient is a variable phenomenon, that's not a nice way to describe this, but each patient has a different potential, has different characteristics. Some people have a higher pain tolerance, et cetera, et cetera. Of course the surgeons vary enormously and clearly, you want to have Dr. operate on you and not someone who's doing two cases every decade of endometriosis. The surgical skills clearly make a big thing, but empathy as well.
The whole of the rest of the healing process, the whole of the rest of support, encouragement, identification, and the whole team that goes with people. So, at the end of the day, I think the management of endometriosis defies protocols, defies rules. It is the art of medicine. What any good doctor has always known is that you tailor your treatment for the individual patient and the art must be built on the science, but not dominated by it. Thank you very much.