A critical appraisal of endometriosis

David Olive, MD and Dan Martin, MD
Click here to view the video (Download RealPlayer free)

Dan Martin, MD:  I’m Dr. Dan Martin from Memphis, Tennessee, at the University of Tennessee. We are at the American Society of Reproductive Medicine meeting in San Antonio, Texas. With me today is Dr. David Olive of the University of Wisconsin in Madison. David, how are you today?

David Olive, MD:  Hi, I’m doing fine.

Dan Martin, MD:  We’re here today to discuss yesterday’s post-graduate course on endometriosis. Were there any new findings in your meeting yesterday?

David Olive, MD:  Well, yesterday’s course was designed to be a comprehensive review of all of endometriosis. We covered virtually every aspect of the disease. We talked about pathophysiology, and all of the basic science research that’s gone into trying to uncover the basis of endometriosis. We talked about medical therapy, surgical therapy, assisted reproduction, and we talked about some recent advances that are attempting to be made in terms of the treatment of the disease; primarily medical but also in terms of the state-of-the-art, where we’re at surgically.

Dan Martin, MD:  I believe the first talk was by Dr. Kathy Sharpe-Timms, of Missouri. She talked to a large degree on her immunologic evaluation and work at this point.

David Olive, MD:  Kathy has really broken down the entire pathogenetic process of endometriosis to the various components that are required in order to place endometrium in the pelvis. To allow it to plant and grow properly, and all of the work that’s been done on each of the factors involved in those processes. A number of basic scientists around the country now have made great headway in terms of not only localising the important enzymes, and immunologic factors that are involved, but also making headway in terms of the genetics that are involved in allowing people to be more susceptible to processes that cause endometriosis.

Dan Martin, MD:  Was she able to tell us whether Dr. Sampson was right or not?

David Olive, MD:  I think what she told us was that Dr. Sampson was probably right to a major degree, and that although there probably are other mechanisms, they probably take a back seat to the transplantation theory.

Dan Martin, MD:  And Dr. Eric Surrey also presented from Colorado?

David Olive, MD:  Yes, Dr. Surrey spoke about medical therapies, both in terms of the treatment of endometriosis associated pain, and endometriosis associated infertility.

Dan Martin, MD:  Were there any new findings there?

David Olive, MD:  I think some of the newer findings related to pain were the most recent data on addback therapy, which makes it look as good as we have always anticipated that it would be. I think in terms of infertility, there’s nothing really new in terms of medical therapy, aside from the recognition that assisted reproduction is probably the way to go if you’re going to utilise medical therapy to some extent.

Dan Martin, MD:  I believe you developed data that showed that excision is better than coagulation, but that coagulation and medical suppression are equal to excision.

David Olive, MD:  Right, after you showed us all the different methods of treating endometriosis surgically. You pointed out that there were types of coagulation or ablation, as well as excision of the disease, and the different methods that could be utilised for each. What I tried to do was review the data on that. In this year we have data that suggests that both excision and ablation are better than doing nothing, but the best evidence we have suggests that excision is a better modality to utilise than ablation. So, if you have a choice of the two, it’s better to cut the disease out than simply to fry it, or to try and vaporise it with a CO₂ laser.

The disadvantage comes in terms of complications. It appears that a good number of complications can, and do, exist when people excise. If you’re a good surgeon, if you’re a great surgeon, you may be able to minimise your complications. But I think our biggest concern is that the average surgeon may not be able to keep the complications to a minimum. The consequences of the surgery may offset the advantages.

Dan Martin, MD:  I believe one interesting talk you did on statistics and how statistics work, suggested that one of the options we might have in a research study is not to randomise the patients, but to randomise the surgeons.

David Olive, MD:  That’s true. We have just an incredible shortage of randomised trials, and certainly in the surgical approach to treating endometriosis, the number of randomised trials that we have can be counted on one hand. So it would be nice if we could create large, multicentre, surgical trials. The trouble is, people have their own ways of treating endometriosis and they are good at it. And so to ask them to randomise to two different techniques would be very difficult to do.

Instead, what might be better is if we could randomise to the surgeons. If I can randomise to surgeon A, who does treatment A, or surgeon B, who does treatment B, and each of them happens to be very good at what they do, then we could get a real idea of which of the treatments happens to be better.

Dan Martin, MD:  Were there other specific points that you wanted to be sure the clinicians would understand?

David Olive, MD:  I think it’s important to understand that not all trials are created equally. There are good randomised trials and poor randomised trials. There are other types of studies that have been utilised. The important thing is to know that there is a hierarchy of evidence; that some pieces of evidence are better. It’s nice to have randomised trials, but in the absence of them, there are pieces of data that in this year represent the best available data, and that’s what we have to go with.

For instance, we don’t have randomised data that suggests that there’s a better way to do surgery, but we do have some comparative data, albeit non-randomised, that suggests that excision is better than ablation. That’s what we have to go with in lieu of a randomised trial. I think the point to the clinician is to look at information with a jaundiced eye; try and understand that there is good and poor quality. It’s not all created equally, and weighed equally, in terms of making a judgment.

Dan Martin, MD:  What other ideas did you come away with for research in the future?

David Olive, MD:  I think one of the hot areas right now is the development of new medications as opposed to other techniques for treating endometriosis. As we’ve learned more about the basic science of the disease, as we understand more about the specific compounds that are required to allow implantation, to allow growth, and the types of things that might inhibit those actions, we can now target specific drugs for those molecules.

For instance, we’ve developed a large number of immunologic antagonists that can affect one specific aspect of the immune system. We’ve developed specific drugs for specific enzymes that are involved in the implantation, or the vessel development area of endometriosis, such that we can target those areas. Perhaps attack them very specifically, and fight either development or maintenance of the disease utilising that technique.

It’s a very exciting time I think for endometriosis drug development because more than anything else we have new targets to develop those drugs towards.

Dan Martin, MD:  Can you discuss thalidomide and its uses in this situation, which I found to be interesting in Dr. Sharpe-Timm’s discussion.

David Olive, MD:  Thalidomide is a well-known drug that has a very storied background in terms of birth defects. But its basic action is to prevent new vessel development. We certainly know that endometriosis requires a blood supply in order to implant and grow. The theory is that if you have thalidomide on board it might prevent the development of new endometriosis. Trials in rodents have suggested that it might well be effective in this regard.

There are also a number of other drugs, not just the old drug thalidomide. A number of other drugs that are now being targeted for exactly that purpose; to try and prevent the development of new vasculature that would allow endometriosis to implant and grow, VEGF inhibitors. VEGF is an important molecule in the entire process of developing new blood vessels.

VEGF inhibitors are now being developed actively by a number of different drug companies for a number of different areas, primarily in oncology, but that certainly might have applications in the endometriosis arena too.

Dan Martin, MD:  You had suggestions for preparing patients for their first visit for chronic pelvic pain associated with endometriosis. Things that might help patients be ready for that.

David Olive, MD:  I gave a discussion about how the clinician should approach the patient with chronic pelvic pain, and I think one of the problems is that we get into a rut when we talk about endometriosis and pain. A patient walks in, and she has some pain and we think, “Ah, must be endometriosis” Or, “It’s gynaecologic pain, I don’t know what to do but we probably should just treat with Lupron, or we should just treat with oral contraceptives, or we should just treat with non-steroidals.”

My suggestion was, first of all, that the clinician be thinking about other diseases because the pelvis contains a lot of structures, many of which can cause pain, many of which are not gynaecologic in origin. I also thought that it would probably be a good idea to have the patient come prepared. So send out a questionnaire, or a packet to the patient that contains information about what the visit is going to be like, what sort of things are going to be covered. A questionnaire that’s fairly comprehensive about all of the different aspects of their pain, and all the different types of disorders that could cause pain within the pelvis, might be helpful to the clinician to have on board as the patient first comes into their office.

That’s what we do at our centre, we send out a packet. The patient fills it out and they come prepared. They give us the information and now we’re prepared to actually see them and get the most out of their hour visit.

Dan, maybe you can tell us a little bit about what you talked about yesterday, which was basically an overview of surgical techniques. And the advantages and disadvantages as you saw them of the different techniques as they’re applied to endometriosis.

Dan Martin, MD:  We have a large number of techniques available. A large number of different types of equipment, including lasers, harmonic scalpels, bipolar electric surgery, monopolar electric surgery, and other modalities; all of which seem to work well in the hands of anyone who becomes expert with them. So I talked very little about that as I think that’s going to be more related to operator familiarity with the equipment, and expertise with it, rather than the equipment itself.

Two of the major areas that I discussed, which were important to me, were knowledge of anatomy as it might apply to making certain decisions on how to perform the surgery.

One of the specific areas was Harry Reich’s 1991 technique of using a recto vaginal probe to determine cul-de-sac obliteration. As we understand, when the cul-de-sac is obliterated, the rectal vaginal septum is approached and the rectal sigmoid colon is often involved. In those situations, any surgery that we do increases significantly the risk to the patient. If we use that probe tip to see if the rectal vaginal area is intact, it will help us determine those areas of endometriosis which appear to be separate from the bowel, and those areas which may involve the bowel.

David Olive, MD:  You also suggested another technique for that. The vagina was filled with fluid through a Foley catheter in order to distend the area near the cul-de-sac, was it not?

Dan Martin, MD:  Yes, this is an interesting technique published this year by Dessole [1].  He calls this a vagino-sonogram.  He places a Foley cather in the vagina and then a sonogram probe.  With these in place, 200 to 400 ccs of saline are placed within the vagina.  Using this, he has significantly increased his ability to find recto-vaginal nodules, and recto-vaginal endometriosis compared with simple sonography and other techniques alone.

David Olive, MD:  What other new techniques were you talking about that were published recently that may help the surgeon identify deep disease?

Dan Martin, MD:  T he other techniques we continue to have research on are MRIs, on general sonography, on rectal sonography and others. There’s still some controversy about how useful they are, or are not, but those would be techniques in development.  

References

1.  Dessole S. Sonovaginography is a new technique for assessing rectovaginal endometriosis. Fertil Steril  2003; 79: 1023-1027.