Hi there.
I saw that there was a link to a letter to the editor of Fertility and Sterility from 2005 by a Dr. Clark in England posted in one of the chat rooms frequented by women with endometriosis. The letter referred to excision of endometriosis and the lack of randomised controlled trials of excision, concluding that unless and until it is proven by these randomised trials to be superior to other therapies, then it should not be recommended as a treatment. There are several issues raised in this letter that I disagree with, and I will try to explain them as simply as possible, although some of the concepts are difficult even for some doctors to understand. But here we go...
First, Dr. Clark is of the mindset that prospective randomised controlled trials (RCTs) are the only way to document effectiveness of a treatment. To understand why he is wrong takes a little background into medical research and the different types of studies. When patients are enrolled prior to treatment and randomly allocated to one of 2 or 3 groups that will undergo different treatments for the same disease, then followed to assess results, this is called a prospective (done in real time) randomized (randomly assigned) controlled (the control group is one group that either has no treatment or a well established treatment) trial. Placebo controlled trials are typically done to see if a given drug has more effectiveness than the placebo effect, which is where people think they're getting therapy so they feel better. Placebo effects are well documented for both surgery and medical treatment, and about 30% of people typically respond to placebo for a limited amount of time. Once a drug has been on the market for a while and we know it works (for example cholesterol lowering drugs), it would be unethical to have a treatment group that gets no therapy (placebo), so one drug is compared with another drug (ie Lipitor vs Vytorin) in a randomized fashion to see which drug lowers total cholesterol and LDL the most. RCTs are typically felt to be the best quality evidence available because of the lack of bias (imposing the author's own perspective on the results). However, RCTs are rarely done to study surgery, and their quality depends on how they were set up. The Women's Health Initiative (WHI) is a perfect example of a huge (15,000 pts) study that was a randomized, blinded, placebo controlled waste of money (your money as it was funded by the NIH). This was the study publicized by CNN and all the network news programs about 4-5 yrs ago where all the TV people said "stop your prempro!" because it causes heart attacks and breast cancer. The goal of the study was to see if hormone replacement therapy actually protects women from heart disease as we thought for many years based on cohort studies (see below). Unfortunately, the study design was flawed and instead of studying women who were going through menopause around age 50, they chose women with an average age of 64 who were in most cases 10 years or more past the menopausal symptoms and off HRT for that long. Then, they started the treatment group women on hormones (prempro), and tabulated the incidence of breast cancer, heart attacks, strokes, and in a sub-analysis, mental function. I don't have time to go into all the details, but suffice it to say they were shocked at the findings, and actually stopped the study early. The women in the treatment group had a higher incidence of heart attacks and dementia, contrary to what had previously been thought. After further review and several more studies designed to look at hormone replacement in women who need it (around age 50 and within 1 year of starting menopause), guess what? The women on estrogen DID have a lower risk of heart attacks AND had better mental function. The multi-million dollar RCT was wrong, and it was all because of a faulty design. Just like the Titanic (well, sorta).
The next type of study we'll examine is called a cohort study. These can be done either prospectively or retrospectively, and involve groups (cohorts) of patients that undergo a particular treatment and subsequent followup. These are the type of studies that are most often done to assess surgical outcomes. Typically, a specific type of patient is selected (ie stage IV endometriosis with no previous surgery) and a specific type of procedure is done to them (ie excision of rectovaginal endometriosis via laparoscopy) and certain outcome measures are followed over a period of time. The more specific the outcomes (quality of life questionnaires, rectal pain, lack of tenderness on exam, etc) and the longer that patients are followed without losses (ie if 100 pts had surgery and 90 are followed for 5 years then 10% are lost to follow-up) then the better the quality of information. Most of the data regarding the surgical treatment of endometriosis is in this class of studies, and most of the studies on excision clearly state the outcomes measured, and also the numbers lost to follow-up. When multiple studies done on different continents by different surgeons all agree with nearly the same results, it is probably the best quality evidence that could possibly exist. This is the case with the excision literature. One study is based on laparotomies (open surgery) with excision done on all stages of endo (Wheeler and Malinak, 1987). Redwine in 1991 wrote about a cohort of women who underwent conservative excision (without hysterectomy or oophorectomy) via laparoscopy, followed for 7 yrs. Redwine and Wright in 2001 studied women with complete obliteration of the culdesac who underwent excision, then followed them for on average 5 years. Abbott and Hawe in 2003 studied women who underwent excision in England and Australia with a 2-5 yr follow-up period. ALL of these studies had nearly identical results - a 20% likelihood of persistent endometriosis over a long follow-up period. To me, this is much better evidence that excision works than any randomized controlled study could ever be.
Another note on the RCT. I don't believe it's ethical to randomize women with pain into a surgical treatment arm vs a surgical placebo arm (making the incisions and not removing the disease). The only ethical way to do a RCT of surgical treatment of endo would be to compare excision and ablation of early stage disease. We shouldn't do it for stage IV disease, because ablation of deep disease doesn't work, as proven by cohort studies. This study of excision vs ablation for mild disease was actually done in 2004, but with only 12 pts in each group followed for 6 months. Not surprisingly, there were no differences in outcomes. Again, it seems that the better quality data comes not from the esteemed RCT, but from the consistency of results in cohort studies which have remained the same over time and continents.
Dr. Clark's second error is that he confuses chronic pelvic pain (CPP) with endometriosis. While it is true that endometriosis is one of the conditions that comprises CPP, it is the only one that is amenable to surgical excision. Several factors need consideration in order to understand the dilemma at hand. The main symptom of endometriosis is pain, but there are many other things that can cause similar pelvic pain. One of the problems we have in studying endo and responses to treatment is that we can't re-operate on everyone to assess whether or not they had resolution of their endometriosis after excision. We re-operate on the patients who have recurrence of their pain, and in general we find that about 60% of them do Not have endometriosis, ie, they're cured. Ironically, it's the patients with the deep disease (typically stage IV, some stage IIs) that have the best chance of pain relief after excision. Why is this? Most people think it's because deep endo almost always causes pain, and superficial disease may be asymptomatic. When a patient with pelvic pain from another cause (such as interstitial cystitis or IBS) undergoes a laparoscopy and is found to have stage I endo and treated for it, the initial assumption is that the pain was from the endo. But maybe the pain was actually from the IC, and the endo was a red herring. You see the problem, I think. This is why it is troubling to follow patients by symptomatology, yet we can't reoperate on every patient 5 years after their initial surgery just to see if the endo is gone, especially if they are asymptomatic.
Without a doubt there is room for more research to be done in order to direct clinicians towards the best way to treat their patients with endometriosis. This doesn't mean, however, that we "throw the baby out with the bathwater" just because we don't have the type of evidence some people want. We have to practice evidence-based medicine, yet there is always the need for common sense in order to interpret what we read.
I hope this is understandable to you all. One thing I've been impressed with since I've been here in Bend is how great an understanding of medicine many of our endo patients have. It's refreshing to have patients who truly understand treatment options, risks, benefits, and alternatives; not just not and say "Yes, doctor".
Anyway, have a great week, and let me know if you have any more questions.
Dr. Mos
ps - for those of you that wrote, next week we'll discuss the finances of medicine.
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9 comments:
>>Most people think it's because deep endo almost always causes pain, and superficial disease may be asymptomatic<<
As an endo surgeon, you should know that the pain of endo does not in most cases, correspond to the stage of the disease. In fact, patients with Stage II often have more severe pain that patients with Stage IV, who are sometimes asymptomatic and only want surgery because they are having trouble trying to conceive, this is when the find out they have endo.
Deep endo does not 'almost always' cause pain. And sometimes, superficial disease does.
>>We re-operate on the patients who have recurrence of their pain, and in general we find that about 60% of them do Not have endometriosis, ie, they're cured<< Really? Then why are they having recurring pain (if other diseases, like IBS or IC are ruled out). Simply because you can't see it doesn't mean it isn't there and is not affecting the pelvic area.
As a surgeon, you should know endo is a chronic disease that can never be cured. Patients may be asyptomatic, but that does not mean they don't have any more endo inside of them!
And what about the 20% of your patients that do have a legitimate recurrence of endo? Apparently, they aren't CURED either.
Saying you can cure endo is like saying you can cure diabetes or Chron's disease. Ridiculous!
There is a difference between saying that everyone will be cured after surgery (100% cure rate) and saying that a significant percentage of women who undergo excision have permanent pain relief and no evidence of endometriosis (56-60% cure rate).
If someone has endometriosis that is excised at their 1st surgery, then has a second surgery for pain but is found to not have endometriosis (proven by biopsies that confirm the absence of endo or any other disease) their endometriosis was cured but their pelvic pain was not. This is a difficult concept for people (including doctors and researchers) to understand, but it is vital for the following reasons. If endometriosis was incurable, then why bother operating on it? If it is thought to be incurable, or even recurrent with every monthly menses, then the 60% of patients who do have good outcomes with resolution of their disease and their pain would be deprived of the chance to get better. Nobody is suggesting that all pelvic pain can be cured by surgery. The key is to understand the difference between endometriosis and pelvic pain. By the way, type II diabetes can be cured by diet and exercise.
Dr. Mos
Well, if there is a cure for type II diabetes, I am sure the hundreds of endocrinolgists would love to know about it. Unfortunately, treatments (like diet modification & excersise) only help control & manage blood sugar. If you take away their diet & exercise, they still have diabetes. Treatments are not cures. That's why it is a chronic & incurable disease. But it can be managed. Much like endo.
Thank you for clarifying that there is a difference between saying "cured" and saying "a significant percentage ... have no evidence of endo". That was the clarification I was looking for.
However, are you saying that endo can not recurr? Ex: after 2nd surgery, there's no evidence of endo, ok, so the cause of pelvic pain might be something else, do you never operate on this patient again, never do another lap, not even 2 or 3 years later?
As for the answer to your question, why bother operating on endo if it is incurable, well, there's a simple answer: to help the patient be pain free. Any endo will cause problems and pain, as well as any adhesions. If these are removed, then the patient will be relatively pain free for some time and will have a better quality of life. (this is what happens with Chron's disease, multiple operations). Isn't that what surgery is for? To help the patient have a better quality of life & to be pain free?
I am not suggesting that pelvic pain can be cured by surgery, my point is that endo cannot be cured by surgery either, only managed.
After all, according to your own statistics, 40% of patients will experience a recurrence of pelvic pain, which may or may not be endo.
Can you comment on ovarian remnant syndrome? Dr. Redwine says that they may or may not respond to hormone treatments. My doctor told me they only way they don't respond is if they are cancerous. I have no doubt excision is the way to go so this is not to dispute that but would like to know if this is the case and any other info you have on the subject. Thank you.
First, one more thing on the word "cure".
What would you call someone who has had their endometriosis excised, and subsequently has no more pain. This patient then developed dysfunctional bleeding and at the time of her hysterectomy had no visible endo. Biopsies were done at common sites of endo, and all were negative for endometriosis.
If you don't believe in curing endo, then what do you call this?
Next, regarding ovarian remnant syndrome: there is no guarantee that ovarian tissue will respond to hormonal therapy. Women with ovarian remnant syndrome often don't respond to hormonal suppression, and the best way to resolve the pain issues is to remove the remnant of ovary along the pelvic sidewall. This usually entails removing the peritoneum of the broad ligament where the ovarian tissue is attached, which is also where endometriosis likes to hang out.
There's no reason to fear cancer just because your pain is persistent. One of the worst things about ovarian cancer is that it doesn't cause "typical" pain. If it did, no doubt we'd catch it earlier than we usually do.
Hope this helps.
Dr. Mos
>>First, one more thing on the word "cure".
What would you call someone who has had their endometriosis excised, and subsequently has no more pain. This patient then developed dysfunctional bleeding and at the time of her hysterectomy had no visible endo. Biopsies were done at common sites of endo, and all were negative for endometriosis.
If you don't believe in curing endo, then what do you call this?<<
I would say that this particular individual (and medicine should realize that every body is an individual and not every body is alike) falls into the 60% "cure" rate that you proclaim.
I would also say it was responsible that you did a subsequent surgery & biopsies.
However, this is a patient with just bleeding, not pain. Many patients after excision develop pain. Do you not open them up again to find out what is going on? Or is a patient that presents with bleeding (something that can be seen) more important than someone who complains of recurrent pain? As for the bleeding of said patient, that could be an indication of something altogether different, such as malignacy etc. It is completely separate from endometriosis, which causes debilitating pain and a host of other quality of life issues.
I would definitely call that patient cured of her endometriosis. Endometriosis excision can't cure menorrhagia (heavy bleeding) any more than it can cure brain cancer, but it can cure endometriosis.
I'm not sure what you're trying to get to with the question "is bleeding more important than pain?"
Some docs certainly are quicker to treat bleeding pts rather than pain pts because pain is harder to cure. Someone whos' bleeding will be cured of that by just removing her uterus (easy), but for someome with pain, you've got to figure out where the pain is coming from, how to fix it, then be willing to stick with them and follow them until you can make it better.
Not all pelvic pain is from endometriosis, and endo is easier to cure than generic pelvic pain.
Hope that helps.
Dr. Mos
Dear Dr Mosbrucker,
I just wanted to emphasize another reason why some studies are not reliable: the ghostwriting by the pharmaceutical industry. When there are TAP advisors in some studies saying Lupron is effective and well tolerated, it might be that those advisors never saw a patient...
Contract Research Organizations and other specialised companies payed by the pharma companies are often the real authors of these studies.
Here's a paper describing how this works:
Ghost Management: How Much of the Medical Literature Is Shaped Behind the Scenes by the Pharmaceutical Industry?
http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0040286&ct=1
Keep doing the good work! Excision surgery is the ONLY safe and efficient way to deal with endometriosis!
Elena
(French supporter of Dr Redwine and his team)
Elena,
I tried to access that article, but couldn't get to it.
Any chance you could fax a copy to me? 541-383-0021.
Thanks, I'd love to read it, and I think you're absolutely correct about the pharmaceutical industry coercing physicians and manipulating research.
Cindy
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