Wrong questions lead to wrong answers

The PRE-EMPT trial recruiting actually in the UK  is likely to be a biased trial which can generate only biased results.

“Thirty two hospitals throughout the UK have joined a large national clinical trial to find out if long acting progestogen treatment (either Mirena Coil® or Depo-Provera®) is more effective compared to the oral contraceptive pill in preventing the recurrence of symptoms and improving quality of life following conservative surgery for endometriosis”.

With all restrictions imposed by the fact that I do not have access to the details of trial, the following comments are made

The first question is whether it is useful to give medical treatment following endometriosis surgery. Since no treatment is not an option , this trial is biased since it seems established that medical treatment is needed to prevent recurrences. To the best of my knowledge, there is no solid evidence that medical treatment prevents recurrences or stops growth in all women. Indeed a pregnancy can lead to bowel perforations in some women with deep endometriosis. For superficial endometriosis the evidence is very scanty and not conclusive. Today it cannot be excluded that growth of endometriosis persist during medical treatment. It even cannot be excluded that endometriosis becomes more aggressive during medical treatment, similar to breast cancer which is less estrogen receptor positive in an estrogen poor environment.

The second problem is the comparison of oral contraception with Mirena or Depo-provera. Indeed oral contraception and depo-provera suppress ovarian activity whereas Mirena does not. In addition the lack of randomisation between Mirena and Depo-provera opens the door to advise Mirena selectively to women with adenomyosis.

Medical treatment is not a solution for incomplete surgery. This is a problem if the trial is done without video-registration permitting to check that all endometriosis was diagnosed and that excision was complete.

Medical treatment and adenomyosis. The pain reduction of endometriosis surgery in women with adenomyosis is less than in women without adenomyosis. Given the age range of 16 to 45 years let us hope that strict criteria for stratification of women with and without adenomyosis exist. Given the choice of the 3 drugs, this however, is not very likely.

Subtle, typical, cystic and deep endometriosis. It will be interesting to see whether women with subtle endometriosis only are considered women with endometriosis. Indeed, there is no evidence that subtle lesions only cause pain or progress to more severe disease. To judge recurrence rates of cystic ovarian endometriosis, ovarian activity should be the first variable to standardize, what is not done given the choice between Mirena and Depo Provera. Deep endometriosis is not that frequent and there is reasonable doubt that not all 32 participating hospitals are equally skilled in deep endometriosis excision, thus introducing another bias.

The lack of blinding and the placebo effect

Philippe R. Koninckx and Anastasia Ussia

Gruppo Italo Belga

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