Trial Information

A Multicenter Study Comparing Mirena and Systemic Progestin for Endometrial Hyperplasia

Background:

Endometrial cancer is the most common gynecologic cancer in the Western world and the
incidence is still increasing. Endometrial cancer is principally developing through
preliminary stages called endometrial hyperplasia and 10-30 per cent will develop into
carcinoma when left untreated. The incidence of endometrial cancer in Norway is presently
about 650 cases per year and about 3000 cases of endometrial hyperplasia are estimated.
Thus,correct and optimal treatment of endometrial hyperplasia will contribute to prevent
endometrial cancer development and also in the long term, to reduce the incidence of
endometrial cancer. Correct treatment of endometrial hyperplasia includes operative
treatment with hysterectomy of the high risk cases and conservative treatment and follow up
for patients with lower risk. As diagnostics of endometrial hyperplasia has been a challenge
to pathologists, overtreatment of patients with low risk of cancer development is
unfortunately still a problem. In the present study an objective scoring system, D-score, is
used to classify the patients into low and high risk hyperplasia. D-score in an objective
morphometric analysis and the scoring system has proved reliable to predict the prognosis of
each single case as to cancer development or not. By tradition low risk endometrial
hyperplasia is treated conservatively with progestin hormones, however, no national routines
really exist according to dose, type of progestin, treatment time or distribution route,
however, varying doses of per oral treatment is mostly used.

Progestins hormones are known to have a growth regulatory effect on the uterine mucosa.
However, treatment success after per oral therapy has shown that up to 50% are
non-responders after per oral treatment. On the other hand a few recent studies have
reported successful results after using the LNG-IUD as treatment for endometrial hyperplasia
with 100 per cent treatment response.

The levonorgestrel impregnated impregnated intrauterine originally constructed for
menorrhagia and contraceptive use, is delivering more than hundred times increased
concentration of progesterone to the uterine mucosa compared to per oral therapy. Thus , the
favourable treatment is attributable to the increased concentration of progestins obtained
in the uterine mucosa. Another advantage is that treatment can last for years and that
side-effects seen for per oral treatment after progestin therapy can be avoided.

Inclusion:

Most of the patients in the present study are seeing their gynecologist due to irregular
bleedings.Biopsy is routinely taken by the gynecologist to exclude malignancy or verify
hyperplasia. The biopsy is investigated routinely by a the local pathologist. If the
diagnosis of hyperplasia is verified and the patient fulfils the inclusion criteria, the
histological specimen is sent to the laboratory in Tromsø for D-score. When D-score is >0,
the patient may be included in the study.

D-score:

The D-score system is dividing the patients into three risk groups:

1. Patients having a D-score <0 are shown to have a high risk of cancer development are
recommended hysterectomy.

2. Patients having D-score >1 have very low risk of cancer development and are recommended
progestin treatment.

3. Patients having D-score 0-1 have an uncertain risk of cancer development and may be
treated conservatively. Only patients with D-score > 0 may be included in the study.

Randomization:

When the gynecologist receive the diagnosis and the D-score results and the D-score is in
accordance with the inclusion criteria, the patients is asked by her gynecologist to be
included in the study.

If consent is given, the randomization is performed by telephone contact with the
randomization office , UNN, Tromsø, after written informed consent. The patient is free to
leave the study any time without argument.

Treatment:

After randomization the treatment according to assigned treatment arm can be started. During
the therapy period the patient will be controlled with repeat biopsy after 3 months and at
the end of treatment after 6 months. D-score is repeated if hyperplasia persists. If a
negative D-score is performed, the patient will have to leave the study. If D-score is
still positive the patient will also leave the study, new therapy is then decided by the
local gynecologist.

Control:

All patients will be controlled with repeat biopsy every six month for two years after end
of therapy. If recurrence of hyperplasia occurs the patient will leave the study and receive
other therapy decided by her own gynecologist after repeated D-score.

Side effects:

All side effects which can be related to treatment during treatment and/or follow-up will be
reported.