A Study Comparing Mirena and Systemic Progestin for Endometrial Hyperplasia

Overview

Randomized controlled multi-center study with three arms including 200 patients with low risk endometrial hyperplasia. After confirmed diagnosis the patients will receive one of the following treatments:

1. Provera (Medroxyprogesterone (MPA)/progestin) 10 mg per oral treatment for 6 months 10 day each cycle,

2. MPA 10 mg continuously for 6 months,

3. Mirena (Levonorgestrel) impregnated IUD for 6 months.

Full Title of Study: “A Multicenter Study Comparing Mirena and Systemic Progestin for Endometrial Hyperplasia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: December 2013

Detailed Description

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.

Interventions

  • Drug: Provera (medroxyprogesterone/progestin)
    • 10 mg tablet, 1 tablet per day taken 10 days per month Duration is 6 months
  • Drug: Provera (medroxyprogesterone)
    • 10 mg per oral tablet. One tablet per day for 6 months
  • Device: Mirena (levonorgestrel)
    • Inserted in the uterine cavity and kept in situ for 6 months

Arms, Groups and Cohorts

  • Active Comparator: MPA 10 mg per oral cyclic for 6 months
    • The peroral treatment is used 10 days each month
  • Active Comparator: MPA 10 mg per os continuous 6 months
    • Per oral MPA 10 mg is taken daily for 6 months
  • Active Comparator: LNG-IUD for 6 months
    • Levonorgestrel impregnated IUD is inserted into the uterine cavity and kept in situ for 6 months

Clinical Trial Outcome Measures

Primary Measures

  • Regression of hyperplasia related to treatment arm after 6 months of therapy
    • Time Frame: Six months

Secondary Measures

  • Recurrence of hyperplasia related to treatment arm during follow-up period
    • Time Frame: Two years
  • Side effects during treatment
    • Time Frame: Two years

Participating in This Clinical Trial

Inclusion Criteria

  • Histologically confirmed endometrial hyperplasia,
  • D-score > 0,
  • Age 30-70 years,
  • No contra-indications against progestin hormones,
  • Written consent,
  • Patients who have been treated with transcervical resection need a histologically confirmed diagnosis of hyperplasia taken after the TCR

Exclusion Criteria

  • D-score < 0,
  • Age < 30 or > 70,
  • Increased sensitivity to progestins,
  • Pregnancy,
  • Infection or cancer in genitalia or mammary gland,
  • Liver disease,
  • Serious thrombophlebitis.

Gender Eligibility: Female

Minimum Age: 30 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University Hospital of North Norway
  • Collaborator
    • Helse Nord
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Anne Ørbo, MD, PhD, Principal Investigator, University of Tromso

References

Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer. 1985 Jul 15;56(2):403-12.

Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol. 1989 Jan;160(1):126-31.

Orbo A, Baak JP, Kleivan I, Lysne S, Prytz PS, Broeckaert MA, Slappendel A, Tichelaar HJ. Computerised morphometrical analysis in endometrial hyperplasia for the prediction of cancer development. A long-term retrospective study from northern Norway. J Clin Pathol. 2000 Sep;53(9):697-703.

Vereide AB, Arnes M, Straume B, Maltau JM, Ørbo A. Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol. 2003 Dec;91(3):526-33.

Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol (Oxf). 1982 Dec;17(6):529-36.

Scarselli G, Tantini C, Colafranceschi M, Taddei GL, Bargelli G, Venturini N, Branconi F. Levo-norgestrel-nova-T and precancerous lesions of the endometrium. Eur J Gynaecol Oncol. 1988;9(4):284-6.

Ørbo A, Arnes M, Hancke C, Vereide AB, Pettersen I, Larsen K. Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only. Gynecol Oncol. 2008 Oct;111(1):68-73. doi: 10.1016/j.ygyno.2008.06.014. Epub 2008 Aug 6.

Baak JP, Nauta JJ, Wisse-Brekelmans EC, Bezemer PD. Architectural and nuclear morphometrical features together are more important prognosticators in endometrial hyperplasias than nuclear morphometrical features alone. J Pathol. 1988 Apr;154(4):335-41.

Perino A, Quartararo P, Catinella E, Genova G, Cittadini E. Treatment of endometrial hyperplasia with levonorgestrel releasing intrauterine devices. Acta Eur Fertil. 1987 Mar-Apr;18(2):137-40.

Vereide AB, Kaino T, Sager G, Ørbo A; Scottish Gynaecological Clinical Trials Group. Bcl-2, BAX, and apoptosis in endometrial hyperplasia after high dose gestagen therapy: a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol. 2005 Jun;97(3):740-50.

Vereide AB, Kaino T, Sager G, Arnes M, Ørbo A. Effect of levonorgestrel IUD and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (PRA and PRB), and estrogen receptors (ER-alpha and ER-beta) in human endometrial hyperplasia. Gynecol Oncol. 2006 May;101(2):214-23. Epub 2005 Dec 1.

Moe BT, Vereide AB, Orbo A, Jaeger R, Sager G. Levonorgestrel, medroxyprogesterone and progesterone cause a concentration-dependent reduction in endometrial cancer (Ishikawa) cell density, and high concentrations of progesterone and mifepristone act in synergy. Anticancer Res. 2009 Apr;29(4):1047-52.

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