• Number of patients who have responded to their respective treatment as determined by their re-evaluation biopsy and hysterectomy specimens [ Designated as safety issue: No ]
• Frequency and severity of adverse effects as assessed by CTCAE v3.0 [ Designated as safety issue: Yes ]
• Discordance in diagnosis between the re-evaluation biopsy and the hysterectomy [ Designated as safety issue: No ]
• Relationship between the endometrial thickness and post-treatment diagnosis for those women whom a pre-treatment transvaginal ultrasound is available [ Designated as safety issue: No ]
• PTEN biomarker [ Designated as safety issue: No ]
• Hormone responsivity measures (receptor studies) [ Designated as safety issue: No ]
• Patterns of protein and glycoprotein expression [ Designated as safety issue: No ]

• Number of patients who have responded to their respective treatment as determined by their re-evaluation biopsy and hysterectomy specimens
• Frequency and severity of adverse effects as assessed by CTCAE v3.0
• Discordance in diagnosis between the re-evaluation biopsy and the hysterectomy
• Relationship between the endometrial thickness and post-treatment diagnosis for those women whom a pre-treatment transvaginal ultrasound is available
• PTEN
• Hormone responsivity measures (receptor studies)
• Patterns of protein and glycoprotein expression

• Karyometry [ Designated as safety issue: No ]
• Morphology [ Designated as safety issue: No ]
• Histopathology [ Designated as safety issue: No ]
• Presence or absence of myoinvasion in the hysterectomy specimens [ Designated as safety issue: No ]
• Presence or absence of deep myoinvasion in the hysterectomy specimens [ Designated as safety issue: No ]

• Karyometry
• Morphology
• Histopathology
• Presence or absence of myoinvasion in the hysterectomy specimens
• Presence or absence of deep myoinvasion in the hysterectomy specimens

RATIONALE: Estrogen can cause the growth of endometrial cancer cells. Hormone therapy using megestrol may fight endometrial cancer by blocking the use of estrogen by the abnormal cells.

PURPOSE: This randomized phase II trial is studying how well megestrol works in treating patients with endometrial neoplasia or endometrial hyperplasia.

OBJECTIVES:

Primary

• To determine the frequency of remission of a community biopsy diagnosis of atypical endometrial hyperplasia (AEH) or endometrial intraepithelial neoplasia (EIN) at the time of hysterectomy in patients treated with continuous versus interrupted progestin therapy versus patients who receive no progestin treatment.
• To determine the frequency of complete remission of central pathology panel diagnosed EIN patients treated with continuous versus interrupted progestin therapy versus patients who receive no progestin treatment.

Secondary

• To evaluate the differences between the outcome assessments based on the re-evaluation endometrial biopsy done prior to hysterectomy and histopathologic review of the hysterectomy specimen.
• To evaluate whether endometrial thickness on transvaginal or transabdominal ultrasound correlates with AEH or EIN and/or invasive cancer with or without myometrial invasion.
• To examine the association of histologic response to megestrol.
• To identify patterns of protein and glycoprotein expression associated with invasive cancer in serum specimens obtained from patients with a diagnosis of AEH or EIN who have been randomized to the control arm.
• To assess differences in plasma concentrations of megestrol acetate among the three arms using high-performance liquid chromatography (HPLC).
• To assess patient compliance to their treatment regimen using HPLC to determine plasma concentrations of megestrol.
• To explore the correlation between megestrol concentrations using HPLC and pharmacodynamic response as assessed in hysterectomy specimens.

OUTLINE: Patients are stratified according to the collection method of the initial/intake biopsy (dilatation and curettage vs all other methods). Patients are randomized to 1 of the following treatment regimens:

• Regimen 1: Patients receive oral megestrol twice daily every day for 12 weeks. Approximately six weeks after treatment starts, clinical blood tests will be obtained and research serum and plasma collected. Twelve weeks will constitute one course of treatment and a pill count should be performed at the completion of the treatment course to determine compliance. After progestin therapy the patient will have an induced withdrawal bleed. Patients in this arm will undergo a re-evaluation biopsy and hysterectomy a minimum of two weeks and a maximum of eight weeks after completing the megestrol treatment.
• Regimen 2: Patients receive oral megestrol twice daily for two weeks continuously followed by no treatment for two weeks. This cycle will be repeated for a total of 12 weeks. Approximately six weeks after treatment starts, clinical blood tests will be obtained and research serum and plasma collected. Twelve weeks will constitute one course of treatment and a pill count should be performed at the completion of the treatment course to determine compliance. After progestin therapy the patient will have an induced withdrawal bleed. Patients in this arm will undergo a re-evaluation biopsy and hysterectomy a minimum of two weeks and a maximum of eight weeks after the megestrol treatment.
• Regimen 3: Patients do not receive megestrol. At the discretion of the managing physician, patients undergo the re-evaluation biopsy and hysterectomy anytime between 2-20 weeks after enrollment and randomization.

Patients undergo biopsy and blood sample collection periodically for immunological and pharmacodynamic studies. Samples are analyzed for presence or absence of myoinvasion or deep myoinvasion in hysterectomy specimens, hormone receptivity status, and to compare PTEN status against treatment via karyometry or morphometry, expression of VEGF and tenascin-C (TN-C) via ELISA, presence of TN-C fragmentation via western immunoblots, additional biomarkers via proteomic analysis, protein and glycoprotein expression patterns via electrophoresis and image analysis, and plasma megestrol concentrations via high-performance liquid chromatography (HPLC).

There will be no additional follow-up on this study after the patient's hysterectomy.

• Endometrial Cancer
• Precancerous/Nonmalignant Condition

• Drug: megestrol acetate
• Procedure: conventional surgery

• Experimental: Patients receive oral megestrol twice daily every day for 12 weeks. Approximately 6 weeks after treatment starts, clinical blood tests will be obtained and research serum and plasma collected. Twelve weeks will constitute one course of treatment and a pill count should be performed at the completion of the treatment course to determine compliance. After progestin therapy the patient will have an induced withdrawal bleed. Patients in this arm will undergo a re-evaluation biopsy and hysterectomy a minimum of 2 weeks and a maximum of 8 weeks after completing the megestrol treatment.
• Experimental: Patients receive oral megestrol twice daily for two weeks continuously followed by no treatment for 2 weeks. This cycle will be repeated for a total of 12 weeks. Approximately 6 weeks after treatment starts, clinical blood tests will be obtained and research serum and plasma collected. Twelve weeks will constitute one course of treatment and a pill count should be performed at the completion of the treatment course to determine compliance. After progestin therapy the patient will have an induced withdrawal bleed. Patients in this arm will undergo a re-evaluation biopsy and hysterectomy a minimum of 2 weeks and a maximum of 8 weeks after the megestrol treatment.
• Active Comparator: Patients do not receive megestrol. At the discretion of the managing physician, patients undergo the re-evaluation biopsy and hysterectomy anytime between 2-20 weeks after enrollment and randomization.

DISEASE CHARACTERISTICS:

• Inclusion Criteria:

  • Histologically confirmed atypical endometrial hyperplasia (AEH) or endometrial intraepithelial neoplasia (EIN)

    • Diagnosed by dilatation and curettage (D&C), Novak curettage, Vabra aspirate, or Pipelle endometrial biopsy at the enrolling institution within 6 weeks of enrollment
    • Must agree to a hysterectomy

• Exclusion Criteria:

  • Patients with recognized endometrial carcinoma

PATIENT CHARACTERISTICS:

• Inclusion Criteria:

  • GOG performance status 0-2
  • WBC ≥ 3,000/mm^3
  • Platelets ≥ 100,000/mm^3
  • Granulocytes ≥ 1,500/mm^3
  • Creatinine ≤ 2 mg/dL
  • Bilirubin ≤ 1.5 x institutional upper limit normal
  • SGOT and alkaline phosphatase ≤ 3 x institutional upper limit normal
  • Patients of childbearing potential must have a negative serum pregnancy test within 14 days of enrollment and must use appropriate nonhormonal contraception while on study

• Exclusion Criteria:

  • GOG performance status of 3 or 4
  • Patients who cannot complete the study
  • Patients who are considered inoperable
  • Patients with current or prior history of breast cancer
  • Patients with invasive malignancies, with the exception of nonmelanoma skin cancer who had (or have) any evidence of the other cancer present within the past 5 years or whose previous cancer treatment contraindicates this protocol therapy
  • Patients who are pregnant or lactating
  • Patients with a history of thrombophlebitis, thromboembolic phenomena, or cerebrovascular disorders

PRIOR CONCURRENT THERAPY:

• Exclusion Criteria:

  • Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded
  • Patients who have received prior chemotherapy for any abdominal or pelvic tumor are excluded