Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II Randomised Clinical Trial of Mirena® ± Metformin ± Weight Loss Intervention in Patients With Early Stage Cancer of the Endometrium
Brief Summary: Currently the standard treatment for early stage endometrial cancer or endometrial hyperplasia with atypia is a total hysterectomy (an operation to remove the uterus) and removal of both ovaries. While highly effective, this surgery carries significant side effects for:

* young women who still wish to have children and would lose fertility; and
* women with one or more disorders (or diseases) in addition to the early stage endometrial cancer or endometrial hyperplasia with atypia and/or morbid obesity who are at risk for surgical complications making surgery unsafe.

This study will access a new approach to the treatment of endometrial cancer to spare women of having to undergo major surgery that may be unwanted or unnecessary.

Mirena is approved in Australia for contraception, to treat heavy bleeding, and to prevent thickening of the lining of the uterus (endometrial hyperplasia) during oestrogen replacement therapy (HRT). However it is not approved to treat early stage endometrial cancer or endometrial hyperplasia with atypia. This research project will test to see if Mirena is an effective treatment for early stage endometrial cancer and endometrial hyperplasia with atypia.

Metformin is approved in Australia to treat Diabetes. However it is not approved to treat early stage endometrial cancer or endometrial hyperplasia with atypia. Therefore, it is an experimental treatment for early stage endometrial cancer and endometrial hyperplasia with atypia. This means that it must be tested to see if it is an effective treatment for early stage endometrial cancer and endometrial hyperplasia with atypia.

Weight loss interventions are feasible and safe, and already being implemented by gynaecologic oncologist to make women eligible for surgery. Weight loss of 7% body weight induces a large biological effect (for example reduces incidence of diabetes by 58%, and hypertension by 26%).


Options:
A: Inclusion Criteria:

* Diagnosed with Stage I-IIIA breast cancer within the previous 10 years
* Have completed initial treatments (i.e., surgery, adjuvant chemotherapy, radiation therapy)
* Have initial BMI \>25.0 kg/m2
* A minimum of 15 kg over ideal weight
* Willingness and ability to attend group meetings and to maintain contact with the investigators for 18 months
* Ability to provide dietary and exercise data by telephone at prescribed intervals.

Exclusion Criteria:

* Inability to participate in physical activity because of severe disability
B: Inclusion Criteria:

* Diagnosis of breast cancer (stages I (≥1 cm), stage II, or stage IIIA, B, C excluding distant metastasis) diagnosed between 6 months and 5 years earlier; after initial therapies are completed, diagnosed between six months and five years earlier
* BMI between 25 to 45 kg/m2
* Able to comply with all required study procedures and schedule

Exclusion Criteria:

* Serious medical condition or psychiatric illness
* Inability to be moderately physically active
* Obesity of known endocrine origin (e.g., untreated hypothyroidism, PCOS)
* Currently enrolled in a weight loss program
* Current use of weight loss medication or supplements
* Previous surgical procedures for weight reduction
* Planning weight loss surgery in the next 2 years.
* 6+ months use of meds likely to cause weight gain or prevent weight loss
* Planned surgical procedure that can impact the conduct of the study
* Currently pregnant/breastfeeding
* Planning to become pregnant within the next 2 years
* Have plans to relocate from area within 2 years
* Family relative or close friend is a trial staff member or a study participant
* Any condition which in the opinion of the investigator makes the subject unsuitable for inclusion in this study
C: DISEASE CHARACTERISTICS:

* Diagnosed colorectal, prostate, or female breast cancer

  * At least 5 years beyond date of diagnosis with no clinical evidence of progressive disease or second primaries
* Body mass index ≥ 25 kg/m\^2 and \< 40 kg/m\^2
* Currently exercising \< 150 minutes/week
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Menopausal status not specified
* No serious intercurrent medical condition or disability that could preclude study treatment, including any of the following:

  * Severe orthopedic condition or scheduled hip or knee replacement within the next 6 months
  * Paralysis
  * End-stage renal disease
  * Dementia
  * Unstable angina
  * Heart attack, congestive heart failure, or pulmonary condition that required oxygen or hospitalization within the past 6 months
* Ability to read, write, and speak English

PRIOR CONCURRENT THERAPY:

* No concurrent warfarin
D: Inclusion Criteria:

1. Females with a BMI \> 30 kg/m2 wishing to retain fertility or females who are at high risk of surgical complications due to co-morbidities or obesity
2. Over 18 years of age at time of randomisation
3. Histologically confirmed complex endometrial hyperplasia with atypia or grade 1 endometrioid endometrial adenocarcinoma on a curette or endometrial biopsy
4. CT or MRI scan of pelvis, abdomen and chest (or chest X-Ray) suggesting the absence of extrauterine disease
5. Myometrial invasion on MRI of not more than 50%, for women with histologically confirmed Endometrial Cancer only (for women who are unable to fit into an MRI machine inclusion into trial is at investigators discretion)
6. No lymph vascular invasion on curetting or pipelle, if able to be assessed on sample
7. Serum CA125 ≤ 30 U/mL
8. No hypersensitivity or contraindications for Mirena
9. Ability to comply with endometrial biopsies at specified intervals
10. Negative serum or urine pregnancy test in pre-menopausal women and women \< 2 years after the onset of menopause
11. Creatinine \< 150µmol/L (1.7 mg/dL) to be randomised into Mirena + Metformin arm (can still be eligible to be randomised to Mirena only or Mirena + Weight Loss, see section 5.4 Other Eligibility Criteria Considerations)

Exclusion Criteria:

1. ECOG performance status \> 3
2. Grade 1 endometrioid adenocarcinoma of the endometrium with myometrial invasion deeper than 50% on MRI or any patients with grade 2 or grade 3 endometrioid adenocarcinoma
3. Histological (cell) type other than endometrioid adenocarcinoma (sarcomas or high risk endometrial e.g. papillary serous, clear cell)
4. Pregnant or planning to become pregnant during trial period
5. Has had prior treatment or undergoing current treatment for EAC or EHA
6. Patients with a history of pelvic or abdominal radiotherapy
7. Unwilling to have additional endometrial biopsies or curettes and unable to attend three monthly clinical assessments
8. Unable to provide informed consent
9. Unable or unwilling to complete questionnaires
10. Evidence of extrauterine spread on medical imaging
11. Congenital or acquired uterine anomaly which distorts the uterine cavity
12. Acute pelvic inflammatory disease
13. Conditions associated with increased susceptibility to infections with microorganisms (e.g., AIDS, leukaemia, IV drug abuse) according to the patients Medical History
14. Genital actinomycosis
15. Current other cancer, except low grade malignancies that do not require any systemic treatment or treatment to the pelvis
16. Breastfeeding mothers
17. Mirena inserted greater than 12 weeks before randomisation/enrolment
18. Previous use of Mirena within the last 5 years from randomisation/enrolment
19. Contraindications to both Metformin and weight loss

Answer: D