This is a single-center, randomized, open-label, controlled clinical trial evaluating whether adding orlistat to standard progestin therapy can improve treatment response in patients receiving fertility-sparing treatment for early-stage endometrial cancer (grade 1-2) or atypical endometrial hyperplasia.
Progestin is the standard drug used to preserve the uterus and fertility in these patients, but about 30% of patients respond poorly because the progesterone receptor (PR) in the endometrium is lost or reduced. Laboratory studies by the research team have shown that orlistat, a widely used oral weight-loss drug that blocks fat absorption, can raise PR levels and restore sensitivity to progestin.
The study will enroll 48 patients (age 45 years or younger, body mass index 24 kg/m2 or higher) who still have residual disease and low PR expression after at least 3 months of first-line progestin therapy. Participants will be randomly assigned in a 1:1 ratio to receive either progestin plus orlistat (experimental group) or progestin alone (control group) for 3 months, followed by 24 months of follow-up. The main goal is to compare the change in PR expression from baseline after 3 months of treatment. The study will also assess how many patients achieve complete disease reversal, time to complete response, recurrence, pregnancy and live-birth rates, safety, and changes in body weight and metabolic measures.
Histologically confirmed grade 1-2 endometrioid endometrial adenocarcinoma or atypical endometrial hyperplasia (AEH), independently confirmed by two senior pathologists
Lesion confined to the endometrium on MRI or transvaginal ultrasound; FIGO (2009) stage IA without myometrial invasion (for G1, superficial invasion less than one half is allowed; G2 must have no myometrial invasion)
Age 45 years or younger
Received first-line MPA 250-500 mg/day or MA 160-320 mg/day for at least 3 months, with hysteroscopy plus curettage confirming failure to achieve complete response (persistent EC/AEH lesion)
Tumor invading more than one half of the myometrium; FIGO (2009) stage IB or higher
Grade G3 or non-endometrioid histology (serous, clear cell, carcinosarcoma, etc.)
Coexisting other endometrial cancer or other reproductive-system malignancy; coexisting breast cancer or other hormone-dependent tumor precluding progestin use
Allergy to orlistat or any formulation component, or prior severe adverse reaction (including severe hepatic injury) to orlistat
Parallel
Orlistat
DrugOral orlistat 120 mg three times daily, taken with meals or within 1 hour after a meal, for 3 months. A dose may be omitted if a meal is skipped or contains no fat.
Progestin
DrugHigh-potency progestin given orally as background therapy in both groups: medroxyprogesterone acetate 250-500 mg/day or megestrol acetate 160-320 mg/day, with the specific agent and dose individualized by the investigator based on body weight, liver function, and prior dose.
Relative change in progesterone receptor (PR) expression from baseline at 3 months (delta PR%)
Relative change in PR expression measured by immunohistochemistry (H-score or percentage of PR-positive cells) in endometrial tissue obtained by hysteroscopic biopsy at 3 months versus baseline. An effective PR increase is defined as delta PR% \>= 1%, calculated as (PR at 3 months minus PR at baseline) / PR at baseline x 100%.
Pathological complete response rate at 3 months
Proportion of participants achieving complete response (CR), defined as complete reversal of the endometrium to normal proliferative or secretory endometrium with no residual endometrial cancer or atypical hyperplasia, assessed by hysteroscopic biopsy and curettage and judged independently by two blinded pathologists.
Pathological complete response rate at 6 months
Proportion of participants achieving pathological complete response at 6 months, assessed by hysteroscopic biopsy and curettage.
Relative change in PR expression from baseline at 6 months (delta PR%)
Relative change in PR immunohistochemistry H-score in paired endometrial tissue at 6 months versus baseline.
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