A Study of Short-Course Radiation Therapy With Chemotherapy in People With Endometrial Cancer

Inclusion Criteria: Patients must have newly diagnosed endometrial carcinoma. The following histologic subtypes are eligible for inclusion: endometrioid, serous, clear cell, dedifferentiated/undifferentiated, mixed epithelial, adenocarcinoma not otherwise specified, and carcinosarcoma. Surgery must have included a hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node surgical assessment (sentinel lymph node mapping and/or sampling). Para-aortic lymph node surgical assessment is optional. Patients must have FIGO (2009) stage IIIA or IIIC1 disease (as determined by surgical staging). Patients must consent to testing with MSK-IMPACT part A and are encouraged to consent to both parts A and C. Age ≥ 18 years. Patients must have an Karnofsky Performance Status (KPS) ≥ 70. Neurologic function: Neuropathy (sensory and motor) grade ≤ 1. No residual gross disease after surgery. No prior radiation therapy, chemotherapy or hormonal therapy for treatment of endometrial cancer. No active infection requiring antibiotics, except for uncomplicated urinary tract infection. Patients must have adequate organ function, defined by the following laboratory results no more than 14 days prior to first study treatment: Absolute neutrophil count (ANC) ≥ 1500/mcL Platelet count ≥ 100,000/mcL AST/ALT ≤ 3X upper limit of normal (ULN) Total bilirubin ≤ 1.5X ULN. Patients with known Gilbert's disease and a total bilirubin ≤ 3X ULN may be enrolled. Creatinine ≤ 1.5X ULN Entry into study is limited to no more than 12 weeks from the date of surgery. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients of childbearing age will by definition have undergone hysterectomy and bilateral oophorectomy prior to study enrollment. Participants must agree not to breastfeed during the study or for 150 days after the last dose of study treatment. Exclusion Criteria: Patients whose endometrial cancers harbor pathogenic POLE mutations, as determined MSK-IMPACT testing. Patients whose endometrial cancers are mismatch repair deficient, as determined by immunohistochemical staining for MLH1, PMS2, MSH2, and MSH6 and/or MSI-H by MSK-IMPACT testing. Patients whose endometrial cancers have ≥ 1 molecular feature(s) (P53, MMR, and/or POLE status) that could not be determined (e.g., not enough tumoral material or testing failed). At the time of radiation simulation, patient is unable to meet dosimetric constraints in Section 10.1.3. Active inflammatory bowel disease, such as Crohn's disease or ulcerative colitis. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. This includes but is not limited to: uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, and superior vena cava syndrome. Patients with psychiatric or substance use disorders that would interfere with cooperation with the requirements of the trial. Patients unfit for pelvic radiation therapy due to the following: Has had radiation therapy encompassing >20% of the bone marrow within 2 weeks, or any radiation therapy within 1 week prior to day 1 of protocol therapy Patients with a history of pelvic radiation. Patients with a history or current diagnosis of a vesicovaginal, enterovaginal, or colovaginal fistula. Any hematological abnormality or disorder that would be a contraindication to radiation per the treating physician.