Radiation Therapy, Paclitaxel, and Carboplatin in Treating Patients With High-Risk Endometrial Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well radiation therapy, paclitaxel, and carboplatin work in treating patients with high-risk endometrial cancer. Radiation therapy uses high energy x rays to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Giving radiation therapy with chemotherapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate progression-free survival. II. To assess and document location of disease recurrence (distant vs local vs both) using this treatment regimen. II. To evaluate the toxicity of radiation therapy sandwiched between cycles of paclitaxel/carboplatin chemotherapy in patients with high-risk endometrial cancer. III. To evaluate the associations of cancer recurrence with tumor tissue expression levels of insulin-like growth factor-I (IGF-I), IGF-II, insulin-like growth factor binding protein 1 (IGFBP-1) and -3, insulin receptor, IGF-I receptor, estrogen receptor, and progesterone receptor. OUTLINE: CHEMOTHERAPY (weeks 1-9, 13-21): Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses during weeks 1-9 and 3 courses during weeks 13-21. RADIATION THERAPY (weeks 8-13 or 8-15): Patients with stage I disease undergo high dose rate (HDR) brachytherapy once weekly for a total of 5 fractions during weeks 8-13. All other patients undergo external beam radiation therapy (EBRT) once daily (QD) 5 days a week for a total of 25 fractions during weeks 8-12 and HDR brachytherapy once weekly for a total of 3 fractions during weeks 13-15. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Official Title
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A Pilot Phase II Trial of Radiation Therapy Sandwiched Between Paclitaxel and Carboplatin in Patients With High-Risk Endometrial Cancer After Standard Surgical Staging

Conditions
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Endometrial Adenocarcinoma, Stage IA Uterine Corpus Cancer, Stage IB Uterine Corpus Cancer, Stage II Uterine Corpus Cancer, Stage IIIA Uterine Corpus Cancer, Stage IIIB Uterine Corpus Cancer, Stage IIIC Uterine Corpus Cancer, Stage IVA Uterine Corpus Cancer, Stage IVB Uterine Corpus Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Carboplatin
* Radiation: Internal Radiation Therapy
* Radiation: External Beam Radiation Therapy
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-documented high-risk endometrioid adenocarcinoma with no visible residual disease, defined by the following criteria: Surgical stage I disease with < 50 myometrial invasion and grade 3 tumor (IAG3) with lymphovascular space involvement; Surgical stage I disease with >= 50% myometrial invasion and grade 2 or 3 tumor (IBG2, IBG3); Any surgical stage II disease (II); Any surgical stage III disease (IIIA, IIIB, IIIC); and Any surgical stage IV disease with no residual macroscopic tumor Surgical staging to include total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and lymph node samplings as per standard Gynecologic Oncology Group (GOG) criteria Eastern Cooperative Oncology Group (ECOG) performance status of < 2 Written voluntary informed consent Exclusion Criteria: Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamate pyruvate transaminase (SGPT) > 2.5 times the institutional upper limit of normal Total serum bilirubin > 1.5 mg/dl History of chronic or active hepatitis Serum creatinine > 2.0 mg/dl Platelets < 100,000/mm^3 Absolute neutrophil count (ANC) < 1500/mm^3 Hemoglobin < 8.0 g/dl (the patient may be transfused prior to study entry) Patient has severe or uncontrolled concurrent medical disease (e.g. uncontrolled diabetes, unstable angina, myocardial infarction within 6 months, congestive heart failure, etc.) Patient with any prior chemotherapy or radiotherapy for pelvic malignancy Patients with dementia or altered mental status that would prohibit the giving and understanding of informed consent at the time of study entry Patients with any history of cancer with the exception of non-melanoma skin cancer are excluded if there is any evidence of other malignancy being present within the past five years

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (paclitaxel, carboplatin, radiation therapy)<br>CHEMOTHERAPY (weeks 1-9, 13-21): Patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 courses during weeks 1-9 and 3 courses during weeks 13-21. RADIATION THERAPY (weeks 8-13 or 8-15): Patients with stage I disease undergo HDR brachytherapy once weekly for a total of 5 fractions during weeks 8-13. All other patients undergo EBRT QD 5 days a week for a total of 25 fractions during weeks 8-12 and HDR brachytherapy once weekly for a total of 3 fractions during weeks 13-15. | Drug: Paclitaxel<br>* Given IV<br>* Other names: TAX;Drug: Carboplatin<br>* Given IV<br>Radiation: Internal Radiation Therapy<br>* Undergo HDR brachytherapy<br>* Other names: Radiation Brachytherapy;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: External Beam RT;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS will be analyzed using standard survival analytic methods, including the Kaplan-Meier approach for estimating the survival distribution. Median time to progression and 95% confidence intervals will be estimated from the Kaplan-Meier curves. | From randomization until documented tumor recurrence or death from any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression Levels of IGF-1 | Associations of PFS with tumor tissue expression levels of IGF-1 will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years | 
| Expression Levels of IGF-2 | Associations of PFS with tumor tissue expression levels of IGF-2 will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years | 
| Expression Levels of IGFBP-1 | Associations of PFS with tumor tissue expression levels of IGFBP-1 will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years | 
| Expression Levels of IGFBP-3 | Associations of PFS with tumor tissue expression levels of IGFBP-3 will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years | 
| Expression Levels of Insulin Receptor | Associations of PFS with tumor tissue expression levels of insulin receptor will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years | 
| Expression Levels of IGF-1 Receptor | Associations of PFS with tumor tissue expression levels of IGF-1 receptor will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years | 
| Expression Levels of Estrogen Receptor | Associations of PFS with tumor tissue expression levels of estrogen receptor will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years | 
| Expression Levels of Progesterone Receptor | Associations of PFS with tumor tissue expression levels of progesterone receptor will be evaluated. Provided the number of events is sufficient, Cox proportional hazards models will be fit to the data to explore these associations. | Up to 5 years |