Pelvic Radiation Therapy or Vaginal Implant Radiation Therapy, Paclitaxel, and Carboplatin in Treating Patients With High-Risk Stage I or Stage II Endometrial Cancer

Study Overview
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Brief Summary
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This randomized phase III trial studies pelvic radiation therapy to see how well it works compared with vaginal implant radiation therapy, paclitaxel, and carboplatin in treating patients with high-risk stage I or stage II endometrial cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Implant radiation therapy uses radioactive material placed directly into or near a tumor 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. It is not yet known whether pelvic radiation therapy alone is more effective than vaginal implant radiation therapy, paclitaxel, and carboplatin in treating patients with endometrial cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if treatment with vaginal cuff brachytherapy followed by three cycles of chemotherapy reduces the rate of recurrence or death (i.e. increases recurrence-free survival) when compared to pelvic radiation therapy. SECONDARY OBJECTIVES: I. To compare survival between the two treatment groups. II. To compare patterns of failure between the two treatment groups. III. To compare physical functioning, fatigue and neurotoxicity between the two treatment groups. IV. To examine associations between primary comorbid illnesses and obesity on survival, fatigue and physical functioning. V. To evaluate the psychometric properties (such as construct validity, reliability, sensitivity to treatment and responsiveness over time) of the Patient-Reported-Outcomes Measurement Information System (PROMIS) Fatigue Short form 1, and to evaluate fatigue measurement equivalence between women with endometrial cancer and age-matched women from the general United States (US) population. TERTIARY OBJECTIVES: I. To evaluate the ability of gene expression signatures in early stage endometrial cancer to predict recurrence and to explore the association between gene expression signatures in early stage endometrial cancer and clinical characteristics and outcome. II. To bank whole blood specimens for future research. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients undergo conventional or intensity-modulated pelvic radiation therapy once daily, 5 days a week, for 5-6 weeks (total of 25-28 fractions) in the absence of disease progression or unacceptable toxicity. Patients with stage II disease or stage I disease with a confirmed diagnosis of clear cell and/or papillary serous histology may also undergo 1 or 2 intravaginal (i.e., vaginal cuff) brachytherapy boost treatments. ARM II: Patients undergo vaginal cuff brachytherapy comprising 3-5 high-dose rate brachytherapy treatments over approximately 2 weeks or 1 or 2 low-dose rate brachytherapy treatments over 1-2 days. Beginning within 3 weeks after initiating brachytherapy, patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 30-60 minutes on day 1. Chemotherapy repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter for up to 5 years.

Official Title
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A Phase III Trial of Pelvic Radiation Therapy Versus Vaginal Cuff Brachytherapy Followed by Paclitaxel/Carboplatin Chemotherapy in Patients With High Risk, Early Stage Endometrial Carcinoma

Conditions
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Endometrial Clear Cell Adenocarcinoma, Endometrial Serous Adenocarcinoma, Fatigue, Neurotoxicity Syndrome, Obesity, Stage I Uterine Corpus Cancer AJCC v7, Stage II Uterine Corpus Cancer AJCC v7

Intervention / Treatment
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* Radiation: 3-Dimensional Conformal Radiation Therapy
* Drug: Carboplatin
* Radiation: Intensity-Modulated Radiation Therapy
* Radiation: Internal Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be considered eligible to participate in this trial, all patients must have undergone hysterectomy; bilateral salpingo-oophorectomy (open or laparoscopic approach) is strongly encouraged Peritoneal cytology should be obtained on entering the peritoneal cavity, as described in the Gynecologic Oncology Group (GOG) Surgical Procedures Manual (https://gogmember.gog.org/manuals/pdf/surgman.pdf); pelvic and para-aortic lymphadenectomy are optional, but strongly encouraged (as staged patients enrolled on GOG-0210-molecular markers in endometrial carcinoma are eligible for this study) The procedures may be performed via laparotomy or laparoscopy (including robot-assisted) as per the surgeon?s preference; the surgeon must record in the operative report whether a lymphadenectomy was performed (see link above to Surgical Procedures Manual) or not; a specific number of lymph nodes removed will not be utilized for eligibility, but the operative report should reflect that the procedure performed was consistent with the procedures described in the GOG Surgical Manual If either a bilateral salpingo-oophorectomy or nodal dissection was not performed, post-operative pre-treatment computed tomography (CT)/magnetic resonance imaging (MRI) is required and must not demonstrate evidence suggestive of metastatic disease (adnexa, nodes, intraperitoneal disease); post-operative, pre-treatment CT/MRI must be performed if a pelvic and para-aortic nodal dissection was not performed For the purposes of description, patients will be staged according to the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system; eligibility is defined based on clinical-pathologic features; patients with endometrial carcinoma (endometrioid types) confined to the corpus uteri or with endocervical glandular involvement fitting one of the following high-intermediate risk factor categories: Age >= 70 years with one risk factor Age >= 50 with 2 risk factors Age >= 18 years with 3 risk factors Risk factors: grade 2 or 3 tumor, (+) lymphovascular space invasion, outer ? myometrial invasion; patients with these risk criteria may be enrolled with either positive or negative cytology Patients with stage II endometrial carcinoma (any histology) with cervical stromal invasion (occult or gross involvement), with or without high-intermediate risk factors Patients with serous or clear cell histology (with or without other high-intermediate risk factors) are eligible provided the disease is uterine-confined (with or without cervical stromal invasion or endocervical glandular involvement), and with peritoneal cytology negative for malignancy Patients must have GOG performance status 0, 1, or 2 Absolute neutrophil count (ANC) >= 1,500/mcl (equivalent to Common Toxicity Criteria [CTCAE version [v] 3.0] grade 1) Platelets >= 100,000/mcl (CTCAE v3.0 grade 0-1) Serum creatinine =< institutional upper limit normal (ULN), CTCAE v 3.0 grade 0 Note: If serum creatinine > ULN, a 24-hour creatinine clearance must be collected and must be > 50 mL/min Bilirubin =< 1.5 x ULN (CTCAE v3.0 grade 1) Serum glutamic oxaloacetic transaminase (SGOT) =< 2.5 x ULN (CTCAE grade 0-1) Alkaline phosphatase =< 2.5 x ULN (CTCAE grade 0-1) Neuropathy (sensory and motor) =< CTCAE v3.0 grade 1 Patients who have met the pre-entry requirements; testing values/results must meet eligibility criteria Patients must have signed an approved informed consent and authorization permitting release of personal health information Exclusion Criteria: Patients who have already received non-surgical therapy for endometrial cancer including chemotherapy, radiation (example, pre-operative or post-operative brachytherapy), hormonal or biologic therapy Patients identified with pathologically confirmed spread of cancer beyond the uterus and cervix to pelvic or para-aortic lymph nodes, adnexal structures, and/or other anatomic sites, or patients with serous or clear cell histology and with positive cytologic washings Patients with nodal (for patients who did not have nodal dissection performed) or distant disease determined based on imaging studies; patients with suspicious nodes that have been biopsied (re-staging operation, fine needle aspiration [FNA]) and are pathologically negative will be eligible Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last 5 years; patients are excluded if their previous cancer treatment contraindicates this protocol therapy; specifically, patients who have received prior radiotherapy directed to treat disease within the abdominal cavity or pelvis are excluded Prior radiation of localized cancer of the breast, head and neck, thyroid, or skin is permitted, provided that it was completed more than 5 years prior to registration, and the patient remains free of recurrent or metastatic disease Patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than 5 years prior to registration, and the patient remains free of recurrent or metastatic disease Patients who have contraindications to pelvic radiation therapy (RT) (e.g. pelvic kidney, connective tissue disease, inflammatory bowel disease, etc.) should be screened in advance and not be considered eligible for the trial Patients with recurrent endometrial cancer Patients with surgical or clinical, FIGO 2009 stage III or IV endometrial carcinoma Patients with non-epithelial uterine malignancies such as uterine carcinosarcoma or leiomyosarcoma

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (pelvic radiation therapy)<br>Patients undergo conventional or intensity-modulated pelvic radiation therapy once daily, 5 days a week, for 5-6 weeks (total of 25-28 fractions) in the absence of disease progression or unacceptable toxicity. Patients with stage II disease or stage I disease with a confirmed diagnosis of clear cell and/or papillary serous histology may also undergo 1 or 2 intravaginal (i.e., vaginal cuff) brachytherapy boost treatments. | Radiation: 3-Dimensional Conformal Radiation Therapy<br>* Undergo pelvic radiation therapy<br>* Other names: Radiation Conformal Therapy;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo pelvic radiation therapy<br>* Other names: Intensity-Modulated Radiotherapy;Radiation: Internal Radiation Therapy<br>* Undergo vaginal cuff brachytherapy<br>* Other names: Radiation Brachytherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (brachytherapy, paclitaxel, carboplatin)<br>Patients undergo vaginal cuff brachytherapy comprising 3-5 high-dose rate brachytherapy treatments over approximately 2 weeks or 1 or 2 low-dose rate brachytherapy treatments over 1-2 days. Beginning within 3 weeks after initiating brachytherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30-60 minutes on day 1. Chemotherapy repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Radiation: Internal Radiation Therapy<br>* Undergo vaginal cuff brachytherapy<br>* Other names: Radiation Brachytherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Recurrence or Death Events at Primary Analysis | Recurrence-Free Survival is the period from study entry until disease recurrence, death, or date of last contact | Within 4 weeks after completing or discontinuing study therapy, then every 6 months for 2 years, then annually for 3 years, then as clinically indicated, assessed up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death Events | The number of death events is reported. Overall survival is reported by the number of deaths occurring while on study. | Overall survival is measured from study enrollment for up to 10 years. | 
| Number of Participants With Sites of Recurrence | Three competing risk analyses were carried out for three different types of recurrences: 1) any vaginal, 2) any pelvic or any PA nodes and 3) any distant. More than one type of recurrence can be counted for an individual patient. A death prior to a specific type of recurrence was considered a competing event. | Within 4 weeks after completing or discontinuing study therapy, then every 6 months for 2 years, then annually for 3 years, then as clinically indicated thereafter, up to 10 years | 
| Patient Reported Fatigue | Patient reported fatigue as measured with the Functional Assessment of Chronic Illness Therapy- Fatigue scale (FACIT-Fatigue). The FACIT-Fatigue contains 13 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative items, reversal was performed prior to score calculation. According to the FACIT measurement system, the Fatigue score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The FACIT-Fatigue score ranges 0-52 with a large score suggests less fatigue. | Prior to study treatment (baseline), 4 weeks post the starting of study treatment, 10-11 weeks post the starting of study treatment, 8 months post the starting of study treatment, 14 months post the starting of study treatment | 
| Patient-reported Neurotoxicity | Patient reported neurotoxicity symptoms as measured with the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - neurotoxicity subscale (short version) (FACT/GOG-Ntx subscale). The FACT/GOG-Ntx subscale contains 4 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative items, reversal was performed prior to score calculation. According to the FACIT measurement system, the Ntx score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The Ntx score ranges 0-16 with a large score suggesting less neurotoxicity. | Prior to study treatment (baseline), 4 weeks post the starting of study treatment, 10-11 weeks post the starting of study treatment, 8 months post the starting of study treatment, 14 months post the starting of study treatment. | 
| Patient-reported Quality of Life | Patient reported quality of life as measured with the Treatment Outcome Index of the Functional Assessment of Cancer Therapy for endometrial cancer (FACT-En TOI). The FACT-En TOI is a scale for assessing general QOL of endometrial cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Endometrium Cancer subscale (16 items). Each item in the FACT-En TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). . The FACT-En TOI score is calculated as the sum of the subscale scores if more than 80% of the FACT-En TOI items provide valid answers and all of the component subscales have valid scores. The FACT-En TOI score ranges 0-120 with a large score suggests better QOL | Prior to study treatment (baseline), 4 weeks post the starting of study treatment, 10-11 weeks post the starting of study treatment, 8 months post the starting of study treatment, 14 months post the starting of study treatment |