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

Phase 3

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

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

Registration Number: NCT00807768

Lead Sponsor: Gynecologic Oncology Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: UNKNOWN

Sex: Female

Target Recruitment: 601

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (pelvic radiation therapy)	Laboratory Biomarker Analysis	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 (brachytherapy, paclitaxel, carboplatin)	Internal Radiation Therapy	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.
Arm I (pelvic radiation therapy)	Quality-of-Life Assessment	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 I (pelvic radiation therapy)	Intensity-Modulated Radiation Therapy	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 I (pelvic radiation therapy)	3-Dimensional Conformal Radiation Therapy	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 I (pelvic radiation therapy)	Internal Radiation Therapy	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 I (pelvic radiation therapy)	Questionnaire Administration	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 (brachytherapy, paclitaxel, carboplatin)	Questionnaire Administration	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.
Arm II (brachytherapy, paclitaxel, carboplatin)	Laboratory Biomarker Analysis	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.
Arm II (brachytherapy, paclitaxel, carboplatin)	Quality-of-Life Assessment	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.
Arm II (brachytherapy, paclitaxel, carboplatin)	Carboplatin	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.
Arm II (brachytherapy, paclitaxel, carboplatin)	Paclitaxel	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Recurrence or Death Events at Primary Analysis	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	Recurrence-Free Survival is the period from study entry until disease recurrence, death, or date of last contact

Secondary Outcome Measures

Name	Time	Method
Patient-reported Quality of Life	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 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
Number of Participants With Death Events	Overall survival is measured from study enrollment for up to 10 years.	The number of death events is reported. Overall survival is reported by the number of deaths occurring while on study.
Number of Participants With Sites of Recurrence	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	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.
Patient Reported 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 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.
Patient-reported 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 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.

Trial Locations

Locations (538): University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
University of South Alabama Mitchell Cancer Institute
🇺🇸
Mobile, Alabama, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Saint Joseph's Hospital and Medical Center
🇺🇸
Phoenix, Arizona, United States
Arizona Oncology Associates-West Orange Grove
🇺🇸
Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸
Tucson, Arizona, United States
Sutter Cancer Centers Radiation Oncology Services-Auburn
🇺🇸
Auburn, California, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
🇺🇸
Burbank, California, United States
Sutter Cancer Centers Radiation Oncology Services-Cameron Park
🇺🇸
Cameron Park, California, United States
Mercy San Juan Medical Center
🇺🇸
Carmichael, California, United States
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University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States