Carboplatin and Paclitaxel With or Without Cisplatin and Radiation Therapy in Treating Patients With Stage I, Stage II, Stage III, or Stage IVA Endometrial Cancer

Phase 3

Conditions: Endometrial Clear Cell Adenocarcinoma
Endometrial Serous Adenocarcinoma
Stage IA Uterine Corpus Cancer AJCC v7
Stage IB Uterine Corpus Cancer AJCC v7
Stage IVA Uterine Corpus Cancer AJCC v7
Stage II Uterine Corpus Cancer AJCC v7
Stage IIIA Uterine Corpus Cancer AJCC v7
Stage IIIB Uterine Corpus Cancer AJCC v7
Stage IIIC Uterine Corpus Cancer AJCC v7

Interventions: Drug: Carboplatin
Drug: Paclitaxel
Drug: Cisplatin
Radiation: Internal Radiation Therapy
Other: Quality-of-Life Assessment
Radiation: Radiation Therapy

Registration Number: NCT00942357

Lead Sponsor: Gynecologic Oncology Group

Brief Summary: This randomized phase III trial studies carboplatin and paclitaxel to see how well they work with or without cisplatin and radiation therapy in treating patients with stage I-IVA endometrial cancer. Drugs used in chemotherapy, such as carboplatin, paclitaxel, and cisplatin, 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether carboplatin and paclitaxel are more effective with or without cisplatin and radiation therapy in treating patients with endometrial cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (experimental arm) reduces the rate of recurrence or death (i.e., increases recurrence-free survival) when compared to chemotherapy consisting of carboplatin and paclitaxel for 6 cycles (control arm) in patients with stages III-IVA endometrial carcinoma (\< 2 cm residual disease) or patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I or II serous (uterine papillary serous carcinoma \[UPSC\]) or clear cell endometrial carcinoma and positive cytology.

SECONDARY OBJECTIVES:

I. To determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (experimental arm) reduces the rate of death (i.e., increases survival) when compared to chemotherapy consisting of carboplatin and paclitaxel for 6 cycles (control arm) in patients with stages III-IVA endometrial carcinoma (\< 2 cm residual disease) or patients with FIGO 2009 stage I or II serous (UPSC) or clear cell endometrial carcinoma and positive cytology.

II. To compare the regimens with respect to acute and late adverse effects of therapy.

III. To determine the impact of patient-reported quality of life during and following treatment for up to 1 year with the two treatment regimens.

TERTIARY OBJECTIVES:

I. To bank formalin-fixed, paraffin-embedded (FFPE) tumor tissue and whole blood specimens for future research.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cisplatin intravenously (IV) on days 1 and 29. Patients also undergo radiation therapy once daily (QD), 5 days a week, for 5-6 weeks. Some patients may then undergo brachytherapy over 2-3 weeks. Beginning within 8 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Recruitment & Eligibility

Status: UNKNOWN

Sex: Female

Target Recruitment: 813

Inclusion Criteria

All patients with surgical stage III or IVA endometrial carcinoma per FIGO 2009 staging criteria including clear cell and serous papillary and undifferentiated carcinoma
- Surgical stage III disease includes those patients with positive adnexa, parametrial involvement, tumor invading the serosa, positive pelvic and/or para-aortic nodes, or vaginal involvement
- Surgical stage IVA patients with bladder or bowel mucosal involvement, but no spread outside the pelvis
Patients with FIGO 2009 surgical stage I or II endometrial clear cell or serous carcinoma and with positive peritoneal cytology
Surgery must have included a hysterectomy and bilateral salpingo-oophorectomy; pelvic lymph node sampling and para-aortic lymph node sampling are optional
Patients with a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2
White blood cell (WBC) >= 3,000/mcl
Absolute neutrophil count (ANC) >= 1,500/mcl
Platelet count >= 100,000/mcl
Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN)
Alkaline phosphatase =< 2.5 times ULN
Bilirubin =< 1.5 times ULN
Creatinine =< institutional ULN
Patients who have met the pre-entry requirements; testing values/results must meet eligibility criteria
Patients who have signed an approved informed consent and authorization permitting release of personal health information
Entry into the study is limited to no more than 8 weeks from the date of surgery

Exclusion Criteria

Patients with carcinosarcoma
Patients with recurrent endometrial cancer
Patients with residual tumor after surgery (any single site) exceeding 2 cm in maximum dimension
Patients who have had pelvic or abdominal radiation therapy
Patients with positive pelvic washings as the only extra-uterine disease are NOT eligible if the histology is other than clear cell or papillary serous carcinoma
Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of active malignancy within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
Patients with a history of serious co-morbid illness or uncontrolled illnesses that would preclude protocol therapy
Patients with an estimated survival of less than three months
Patients with FIGO 2009 stage IVB endometrial cancer
Patients with parenchymal liver metastases
Patients who have received prior chemotherapy for endometrial cancer
Patients with a history of myocardial infarction, unstable angina, or uncontrolled arrhythmia within 3 months from enrollment

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (cisplatin, radiation therapy, paclitaxel, carboplatin)	Carboplatin	Patients receive cisplatin IV on days 1 and 29. Patients also undergo radiation therapy QD, 5 days a week, for 5-6 weeks. Some patients may then undergo brachytherapy over 2-3 weeks. Beginning within 8 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, paclitaxel, carboplatin)	Internal Radiation Therapy	Patients receive cisplatin IV on days 1 and 29. Patients also undergo radiation therapy QD, 5 days a week, for 5-6 weeks. Some patients may then undergo brachytherapy over 2-3 weeks. Beginning within 8 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, paclitaxel, carboplatin)	Quality-of-Life Assessment	Patients receive cisplatin IV on days 1 and 29. Patients also undergo radiation therapy QD, 5 days a week, for 5-6 weeks. Some patients may then undergo brachytherapy over 2-3 weeks. Beginning within 8 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, paclitaxel, carboplatin)	Radiation Therapy	Patients receive cisplatin IV on days 1 and 29. Patients also undergo radiation therapy QD, 5 days a week, for 5-6 weeks. Some patients may then undergo brachytherapy over 2-3 weeks. Beginning within 8 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm II (paclitaxel and carboplatin)	Paclitaxel	Patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Arm II (paclitaxel and carboplatin)	Quality-of-Life Assessment	Patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, paclitaxel, carboplatin)	Cisplatin	Patients receive cisplatin IV on days 1 and 29. Patients also undergo radiation therapy QD, 5 days a week, for 5-6 weeks. Some patients may then undergo brachytherapy over 2-3 weeks. Beginning within 8 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, paclitaxel, carboplatin)	Paclitaxel	Patients receive cisplatin IV on days 1 and 29. Patients also undergo radiation therapy QD, 5 days a week, for 5-6 weeks. Some patients may then undergo brachytherapy over 2-3 weeks. Beginning within 8 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm II (paclitaxel and carboplatin)	Carboplatin	Patients receive paclitaxel IV over 3 hours and carboplatin IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Recurrence, Progression or Death	Disease was to be assessed at baseline, end of treatment and every 6 months for two years, and annually up to 5 years.	Number of participants enrolled with recurrence or progression of disease or death up to date of last contact. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion or the appearance of new lesions.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Acute Adverse Effects as Graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version (CTCAE) Version 3.0	Assessed throughout the treatment period and for 21-30 days after discontinuation of treatment	The maximum grade of all treatment emergent adverse events without regard to attribution. General guidelines for severity of adverse events are as follows: Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life threatening and Grade 5 is death.
Number of Participants With Late Adverse Events as Graded by the NCI CTCAE Version 3.0	Assessed every 6 months for 3 years	The maximum grade of Adverse events reported during follow-up until progression of disease, a change of therapy or otherwise off study for a maximum of 3 years without regard to attribution. General guidelines for severity of adverse events are as follows: Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life threatening and Grade 5 is death.
Overall Survival	From entry into the study to death or the date of last contact, assessed up to 8 years	Independence between the two endpoints, RFS and survival, and randomized treatment will be assessed with a stratified logrank test for an intent-to-treat analysis of eligible patients.
Patient-reported Peripheral Neuropathy Symptoms	Prior to study treatment (baseline), Arm 1: 1 week post completion of radiation therapy, Arm 2: Prior to cycle 3 (6 weeks post starting of study treatment), 18 weeks post the starting of study treatement, 70 weeks post the starting of study treatment	Patient reported peripheral neuropathy symptoms was 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 suggests less peripheral neuropathy symptoms.
Patient-reported Quality of Life (QOL)	Prior to study treatment (baseline), Arm 1: 1 Week post completion of radiation therapy, Arm 2: Prior to cycle 3 (6 weeks post starting of study treatment), 18 weeks post the starting of study treatment, 70 weeks post the starting of study treatment	Patient reported quality of life was measured with the Treatment Outcome Index of the Functional Assessment of Cancer Therapy for endometrial cancer (FACT-En TOI). It 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 was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). According to the FACIT measurement system, a subscale 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 subscale. The FACT-En TOI score is calculated as the sum of the subscale scores, ranges are 0-120 with a large score suggesting a better QOL.

Trial Locations

Locations (666): University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
Tennessee Valley Gynecologic Oncology
🇺🇸
Huntsville, Alabama, United States
University of South Alabama Mitchell Cancer Institute
🇺🇸
Mobile, Alabama, United States
Alaska Breast Care and Surgery LLC
🇺🇸
Anchorage, Alaska, United States
Alaska Women's Cancer Care
🇺🇸
Anchorage, Alaska, United States
Anchorage Oncology Centre
🇺🇸
Anchorage, Alaska, United States
Katmai Oncology Group
🇺🇸
Anchorage, Alaska, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Saint Joseph's Hospital and Medical Center
🇺🇸
Phoenix, Arizona, United States
Mayo Clinic in Arizona
🇺🇸
Scottsdale, Arizona, United States
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University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States