Chemotherapy and Pelvic Radiation Therapy With or Without Additional Chemotherapy in Treating Patients With High-Risk Early-Stage Cervical Cancer After Radical Hysterectomy

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as cisplatin, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether chemotherapy and radiation therapy are more effective when given with or without additional chemotherapy in treating cervical cancer. PURPOSE: This randomized phase III trial is studying chemotherapy and pelvic radiation therapy to see how well they work when given with or without additional chemotherapy in treating patients with high-risk early-stage cervical cancer after radical hysterectomy.

Detailed Description
-----------------
OBJECTIVES: Primary To determine if administering adjuvant systemic chemotherapy after chemoradiotherapy will improve disease-free survival compared to chemoradiotherapy alone in patients with high-risk early-stage cervical carcinoma found to have positive nodes and/or positive parametria after radical hysterectomy. Secondary To evaluate adverse events. To evaluate overall survival. To evaluate quality of life. To evaluate chemotherapy-induced neuropathy. To perform a post-hoc dose-volume evaluation between patients treated with standard radiotherapy and patients treated with intensity-modulated radiotherapy (IMRT) with respect to toxicity and local control. To collect fixed tissue samples to identify tumor molecular signatures that may be associated with patient outcomes, such as adverse events, disease-free survival, and overall survival. To collect blood samples to identify secreted factors from serum and plasma that may be associated with adverse events or outcome and to identify single nucleotide polymorphisms (SNPs) in genes from buffy coat that may be associated with a genetic predisposition to tumor formation itself or a response to cytotoxic therapy. OUTLINE: This is a multicenter study. Patients are stratified according to planned use of brachytherapy (no vs. yes), radiotherapy modality - [standard external beam radiotherapy (EBRT) vs. intensity-modulated radiotherapy (IMRT)], and radiotherapy dose (45 Gy vs. 50.4 Gy). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients undergo standard EBRT or IMRT to the pelvis once daily 5 days a week for 5-6 weeks. Patients also receive concurrent cisplatin IV over 1 hour once weekly for 6 weeks. NOTE: Some patients may also undergo brachytherapy beginning within 7 days after completion of radiotherapy. Arm II: Patients receive chemoradiotherapy as in arm I. Beginning 4-6 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed by the Functional Assessment of Cancer Therapy - Gynecologic Oncology Group (FACT-GOG/NTX4), FACT-Cx, and FACIT-D questionnaires at baseline; at the completion of chemoradiotherapy; and then at 6, 12, and 24 months after completion of chemoradiotherapy. Blood and tissue samples may be collected for gene expression analysis by immuno-histochemistry (IHC) and for biomarker and polymorphism studies. After completion of study treatment, patients are followed up very 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
-----------------
Phase III Randomized Study of Concurrent Chemotherapy and Pelvic Radiation Therapy With or Without Adjuvant Chemotherapy in High-Risk Patients With Early-Stage Cervical Carcinoma Following Radical Hysterectomy

Conditions
-----------------
Cervical Cancer

Intervention / Treatment
-----------------
* Drug: carboplatin
* Drug: cisplatin
* Drug: paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed squamous, adenosquamous, or adenocarcinoma of the cervix with any/all of the following high-risk features after surgery: Positive pelvic nodes Positive parametrium Positive para-aortic nodes that have been completely resected and are PET/CT scan-negative PET only required if positive para-aortic nodes during surgery Clinical stage IA2, IB, or IIA disease (this corresponds to surgical tumor node metastasis (TNM) staging of T1-T2, N1, M0) Must have undergone radical hysterectomy (open, laparoscopically, or robotic) and staging within the past 70 days Para-aortic and pelvic node sampling required If the patient did not have a para-aortic lymph node sampling/dissection, but had common iliac node dissection that was negative, a PET-CT is recommended, but not required A negative pre- or post-operative PET scan or PET-CT scan of the para-aortic nodes is required if the patient did not undergo para-aortic or common iliac nodal sampling/dissection No gross residual disease No neuroendocrine histology No distant metastases PATIENT CHARACTERISTICS: Zubrod performance status 0-1 Absolute neutrophil count (ANC) ≥ 1,800/mm³ Platelets ≥ 100,000/mm³ White blood cell count (WBC) ≥ 4,000/mm³ Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed) Serum creatinine ≤ 1.5 mg/dL Bilirubin ≤ 1.5 times upper limit of normal Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) normal Alkaline phosphatase normal Known HIV positivity allowed provided cluster of differentiation 4 (CD4) count is ≥ 350/mm³ within the past 14 days No other invasive malignancy within the past 3 years, except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix No severe, active co-morbidity, including any of the following: Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months Transmural myocardial infarction within the past 6 months Acute bacterial or fungal infection requiring IV antibiotics at the time of study entry Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of study entry Coagulation defects No prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior systemic chemotherapy for the current cervical cancer Prior chemotherapy for a different cancer is allowed No prior radiotherapy to the pelvis that would result in overlap of radiotherapy fields

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: Cisplatin/Radiation Therapy<br>Patients undergo standard EBRT or IMRT to the pelvis once daily 5 days a week for 5-6 weeks. Patients also receive concurrent cisplatin IV over 1 hour once weekly for 6 weeks. | Drug: cisplatin<br>* Given IV<br>|
| Experimental: Arm II: Cisplatin/Radiation Therapy + Carboplatin/Paclitaxel<br>Patients receive chemoradiotherapy as in arm I. Beginning 4-6 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>Drug: cisplatin<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival |  | From randomization to date of first failure (local, regional, or distant metastases failure or death due to any cause) or last follow-up. Analysis occurs after 43 disease-free survival failure events on Cisplatin/RT Arm. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | From randomization to date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 4 years. | 
| Chemotherapy-induced neuropathy as measured by FACT-GOG/NTX4 |  | From completion of concurrent chemoradiation to 12 months. | 
| Quality of life as measured by FACT-Cx and FACIT-D |  | From completion of concurrent chemoradiation to 12 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cervical adenocarcinoma, cervical adenosquamous cell carcinoma, cervical squamous cell carcinoma, stage IA cervical cancer, stage IB cervical cancer, stage IIA cervical cancer