Chemotherapy and Pelvic Radiation Therapy with or without Additional Chemotherapy in Treating Patients with High-Risk Early-Stage Cervical Cancer after Radical Hysterectomy

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. 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.

Inclusion Criteria

• Patients must have undergone radical hysterectomy (open, laparoscopically or robotic) and staging including pelvic node sampling or dissection for cervical carcinoma within 70 days prior to study entry (NOTE: if the patient did not have a para-aortic lymph node sampling/dissection, but had common iliac node dissection that was negative, a positron emission tomography [PET]-computed tomography [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)
• Patients with clinical stage IA2, IB or IIA squamous, adenosquamous, or adenocarcinoma of the cervix who have any/all of the following high-risk features after surgery: * Positive pelvic nodes * Positive parametrium * Positive para-aortic nodes- completely resected, PET/CT negative (PET only required if positive para-aortic nodes during surgery)
• No distant metastases, based upon the following minimum diagnostic workup (NOTE: patients with positive para-aortic nodes- completely resected, PET/CT negative are eligible): * History/physical examination within 56 days prior to study entry * Contrast-enhanced imaging of the abdomen and pelvis by either CT, magnetic resonance imaging (MRI), or whole body PET-CT (with or without contrast) within 90 days prior to registration (NOTE: whole body PET-CT is preferred) * Chest x-ray (posterioranterior [PA] and lateral) or chest CT within 70 days prior to study entry (except for those who have had whole body PET-CT)
• Zubrod performance status 0-1
• Absolute neutrophil count (ANC) >= 1,800 cells/mm^3
• Platelets >= 100,000 cells/mm^3
• Hemoglobin >= 10.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable)
• White blood cell count >= 4000 cells/mm^3
• Serum creatinine =< 1.5 mg/dL within 14 days prior to study entry
• Bilirubin =< 1.5 times normal 14 days prior to study entry
• Alkaline phosphatase within upper limits of institutional normal within 14 days prior to study entry
• Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) and/or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) within upper limits of institutional normal within 14 days prior to study entry
• Patients with known human immunodeficiency virus (HIV) positive must have a cluster of differentiation (CD)4 cell count be >= 350 cells/mm^3 within 14 days prior to study entry (note, however, that HIV testing is not required for entry into this protocol)
• Patient must provide study-specific informed consent prior to study entry

Exclusion Criteria

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)
• Patients can not have any neuroendocrine histology in pathology
• Prior systemic chemotherapy for the current cervical cancer; note that prior chemotherapy for a different cancer is allowable
• Prior radiation therapy to the pelvis that would result in overlap of radiation therapy fields
• Severe, active co-morbidity, defined as follows: * Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months * Transmural myocardial infarction within the last 6 months * Acute bacterial or fungal infection requiring intravenous 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; note, however, that coagulation parameters are not required for entry into this protocol
• Prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin
• Patients who have gross residual disease or distant metastatic disease

PRIMARY OBJECTIVES:

I. To determine if adjuvant systemic chemotherapy following chemoradiation therapy will improve disease-free survival compared to chemoradiation therapy alone in patients with high-risk early-stage cervical carcinoma found to have positive nodes and/or positive parametria after a radical hysterectomy.

SECONDARY OBJECTIVES:

I. To evaluate adverse events.

II. To evaluate overall survival.

III. To evaluate quality of life.

IV. To evaluate chemotherapy-induced neuropathy.

V. To perform a post-hoc dose-volume evaluation between patients treated with standard radiotherapy and patients treated with intensity-modulated radiotherapy with respect to toxicity and local control.

VI. To collect fixed tissue to identify tumor molecular signatures that may be associated with patient outcomes, such as adverse events, disease-free survival, and overall survival.

VII. To collect blood 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: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo standard external beam radiation therapy (EBRT) or intensity-modulated radiation therapy (IMRT) to the pelvis once daily 5 days a week for 5-6 weeks. Patients also receive concurrent cisplatin intravenously (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.

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.

Lead Organization
NRG Oncology

Principal Investigator
Anuja Jhingran