OBJECTIVES >
1.1 Primary 
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. 
1.2 Secondary
1.2.1 To evaluate adverse events
1.2.2 To evaluate overall survival
1.2.3 To evaluate quality of life
1.2.4 To evaluate chemotherapy-induced neuropathy
1.2.5 To perform a post-hoc dose-volume evaluation between cases treated with standard RT and cases treated with IMRT with respect to toxicity and local control
1.2.6 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
1.2.7 To collect blood to: Identify secreted factors from serum and plasma that may be associated with adverse events or outcome, and Identify SNPs in genes from buffy coat that may be associated with a genetic predisposition to tumor formation itself or a response to cytotoxic therapy

Treatment

- Arm A
Concurrent weekly cisplatin 40mg/m2 (maximum dose 70mg) and RT ( All patients will be treated to either 45 Gy in 25 fractions or 50.4 Gy in 28 fractions (1.8 Gy/fraction). Patients will be treated once per day, 5 days per week.)  ± brachytherapy

-Arm B
Concurrent weekly cisplatin 40mg/m2 (maximum 70mg) and RT(- Arm A
Concurrent weekly cisplatin 40mg/m2 (maximum dose 70mg) and RT ( All patients will be treated to either 45 Gy in 25 fractions or 50.4 Gy in 28 fractions (1.8 Gy/fraction). Patients will be treated once per day, 5 days per week.) ± brachytherapy 
Patients randomized to the chemotherapy treatment arm (Arm 2) will receive paclitaxel 135mg/m2 and carboplatin AUC 5 once every 21 days for 4 cycles, to start 4 to 6 weeks following completion of chemoradiation.

Arm Label

Target Number of Participant

Arm Type

Arm Description

All patients will receive concurrent chemotherapy with weekly cisplatin intravenously during external beam radiation therapy for a total of 6 cycles.  
Cisplatin >
- Dose : 40 mg/m2, maximum dose 70 mg
- Schedule : IV weekly over 1 hour, during external beam radiation x 5-6 weeks (see Section 7.1.1.3 for administration details)

Arm Label

Target Number of Participant

Arm Type

Arm Description

All patients will receive concurrent chemotherapy with weekly cisplatin intravenously during external beam radiation therapy for a total of 6 cycles. Patients randomized to the chemotherapy treatment arm (Arm 2) will receive paclitaxel and carboplatin once every 21 days for 4 cycles, to start 4 to 6 weeks following completion of chemoradiation. 
Cisplatin >
- Dose : 40 mg/m2, maximum dose 70 mg
- Schedule : IV weekly over 1 hour, during external beam radiation x 5-6 weeks (see Section 7.1.1.3 for administration details)
Paclitaxel >
- Dose : 135 mg/m2, maximum dose at BSA 2.0m2
- Schedule : IV over 3 hours, every 21 days x 4 
Carboplatin >
- Dose : AUC5
- Schedule : IV over 30 mins, every 21 days x 4 (see Section 7.1.2 for administration details)

Gender

Age

Description

1. 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 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]
2. 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)
3. 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, 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 (PA and lateral) or chest CT within 70 days prior to study entry (except for those who have had whole body PET-CT per Section 3.1.3.). 
4. Zubrod performance status 0-1.
5. Age ≥ 18
6. CBC/differential obtained 14 days prior to study entry, with adequate bone marrow function defined as follows:
• Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3 
• Platelets ≥ 100,000 cells/mm3
• Hemoglobin ≥ 10.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 10.0 g/dl is acceptable.)
 White blood cell count ≥ 4000 cells/mm3
7. Adequate hepatic and renal function defined as follows:
• 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 
• ALT/SGPT and/or AST/SGOT within upper limits of institutional normal within 14 days prior to study entry 
• Patients with known HIV positive must have a CD4 cell count be ≥ 350 cells/mm3 within 14 days prior to study entry (note, however, that HIV testing is not required for entry into this protocol.) Excluding HIV positive patients with invasive cervical 
cancer and low CD4 cell counts is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
8. Patient must provide study-specific informed consent prior to study entry.

1. 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)
2. Patients can not have any neuroendocrine histology in pathology.
3. Prior systemic chemotherapy for the current cervical cancer; note that prior chemotherapy for a different cancer is allowable. 
4. Prior radiation therapy to the pelvis that would result in overlap of radiation therapy fields 
5. 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.
6. Prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin. 
7. Patients who have gross residual disease or distant metastatic disease.

Disease free survival

Disease Free Survival(DFS) time will be measured from the date of randomization to the first date of DFS failure(local, regional or distant metastases failure or death due to any cause) or last follow-up

Adverse events

Adverse Events is measured by Common Terminology Criteria for Adverse Events (CTCAE) 4.0 criteria. All patients will be followed for ongoing adverse events until 30 days from the end of study last administration or investigational agent/intervention.

Overall survival

Survival time will be measured from the date of randomization to the date of death or last follow-up

Chemotherapy-induced neuropathy as measured by The Functional Assessment of Cancer Therapy(FACT)-Gynecologic Onocology Group(GOG)/Neurotoxicity(NTX)4

The Functional Assessment of Cancer Therapy(FACT)-Gynecologic Onocology Group(GOG)/Neurotoxicity(NTX)4 will be collected at 6, 12 and 24.

Quality of Life(QoL) as assessed by The Functional Assessment of Cancer Therapy-Cervix(FACT-Cx)& Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea(FACIT-D)

The Functional Assessment of Cancer Therapy-Cervix(FACT-Cx) and the Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea(FACIT-D) will be collected at 6, 12 and 24.

Associations between tumor molecular signatures, from fixed tissue, and outcomes such as adverse events, disease free survival and overall survival

Fixed tissue for consenting subjects will be taken at surgery.

Associations between secreted factors from serum and plasma with adverse envets or outcome

Serum and plasma for consenting subjects will be taken prior to treatment and at completion of chemotherapy.

Associations between Single Nucleotide Polymorphism(SNPs) in genes from buffy coat and a genetic predisposition to tumor formation itself or a response to cytotoxic therapy

Whole blood for Deoxyribonucleic acid(DNA) can be taken prior to treatment or at completionof treatment.