A Phase II Study of Extended Field IMRT External Beam Irradiation and Intracavitary Brachytherapy

Study Overview
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Brief Summary
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Recent studies have shown that the chance of survival among women with advanced cervical cancer is increased when they receive concurrent chemotherapy and radiation to the pelvis. However, patients who have advanced disease show loco-regional failure as well as a high incidence of distant metastasis. Positron emission tomography (PET) scanning has high sensitivity and specificity in the detection of pelvic and para-aortic lymph node metastases. While the detection of para-aortic metastases by PET significantly impacts prognosis, PET has been known to show positive lymph node metastasis in the pelvis only while not detecting micrometastatic disease in the para-aortic lymph nodes (despite the fact that they are histologically known). In addition, patients with positive para-aortic lymph nodes on PET, greater amounts (more than 45 Gy) of radiation must be used to improve the probability of controlling the cancer. However, doses greater than this have been limited because of the dose and volume limits to the small bowel. But, Intensity Modulated Radiation Therapy (IMRT) is a new way of calculating and delivering radiation therapy. Compared to external beam radiation, IMRT has the improved ability to deliver large doses of radiation to specific targets while minimizing the exposure to surrounding normal tissue. With IMRT, however, the effective dose/volume can be increased more safely and lower the toxicity of surrounding tissue, thus making prophylactic dosing to para-aortic lymph nodes not detected by PET safer and more effective.

Detailed Description
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Prior to entrance on the study, patients will undergo a history and physical and evaluation of Karnofsky Performance Status. They will have a biopsy of their tumor and will undergo a fluorodeoxyglucose (FDG) PET scan and must include evaluation of para-aortic lymph nodes. Blood work will be done (complete blood count (CBC), differential, platelets, blood urea nitrogen(BUN), serum creatinine, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase. Also, pre-treatment, patients will receive a chest x-ray and an intravenous push (IVP) (unless a computed tomography (CT) with contrast has been performed). Additionally, patient may undergo a CT, magnetic resonance (MRI) and/or lymphangiogram. Patients will then be registered to a treatment arm, depending on the outcome of their PET scan. Patients with positive pelvic lymph nodes but no positive para-aortic lymph nodes by PET will be assigned to Treatment Arm 1. Patients with positive pelvic lymph nodes and positive para-aortic lymph nodes by PET will be assigned to treatment arm 2. Treatment Group 1. Either a conventional or CT simulation may be performed. Patients will be treated with IMRT extended field external beam radiation therapy (to cover pelvis and para-aortic lymph nodes) and intracavitary radiation (6 high dose radiation (HDR) treatments) concurrently with cisplatin (40 mg/m^2/week) Treatment Group 2. A CT simulation must be performed. Patients will be treated with extended field external beam radiation therapy to the pelvis and with IMRT to cover the para-aortic lymph nodes to 60 Gy, 50.4 Gy to the para-aortic lymph node bed in conjunction with external beam pelvic radiation therapy as appropriate for disease stage and intracavitary radiation (6 HDR treatments) concurrently with cisplatin (40 mg/m^2/week).

Official Title
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A Phase II Study of Extended Field IMRT External Beam Irradiation and Intracavitary Brachytherapy With Concurrent Weekly Cisplatin in Patients With Stage I-IVA Cervical Cancer Who Have FDG PET Positive Pelvic or Para-Aortic Lymph Nodes

Conditions
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Cervical Cancer

Intervention / Treatment
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* Radiation: IMRT extended field external beam radiation therapy
* Radiation: Brachytherapy
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have carcinoma of the uterine cervix. Patients with squamous cell, adenocarcinoma, and adenosquamous carcinoma are eligible. International Federation of Gynecology and Obstetrics (FIGO) Stage I to IVA Patients must have no evidence of metastatic disease outside of the pelvis (except to the para-aortic nodes), by PET. Patients must have a Karnofsky Performance Status of >= 60 and no medical contraindications to the administration of chemotherapy. Age >= 18. Adequate bone marrow function: white blood cells (WBC) >= 4000/mm3, platelets >= 100,000 mm3. Adequate renal function: BUN <= 25 mg/dl, creatinine <= 1.2 mg/dl (urinary diversion is permitted to improve renal function). Patients must have bilirubin <= 1.5 mg/dl. Signed study-specific informed consent. Exclusion Criteria: No positive lymph nodes by FDG PET Positive supraclavicular lymph nodes by FDG PET Scan or evidence of more distant disease. FIGO Stage IVB+ Cervical Cancer No prior (within 5 years) or simultaneous malignancies (other than cutaneous basal cell carcinoma). Karnofsky Performance Status <60. Patients with significant medical illness preventing the use of full dose chemotherapy are excluded. Patients with the following histologies are excluded: small cell, carcinoid, glassy cell, clear cell and adenoid cystic. Life expectancy < 6 months. Patients with poorly controlled diabetes mellitus (fasting blood glucose level > 200 mg/dL) are not eligible. No prior surgery for treatment of disease other than exploratory laparotomy or biopsy. No previous systemic chemotherapy. No pelvic radiation therapy is permitted other than transvaginal irradiation to control bleeding. Pregnant women are ineligible and those of child-bearing potential should practice contraception. Patients with abnormal liver function tests

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group 1<br>Pelvic Lymph Nodes Only Positive on FDG PET. IMRT External Beam radiation to the para-aortic region (45 Gy) Pelvis intracavitary brachytherapy (6 HDR treatments) Weekly cisplatin 40 mg/m^2 | Radiation: IMRT extended field external beam radiation therapy<br> <br> Radiation: Brachytherapy<br> <br> Drug: Cisplatin<br> <br> |
| Experimental: Treatment Group 2<br>Para-Aortic Lymph Nodes Positive on FDG PET IMRT (50.4 Gy to para-aortic lymph node bed with a 10.8 Gy boost to nodes) IMRT external beam pelvic radiation therapy as appropriate for stage Intracavitary brachytherapy (6 HDR treatments) Weekly cisplatin (40 mg/m^2) | Radiation: IMRT extended field external beam radiation therapy<br> <br> Radiation: Brachytherapy<br> <br> Drug: Cisplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance of IMRT Extended-field External Radiotherapy to Pelvis and Para-aortic Region, Combined With Intracavitary Irradiation, and Cisplatin Chemotherapy as Measured the Number of Participants With by Grade 4 or Higher Toxicity | -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for all toxicity reporting. | 1 year post start of radiation therapy | 
| Number of Participants With Acute Toxicity of IMRT Extended-field External Radiotherapy to Pelvis and Para-aortic Region, Combined With Intracavitary Irradiation, and Cisplatin Chemotherapy (Grade 3 or Higher) |  | 30 days after completion of radiation therapy | 
| Efficacy of IMRT Extended-field Radiation Combined With Intracavitary Irradiation, and Cisplatin Chemotherapy as Measured by PET Scan Disease Status |  | 1st PET scan after completion of treatment (approximately month 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of IMRT to the Para-aortic Lymph Nodes, IMRT External Beam Radiotherapy to the Pelvis, Intracavitary Irradiation, and Cisplatin Chemotherapy as Measured by the Frequency of Distant Metastasis |  | 5 years after completion of radiation therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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para-aortic lymph nodes