Radiation Therapy and Cisplatin With or Without Amifostine for Patients With Stage IIIB or IVA Cervical Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cisplatin, use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining radiation therapy with chemotherapy may kill more tumor cells. Drugs such as amifostine may protect normal cells from the side effects of radiation therapy. PURPOSE: Phase I/II trial to study the effectiveness of combining cisplatin and radiation therapy with or without amifostine in treating patients who have stage IIIB or stage IVA cancer of the cervix.

Detailed Description
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OBJECTIVES: Determine the feasibility and tolerability of external beam radiotherapy, brachytherapy, and cisplatin in patients with para-aortic or high common iliac lymph node-positive carcinoma of the uterine cervix. Determine the feasibility and tolerability of this regimen with the addition of amifostine in these patients. Determine the efficacy of these 2 regimens, in terms of improving pelvic and para-aortic tumor control and distant metastases, in these patients. OUTLINE: Phase I: Patients undergo external beam radiotherapy to the pelvis and para-aortic region 5 days a week for 5 weeks. Patients also undergo either intracavitary low-dose rate (LDR) brachytherapy in 2 applications beginning within 2 weeks after completion of external beam radiotherapy at 2-3 week intervals or 6 fractions of high-dose rate intracavitary brachytherapy over 8 weeks beginning as early as week 2 of external beam radiotherapy. Patients also receive cisplatin IV over 1 hour weekly for 6 weeks concurrently with external beam radiotherapy and once with LDR brachytherapy. Phase II proceeds only if toxicity in phase I is within expected parameters. Phase II: Patients receive external beam radiotherapy, brachytherapy, and cisplatin as in phase I. Patients also receive amifostine subcutaneously daily just before external beam radiotherapy and cisplatin. Treatment continues for up to 8 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Official Title
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A Two Part Phase I/II Study Of Extended Field External Irradiation And Intracavitary Brachytherapy Combined With Chemotherapy And Amifostine In Carcinoma Of The Cervix With Positive Para-Aortic Or High Common Iliac Lymph Nodes

Conditions
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Cervical Cancer, Radiation Toxicity

Intervention / Treatment
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* Drug: Amifostine trihydrate
* Drug: Cisplatin
* Radiation: Intracavitary brachytherapy
* Radiation: External beam radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven, locally advanced carcinoma of the uterine cervix TNM classification stage IIIB or IVA Disease metastatic to para-aortic or high common iliac lymph nodes Prior complete surgical resection of involved lymph nodes or gross residual tumor involvement of a lymph node allowed The following cellular types are eligible: Squamous cell carcinoma Adenocarcinoma Adenosquamous carcinoma The following cellular types are ineligible: Small cell carcinoma Carcinoid tumor Glassy cell carcinoma Clear cell carcinoma Cystadenocarcinoma No metastatic disease outside of the pelvis (except to the para-aortic nodes) PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-1 Life expectancy At least 6 months Hematopoietic White blood cell count (WBC) at least 3,000/mm^3 Platelet count at least 100,000/mm^3 Hepatic Bilirubin no greater than 1.5 mg/dL Alanine amino transferase (ALT) no greater than 2 times normal Renal Creatinine no greater than 1.5 mg/dL (urinary diversion allowed) Corrected calcium normal Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No concurrent significant medical condition that would preclude study participation No insulin-dependent diabetes No other malignancy within the past 3 years except cutaneous basal cell skin cancer PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy No prior systemic chemotherapy Endocrine therapy Not specified Radiotherapy No prior pelvic irradiation except transvaginal radiotherapy to control bleeding Surgery See Disease Characteristics No prior tumor-directed surgery except lymph node biopsy/staging

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiation therapy plus cisplatin<br>Patients receive extended field external beam radiation therapy (RT) to the para-aortic region and pelvis, intracavitary brachytherapy with concurrent weekly cisplatin. | Drug: Cisplatin<br>* Cisplatin will be given weekly with external beam radiation therapy and once with brachytherapy for a total of six doses. Patients receive 40 mg/m^2 by IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36.<br>Radiation: Intracavitary brachytherapy<br>* For low dose rate (LDR) brachytherapy, cesium will be given in one to two intracavitary applications, within two weeks of completion of external radiation. The interval between the two applications will be one to three weeks. It is recommended that the total course of treatment be completed in less than eight weeks. High dose rate (HDR) brachytherapy may start as early as week two of external radiation. The minimum cumulative external and intracavitary dose should be 85 Gy.<br>Radiation: External beam radiation therapy<br>* Patients will receive 1.8 Gy daily for five weeks for a total dose of 45 Gy; involved lateral parametrium and/or pelvic nodes should be boosted for a total dose (including intracavitary treatment) of 60 Gy ± 5%.<br>|
| Experimental: Radiation therapy plus cisplatin and amifostine<br>Patients receive extended field external beam radiation therapy (RT) to the para-aortic region and pelvis, intracavitary brachytherapy with concurrent weekly cisplatin and amifostine trihydrate. | Drug: Amifostine trihydrate<br>* Amifostine will be delivered before each radiation treatment. Amifostine (500 mg) will be given as two equally-divided subcutaneous injections.<br>* Other names: ethanethiol;Drug: Cisplatin<br>* Cisplatin will be given weekly with external beam radiation therapy and once with brachytherapy for a total of six doses. Patients receive 40 mg/m^2 by IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36.<br>Radiation: Intracavitary brachytherapy<br>* For low dose rate (LDR) brachytherapy, cesium will be given in one to two intracavitary applications, within two weeks of completion of external radiation. The interval between the two applications will be one to three weeks. It is recommended that the total course of treatment be completed in less than eight weeks. High dose rate (HDR) brachytherapy may start as early as week two of external radiation. The minimum cumulative external and intracavitary dose should be 85 Gy.<br>Radiation: External beam radiation therapy<br>* Patients will receive 1.8 Gy daily for five weeks for a total dose of 45 Gy; involved lateral parametrium and/or pelvic nodes should be boosted for a total dose (including intracavitary treatment) of 60 Gy ± 5%.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Acute Grade 3/4 Toxicity (Excluding Grade 3 Leukopenia) | To determine the feasibility and tolerance of extended-field external radiotherapy to the pelvis and para-aortic region and intracavitary irradiation combined with weekly cisplatin using the rate of acute grade 3/4 toxicity rate (excluding grade 3 leukopenia). The first part of this study was designed to determine the acute grade 3/4 toxicity rate (excluding grade 3 leukopenia), to have a starting point for the second part (second arm) of the study. | From start of treatment to 90 days | 
| Number of Patients With Acute Grade 3/4 Toxicity (Excluding Grade 3 Leukopenia) | The second part of this study (second arm) was designed to detect a 40% relative reduction (absolute from 77% to 46%) in the acute grade 3/4 toxicity (excluding grade 3 leukopenia) rate, with the addition of amifostine. A one-sided alpha of 0.05 and 80% power required 16 evaluable patients to detect the hypothesized difference. If ≤ 8 had the toxicity, it would be concluded that adding amifostine decreased this toxicity rate by at least 40%. | From start of treatment to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pelvic Tumor Control |  | From registration to date of pelvic tumor failure or last follow-up. Analysis occurs after all patients have been potentially followed for 2 years. | 
| Distant Metastases |  | From registration to date of distant mets or last follow-up. Analysis occurs after all patients have been potentially followed for 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiation toxicity, stage III cervical cancer, stage IVA cervical cancer, cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous cell carcinoma