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

• ClinicalTrials.gov Identifier: NCT00012012
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: January 7, 2015
• Last Update Posted: January 7, 2015
• Sponsor: Radiation Therapy Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Radiation Therapy Oncology Group

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cervical Cancer; Radiation Toxicity	Drug: Amifostine trihydrate; Drug: Cisplatin; Radiation: Intracavitary brachytherapy; Radiation: External beam radiation therapy	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: August 2001
• Actual Primary Completion Date: September 2007
• Actual Study Completion Date: June 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Radiation therapy plus cisplatin; Patients receive extended field external beam radiation therapy (RT) to the para-aortic region and pelvis, intracavitary brachytherapy with concurrent weekly cisplatin.	Drug: Cisplatin; 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.; Radiation: Intracavitary brachytherapy; 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.; Radiation: External beam radiation therapy; 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%.
Experimental: Radiation therapy plus cisplatin and amifostine; 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; Amifostine will be delivered before each radiation treatment. Amifostine (500 mg) will be given as two equally-divided subcutaneous injections.; Other Name: ethanethiol; Drug: Cisplatin; 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.; Radiation: Intracavitary brachytherapy; 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.; Radiation: External beam radiation therapy; 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%.

Outcome Measures

Primary Outcome Measures :

1. Rate of Acute Grade 3/4 Toxicity (Excluding Grade 3 Leukopenia) [ Time Frame: From start of treatment to 90 days ]
   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.
2. Number of Patients With Acute Grade 3/4 Toxicity (Excluding Grade 3 Leukopenia) [ Time Frame: From start of treatment to 90 days ]
   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%.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Florida

Integrated Community Oncology Network

Jacksonville Beach, Florida, United States, 32250

Baptist Cancer Institute - Jacksonville

Jacksonville, Florida, United States, 32207

Florida Oncology Associates at Southside Cancer Center

Jacksonville, Florida, United States, 32207

Baptist Medical Center South

Jascksonville, Florida, United States, 32258

Florida Oncology Associates

Orange Park, Florida, United States, 32073

Florida Cancer Center - Palatka

Palatka, Florida, United States, 32177

Flagler Cancer Center

Saint Augustine, Florida, United States, 32086

United States, Michigan

Borgess Medical Center

Kalamazooaa, Michigan, United States, 49001

West Michigan Cancer Center

Kalamazoo, Michigan, United States, 49007-3731

Bronson Methodist Hospital

Kalamazoo, Michigan, United States, 49007

United States, Nevada

University Medical Center of Southern Nevada

Las Vegas, Nevada, United States, 89102

CCOP - Nevada Cancer Research Foundation

Las Vegas, Nevada, United States, 89106

United States, New Jersey

Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton

Marlton, New Jersey, United States, 08053

Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare

Vineland, New Jersey, United States, 08360

United States, Ohio

Akron City Hospital

Akron, Ohio, United States, 44309-2090

Cancer Treatment Center

Wooster, Ohio, United States, 44691

United States, Pennsylvania

Mercy Cancer Institute at Mercy Hospital

Pittsburgh, Pennsylvania, United States, 15219

Sponsors and Collaborators

Radiation Therapy Oncology Group

National Cancer Institute (NCI)

Investigators

• Study Chair: William Small, MD; Robert H. Lurie Cancer Center

More Information

Publications of Results:

Small W Jr, Winter K, Levenback C, Iyer R, Hymes SR, Jhingran A, Gaffney D, Erickson B, Greven K. Extended-field irradiation and intracavitary brachytherapy combined with cisplatin and amifostine for cervical cancer with positive para-aortic or high common iliac lymph nodes: results of arm II of Radiation Therapy Oncology Group (RTOG) 0116. Int J Gynecol Cancer. 2011 Oct;21(7):1266-75. doi: 10.1097/IGC.0b013e31822c2769.

Small W Jr, Winter K, Levenback C, Iyer R, Gaffney D, Asbell S, Erickson B, Jhingran A, Greven K. Extended-field irradiation and intracavitary brachytherapy combined with cisplatin chemotherapy for cervical cancer with positive para-aortic or high common iliac lymph nodes: results of ARM 1 of RTOG 0116. Int J Radiat Oncol Biol Phys. 2007 Jul 15;68(4):1081-7. doi: 10.1016/j.ijrobp.2007.01.026. Epub 2007 Mar 29.

Other Publications:

Viswanathan AN, Moughan J, Small W Jr, Levenback C, Iyer R, Hymes S, Dicker AP, Miller B, Erickson B, Gaffney DK. The quality of cervical cancer brachytherapy implantation and the impact on local recurrence and disease-free survival in radiation therapy oncology group prospective trials 0116 and 0128. Int J Gynecol Cancer. 2012 Jan;22(1):123-31. doi: 10.1097/IGC.0b013e31823ae3c9.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00012012
• Other Study ID Numbers: RTOG-0116; CDR0000068472
• First Posted: January 27, 2003
• Results First Posted: January 7, 2015
• Last Update Posted: January 7, 2015
• Last Verified: December 2014

Keywords provided by Radiation Therapy Oncology Group:

radiation toxicity; stage III cervical cancer; stage IVA cervical cancer; cervical squamous cell carcinoma; cervical adenocarcinoma; cervical adenosquamous cell carcinoma

Additional relevant MeSH terms:

Uterine Cervical Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Amifostine; Radiation-Protective Agents; Protective Agents; Physiological Effects of Drugs