Cisplatin and Radiation Therapy With or Without Carboplatin and Paclitaxel in Patients With Locally Advanced Cervical Cancer

Phase 3

Completed

Conditions: Stage IB Cervical Cancer AJCC v6 and v7
Cervical Adenosquamous Carcinoma
Stage IIIB Cervical Cancer AJCC v6 and v7
Stage IIA Cervical Cancer AJCC v7
Cervical Squamous Cell Carcinoma, Not Otherwise Specified
Stage IVA Cervical Cancer AJCC v6 and v7
Cervical Adenocarcinoma
Stage IIB Cervical Cancer AJCC v6 and v7

Interventions: Radiation: Brachytherapy
Drug: Cisplatin
Drug: Carboplatin
Radiation: External Beam Radiation Therapy
Drug: Paclitaxel
Other: Quality-of-Life Assessment

Registration Number: NCT01414608

Lead Sponsor: GOG Foundation

Brief Summary: This randomized phase III trial studies how well giving cisplatin and radiation therapy together with or without carboplatin and paclitaxel works in treating patients with cervical cancer has spread from where it started to nearby tissue or lymph nodes. Drugs used in chemotherapy, such as cisplatin, carboplatin, and paclitaxel, work in different ways to stop the growth of \[cancer/tumor\] cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. External radiation therapy uses high-energy x rays to kill tumor cells. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. It is not yet known whether giving cisplatin and external and internal radiation therapy together with carboplatin and paclitaxel kills more tumor cells.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine if the addition of adjuvant chemotherapy to standard cisplatin-based chemoradiation improves overall survival.

SECONDARY OBJECTIVES:

I. To determine the progression-free survival rates. II. To determine acute and long-term toxicities. III. To determine patterns of disease recurrence. IV. To determine the association between radiation protocol compliance and outcomes.

V. To determine patient quality of life, including psycho-sexual health.

TERTIARY OBJECTIVES:

I. To determine the association between the results of a follow-up positron emission tomography (PET) scan performed 4-6 months post completion of chemoradiation and outcomes for all patients in the trial.

II. To determine the biological predictors of patients' outcomes based on translational laboratory studies of blood and tissue specimens.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cisplatin intravenously (IV) over 60-90 minutes on days 1, 8, 15, 22, and 29. Patients also undergo external-beam radiation therapy once daily, 5 days a week, for approximately 5 weeks. Patients then undergo high-dose rate, pulsed-dose rate, or low-dose rate intracavitary brachytherapy.

ARM II: Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients may undergo baseline tumor biopsy and blood collection for future correlative studies.

Patients complete the European Organization for Research and Treatment of Cancer (EORTC) Core questionnaire (QLQ-C30), the EORTC cervix cancer module (CX24), the ovarian cancer module (OV28), and the Sexual function-Vaginal Changes Questionnaire (SVQ) questionnaires at baseline, during, and after completion of study treatment.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 926

Inclusion Criteria

Eligible patients will have locally advanced cervical cancer suitable for primary treatment with chemoradiation with curative intent, in addition to:
- Federation of Gynecology and Obstetrics (FIGO) 2008 stage IB1 & node positive, IB2, IIA, IIB, IIIB, or IVA disease
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Histological diagnosis of squamous cell carcinoma, adenocarcinoma or adenosquamous cell carcinoma of the cervix
White blood cells (WBC) >= 3.0 x 10^9/L
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
Platelet count >= 100 x 10^9/L
Bilirubin =< 1.5 times upper limit of normal (ULN)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN (if both tests are done, both results need to be =< 2.5 x ULN)
Creatinine =< ULN (Common Toxicity Criteria [CTC] grade 0) OR calculated creatinine clearance (Cockcroft-Gault formula) >= 60 mL/min OR >= 50 mL/min by ethylenediaminetetraacetic acid (EDTA) creatinine clearance
Written informed consent

Exclusion Criteria

Any previous pelvic radiotherapy
Para-aortic nodal involvement above the level of the common iliac nodes or L3/L4 (if biopsy proven, PET positive, or >= 15 mm short-axis diameter on computed tomography [CT])
FIGO 2008 stage IIIA disease
Patients assessed at presentation as requiring interstitial brachytherapy treatment
Patients with bilateral hydronephrosis unless at least one side has been stented and renal function fulfills the required inclusion criteria
Previous chemotherapy for this tumor
Evidence of distant metastases
Prior diagnosis of Crohn's disease or ulcerative colitis
Peripheral neuropathy >= grade 2 (per Common Terminology Criteria for Adverse Events [CTCAE] version [v]4)
Patients who have undergone a previous hysterectomy or will have a hysterectomy as part of their initial cervical cancer therapy; this includes patients with a prior history of supracervical hysterectomy
Patients with other invasive malignancies, with the exception of non-melanoma skin cancer and in situ melanoma, who had (or have) any evidence of the other cancer present within the last 5 years
Patients who are pregnant or lactating
Any contraindication to the use of cisplatin, carboplatin, or paclitaxel chemotherapy
Serious illness or medical condition that precludes the safe administration of the trial treatment including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Patients who are known to be human immunodeficiency virus (HIV) positive

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (cisplatin, radiation therapy, brachytherapy, chemo)	Quality-of-Life Assessment	Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, brachytherapy)	Quality-of-Life Assessment	Patients receive cisplatin IV over 60-90 minutes on days 1, 8, 15, 22, and 29. Patients also undergo external-beam radiation therapy once daily, 5 days a week, for approximately 5 weeks. Patients then undergo high-dose rate, pulsed-dose rate, or low-dose rate intracavitary brachytherapy.
Arm I (cisplatin, radiation therapy, brachytherapy)	Brachytherapy	Patients receive cisplatin IV over 60-90 minutes on days 1, 8, 15, 22, and 29. Patients also undergo external-beam radiation therapy once daily, 5 days a week, for approximately 5 weeks. Patients then undergo high-dose rate, pulsed-dose rate, or low-dose rate intracavitary brachytherapy.
Arm II (cisplatin, radiation therapy, brachytherapy, chemo)	External Beam Radiation Therapy	Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, brachytherapy)	External Beam Radiation Therapy	Patients receive cisplatin IV over 60-90 minutes on days 1, 8, 15, 22, and 29. Patients also undergo external-beam radiation therapy once daily, 5 days a week, for approximately 5 weeks. Patients then undergo high-dose rate, pulsed-dose rate, or low-dose rate intracavitary brachytherapy.
Arm II (cisplatin, radiation therapy, brachytherapy, chemo)	Brachytherapy	Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm I (cisplatin, radiation therapy, brachytherapy)	Cisplatin	Patients receive cisplatin IV over 60-90 minutes on days 1, 8, 15, 22, and 29. Patients also undergo external-beam radiation therapy once daily, 5 days a week, for approximately 5 weeks. Patients then undergo high-dose rate, pulsed-dose rate, or low-dose rate intracavitary brachytherapy.
Arm II (cisplatin, radiation therapy, brachytherapy, chemo)	Cisplatin	Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm II (cisplatin, radiation therapy, brachytherapy, chemo)	Paclitaxel	Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Arm II (cisplatin, radiation therapy, brachytherapy, chemo)	Carboplatin	Patients receive cisplatin and undergo external-beam radiation and brachytherapy as in arm I. Beginning 4 weeks later, patients also receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Overall Survival Rate at 5 Years	5 years from study randomization	Estimate for probability of overall survival at 5 years by Kaplan-Meier method, where overall survival is defined as the time from randomization to time of death due to any cause or the date of last contact, whichever occurs first.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (Grade 3 or Higher) in First Year	1 year after randomization	Number of participants with a maximum grade of 3 or higher for pre-specified adverse events that occurred during the first year after randomization. Adverse events are graded and categorized using CTCAE v4.0.
Progression-free Survival Rate at 5 Years	5 years from study randomization	Estimate for probability of progression free at 5 years by Kaplan-Meier method, where progression-free survival is defined as the time from randomization to the time of disease progression, death from any cause or date of last contact, whichever occurs first. Disease progression is defined by increasing clinical, radiological or pathological evidence of disease from participant entry to when investigator deems a progression. RECIST V1.0 was not used to determine response on this study.
Radiation Protocol Compliance	Average duration of 7 weeks	Radiation protocol compliance measured by external beam dose delivered
Quality of Life for Global Health Status	Baseline and 12 months	Quality of Life measured by change of global health status score from baseline to 12 months follow-up. A cancer-specific questionnaire with 30 items which summarize as five functioning scales, a global health status/quality of life scale, three symptom scales and six single items assessing additional symptoms and perceived financial impact. The minimum global health status score was 0 and the maximum global health status score was 100. A higher global health status score means better outcome.
Patterns of Disease Recurrence	through study completion an average of 60 months	Number of patients for the site of disease recurrence. Disease was considered as persistent if participant had evidence of disease at study entry and disease did not progress during study. Disease status was considered locoregional alone if a participant had disease progression in the pelvis region including vagina after study entry. Disease status was considered distant if a participant had disease progression outside the pelvis (for example the abdomen and lung) after study entry. Criteria used to determine the no progression group includes participants that expired without documentation of progression.

Trial Locations

Locations (325): University of Alabama at Birmingham Cancer Center
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Birmingham, Alabama, United States
University of South Alabama Mitchell Cancer Institute
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Mobile, Alabama, United States
Alaska Women's Cancer Care
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Anchorage, Alaska, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Cancer Center at Saint Joseph's
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Phoenix, Arizona, United States
Gynecologic Oncology Group of Arizona
🇺🇸
Phoenix, Arizona, United States
Saint Joseph's Hospital and Medical Center
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Phoenix, Arizona, United States
Arizona Oncology Associates-Biltmore Cancer Center
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Phoenix, Arizona, United States
Arizona Oncology Associates-West Orange Grove
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Tucson, Arizona, United States
Arizona Oncology Associates-Wilmot
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Tucson, Arizona, United States
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University of Alabama at Birmingham Cancer Center
🇺🇸Birmingham, Alabama, United States