Brief Summary
RATIONALE: Drugs used in chemotherapy, such as cisplatin, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether chemotherapy and radiation therapy are more effective when given with or without additional chemotherapy in treating cervical cancer.
PURPOSE: This randomized phase III trial is studying chemotherapy and pelvic radiation therapy to see how well they work when given with or without additional chemotherapy in treating patients with high-risk early-stage cervical cancer after radical hysterectomy.
PURPOSE: This randomized phase III trial is studying chemotherapy and pelvic radiation therapy to see how well they work when given with or without additional chemotherapy in treating patients with high-risk early-stage cervical cancer after radical hysterectomy.
Brief Title
Chemotherapy and Pelvic Radiation Therapy With or Without Additional Chemotherapy in Treating Patients With High-Risk Early-Stage Cervical Cancer After Radical Hysterectomy
Detailed Description
OBJECTIVES:
Primary
* To determine if administering adjuvant systemic chemotherapy after chemoradiotherapy will improve disease-free survival compared to chemoradiotherapy alone in patients with high-risk early-stage cervical carcinoma found to have positive nodes and/or positive parametria after radical hysterectomy.
Secondary
* To evaluate adverse events.
* To evaluate overall survival.
* To evaluate quality of life.
* To evaluate chemotherapy-induced neuropathy.
* To perform a post-hoc dose-volume evaluation between patients treated with standard radiotherapy and patients treated with intensity-modulated radiotherapy (IMRT) with respect to toxicity and local control.
* To collect fixed tissue samples to identify tumor molecular signatures that may be associated with patient outcomes, such as adverse events, disease-free survival, and overall survival.
* To collect blood samples to identify secreted factors from serum and plasma that may be associated with adverse events or outcome and to identify single nucleotide polymorphisms (SNPs) in genes from buffy coat that may be associated with a genetic predisposition to tumor formation itself or a response to cytotoxic therapy.
OUTLINE: This is a multicenter study. Patients are stratified according to planned use of brachytherapy (no vs. yes), radiotherapy modality - \[standard external beam radiotherapy (EBRT) vs. intensity-modulated radiotherapy (IMRT)\], and radiotherapy dose (45 Gy vs. 50.4 Gy). Patients are randomized to 1 of 2 treatment arms.
* Arm I: Patients undergo standard EBRT or IMRT to the pelvis once daily 5 days a week for 5-6 weeks. Patients also receive concurrent cisplatin IV over 1 hour once weekly for 6 weeks.
NOTE: Some patients may also undergo brachytherapy beginning within 7 days after completion of radiotherapy.
* Arm II: Patients receive chemoradiotherapy as in arm I. Beginning 4-6 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Quality of life is assessed by the Functional Assessment of Cancer Therapy - Gynecologic Oncology Group (FACT-GOG/NTX4), FACT-Cx, and FACIT-D questionnaires at baseline; at the completion of chemoradiotherapy; and then at 6, 12, and 24 months after completion of chemoradiotherapy.
Blood and tissue samples may be collected for gene expression analysis by immuno-histochemistry (IHC) and for biomarker and polymorphism studies.
After completion of study treatment, patients are followed up very 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Primary
* To determine if administering adjuvant systemic chemotherapy after chemoradiotherapy will improve disease-free survival compared to chemoradiotherapy alone in patients with high-risk early-stage cervical carcinoma found to have positive nodes and/or positive parametria after radical hysterectomy.
Secondary
* To evaluate adverse events.
* To evaluate overall survival.
* To evaluate quality of life.
* To evaluate chemotherapy-induced neuropathy.
* To perform a post-hoc dose-volume evaluation between patients treated with standard radiotherapy and patients treated with intensity-modulated radiotherapy (IMRT) with respect to toxicity and local control.
* To collect fixed tissue samples to identify tumor molecular signatures that may be associated with patient outcomes, such as adverse events, disease-free survival, and overall survival.
* To collect blood samples to identify secreted factors from serum and plasma that may be associated with adverse events or outcome and to identify single nucleotide polymorphisms (SNPs) in genes from buffy coat that may be associated with a genetic predisposition to tumor formation itself or a response to cytotoxic therapy.
OUTLINE: This is a multicenter study. Patients are stratified according to planned use of brachytherapy (no vs. yes), radiotherapy modality - \[standard external beam radiotherapy (EBRT) vs. intensity-modulated radiotherapy (IMRT)\], and radiotherapy dose (45 Gy vs. 50.4 Gy). Patients are randomized to 1 of 2 treatment arms.
* Arm I: Patients undergo standard EBRT or IMRT to the pelvis once daily 5 days a week for 5-6 weeks. Patients also receive concurrent cisplatin IV over 1 hour once weekly for 6 weeks.
NOTE: Some patients may also undergo brachytherapy beginning within 7 days after completion of radiotherapy.
* Arm II: Patients receive chemoradiotherapy as in arm I. Beginning 4-6 weeks after completion of chemoradiotherapy, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Quality of life is assessed by the Functional Assessment of Cancer Therapy - Gynecologic Oncology Group (FACT-GOG/NTX4), FACT-Cx, and FACIT-D questionnaires at baseline; at the completion of chemoradiotherapy; and then at 6, 12, and 24 months after completion of chemoradiotherapy.
Blood and tissue samples may be collected for gene expression analysis by immuno-histochemistry (IHC) and for biomarker and polymorphism studies.
After completion of study treatment, patients are followed up very 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Cervical Cancer
Eligibility Criteria
DISEASE CHARACTERISTICS:
* Histologically confirmed squamous, adenosquamous, or adenocarcinoma of the cervix with any/all of the following high-risk features after surgery:
* Positive pelvic nodes
* Positive parametrium
* Positive para-aortic nodes that have been completely resected and are positron emission tomography (PET)/computed tomography (CT) scan-negative
* PET only required if positive para-aortic nodes during surgery
* Clinical stage IA2, IB, or IIA disease (this corresponds to surgical tumor node metastasis (TNM) staging of T1-T2, N1, M0)
* Must have undergone radical hysterectomy (open, laparoscopically, or robotic) and staging within the past 70 days
* Para-aortic and pelvic node sampling required
* 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
* No gross residual disease
* No neuroendocrine histology
* No distant metastases
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* Absolute neutrophil count (ANC) ≥ 1,800/mm³
* Platelets ≥ 100,000/mm³
* White blood cell count (WBC) ≥ 4,000/mm³
* Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
* Serum creatinine ≤ 1.5 mg/dL
* Bilirubin ≤ 1.5 times upper limit of normal
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) normal
* Alkaline phosphatase normal
* Known HIV positivity allowed provided cluster of differentiation 4 (CD4) count is ≥ 350/mm³ within the past 14 days
* No other invasive malignancy within the past 3 years, except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix
* No severe, active co-morbidity, including any of the following:
* Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
* Transmural myocardial infarction within the past 6 months
* Acute bacterial or fungal infection requiring IV 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
* No prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* No prior systemic chemotherapy for the current cervical cancer
* Prior chemotherapy for a different cancer is allowed
* No prior radiotherapy to the pelvis that would result in overlap of radiotherapy fields
* Histologically confirmed squamous, adenosquamous, or adenocarcinoma of the cervix with any/all of the following high-risk features after surgery:
* Positive pelvic nodes
* Positive parametrium
* Positive para-aortic nodes that have been completely resected and are positron emission tomography (PET)/computed tomography (CT) scan-negative
* PET only required if positive para-aortic nodes during surgery
* Clinical stage IA2, IB, or IIA disease (this corresponds to surgical tumor node metastasis (TNM) staging of T1-T2, N1, M0)
* Must have undergone radical hysterectomy (open, laparoscopically, or robotic) and staging within the past 70 days
* Para-aortic and pelvic node sampling required
* 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
* No gross residual disease
* No neuroendocrine histology
* No distant metastases
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* Absolute neutrophil count (ANC) ≥ 1,800/mm³
* Platelets ≥ 100,000/mm³
* White blood cell count (WBC) ≥ 4,000/mm³
* Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
* Serum creatinine ≤ 1.5 mg/dL
* Bilirubin ≤ 1.5 times upper limit of normal
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) normal
* Alkaline phosphatase normal
* Known HIV positivity allowed provided cluster of differentiation 4 (CD4) count is ≥ 350/mm³ within the past 14 days
* No other invasive malignancy within the past 3 years, except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix
* No severe, active co-morbidity, including any of the following:
* Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
* Transmural myocardial infarction within the past 6 months
* Acute bacterial or fungal infection requiring IV 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
* No prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* No prior systemic chemotherapy for the current cervical cancer
* Prior chemotherapy for a different cancer is allowed
* No prior radiotherapy to the pelvis that would result in overlap of radiotherapy fields
Inclusion Criteria
DISEASE CHARACTERISTICS:
* Histologically confirmed squamous, adenosquamous, or adenocarcinoma of the cervix with any/all of the following high-risk features after surgery:
* Positive pelvic nodes
* Positive parametrium
* Positive para-aortic nodes that have been completely resected and are positron emission tomography (PET)/computed tomography (CT) scan-negative
* PET only required if positive para-aortic nodes during surgery
* Clinical stage IA2, IB, or IIA disease (this corresponds to surgical tumor node metastasis (TNM) staging of T1-T2, N1, M0)
* Must have undergone radical hysterectomy (open, laparoscopically, or robotic) and staging within the past 70 days
* Para-aortic and pelvic node sampling required
* 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
* No gross residual disease
* No neuroendocrine histology
* No distant metastases
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* Absolute neutrophil count (ANC) ≥ 1,800/mm³
* Platelets ≥ 100,000/mm³
* White blood cell count (WBC) ≥ 4,000/mm³
* Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
* Serum creatinine ≤ 1.5 mg/dL
* Bilirubin ≤ 1.5 times upper limit of normal
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) normal
* Alkaline phosphatase normal
* Known HIV positivity allowed provided cluster of differentiation 4 (CD4) count is ≥ 350/mm³ within the past 14 days
* No other invasive malignancy within the past 3 years, except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix
* No severe, active co-morbidity, including any of the following:
* Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
* Transmural myocardial infarction within the past 6 months
* Acute bacterial or fungal infection requiring IV 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
* No prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* No prior systemic chemotherapy for the current cervical cancer
* Prior chemotherapy for a different cancer is allowed
* No prior radiotherapy to the pelvis that would result in overlap of radiotherapy fields
* Histologically confirmed squamous, adenosquamous, or adenocarcinoma of the cervix with any/all of the following high-risk features after surgery:
* Positive pelvic nodes
* Positive parametrium
* Positive para-aortic nodes that have been completely resected and are positron emission tomography (PET)/computed tomography (CT) scan-negative
* PET only required if positive para-aortic nodes during surgery
* Clinical stage IA2, IB, or IIA disease (this corresponds to surgical tumor node metastasis (TNM) staging of T1-T2, N1, M0)
* Must have undergone radical hysterectomy (open, laparoscopically, or robotic) and staging within the past 70 days
* Para-aortic and pelvic node sampling required
* 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
* No gross residual disease
* No neuroendocrine histology
* No distant metastases
PATIENT CHARACTERISTICS:
* Zubrod performance status 0-1
* Absolute neutrophil count (ANC) ≥ 1,800/mm³
* Platelets ≥ 100,000/mm³
* White blood cell count (WBC) ≥ 4,000/mm³
* Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
* Serum creatinine ≤ 1.5 mg/dL
* Bilirubin ≤ 1.5 times upper limit of normal
* Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) normal
* Alkaline phosphatase normal
* Known HIV positivity allowed provided cluster of differentiation 4 (CD4) count is ≥ 350/mm³ within the past 14 days
* No other invasive malignancy within the past 3 years, except nonmelanomatous skin cancer or carcinoma in situ of the breast, oral cavity, or cervix
* No severe, active co-morbidity, including any of the following:
* Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
* Transmural myocardial infarction within the past 6 months
* Acute bacterial or fungal infection requiring IV 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
* No prior allergic reaction to carboplatin, paclitaxel, and/or cisplatin
PRIOR CONCURRENT THERAPY:
* See Disease Characteristics
* No prior systemic chemotherapy for the current cervical cancer
* Prior chemotherapy for a different cancer is allowed
* No prior radiotherapy to the pelvis that would result in overlap of radiotherapy fields
Gender
Female
Gender Based
false
Keywords
cervical adenocarcinoma
cervical adenosquamous cell carcinoma
cervical squamous cell carcinoma
stage IA cervical cancer
stage IB cervical cancer
stage IIA cervical cancer
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT00980954
Org Class
Network
Org Full Name
Radiation Therapy Oncology Group
Org Study Id
RTOG-0724
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Phase III Randomized Study of Concurrent Chemotherapy and Pelvic Radiation Therapy With or Without Adjuvant Chemotherapy in High-Risk Patients With Early-Stage Cervical Carcinoma Following Radical Hysterectomy
Primary Outcomes
Outcome Description
Disease-free survival (DFS) is estimated by the Kaplan-Meier method. The distribution of DFS estimates between the two arms is compared using the log rank test. DFS time is measured from the date of randomization to the date of first DFS failure (local, regional or distant metastases failure or death due to any cause) or last follow-up (censored). Analysis was to occur after disease or death was reported for 50 participants.
Outcome Measure
Disease-free Survival (Percentage of Participants Alive Without Disease)
Outcome Time Frame
From randomization to first failure (local, regional, or distant metastases failure or death due to any cause) or last follow-up. Maximum follow-up at the time of analysis was 12.8 years. The 2- and 4-year DFS estimates are reported.
Secondary Ids
Secondary Id
CDR0000654709
Secondary Id
NCI-2011-01973
Secondary Id
RTOG 0724/GOG-0724
Secondary Outcomes
Outcome Description
Overall survival is estimated by the Kaplan-Meier method. The distribution of survival estimates between the two arms is compared using the log rank test. Survival time is measured from the date of randomization to the date of death from any cause or last known follow-up (censored). Analysis was to occur after disease or death was reported for 50 participants.
Outcome Time Frame
From randomization to death or last follow-up. Maximum follow-up time at time of analysis was 12.8 years. The 2- and 4-year survival estimates are reported.
Outcome Measure
Overall Survival (Percentage of Participants Alive)
Outcome Description
The FACT-GOG/NTX4 measures patient-reported symptoms of chemotherapy-induced peripheral neuropathy in cancer patients. Possible scores range from 0 to 16 with higher scores indicating a better condition. Analysis of covariance, using the baseline score as a covariate, will be used to determine if there is a difference between the treatment arms.
Outcome Time Frame
Baseline and 12 months after the completion of concurrent chemoradiation (6 weeks)
Outcome Measure
Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-NTX) at 12 Months
Outcome Description
The diarrhea-specific subscore of the FACIT-D measures patient-reported diarrhea symptoms. Possible scores range from 0 to 44 with higher scores indicating a better quality of life. Analysis of covariance, using the baseline score as a covariate, will be used to determine if there is a difference between the treatment arms.
Outcome Time Frame
Baseline and 12 months after the completion of concurrent chemoradiation (6 weeks)
Outcome Measure
Functional Assessment of Chronic Illness Therapy - Diarrhea (FACIT-D) Diarrhea Subscore at 12 Months
Outcome Description
The cervical cancer subscore of the FACT-Cx measures patient-reported symptoms and problems related to cervical cancer. Possible scores range from 0 to 60 with higher scores indicating a better quality of life. Analysis of covariance, using the baseline score as a covariate, will be used to determine if there is a difference between the treatment arms.
Outcome Time Frame
Baseline and 12 months after the completion of concurrent chemoradiation (6 weeks)
Outcome Measure
Functional Assessment of Cancer Therapy - Cervix (FACT-Cx) Cervical Cancer Subscore at 12 Months
Outcome Description
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Outcome Time Frame
From randomization to the date of last known follow-up. Maximum follow-up time was 12.8 years.
Outcome Measure
Number of Participants by Highest Grade Adverse Event Reported
Outcome Time Frame
From randomization to last follow-up
Outcome Measure
Associations Between Tumor Molecular Signatures, From Fixed Tissue, and Outcomes Such as Adverse Events, Disease Free Survival and Overall Survival
Outcome Time Frame
From randomization to last follow-up.
Outcome Measure
Associations Between Secreted Factors From Serum and Plasma With Adverse Events or Outcome
Outcome Time Frame
From randomization to last follow-up.
Outcome Measure
Associations Between Single Nucleotide Polymorphisms (SNPs) in Genes From Buffy Coat and a Genetic Predisposition to Tumor Formation Itself or a Response to Cytotoxic Therapy
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
David Smotkin
Investigator Email
dsmotkin@montefiore.org
Investigator Phone
718-920-5157
Categories Mesh Debug
Prostate Cancer --- UROGENITAL NEOPLASMS
Cancer --- NEOPLASMS BY SITE
Cancer --- NEOPLASMS
Gynecologic Cancers --- UTERINE CERVICAL DISEASES
Gynecologic Cancers --- UTERINE DISEASES
MeSH Terms
UTERINE CERVICAL NEOPLASMS
UTERINE NEOPLASMS
GENITAL NEOPLASMS, FEMALE
UROGENITAL NEOPLASMS
NEOPLASMS BY SITE
NEOPLASMS
UTERINE CERVICAL DISEASES
UTERINE DISEASES
GENITAL DISEASES, FEMALE
FEMALE UROGENITAL DISEASES
FEMALE UROGENITAL DISEASES AND PREGNANCY COMPLICATIONS
UROGENITAL DISEASES
GENITAL DISEASES
CARBOPLATIN
CISPLATIN
PACLITAXEL
RADIOTHERAPY, INTENSITY-MODULATED
COORDINATION COMPLEXES
ORGANIC CHEMICALS
CHLORINE COMPOUNDS
INORGANIC CHEMICALS
NITROGEN COMPOUNDS
PLATINUM COMPOUNDS
TAXOIDS
CYCLODECANES
CYCLOPARAFFINS
HYDROCARBONS, ALICYCLIC
HYDROCARBONS, CYCLIC
HYDROCARBONS
DITERPENES
TERPENES
RADIOTHERAPY, CONFORMAL
RADIOTHERAPY, COMPUTER-ASSISTED
RADIOTHERAPY
THERAPEUTICS