Cervical Adenocarcinoma, Cervical Adenosquamous Cell Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB Cervical Cancer, Stage IIA Cervical Cancer, Stage IIB Cervical Cancer, Stage III Cervical Cancer, Stage IVA Cervical Cancer
Conditions
Brief summary
This randomized phase III trial is studying cisplatin, radiation therapy, and tirapazamine to see how well they work compared to cisplatin and radiation therapy in treating patients with cervical cancer. Drugs used in chemotherapy, such as cisplatin and tirapazamine, 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. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. Cisplatin and tirapazamine may make tumor cells more sensitive to radiation therapy. It is not yet known whether giving cisplatin together with radiation therapy is more effective with or without tirapazamine in treating cervical cancer.
Detailed description
PRIMARY OBJECTIVE: I. Compare the progression-free survival of patients with stage IB, IIA, IIB, IIIB, or IVA carcinoma of the cervix treated with cisplatin and radiotherapy with vs without tirapazamine. SECONDARY OBJECTIVES: I. Compare overall survival of patients treated with these regimens. II. Compare the toxicity of these regimens in these patients. TERTIARY OBJECTIVES: I. Correlate study treatment with tumor expression of carbonic anhydrase IX (CA-IX) and recurrence-free survival, overall survival, or metastasis in patients treated with these regimens. II. Correlate expression of CA-IX, hypoxia inducible factor-1α, CD-31, thrombospondin-1, CD-105, or vascular endothelial growth factor (VEGF) in primary tumor tissue with recurrence-free survival, overall survival, or metastasis in patients treated with these regimens. III. Correlate pre-treatment and/or post-treatment serum concentrations of angiogenic markers including angiogenin or VEGF with recurrence-free survival, overall survival, or metastasis in patients treated with these regimens. IV. Correlate various combinations of biological markers of hypoxia and angiogenesis with recurrence-free survival, overall survival, or metastasis in patients treated with these regimens. V. Correlate levels of individual biological markers of hypoxia or angiogenesis with clinicopathological characteristics including tumor size, histologic subtype, FIGO stage, depth of invasion, pelvic node status, site of recurrence, and hemoglobin level as well as patient, age, race and performance status in patients treated with these regimens. OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified according to FIGO stage of disease (IB2 vs IIA vs IIB vs IIIB vs IVA), brachytherapy method (low-dose rate vs high-dose rate), surgical staging of para-aortic nodes (yes vs no). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive cisplatin IV over 30-60 minutes once weekly on days 1, 8, 15, 22, 29, and 36 (weeks 1-6). Patients also undergo external beam radiotherapy to the pelvis once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33 (weeks 1-5). Patients then receive either 1 or 2 applications of low-dose rate brachytherapy in weeks 6-8 OR 5 applications of high-dose rate (HDR)\* brachytherapy once weekly in weeks 4-8 and 3-5 days of parametrial boost radiotherapy\*\* beginning after the first brachytherapy implant. Treatment continues in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive tirapazamine IV over 2 hours on days 1, 8, 10, 12, 15, 22, 24, 26, and 29 and cisplatin IV over 1 hour on days 1, 15, and 29. Patients also undergo radiotherapy and brachytherapy as in arm I. Treatment continues in the absence of disease progression or unacceptable toxicity. NOTE: \*No external beam radiotherapy is administered on the day of HDR brachytherapy. If the majority of external beam radiotherapy has been administered, HDR brachytherapy may be administered in 2 applications per week (separated by at least 72 hours) in order to complete all treatment within 8 weeks. NOTE: \*\* Patients may receive a parametrial boost at the discretion of the treating radiation oncologist. After completion of study treatment, patients are followed for at least 5 years.
Interventions
DRUGcisplatin
Given IV
DRUGtirapazamine
Given IV
Sponsors
NCIC Clinical Trials Group
Gynecologic Oncology Group
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the uterine cervix * Stage IB2, IIA, IIB, IIIB, or IVA disease * Stage IIA tumors must be \> 4 cm * Primary, untreated disease * Negative, non-suspicious para-aortic nodes by lymphangiogram, CT scan, MRI, or lymphadenectomy * Must have been adequately clinically staged * Suitable for treatment with radical intent using concurrent chemotherapy and pelvic radiotherapy * No disease involvement of the lower third of the vagina regardless of stage (all stage IIIA, IIIB and IVA with lower one-third involvement) * No carcinoma of the cervical stump * Performance status - GOG 0-3 * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * SGOT ≤ 3 times ULN * Alkaline phosphatase ≤ 3 times ULN * Creatinine ≤ ULN or calculated creatinine clearance ≥ 60mL/min * No New York Heart Association class III-IV heart failure * No history of myocardial infarction * No unstable angina * No uncontrolled hypertension * No pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No septicemia or severe infection * No other invasive malignancy within the past 5 years except nonmelanoma skin cancer * No prior hysterectomy or planned hysterectomy as part of initial cervix cancer therapy * No prior coronary artery bypass surgery * No prior cancer therapy that would preclude study treatment * No concurrent angina medication * No concurrent intensity-modulated radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival - Percentage of Patients Alive and Progression Free | From study entry until first disease progression, death or date of last contact, up to 6 years | Patients' progression status based on clinical, radiological or pathological (histological) evidence of disease after study therapy. Progression includes any death without evidence of disease progression. Progression-free Survival (PFS) is defined as time in month from study enrollment to disease progression, death or date of last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From study entry to death or last contact, up to 6 years | The observed length of life from entry into the study to death or date of last contact. |
| Adverse Events (Grade 3 or Higher) During Treatment Period | All Adverse Events (AEs) occuring during treatment and up to 30 days after stopping the study treatment are reported | Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v3.0. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Eligible and evaluable patients.
Participants by arm
| Arm | Count |
|---|---|
| Concurrent Cisplatin and Radiation Cisplatin, 40 mg/m2 (max = 70 mg) IV on days 1, 8, 15, 22, 29 and 36). Radiation, Pelvic (41.4-45.0 Gy / 23-25 daily fractions) brachytherapy (LDR or HDR) / boost (5.4-9.0 Gy /3-5 daily fractions) to involved parametrium | 194 |
| Concurrent Cisplatin, Tirapazamine and Radiation Cisplatin, 60 mg/m2 IV on days 1, 15 and 29; Tirapazamine,220 mg/m2 (max=385 mg) on days 1, 8, 10, 12, 15, 22, 24, 26 and 29; Radiation, Pelvic (41.4-45.0 Gy / 23-25 daily fractions) brachytherapy (LDR or HDR) / boost (5.4-9.0 Gy /3-5 daily fractions) to involved parametrium | 185 |
| Total | 379 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible - elevated creatinine | 0 | 2 |
| Overall Study | Ineligible - inadequate pathology | 1 | 3 |
| Overall Study | Ineligible - required test not done | 1 | 4 |
| Overall Study | Ineligible - wrong cell type | 2 | 2 |
| Overall Study | Ineligible - wrong primary | 0 | 1 |
| Overall Study | Ineligible - wrong stage | 0 | 3 |
| Overall Study | Inevaluable - inadequate data | 0 | 4 |
Baseline characteristics
| Characteristic | Concurrent Cisplatin and Radiation | Concurrent Cisplatin, Tirapazamine and Radiation | Total |
|---|---|---|---|
| Age, Continuous | 48.9 years STANDARD_DEVIATION 11.3 | 48.4 years STANDARD_DEVIATION 11.3 | 48.7 years STANDARD_DEVIATION 11.3 |
| Age, Customized 20-30 years | 7 participants | 10 participants | 17 participants |
| Age, Customized 31-40 years | 41 participants | 37 participants | 78 participants |
| Age, Customized 41-50 years | 65 participants | 61 participants | 126 participants |
| Age, Customized 51-60 years | 53 participants | 48 participants | 101 participants |
| Age, Customized 61-70 years | 20 participants | 23 participants | 43 participants |
| Age, Customized 71-79 years | 8 participants | 6 participants | 14 participants |
| Brachytherapy High-dose rate | 138 participants | 129 participants | 267 participants |
| Brachytherapy Low-dose rate | 52 participants | 51 participants | 103 participants |
| Brachytherapy None | 4 participants | 5 participants | 9 participants |
| Cooperative Group Enrollment Gynecologic Oncology Group (GOG) | 167 participants | 167 participants | 334 participants |
| Cooperative Group Enrollment National Cancer Institute of Canada (NCIC) | 24 participants | 17 participants | 41 participants |
| Cooperative Group Enrollment Other | 3 participants | 1 participants | 4 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 24 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 161 Participants | 138 Participants | 299 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 23 Participants | 36 Participants |
| Gynecologic Oncology Group (GOG) Performance Status 0 - fully active | 147 participants | 141 participants | 288 participants |
| Gynecologic Oncology Group (GOG) Performance Status 1 - restricted strenuous activity, ambulatory | 46 participants | 41 participants | 87 participants |
| Gynecologic Oncology Group (GOG) Performance Status 2 - ambulatory, difficulty walking | 1 participants | 2 participants | 3 participants |
| Gynecologic Oncology Group (GOG) Performance Status 3 - limited self-care, partly confined to bed | 0 participants | 1 participants | 1 participants |
| Gynecologic Oncology Group (GOG) Performance Status 4 - completely disabled, no self-care | 0 participants | 0 participants | 0 participants |
| Histologic Type Adenocarcinoma, unspecified | 15 participants | 18 participants | 33 participants |
| Histologic Type Adenosquamous carcinoma | 11 participants | 5 participants | 16 participants |
| Histologic Type Other | 4 participants | 4 participants | 8 participants |
| Histologic Type Squamous cell carcinoma | 164 participants | 158 participants | 322 participants |
| International Federation of Gynecologic and Obstetrics (FIGO), Clinical Staging, for Cervical Carcin IB | 33 participants | 32 participants | 65 participants |
| International Federation of Gynecologic and Obstetrics (FIGO), Clinical Staging, for Cervical Carcin IIA | 11 participants | 12 participants | 23 participants |
| International Federation of Gynecologic and Obstetrics (FIGO), Clinical Staging, for Cervical Carcin IIB | 93 participants | 82 participants | 175 participants |
| International Federation of Gynecologic and Obstetrics (FIGO), Clinical Staging, for Cervical Carcin IIIB | 51 participants | 52 participants | 103 participants |
| International Federation of Gynecologic and Obstetrics (FIGO), Clinical Staging, for Cervical Carcin IVA | 6 participants | 7 participants | 13 participants |
| Para-aortic Lymph Node Not sampled | 25 participants | 33 participants | 58 participants |
| Para-aortic Lymph Node Sampled | 169 participants | 152 participants | 321 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 8 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 10 Participants | 16 Participants |
| Race (NIH/OMB) Black or African American | 43 Participants | 30 Participants | 73 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 7 Participants | 14 Participants |
| Race (NIH/OMB) White | 129 Participants | 134 Participants | 263 Participants |
| Sex: Female, Male Female | 194 Participants | 185 Participants | 379 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tumor Grade 1 - Well differentiated | 8 participants | 12 participants | 20 participants |
| Tumor Grade 2 - Moderately differentiated | 105 participants | 103 participants | 208 participants |
| Tumor Grade 3 - Poorly differentiated | 78 participants | 67 participants | 145 participants |
| Tumor Grade Not graded | 3 participants | 3 participants | 6 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 187 / 190 | 179 / 180 |
| serious Total, serious adverse events | 42 / 190 | 65 / 180 |
Outcome results
Primary
Progression-free Survival - Percentage of Patients Alive and Progression Free
Patients' progression status based on clinical, radiological or pathological (histological) evidence of disease after study therapy. Progression includes any death without evidence of disease progression. Progression-free Survival (PFS) is defined as time in month from study enrollment to disease progression, death or date of last contact.
Time frame: From study entry until first disease progression, death or date of last contact, up to 6 years
Population: Eligible and evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concurrent Cisplatin and Radiation | Progression-free Survival - Percentage of Patients Alive and Progression Free | 64.4 percentage of patients |
| Concurrent Cisplatin, Tirapazamine and Radiation | Progression-free Survival - Percentage of Patients Alive and Progression Free | 63.0 percentage of patients |
Secondary
Adverse Events (Grade 3 or Higher) During Treatment Period
Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v3.0.
Time frame: All Adverse Events (AEs) occuring during treatment and up to 30 days after stopping the study treatment are reported
Population: All Treated Patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Anemia | 16 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Genitourinary/Renal | 4 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Number Participants Analyzed | 190 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Hemorrhage | 5 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Other hematologic | 20 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Infection | 14 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Thrombocytopenia | 8 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Metabolic | 28 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Allergy/Immunology | 0 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Musculoskeletal | 0 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Coagulation | 0 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Neuropathy | 1 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Cardiac | 3 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Other Neurological | 5 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Constitutional | 15 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Pain | 10 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Neutropenia | 30 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Pulmonary | 3 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Dermatologic | 0 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Vascular Disorders | 11 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Leukopenia | 51 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Death, Not CTC Coded | 4 participants |
| Concurrent Cisplatin and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Gastrointestinal | 28 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Death, Not CTC Coded | 0 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Coagulation | 1 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Number Participants Analyzed | 180 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Leukopenia | 53 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Thrombocytopenia | 6 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Neutropenia | 26 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Anemia | 12 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Other hematologic | 17 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Allergy/Immunology | 2 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Constitutional | 23 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Dermatologic | 17 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Gastrointestinal | 35 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Genitourinary/Renal | 4 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Hemorrhage | 5 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Infection | 14 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Metabolic | 45 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Musculoskeletal | 5 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Neuropathy | 1 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Other Neurological | 14 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Pain | 38 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Pulmonary | 6 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Vascular Disorders | 7 participants |
| Concurrent Cisplatin, Tirapazamine and Radiation | Adverse Events (Grade 3 or Higher) During Treatment Period | Cardiac | 4 participants |
Secondary
Overall Survival
The observed length of life from entry into the study to death or date of last contact.
Time frame: From study entry to death or last contact, up to 6 years
Population: Eligible and evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Concurrent Cisplatin and Radiation | Overall Survival | 70.6 percentage of patients alive |
| Concurrent Cisplatin, Tirapazamine and Radiation | Overall Survival | 70.5 percentage of patients alive |