Breast Cancer
Conditions
Keywords
stage II breast cancer, stage IV breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, inflammatory breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining chemotherapy, monoclonal antibody therapy, and surgery may be a more effective treatment for breast cancer. PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy, monoclonal antibody therapy, and surgery in treating women who have stage II, stage III, or stage IV breast cancer.
Detailed description
OBJECTIVES: * Determine the cardiac and other toxicity of paclitaxel when administered with trastuzumab (Herceptin) after doxorubicin and cyclophosphamide in women with stage IIB, IIIA, IIIB, IIIC, or previously untreated stage IV breast cancer. * Determine whether the addition of paclitaxel with or without trastuzumab to conventional breast cancer adjuvant therapy (doxorubicin and cyclophosphamide) further decreases tumor size and the number of positive axillary nodes in these patients. * Determine the 5-year disease-free survival and overall survival of patients treated with these regimens. * Determine whether the initial pathologic response in patients receiving neoadjuvant therapy correlates with the eventual 5-year disease-free survival or overall survival. * Compare the number of patients eligible for breast-conserving cancer surgery after treatment with doxorubicin and cyclophosphamide vs paclitaxel and trastuzumab. * Correlate clinical and radiographic response rate with pathologic response rate in the primary tumor and axillary lymph nodes and determine which parameter best determines the pathologic response rate in patients treated with these regimens. OUTLINE: Patients either received neoadjuvant therapy (HER-2 overexpressing and non-overexpressing patients) or adjuvant therapy (HER-2 overexpressing patients only). * Neoadjuvant therapy: Patients receive one of two treatment regimens. * Regimen I (HER-2 non-overexpressing patients or HER-2 overexpressing patients who refuse trastuzumab (Herceptin) therapy): Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes and paclitaxel IV over 3 hours on day 1 every 3 weeks for a total of 4 courses. Patients then undergo surgery with or without adjuvant radiotherapy and/or oral tamoxifen. * Regimen II (HER-2 overexpressing patients only): Patients receive doxorubicin and cyclophosphamide as in regimen I. After completion of course 4, patients receive paclitaxel IV and trastuzumab IV over 90-150 minutes weekly on weeks 13-24. Patients then undergo surgery with or without adjuvant radiotherapy. Patients then receive trastuzumab IV over 30 minutes weekly on weeks 29-69 if they did not receive radiotherapy or on weeks 36-76 if they did receive radiotherapy. * Adjuvant therapy: Patients who receive adjuvant therapy (HER-2 overexpressing patients only) receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1 every 3 weeks for a total of 4 courses. After completion of course 4, patients receive paclitaxel IV and trastuzumab IV over 90 minutes weekly on weeks 13-24. Patients then may undergo radiotherapy followed by trastuzumab IV over 30 minutes weekly on weeks 29-69 if they did not receive radiotherapy or on weeks 36-76 if they did receive radiotherapy. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years. PROJECTED ACCRUAL: A total of 125 patients (100 in the neoadjuvant group and 25 in the adjuvant group) will be accrued for this study within 5 years.
Interventions
BIOLOGICALtrastuzumab
infusion 4 mg/kg load week 1; 2 mg/kg weekly thereafter for 12 weeks
DRUGcyclophosphamide
600 mg/m2, intravenous infusion every 3 weeks for four cycles
DRUGdoxorubicin hydrochloride
60 mg/m2 intravenously, 5-10 minutes, every 3 weeks, up to 12 weeks
DRUGpaclitaxel
90 mg/m2 weekly, intravenously 1 hour after herceptin, given weekly up to 12 weeks or 175 mg/m2, intravenously every 3 weeks, up to 12 weeks (only if not receiving Herceptin®)
PROCEDUREconventional surgery
Surgical excision will take place 12-13 weeks for the neo-adjuvant herceptin setting and 12-13 weeks in the non-herceptin setting. Surgery will take place prior to chemotherapy in the adjuvant herceptin setting
Sponsors
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
1 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed stage IIB, IIIA, IIIB, IIIC, or previously untreated stage IV primary carcinoma of the breast * Fine needle aspiration, core needle biopsy, or incisional biopsy allowed * No excisional biopsy * Any of the following: * Tumor size 2, Nodes 1 (T2N1) or tumor size 3 nodes 0 (T3N0) * Any T with N2 (including axillary lymph nodes matted to one another) or N3 * Any T4, including inflammatory breast cancer * Adjuvant patients with at least 4 positive lymph nodes and HER-2 overexpressing tumor * Supraclavicular or infraclavicular positive lymph nodes without distant metastases * Distant metastases with measurable disease in breast or lymph nodes * Synchronous bilateral primary breast cancer allowed if the more serious cancer meets entry criteria * Measurable or evaluable disease PATIENT CHARACTERISTICS: Age: Not specified Sex: Female Menopausal status: Not specified Performance status: Not specified Life expectancy: Not specified Hematopoietic: White cell count \> 3000 / mm3 Platelet count \> 100,000 / mm3 Hemoglobin \> 9 mg / dl Bilirubin \< 1.5 x normal Creatinine \< 1.5 x normal left ventricular ejection fraction (LVEF) normal by resting nuclear ventriculogram Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Exclusions Prior malignancies except: Effectively treated squamous cell or basal cell skin cancer Carcinoma in situ of the cervix that has been curatively treated by surgery alone Nonbreast malignancy from which patient has been disease-free for 5 years and is at low risk of recurrence
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | 78 weeks (1.5 years) | Doxorubicin + cyclophosphamide in combination with paclitaxel and trastuzumab (AC-TP) Associated Systolic Dysfunction. Systolic function was measured by the ventricular ejection fraction (LVEF). LVEF is a measurement in determining how well your heart is pumping out blood and in diagnosing and tracking heart failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | 78 weeks (1.5 years) | Measured by the Overall Response. Response: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Disease-free Survival (DFS) in Patients Receiving and Not Receiving Herceptin®. | 5 years | Percent of patients receiving and not receiving Herceptin who are alive and disease-free at 5 years. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from University of North Carolina (UNC) at Chapel Hill and Wake Forest University School of Medicine.
Pre-assignment details
85 patients consented to treatment. 3 patients were consented but not treated.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Herceptin With or Without Radiation Patients will receive Adriamycin/Cytoxan (4AC) followed by Taxol plus weekly Herceptin either neo-adjuvantly or adjuvantly. Eligible patients will go on to radiation then all patients will receive additional Herceptin every three weeks for 40 weeks. | 52 |
| Experimental: Non-Herceptin With or Without Radiation Patients with high-risk human epidermal growth factor receptor 2 (HER-2) non-overexpressing tumors and those whose tumors overexpress the protein but who refuse or are ineligible for Herceptin® will be treated with conventional Adriamycin/Cytoxan (4AC) followed by Taxol® without Herceptin®. This will be followed by surgery then either radiation or no radiation. | 30 |
| Total | 82 |
Baseline characteristics
| Characteristic | Experimental: Herceptin With or Without Radiation | Total | Experimental: Non-Herceptin With or Without Radiation |
|---|---|---|---|
| Age, Continuous | 48 years | 48 years | 48 years |
| Clinical Stage IIB | 6 Participants | 15 Participants | 9 Participants |
| Clinical Stage IIIA | 20 Participants | 32 Participants | 12 Participants |
| Clinical Stage IIIB | 8 Participants | 14 Participants | 6 Participants |
| Clinical Stage IIIC | 8 Participants | 8 Participants | 0 Participants |
| Clinical Stage IV | 10 Participants | 13 Participants | 3 Participants |
| Estrogen Receptor Status 0 | 0 Participants | 4 Participants | 4 Participants |
| Estrogen Receptor Status +1 | 0 Participants | 9 Participants | 9 Participants |
| Estrogen Receptor Status +2 | 6 Participants | 9 Participants | 3 Participants |
| Estrogen Receptor Status +3 | 45 Participants | 48 Participants | 3 Participants |
| Estrogen Receptor Status FISH + | 1 Participants | 1 Participants | 0 Participants |
| Estrogen Receptor Status fluorescence in-situ hybridization (FISH) Negative | 0 Participants | 11 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 23 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 35 Participants | 56 Participants | 21 Participants |
| Region of Enrollment United States | 52 participants | 82 participants | 30 participants |
| Sex: Female, Male Female | 52 Participants | 82 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Type of Therapy Adjuvant | 15 Participants | 15 Participants | 0 Participants |
| Type of Therapy Neoadjuvant | 37 Participants | 67 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 52 | 13 / 30 |
| other Total, other adverse events | 51 / 52 | 28 / 30 |
| serious Total, serious adverse events | 7 / 52 | 1 / 30 |
Outcome results
Primary
Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC.
Doxorubicin + cyclophosphamide in combination with paclitaxel and trastuzumab (AC-TP) Associated Systolic Dysfunction. Systolic function was measured by the ventricular ejection fraction (LVEF). LVEF is a measurement in determining how well your heart is pumping out blood and in diagnosing and tracking heart failure.
Time frame: 78 weeks (1.5 years)
Population: LVEF data during AC-TP are complete on 50 patients. 2 are incomplete because of withdrawal (1) and progressive disease (1). 43 of the 52 patients underwent LVEF determination at 1.5 years.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Herceptin Regimen After AC | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Asymptomatic LVEF < 50% | 1 Participants |
| Herceptin Regimen After AC | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Congestive Heart Failure | 0 Participants |
| Herceptin Regimen After TP | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Congestive Heart Failure | 1 Participants |
| Herceptin Regimen After TP | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Asymptomatic LVEF < 50% | 8 Participants |
| Herceptin Regimen at 1.5 Years | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Congestive Heart Failure | 1 Participants |
| Herceptin Regimen at 1.5 Years | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Asymptomatic LVEF < 50% | 3 Participants |
| Herceptin Regimen | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Congestive Heart Failure | 2 Participants |
| Herceptin Regimen | Cardiac Toxicity of Weekly Taxol Given With Weekly Herceptin When Delivered Immediately Following Four Cycles of Standard Dose AC. | Asymptomatic LVEF < 50% | 11 Participants |
Secondary
Disease-free Survival (DFS) in Patients Receiving and Not Receiving Herceptin®.
Percent of patients receiving and not receiving Herceptin who are alive and disease-free at 5 years.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Herceptin Regimen After AC | Disease-free Survival (DFS) in Patients Receiving and Not Receiving Herceptin®. | 69 percentage of patients |
| Herceptin Regimen After TP | Disease-free Survival (DFS) in Patients Receiving and Not Receiving Herceptin®. | 60 percentage of patients |
Secondary
Overall Response
Measured by the Overall Response. Response: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 78 weeks (1.5 years)
Population: Protocol specifies that Response will be examined in patients who were treated neoadjuvantly. Because of this, only patients treated with Herceptin neoadjuvantly and non-Herceptin patients were included in this analysis. One patient was found unevaluable in the AC-P group and was not included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Herceptin Regimen After AC | Overall Response | 32 Participants |
| Herceptin Regimen After TP | Overall Response | 24 Participants |