Combination Chemotherapy in Treating Patients With High-Risk Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. PURPOSE: This randomized phase II trial is studying two different regimens of combination chemotherapy and comparing them to see how well they work in treating patients with high-risk primary stage II or stage III breast cancer.

Detailed Description
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OBJECTIVES: Compare the toxic effects of doxorubicin, cyclophosphamide, and paclitaxel vs cyclophosphamide, thiotepa, and carboplatin in patients with high-risk primary breast cancer. (Arm I closed to accural as of 4/6/2006.) Compare the efficacies of these regimens followed by peripheral blood stem cell rescue in these patients. Determine the efficacy of a bisphosphonate to prevent relapse/metastasis after high-dose chemotherapy in these patients. OUTLINE: This is a randomized study. Patients are stratified by stage of disease. Peripheral blood stem cells (PBSC) are collected after mobilization with filgrastim (G-CSF), administered subcutaneously or IV, twice daily beginning 3 days before collection and continuing until collection is complete. All patients receive conventional-dose adjuvant chemotherapy, probably comprising doxorubicin IV, cyclophosphamide IV, and fluorouracil IV over 1 hour on days 1, 22, 43, and 64. Patients are then randomized to receive 1 of 2 treatment arms of high-dose chemotherapy. (Arm I closed to accrual as of 4/6/2006.) Arm I (ACT) (closed to accrual as of 4/6/2006): Patients receive doxorubicin IV over 24 hours on days -9 to -6, cyclophosphamide IV over 2 hours on day -5, and paclitaxel IV over 24 hours on day -2. PBSC are reinfused on days -2 and 0. G-CSF is administered beginning on day 0 and continuing until blood counts recover. Arm II (STAMP V): Patients receive cyclophosphamide IV, carboplatin IV, and thiotepa IV over 24 hours on days -7 to -4. PBSC are reinfused and G-CSF is administered as in arm I. Within 4-6 weeks of day 0 of high-dose chemotherapy, patients with estrogen and/or progesterone receptor positive tumors receive oral tamoxifen twice daily for 5 years. Patients are also randomized to receive a bisphosphonate comprising pamidronate IV every 4 weeks for 2 years. Quality of life is assessed before therapy, at 30 days after high-dose chemotherapy, and at 6 and 12 months. Patients are followed every 3 months for 1 year and then every 6 months for at least 10 years. PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study within 3 years.

Official Title
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Randomized Phase II Study of Adriamycin/Cytoxan/Taxol (ACT) vs. Cytoxan, Thiotepa, Carboplatin (STAMP V) in Patients With High-Risk Primary Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: filgrastim
* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: paclitaxel
* Drug: thiotepa
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven high-risk primary breast cancer with less than 60% chance of progression-free survival of 3 years from diagnosis Stage II with at least 10 positive axillary nodes OR Stage IIIA or IIIB No histologically proven bone marrow metastasis No CNS metastasis Hormone receptor status: Hormone receptor status known PATIENT CHARACTERISTICS: Age: Physiological age 60 or under Menopausal status: Not specified Performance status: Karnofsky 80-100% Life expectancy: See Disease Characteristics Hematopoietic: Neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hepatic: Bilirubin no greater than 1.5 mg/dL SGOT or SGPT no greater than 2 times upper limit of normal Hepatitis B antigen negative Renal: Creatinine no greater than 1.2 mg/dL Creatinine clearance at least 70 mL/min No prior hemorrhagic cystitis Cardiovascular: Ejection fraction at least 55% by MUGA No prior significant valvular heart disease or arrhythmia Pulmonary: FEV_1 at least 60% of predicted pO_2 at least 85 mm Hg on room air pCO_2 at least 43 mm Hg on room air DLCO at least 60% lower limit of predicted Other: No other prior malignancy except squamous cell or basal cell skin cancer or stage I or carcinoma in situ of the cervix No CNS dysfunction that would preclude compliance HIV negative No sensitivity to E. coli-derived products Not pregnant Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: At least 4 weeks since prior chemotherapy No prior doxorubicin of total dose exceeding 240 mg/m^2 No prior paclitaxel of total dose of at least 750 mg/m^2 No more than 12 months since prior conventional-dose adjuvant chemotherapy Endocrine therapy: At least 4 weeks since prior hormonal therapy Radiotherapy: At least 4 weeks since prior radiotherapy No prior radiation to the left chest wall Surgery: Not specified

Ages Eligible for Study
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Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (ACT) (closed to accrual as of 4/6/2006)<br>Patients receive doxorubicin IV over 24 hours on days -9 to -6, cyclophosphamide IV over 2 hours on day -5, and paclitaxel IV over 24 hours on day -2. PBSC are reinfused on days -2 and 0. G-CSF is administered beginning on day 0 and continuing until blood counts recover. | Biological: filgrastim<br>* Given IV or subcutaneously<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: doxorubicin hydrochloride<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Procedure: peripheral blood stem cell transplantation<br>* Patients receive autologous peripheral blood stem cells<br>|
| Active Comparator: Arm II (STAMP V)<br>Patients receive cyclophosphamide IV, carboplatin IV, and thiotepa IV over 24 hours on days -7 to -4. PBSC are reinfused and G-CSF is administered as in arm I. | Biological: filgrastim<br>* Given IV or subcutaneously<br>Drug: carboplatin<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: thiotepa<br>* Given IV<br>Procedure: peripheral blood stem cell transplantation<br>* Patients receive autologous peripheral blood stem cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Five-Year Relapse-free Survival | RFS events included death or disease recurrence. Patients who did not experience disease recurrence or death were censored at the date of last follow-up. Survival rates were estimates using the Kaplan-Meier method. | Five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Five-Year Overall Survival | Patients who were still alive were censored at the date of last follow-up. Survival rates were estimates using the Kaplan-Meier method. | Five Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer