Combination Chemotherapy in Treating Patients With Breast Cancer
Combination Chemotherapy in Treating Patients With Breast Cancer
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so
 they stop growing or die. Giving drugs at different times or combining more than one drug may
 kill more tumor cells. It is not yet known which chemotherapy regimen is more effective for
 breast cancer.

 PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy consisting
 of either doxorubicin, cyclophosphamide, or paclitaxel given at different times with that of
 combination chemotherapy consisting of doxorubicin plus cyclophosphamide followed by
 paclitaxel in treating women with stage II or stage IIIA breast cancer.
OBJECTIVES: I. Compare the sequential chemotherapy with doxorubicin, paclitaxel and
 cyclophosphamide to combined doxorubicin and cyclophosphamide followed by paclitaxel for
 disease free and overall survival in women with node positive stage II or IIIA breast cancer.
 II. Determine whether increasing the dose density of adjuvant chemotherapy will improve
 disease free and overall survival. III. Compare the toxicity in patients treated with these
 regimens.

 OUTLINE: This is a randomized study. Patients are randomized into one of four arms
 (sequential chemotherapy every 2 weeks vs every 3 weeks vs concurrent chemotherapy followed
 by paclitaxel every 2 weeks vs every 3 weeks). All tumor should be removed by either a
 modified radical mastectomy or a segmental mastectomy plus axillary node dissection. Adjuvant
 chemotherapy is started within 84 days following the last surgical procedure. Arm I: Patients
 receive sequential chemotherapy every 3 weeks. Doxorubicin IV is administered once every 3
 weeks for 4 doses. Paclitaxel IV is then administered over 3 hours once every 3 weeks for 4
 doses. Cyclophosphamide IV is administered once every 3 weeks for 4 doses following
 paclitaxel. Arm II: Patients receive sequential chemotherapy every 2 weeks. Doxorubicin IV is
 administered once every 2 weeks for 4 doses. Paclitaxel IV is then administered over 3 hours
 once every 2 weeks for 4 doses. Cyclophosphamide IV is administered once every 2 weeks for 4
 doses following paclitaxel. Filgrastim (G-CSF) is administered by subcutaneous injection on
 days 3-10 after each dose of doxorubicin, paclitaxel, and cyclophosphamide. Arm III: Patients
 receive combination chemotherapy every 3 weeks. Combination doxorubicin IV and
 cyclophosphamide IV is administered once every 3 weeks for 4 doses. Paclitaxel IV is
 administered over 3 hours once every 3 weeks for 4 doses following combination chemotherapy.
 Arm IV: Patients receive combination chemotherapy every 2 weeks. Combination doxorubicin IV
 and cyclophosphamide IV is administered once every 2 weeks for 4 doses. Paclitaxel IV is
 administered over 3 hours once every 2 weeks for 4 doses following combination chemotherapy.
 G-CSF is administered by subcutaneous injection on days 3-10 after each dose of
 doxorubicin/cyclophophamide and after each dose of paclitaxel. After completion of all
 chemotherapy, patients receive tamoxifen orally for 5 years. Patients undergo radiotherapy
 4-6 weeks after the completion of chemotherapy. Patients are followed every 6 months for 5
 years, then annually until death.

 PROJECTED ACCRUAL: A total of 2,000 patients will be accrued for this study within 22 months.
1. Required Tumor Parameters

 1.1 Patients with operable, histologically confirmed adenocarcinoma of the female
 breast and positive lymph nodes. Node positivity may be determined by either an
 axillary node dissection or a positive sentinel node finding by immunohistochemistry
 or histology. This includes any patient with one or more positive lymph nodes whose
 tumors are T0, T1, 2 or 3 and N1, N2, MO. Patients with metaplastic carcinoma are
 eligible. Bilateral disease does not exclude patients from entry.

 1.2 Tumors that are locally advanced at diagnosis are not eligible. This is left to
 investigator judgment. Patients with tumors fixed to the chest wall, peau d'orange
 skin changes, skin ulcerations, or clinical inflammatory changes (T4 disease) are
 excluded from this study. Dermal lymphatic involvement noted on pathology without
 clinical inflammatory changes will not exclude a patient from this study.

 1.3 Patients with any ERP/PgR status are eligible.

 2. Prior treatment:

 2.1 <84 days from mastectomy or within 84 days of axillary dissection if the patient's
 most extensive breast surgery was a breast sparing procedure.

 2.2 Surgical resection margins - All tumor should be removed by either a modified
 radical mastectomy or a segmental mastectomy. Node dissection: patients may have had
 either an axillary node dissection or sentinel lymph node biopsy before beginning
 treatment on protocol.

 -  Mastectomy: There should be no evidence of gross or microscopic tumor at the
 surgical resection margins noted in the final surgery or pathology reports for
 patients who have had a modified radical mastectomy. Patients with close margins
 (tumor < 1 mm from margin) are eligible.

 -  Segmental mastectomy (lumpectomy): Although clear margins are preferable, DCIS or
 LCIS at the surgical resection margin will not render a patient who has undergone
 a segmental mastectomy ineligible for this study. Invasive tumor at the final
 resection margin will render a patient ineligible.

 2.3 No prior chemotherapy.

 2.4 No prior radiation therapy for this malignancy. Patients who received radiation to
 the breast for DCIS are eligible. Patients who have had segmental mastectomy will be
 treated with radiotherapy according to standard procedures in the treating physician's
 institution after completion of all chemotherapy. Patients who have had modified
 radical mastectomy may also receive radiotherapy at the discretion of the treating
 physician according to institutional guidelines.

 2.5 Patients may receive up to four weeks of tamoxifen therapy for this malignancy and
 still be eligible for study entry. Patients who received tamoxifen for purposes of
 chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications
 (including previous breast cancer) are eligible. Tamoxifen therapy should be
 discontinued before the patient is enrolled on this study.

 3. Age > 18. There is no upper age limit for enrollment on this study.

 4. Required initial laboratory data:

 -  Granulocyte count > 1000/mm3

 -  Platelet count > 100,000/mm3

 -  Bilirubin within upper limits of normal