Combination Chemotherapy, Surgery, and Radiation Therapy With or Without Dexrazoxane and Trastuzumab in Treating Women With Stage III or Stage IV Breast Cancer

Condition(s) targeted: Breast Cancer; Cardiac Toxicity

Intervention: cyclophosphamide (Drug); dexrazoxane hydrochloride (Drug); doxorubicin hydrochloride (Drug); paclitaxel (Drug); trastuzumab (Drug); conventional surgery (Procedure); radiation therapy (Procedure)

Phase: Phase 3

Status: Completed

Sponsored by: Cancer and Leukemia Group B

Official(s) and/or principal investigator(s):
Mark L. Graham, MD, Study Chair, Affiliation: UNC Lineberger Comprehensive Cancer Center

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Chemoprotective drugs, such as dexrazoxane, may protect normal cells from the side effects of chemotherapy. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known if chemotherapy combined with surgery and radiation therapy is more effective with or without dexrazoxane and trastuzumab in treating breast cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy, surgery, and radiation therapy with or without dexrazoxane and trastuzumab in treating women who have stage IIIA, stage IIIB or stage IV breast cancer.

Official title: A 2X2X2 Factorial Randomized Phase III Trial Of Multimodality Therapy Comparing 4 Cycles Of Doxorubicin And Cyclophosphamide With Or Without Dexrazoxane (AC+/-Z) Followed By 12 Weeks Of Weekly Paclitaxel With Or Without Trastuzumab (T+/-H) Followed By Local Therapy Followed By 40 Weeks Of Weekly Trastuzumab Or None In Women With HER-2+ Stage IV Breast Cancer

Study design: Treatment, Randomized, Open Label, Active Control

Detailed description: OBJECTIVES:

- Determine the time to locoregional recurrence, time to completion of treatment, and

overall survival in women with HER-2+ stage IIIA or IIIB or regional stage IV breast cancer treated with doxorubicin and cyclophosphamide with or without dexrazoxane, followed by paclitaxel with or without trastuzumab (Herceptin), followed by surgery and radiotherapy with or without trastuzumab.

- Determine whether addition of trastuzumab to paclitaxel therapy improves response at 24

weeks of therapy in these patients.

- Determine whether addition of trastuzumab to paclitaxel therapy increases the rate of

cardiotoxicity in these patients.

- Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide

compromises response in these patients.

- Determine whether addition of dexrazoxane to doxorubicin and cyclophosphamide reduces

the rate of cardiotoxicity in these patients.

- Determine whether long-term trastuzumab after local therapy improves disease-free

survival in these patients.

- Determine whether long-term trastuzumab after local therapy increases the rate of

cardiotoxicity in these patients.

- Determine the occurrence of any grade 3 or higher toxicity, second malignancies, acute

myelogenous leukemia, or myelodysplastic syndrome in patients treated with these regimens.

- Determine the eventual rate of breast conservation in those patients considered

candidates for breast conservation prior to neoadjuvant treatment.

- Determine the clinical response after doxorubicin and cyclophosphamide with or without

dexrazoxane and the clinical/mammographic/ultrasound response after paclitaxel with or without trastuzumab, compared to the pathologic response at definitive surgery in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to stage (inflammatory vs noninflammatory inoperable stage III/ regional stage IV vs operable stage III). Patients are randomized to 1 of 8 treatment arms.

- Arm I: Patients receive dexrazoxane IV over 10-20 minutes, doxorubicin IV over 5-10

minutes, and cyclophosphamide IV over 30 minutes on days 1, 22, 43, and 64. Patients receive paclitaxel IV over 1 hour and trastuzumab (Herceptin) IV over 30-90 minutes on days 85, 92, 99, 106, 113, 120, 127, 134, 141, 148, 155, and 162. Approximately 1-2 weeks after completion of neoadjuvant chemotherapy, patients undergo breast conservation surgery, modified radical mastectomy, or mastectomy. Patients with unacceptable toxicity or locoregional disease progression may undergo surgery prior to week 24 (i. e., completion of neoadjuvant chemotherapy). Beginning 2-4 weeks after breast conservation surgery or 3-5 weeks after mastectomy, patients undergo radiotherapy daily 5 days a week for 6-8 weeks. Patients receive long-term trastuzumab IV over 30-90 minutes weekly for 40 weeks beginning on week 36 (day 254).

- Arm II: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I.

Patients receive paclitaxel (without trastuzumab) as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.

- Arm III: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I.

Patients receive paclitaxel and trastuzumab as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patient undergo observation only for 40 weeks after completion of radiotherapy.

- Arm IV: Patients receive dexrazoxane, doxorubicin, and cyclophosphamide as in arm I.

Patients receive paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients undergo observation as in arm III.

- Arm V: Patients receive doxorubicin and cyclophosphamide (without dexrazoxane) as in arm

I. Patients receive paclitaxel and trastuzumab as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.

- Arm VI: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive

paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients receive long-term trastuzumab as in arm I.

- Arm VII: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients receive

paclitaxel and trastuzumab as in arm I. Patients undergo surgery and radiotherapy as in arm I. Patients undergo observation as in arm III.

- Arm VIII: Patients receive doxorubicin and cyclophosphamide as in arm V. Patients

receive paclitaxel as in arm II. Patients undergo surgery and radiotherapy as in arm I. Patients undergo observation as in arm III.

Treatment continues in all arms in the absence of distant disease progression.

Beginning within 12 weeks of completion of neoadjuvant chemotherapy, hormone receptor-positive patients may receive oral tamoxifen daily for 5 years.

Patients are followed every 6 months for 5 years and then annually for 5 years.

PROJECTED ACCRUAL: A total of 396 patients will be accrued for this study within 4 years.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically confirmed primary infiltrating adenocarcinoma of the breast

- Confirmed by core needle biopsy or incisional biopsy

- Amplification of HER-2 by FISH OR

- Overexpression (3+) of HER-2 by immunohistochemistry

- Staging criteria after complete clinical and radiographic staging:

- T3, N1, M0 OR

- Any T, N2 or N3, M0 OR

- T4, any N, M0, including clinical or pathological inflammatory disease OR

- Regional stage IV disease with supraclavicular or infraclavicular lymph

nodes as only site of metastasis

- Measurable or evaluable disease

- Prior ductal carcinoma in situ of the ipsilateral breast allowed if treated with

excision only without mastectomy or radiation

- Metaplastic carcinoma allowed

- Synchronous bilateral primary disease allowed (provided at least 1 cancer meets

staging criteria)

- No dermal lymphatic involvement with clinical inflammatory changes

- Hormone receptor status:

- Estrogen receptor positive or negative

- Progesterone receptor positive or negative

PATIENT CHARACTERISTICS:

Age:

- 18 and over

Sex:

- Female

Menopausal status:

- Not specified

Performance status:

- Not specified

Life expectancy:

- Not specified

Hematopoietic:

- Granulocyte count at least 1,000/mm3

- Platelet count at least 100,000/mm3

Hepatic:

- Bilirubin no greater than upper limit of normal (ULN)

- AST no greater than 2 times ULN

Renal:

- Creatinine no greater than 1. 5 times ULN

Cardiovascular:

- LVEF normal by MUGA

- No uncontrolled or severe cardiovascular disease (e. g., myocardial infarction within

the past 6 months, congestive heart failure treated with medications, or uncontrolled hypertension)

Other:

- No other currently active malignancy except nonmelanoma skin cancer

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Patients taking tamoxifen must use effective nonhormonal contraception during and for

2 months after study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- Not specified

Chemotherapy:

- No prior chemotherapy

- No other concurrent chemotherapy

Endocrine therapy:

- No more than 4 weeks of prior tamoxifen for disease

- Prior tamoxifen or raloxifene for longer than 4 weeks as chemoprevention allowed

- No concurrent tamoxifen or raloxifene

- No other concurrent hormonal therapy except for steroids for adrenal failure, hormones

for non-disease-related conditions (e. g., insulin for diabetes), or intermittent dexamethasone as an antiemetic

Radiotherapy:

- See Disease Characteristics

- No prior radiotherapy for index malignancy

- No prior radiotherapy to the ipsilateral breast, regional nodes, mediastinum, or

heart

- Prior radiotherapy to the contralateral breast for ductal carcinoma in situ or early

stage invasive breast cancer allowed provided earlier radiotherapy does not preclude optimal delivery of study radiotherapy and criterion of low risk for metastasis from first malignancy is met

Surgery:

- See Disease Characteristics

- No prior sentinel lymph node biopsy

Veterans Affairs Medical Center - Birmingham, Birmingham, Alabama 35233-1996, United States

Cedars-Sinai Medical Center, Los Angeles, California 90048, United States

UCSF Cancer Center and Cancer Research Institute, San Francisco, California 94143-0128, United States

University of California San Diego Cancer Center, La Jolla, California 92093-0658, United States

Veterans Affairs Medical Center - San Francisco, San Francisco, California 94121, United States

CCOP - Christiana Care Health Services, Wilmington, Delaware 19899, United States

Lombardi Cancer Center, Washington, District of Columbia 20007, United States

Walter Reed Army Medical Center, Washington, District of Columbia 20307-5000, United States

CCOP - Mount Sinai Medical Center, Miami Beach, Florida 33140, United States

University of Chicago Cancer Research Center, Chicago, Illinois 60637-1470, United States

Veterans Affairs Medical Center - Chicago (Westside Hospital), Chicago, Illinois 60612, United States

CCOP - Northern Indiana CR Consortium, South Bend, Indiana 46601, United States

Holden Comprehensive Cancer Center at The University of Iowa, Iowa City, Iowa 52242-1009, United States

Veterans Affairs Medical Center - Togus, Togus, Maine 04330, United States

Marlene & Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201, United States

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States

University of Massachusetts Memorial Medical Center, Worcester, Massachusetts 01655, United States

University of Minnesota Cancer Center, Minneapolis, Minnesota 55455, United States

Veterans Affairs Medical Center - Minneapolis, Minneapolis, Minnesota 55417, United States

Barnes-Jewish Hospital, Saint Louis, Missouri 63110, United States

Ellis Fischel Cancer Center - Columbia, Columbia, Missouri 65203, United States

Missouri Baptist Cancer Center, Saint Louis, Missouri 63131, United States

Veterans Affairs Medical Center - Columbia (Truman Memorial), Columbia, Missouri 65201, United States

University of Nebraska Medical Center, Omaha, Nebraska 68198-3330, United States

CCOP - Southern Nevada Cancer Research Foundation, Las Vegas, Nevada 89106, United States

Norris Cotton Cancer Center, Lebanon, New Hampshire 03756-0002, United States

CCOP - North Shore University Hospital, Manhasset, New York 11030, United States

CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C., Syracuse, New York 13217, United States

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, United States

Mount Sinai Medical Center, NY, New York, New York 10029, United States

New York Presbyterian Hospital - Cornell Campus, New York, New York 10021, United States

Roswell Park Cancer Institute, Buffalo, New York 14263-0001, United States

Schneider Children's Hospital at North Shore, Manhasset, New York 11030, United States

State University of New York - Upstate Medical University, Syracuse, New York 13210, United States

Veterans Affairs Medical Center - Buffalo, Buffalo, New York 14215, United States

Veterans Affairs Medical Center - Syracuse, Syracuse, New York 13210, United States

CCOP - Southeast Cancer Control Consortium, Winston-Salem, North Carolina 27104-4241, United States

Comprehensive Cancer Center at Wake Forest University, Winston-Salem, North Carolina 27157-1082, United States

Duke Comprehensive Cancer Center, Durham, North Carolina 27710, United States

Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, North Carolina 27599-7295, United States

University of North Carolina, Cary, North Carolina 27511, United States

Veterans Affairs Medical Center - Durham, Durham, North Carolina 27705, United States

Arthur G. James Cancer Hospital - Ohio State University, Columbus, Ohio 43210-1240, United States

Western Pennsylvania Hospital, Pittsburgh, Pennsylvania 15224, United States

Rhode Island Hospital, Providence, Rhode Island 02903, United States

University of Tennessee, Memphis Cancer Center, Memphis, Tennessee 38103, United States

Veterans Affairs Medical Center - Memphis, Memphis, Tennessee 38104, United States

Green Mountain Oncology Group, Bennington, Vermont 05201, United States

Vermont Cancer Center, Burlington, Vermont 05401-3498, United States

Veterans Affairs Medical Center - White River Junction, White River Junction, Vermont 05009, United States

MBCCOP - Massey Cancer Center, Richmond, Virginia 23298-0037, United States

Veterans Affairs Medical Center - Richmond, Richmond, Virginia 23249, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: May 2001
Last updated: May 23, 2008