A Randomized Phase III Trial Comparing a Neoadjuvant Regimen of FEC-75 Followed by Paclitaxel Plus Trastuzumab With a Neoadjuvant Regimen of Paclitaxel Plus Trastuzumab Followed by FEC-75 Plus Trastuzumab in Patients With HER-2 Positive Operable Breast Cancer
A Randomized Phase III Trial Comparing a Neoadjuvant Regimen of FEC-75 Followed by Paclitaxel Plus Trastuzumab With a Neoadjuvant Regimen of Paclitaxel Plus Trastuzumab Followed by FEC-75 Plus Trastuzumab in Patients With HER-2 Positive Operable Breast Cancer
This randomized phase III trial is studying giving fluorouracil together with epirubicin and cyclophosphamide followed by paclitaxel and trastuzumab to see how well it works compared with giving paclitaxel together with trastuzumab followed by fluorouracil, epirubicin, cyclophosphamide, and trastuzumab in treating women with palpable breast cancer that can be removed by surgery. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether it is more effective to give combination chemotherapy before or after treatment with paclitaxel plus trastuzumab.
PRIMARY OBJECTIVES:
I. The primary objective of this study is to compare the pathologic complete response rate (pCR) within the breast of a sequential regimen of concurrent weekly paclitaxel and trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75 (Arm 2), to the pCR rate of a sequential regimen of FEC-75 alone followed by concurrent weekly paclitaxel and trastuzumab (Arm 1).
SECONDARY OBJECTIVES:
I. To estimate the cardiotoxicity of a sequential regimen of concurrent weekly paclitaxel and trastuzumab, followed by continued weekly trastuzumab administered concurrently with FEC-75, followed postoperatively by q 3 week trastuzumab for a total duration of trastuzumab therapy through 52 weeks from the first dose (Arm 2), and compare the cardiotoxicity to that of a sequential regimen of FEC-75 alone followed by concurrent weekly paclitaxel and trastuzumab, followed by q 3 week trastuzumab for a total duration of trastuzumab therapy through 52 weeks from the first dose (Arm 1).
II. To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the two regimens evaluated in this study.
III. To compare the clinical response rates (cRR) of the two regimens evaluated in this study.
IV. To compare the non-cardiac toxicity of the two regimens evaluated in this study.
V. To compare breast conservation rates achieved with the two regimens evaluated in this study.
VI. To evaluate disease-free survival and overall survival at 5 years post-randomization.
VII. To correlate pCR rate with potential molecular markers of response.
OUTLINE: Patients are stratified by clinical tumor size (breast tumor size < 2 cm and nodal metastases < 2 cm vs breast tumor size < 2 cm and nodal metastases ≥ 2 cm vs breast tumor size 2-4 cm [any nodal status] vs breast tumor size ≥ 4 cm [any nodal status]), age (< 50 vs ≥ 50) and hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]-negative vs ER- and/or PgR-positive). Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive FEC comprising fluoroucacil intravenously (IV), epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Beginning 21 days after completion of FEC, patients receive paclitaxel IV once weekly and trastuzumab (Herceptin) IV once weekly for 12 weeks. Within 6 weeks after completion of paclitaxel and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab IV once every 3 weeks for up to 52 weeks.
ARM II: Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after completion of paclitaxel and trastuzumab, patients receive FEC comprising fluoroucacil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 4 courses. Patients also receive trastuzumab IV once weekly for an additional 12 weeks. Within 6 weeks after completion of FEC and trastuzumab, patients undergo surgery. Beginning 3-4 weeks after surgery, patients receive trastuzumab as in arm I.
After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 4 years.
Inclusion Criteria:
Diagnosis of invasive adenocarcinoma by core needle biopsy
Primary tumor ≥ 2 cm and/or ≥ 1 biopsy-positive lymph node
HER2-positive disease
Ductal carcinoma in situ (DCIS) or synchronous DCIS of the contralateral breast regardless of prior therapy allowed
Ipsilateral DCIS treated by local excision with or without hormonal therapy allowed
No definitive clinical or radiologic evidence of metastatic disease
No history of invasive breast cancer
Hormone receptor status known
Menopausal status not specified
ECOG performance status of 0 -1
Absolute neutrophil count ≥ 1,200/mm³
Platelet count ≥ 100,000/mm³
Total bilirubin normal unless the patient has a grade 1 bilirubin elevation (normal to 1.5 times upper limit of normal [ULN]) resulting from Gilbert disease or similar syndrome due to slow conjugation of bilirubin
Alkaline phosphatase ≤ 2.5 times ULN
AST ≤ 1.5 times ULN
Creatinine normal
Left ventricular ejection fraction (LVEF) ≥ 55 by multi gated acquisition scan (MUGA) or echocardiogram (ECHO) within the past 3 months
Patients with either skeletal pain or alkaline phosphatase that is > ULN but ≤ 2.5 times ULN allowed if bone scans fail to demonstrate metastatic disease
Prior non-breast malignancies allowed if disease-free for 5 years since completion of initial treatment regimen and deemed by their physician to be at low risk for recurrence
Patients who had the following cancers are eligible if diagnosed and treated within the past 5 years:
No cardiac disease that would preclude the use of epirubicin hydrochloride or trastuzumab (Herceptin®) including any of the following:
Active cardiac disease
Angina pectoris that requires the use of antianginal medication
Cardiac arrhythmia requiring medication
Severe conduction abnormality
Clinically significant valvular disease
Cardiomegaly on chest x-ray
Ventricular hypertrophy on EKG
Patient's with poorly controlled hypertension ( i.e., diastolic greater than 100 mm/Hg)
History of cardiac disease
Myocardial infarction documented as a clinical diagnosis or by EKG or any other tests
Documented congestive heart failure
Documented cardiomyopathy
No sensory or motor neuropathy ≥ grade 2, as defined by the NCI's CTCAE v3.0
Women of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy
Women of child bearing potential must have a negative urine or serum pregnancy test within 2 weeks of registration
Not pregnant or nursing
No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
No non-malignant systemic disease (e.g., cardiovascular, renal, hepatic) that would preclude treatment with either of the treatment regimens
No prior surgical axillary staging procedure
No prior treatment for this breast cancer
No prior therapy with anthracyclines or taxanes for any malignancy
No other investigational agents within the past 30 days
No concurrent sex hormonal therapy (e.g., birth control pills, ovarian hormonal replacement therapy)
No concurrent therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulator (SERM), either for osteoporosis or breast cancer prevention
Louisville, Kentucky 40202, United States
Poughkeepsie, New York 12601, United States