Combination Chemotherapy and Paclitaxel Plus Trastuzumab in Treating Women With Palpable Breast Cancer That Can Be Removed by Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00513292
• Collaborator: (none)
• Enrollment: 280
• Locations: 115
• Arms: 2
• Duration (Months): 67.7
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HER2/Neu Positive; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer	Drug: Cyclophosphamide; Drug: Epirubicin Hydrochloride; Other: Laboratory Biomarker Analysis; Drug: Paclitaxel; Procedure: Therapeutic Conventional Surgery; Biological: Trastuzumab	Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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).

2. To compare the combined pCR rate in the breast and ipsilateral axilla obtained with the two regimens evaluated in this study.

3. To compare the clinical response rates (cRR) of the two regimens evaluated in this study.

4. To compare the non-cardiac toxicity of the two regimens evaluated in this study.

5. To compare breast conservation rates achieved with the two regimens evaluated in this study.

6. To evaluate disease-free survival and overall survival at 5 years post-randomization.

7. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 280 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Feb 21, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: FEC-75 then Paclitaxel/trastuzumab Patients receive FEC comprising fluoroucacil 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.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Epirubicin Hydrochloride; Given IV; Other Names: Ellence IMI-28 Pharmorubicin PFS ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat ; Procedure: Therapeutic Conventional Surgery; Undergo surgery; Biological: Trastuzumab; Given IV; Other Names: ABP 980 Anti-c-ERB-2 Anti-c-erbB2 Monoclonal Antibody Anti-ERB-2 Anti-erbB-2 Anti-erbB2 Monoclonal Antibody Anti-HER2/c-erbB2 Monoclonal Antibody Anti-p185-HER2 c-erb-2 Monoclonal Antibody HER2 Monoclonal Antibody Herceptin Herceptin Biosimilar PF-05280014 Herceptin Trastuzumab Biosimilar PF-05280014 MoAb HER2 Monoclonal Antibody c-erb-2 Monoclonal Antibody HER2 PF-05280014 rhuMAb HER2 Trastuzumab Biosimilar ABP 980 Trastuzumab Biosimilar PF-05280014
Experimental: Paclitaxel/trastuzumab then trastuzumab/FEC-75 Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the 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.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Epirubicin Hydrochloride; Given IV; Other Names: Ellence IMI-28 Pharmorubicin PFS ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Paclitaxel; Given IV; Other Names: Anzatax Asotax Bristaxol Praxel Taxol Taxol Konzentrat ; Procedure: Therapeutic Conventional Surgery; Undergo surgery; Biological: Trastuzumab; Given IV; Other Names: ABP 980 Anti-c-ERB-2 Anti-c-erbB2 Monoclonal Antibody Anti-ERB-2 Anti-erbB-2 Anti-erbB2 Monoclonal Antibody Anti-HER2/c-erbB2 Monoclonal Antibody Anti-p185-HER2 c-erb-2 Monoclonal Antibody HER2 Monoclonal Antibody Herceptin Herceptin Biosimilar PF-05280014 Herceptin Trastuzumab Biosimilar PF-05280014 MoAb HER2 Monoclonal Antibody c-erb-2 Monoclonal Antibody HER2 PF-05280014 rhuMAb HER2 Trastuzumab Biosimilar ABP 980 Trastuzumab Biosimilar PF-05280014

Outcome Measures

Primary Outcome Measures

1. pCR Within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy [Up to 5 years]

   Pathological complete response (pCR) rates will be based on institutional pathology reports. In the final analysis for publication, rates will be based on blinded central review of these institutional pathology reports. The Chi-squared test will be conducted at the two-sided 0.05 level. A 95% confidence interval will be computed for the difference in pCR rates.

Secondary Outcome Measures

1. Combined pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy [Up to 5 years]

   pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy (among those with Metastasis to movable ipsilateral axillary lymph node(s) (cN1-3) disease).

2. Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12 [Baseline, at 12 week]

   The summary of asymptomatic decrease in LVEF.

3. Asymptomatic Decreases From Baseline in LVEF at Week 24 [Baseline, at 24 week]

   The summary of asymptomatic changed in LVEF.

4. LVEFs From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans as Reported at 12 Week [At 12 week]

   All patients who had a MUGA or ECHO performed at week 12 are included in the summary of asymptomatic changed in LVEF at week 12. Difference from pretreatment LVEF (%) at 12 weeks [median change from baseline Inter Quartile Range (IQR)].

5. Change in LVEFs (From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans) From Baseline and at 24 Week [Baseline, at 24 week]

   Difference from pretreatment LVEF (%) at 24 weeks [median change from baseline Inter Quartile Range (IQR)].

6. Breast Conservation [From time surgery to up to 5 years]

   Surgery was categorized as breast conserving surgery ("Partial Mastectomy") or non-conserving surgery ("Total Mastectomy" or "Modified Radical Mastectomy). Reported below is the percentage of patients receiving "Partial Mastectomy". This was calculated by dividing the number of patients receiving "Partial Mastectomy" by the total number of patients undergoing surgery multiplied by 100 (to obtain the percentage).

7. Disease-free Survival (DFS) [From time to registration to time of event, assessed up to 5 years]

   DFS defined as inoperable progressive disease, gross residual disease following definitive surgery, local, regional or distant recurrence, contralateral breast cancer, other second primary cancers, and death prior to recurrence or second primary cancer. DFS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method.

8. Overall Survival (OS) [From time to registration to death, assessed up to 5 years]

   OS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of invasive adenocarcinoma by core needle biopsy

• Fine needle aspiration allowed provided primary tumor size < 2 cm and lymph node metastases are present

• Excisional biopsy of the primary tumor allowed provided biopsy-positive lymph nodes are present

• Primary tumor ≥ 2 cm and/or ≥ 1 biopsy-positive lymph node

• HER2-positive disease

• Confirmation by fluorescent in situ hybridization (FISH) requires gene amplification

• Confirmation by immunohistochemistry (IHC) requires a strongly positive (3+) staining intensity score

• Ductal carcinoma in situ (DCIS) or synchronous DCIS of the contralateral breast regardless of prior therapy allowed

• Synchronous invasive breast cancer not allowed

• Ipsilateral DCIS treated by local excision with or without hormonal therapy allowed

• Those treated with radiation therapy are not 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

• Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy

• 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:

• Carcinoma in situ of the cervix

• Colon carcinoma in situ

• Melanoma in situ

• Basal cell and squamous cell carcinoma of the skin

• 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)

• Patients with hypertension that is well controlled on medication are eligible

• 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

• Prior non-excisional biopsy of an axillary node allowed

• No prior treatment for this breast cancer

• Hormonal therapy allowed if had been given for up to a total of 28 days anytime after diagnosis and before study entry

• Hormonal therapy must stop at or before study entry and be re-started, if indicated, following surgery

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama	United States	36688
2	Eden Hospital Medical Center	Castro Valley	California	United States	94546
3	Marin Cancer Care Inc	Greenbrae	California	United States	94904
4	Saint Rose Hospital	Hayward	California	United States	94545
5	Valley Care Health System - Pleasanton	Pleasanton	California	United States	94588
6	Valley Medical Oncology Consultants	Pleasanton	California	United States	94588
7	Morton Plant Hospital	Clearwater	Florida	United States	33756
8	Broward Health Medical Center	Fort Lauderdale	Florida	United States	33316
9	Lakeland Regional Cancer Center	Lakeland	Florida	United States	33805
10	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
11	Presence Resurrection Medical Center	Chicago	Illinois	United States	60631
12	Saint Francis Hospital and Health Centers	Beech Grove	Indiana	United States	46107
13	Franciscan Saint Francis Health-Indianapolis	Indianapolis	Indiana	United States	46237
14	Reid Hospital and Health Care Services	Richmond	Indiana	United States	47374
15	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
16	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51104
17	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
18	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
19	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
20	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
21	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
22	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
23	Cancer Center of Kansas-Kingman	Kingman	Kansas	United States	67068
24	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
25	Cancer Center of Kansas-Liberal	Liberal	Kansas	United States	67901
26	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
27	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
28	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
29	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
30	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
31	Associates In Womens Health	Wichita	Kansas	United States	67208
32	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas	United States	67208
33	Cancer Center of Kansas - Main Office	Wichita	Kansas	United States	67214
34	Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
35	Wesley Medical Center	Wichita	Kansas	United States	67214
36	Wichita CCOP	Wichita	Kansas	United States	67214
37	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
38	Baptist Health Lexington	Lexington	Kentucky	United States	40503
39	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky	United States	40202
40	Unspecified Site	Rockville	Maryland	United States	20852
41	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
42	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
43	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
44	Essentia Health Cancer Center	Duluth	Minnesota	United States	55805
45	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota	United States	55805
46	Miller-Dwan Hospital	Duluth	Minnesota	United States	55805
47	Mayo Clinic	Rochester	Minnesota	United States	55905
48	Singing River Hospital	Pascagoula	Mississippi	United States	39581
49	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
50	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
51	Sunrise Hospital and Medical Center	Las Vegas	Nevada	United States	89109
52	Portsmouth Regional Hospital	Portsmouth	New Hampshire	United States	03802
53	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
54	UMDNJ - New Jersey Medical School	Newark	New Jersey	United States	07103
55	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
56	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87106
57	University of New Mexico	Albuquerque	New Mexico	United States	87106
58	Presbyterian Kaseman Hospital	Albuquerque	New Mexico	United States	87110
59	Orange Regional Medical Center	Middletown	New York	United States	10940
60	MidHudson Regional Hospital of Westchester Medical Center	Poughkeepsie	New York	United States	12601
61	Staten Island University Hospital	Staten Island	New York	United States	10305
62	Hope Women's Cancer Centers-Asheville	Asheville	North Carolina	United States	28816
63	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
64	Mary Rutan Hospital	Bellefontaine	Ohio	United States	43311
65	Aultman Health Foundation	Canton	Ohio	United States	44710
66	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
67	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
68	Columbus CCOP	Columbus	Ohio	United States	43215
69	Grant Medical Center	Columbus	Ohio	United States	43215
70	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
71	Doctors Hospital	Columbus	Ohio	United States	43228
72	Grandview Hospital	Dayton	Ohio	United States	45405
73	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
74	Miami Valley Hospital	Dayton	Ohio	United States	45409
75	Samaritan North Health Center	Dayton	Ohio	United States	45415
76	Dayton CCOP	Dayton	Ohio	United States	45420
77	Veteran Affairs Medical Center	Dayton	Ohio	United States	45428
78	Grady Memorial Hospital	Delaware	Ohio	United States	43015
79	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
80	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
81	Wayne Hospital	Greenville	Ohio	United States	45331
82	Kettering Medical Center	Kettering	Ohio	United States	45429
83	Fairfield Medical Center	Lancaster	Ohio	United States	43130
84	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
85	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
86	Licking Memorial Hospital	Newark	Ohio	United States	43055
87	Southern Ohio Medical Center	Portsmouth	Ohio	United States	45662
88	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
89	Upper Valley Medical Center	Troy	Ohio	United States	45373
90	Saint Ann's Hospital	Westerville	Ohio	United States	43081
91	Clinton Memorial Hospital	Wilmington	Ohio	United States	45177
92	Greene Memorial Hospital	Xenia	Ohio	United States	45385
93	Genesis HealthCare System	Zanesville	Ohio	United States	43701
94	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma	United States	73505
95	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania	United States	18015
96	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
97	Medical University of South Carolina	Charleston	South Carolina	United States	29425
98	University of Tennessee - Knoxville	Knoxville	Tennessee	United States	37920
99	Nashville Breast Center	Nashville	Tennessee	United States	37203
100	Meharry Medical College	Nashville	Tennessee	United States	37208
101	The Don and Sybil Harrington Cancer Center	Amarillo	Texas	United States	79106
102	Parkland Memorial Hospital	Dallas	Texas	United States	75235
103	Zale Lipshy University Hospital	Dallas	Texas	United States	75235
104	Clements University Hospital	Dallas	Texas	United States	75390
105	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
106	M D Anderson Cancer Center	Houston	Texas	United States	77030
107	Doctor's Hospital of Laredo	Laredo	Texas	United States	78041
108	Covenant Medical Center-Lakeside	Lubbock	Texas	United States	79410
109	Danville Regional Medical Center	Danville	Virginia	United States	24541
110	Sentara Port Warwick	Newport News	Virginia	United States	23606
111	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
112	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
113	Oconomowoc Memorial Hospital-ProHealth Care Inc	Oconomowoc	Wisconsin	United States	53066-3896
114	Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
115	San Juan City Hospital	San Juan		Puerto Rico	00936

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Aman Buzdar, American College of Surgeons

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00513292
• Other Study ID Numbers: NCI-2009-00341; NCI-2009-00341; CDR0000559039; ACOSOG-Z1041; Z1041; ACOSOG-Z1041; U10CA012027
• First Posted: Aug 8, 2007
• Last Update Posted: Jan 23, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Cyclophosphamide; Trastuzumab; Albumin-Bound Paclitaxel; Epirubicin; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	Total Enrolled: 282, 2 patients withdrew consent before starting treatment, 280 patients started the treatment and are eligible for primary analysis.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	138	142
COMPLETED	138	142
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75	Total
Arm/Group Description	Patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Total of all reporting groups
Overall Participants	138	142	280
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51	48	50
Sex: Female, Male (Count of Participants)
Female	138 100%	142 100%	280 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	138 100%	142 100%	280 100%

Outcome Measures

1. Primary Outcome

Title	pCR Within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy
Description	Pathological complete response (pCR) rates will be based on institutional pathology reports. In the final analysis for publication, rates will be based on blinded central review of these institutional pathology reports. The Chi-squared test will be conducted at the two-sided 0.05 level. A 95% confidence interval will be computed for the difference in pCR rates.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

All patients who started study treatment are included in the analysis of the primary endpoint.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	138	142
Number (95% Confidence Interval) [percentage of participants]	56.5 40.9%	54.2 38.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FEC-75 Then Paclitaxel/Trastuzumab, Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
	Comments	The difference in pCR rates between treatment arms for pCR within the Breast, Defined as no Evidence of Invasive Tumor Remaining in the Breast at Surgery Following Completion of Chemotherapy
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.7
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	difference in percentages between arms
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -9.3 to 13.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Combined pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy
Description	pCR Rate in the Breast and Axillary Lymph Nodes Defined as no Evidence of Invasive Tumor Remaining in Either the Breast or Axillary Nodes at Surgery Following Completion of Chemotherapy (among those with Metastasis to movable ipsilateral axillary lymph node(s) (cN1-3) disease).
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

All patients who had clinical N1-3 disease prior to the start of treatment are included in the analysis of the pCR rate in the breast and axillary lymph nodes.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	89	90
Number (95% Confidence Interval) [Percentage (95% confidence Interval)]	48.3	46.7

3. Secondary Outcome

Title	Asymptomatic Decreases From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 12
Description	The summary of asymptomatic decrease in LVEF.
Time Frame	Baseline, at 12 week

Outcome Measure Data

Analysis Population Description

All patients who had a MUGA or ECHO performed at week 12 are included in the summary of asymptomatic changed in LVEF at week 12.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	130	137
no decrease or decrease < 10%, still above LLN	92.3 66.9%	82.5 58.1%
decrease < 10%, below lower limit of normal (LLN)	0.8 0.6%	0 0%
decrease 10-15%, still above lower limit of normal	6.2 4.5%	11.7 8.2%
decrease 10-15%, below lower limit of normal (LLN)	0 0%	0 0%
decrease > 15%, still above lower limit of norm	0.8 0.6%	2.9 2%
decrease > 15%, below lower limit of normal	0 0%	2.9 2%

4. Secondary Outcome

Title	Asymptomatic Decreases From Baseline in LVEF at Week 24
Description	The summary of asymptomatic changed in LVEF.
Time Frame	Baseline, at 24 week

Outcome Measure Data

Analysis Population Description

All patients who had a MUGA or ECHO performed at week 24 are included in the summary of asymptomatic changed in LVEF at week 24.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	126	130
no decrease or decrease < 10%, still above LLN	83.3 60.4%	73.1 51.5%
decrease < 10%, below lower limit of normal (LLN)	0.8 0.6%	3.1 2.2%
decrease 10-15%, still above lower limit of normal	7.9 5.7%	15.4 10.8%
decrease 10-15%, below lower limit of normal (LLN)	2.4 1.7%	0.8 0.6%
decrease > 15%, still above lower limit of normal	1.6 1.2%	6.9 4.9%
decrease > 15%, below lower limit of normal (LLN)	4.0 2.9%	0.8 0.6%

5. Secondary Outcome

Title	LVEFs From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans as Reported at 12 Week
Description	All patients who had a MUGA or ECHO performed at week 12 are included in the summary of asymptomatic changed in LVEF at week 12. Difference from pretreatment LVEF (%) at 12 weeks [median change from baseline Inter Quartile Range (IQR)].
Time Frame	At 12 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	130	137
Median (Inter-Quartile Range) [percent]	2	-3

6. Secondary Outcome

Title	Change in LVEFs (From Regularly Scheduled Multi Gated Acquisition Scan (MUGA)/Echo Scans) From Baseline and at 24 Week
Description	Difference from pretreatment LVEF (%) at 24 weeks [median change from baseline Inter Quartile Range (IQR)].
Time Frame	Baseline, at 24 week

Outcome Measure Data

Analysis Population Description

All patients who had a MUGA or ECHO performed at week 24 are included in the summary of asymptomatic changed in LVEF at week 24.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	126	130
Median (Inter-Quartile Range) [percent]	-3	-4

7. Secondary Outcome

Title	Breast Conservation
Description	Surgery was categorized as breast conserving surgery ("Partial Mastectomy") or non-conserving surgery ("Total Mastectomy" or "Modified Radical Mastectomy). Reported below is the percentage of patients receiving "Partial Mastectomy". This was calculated by dividing the number of patients receiving "Partial Mastectomy" by the total number of patients undergoing surgery multiplied by 100 (to obtain the percentage).
Time Frame	From time surgery to up to 5 years

Outcome Measure Data

Analysis Population Description

All patients that underwent breast surgery were included in this analysis.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	130	138
Number [percentage of participants]	37.7 27.3%	39.1 27.5%

8. Secondary Outcome

Title	Disease-free Survival (DFS)
Description	DFS defined as inoperable progressive disease, gross residual disease following definitive surgery, local, regional or distant recurrence, contralateral breast cancer, other second primary cancers, and death prior to recurrence or second primary cancer. DFS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method.
Time Frame	From time to registration to time of event, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

All patients that began protocol therapy are included in this analysis

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	138	142
Median (95% Confidence Interval) [months]	NA	NA

9. Secondary Outcome

Title	Overall Survival (OS)
Description	OS of Arm I and Arm II patients will be estimated using the Kaplan-Meier method.
Time Frame	From time to registration to death, assessed up to 5 years

Outcome Measure Data

Analysis Population Description

All patients that began protocol therapy were included in this analysis.

Arm/Group Title	FEC-75 Then Paclitaxel/Trastuzumab	Paclitaxel/Trastuzumab Then Trastuzumab/FEC-75
Arm/Group Description	Patients receive Fluorouracil, epirubicin, and cyclophosphamide (FEC) comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies	Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
Measure Participants	138	142
Median (95% Confidence Interval) [months]	NA	NA

Adverse Events

Arm/Group Title	Arm A		Arm B
Arm/Group Description	Patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies		Patients receive paclitaxel IV once weekly and trastuzumab IV once weekly for 12 weeks. Beginning 7 days after the completion of paclitaxel and trastuzumab, patients receive FEC comprising fluorouracil 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. epirubicin hydrochloride: Given IV, cyclophosphamide: Given IV, paclitaxel: Given IV, trastuzumab: Given IV, therapeutic conventional surgery: Undergo surgery, laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/138 (13.8%)		26/142 (18.3%)
Blood and lymphatic system disorders
Blood disorder	1/138 (0.7%)	1	1/142 (0.7%)	1
Febrile neutropenia	1/138 (0.7%)	1	3/142 (2.1%)	4
Hemoglobin decreased	8/138 (5.8%)	12	11/142 (7.7%)	14
Hemolysis	0/138 (0%)	0	1/142 (0.7%)	1
Cardiac disorders
Atrial fibrillation	0/138 (0%)	0	1/142 (0.7%)	1
Left ventricular failure	3/138 (2.2%)	3	5/142 (3.5%)	6
Myocardial ischemia	0/138 (0%)	0	1/142 (0.7%)	1
Sinus tachycardia	1/138 (0.7%)	1	1/142 (0.7%)	1
Supraventricular tachycardia	0/138 (0%)	0	1/142 (0.7%)	1
Eye disorders
Extraocular muscle paresis	0/138 (0%)	0	1/142 (0.7%)	1
Eyelid function disorder	0/138 (0%)	0	1/142 (0.7%)	1
Vision blurred	0/138 (0%)	0	1/142 (0.7%)	1
Gastrointestinal disorders
Abdominal pain	2/138 (1.4%)	3	3/142 (2.1%)	3
Anal pain	0/138 (0%)	0	1/142 (0.7%)	1
Colonic hemorrhage	0/138 (0%)	0	1/142 (0.7%)	1
Constipation	4/138 (2.9%)	4	4/142 (2.8%)	4
Diarrhea	9/138 (6.5%)	12	8/142 (5.6%)	8
Dyspepsia	1/138 (0.7%)	1	2/142 (1.4%)	3
Dysphagia	1/138 (0.7%)	1	0/142 (0%)	0
Ear, nose and throat examination abnormal	4/138 (2.9%)	6	0/142 (0%)	0
Gastritis	0/138 (0%)	0	1/142 (0.7%)	1
Gastrointestinal disorder	1/138 (0.7%)	1	0/142 (0%)	0
Ileus	0/138 (0%)	0	1/142 (0.7%)	1
Nausea	10/138 (7.2%)	11	8/142 (5.6%)	10
Rectal hemorrhage	0/138 (0%)	0	1/142 (0.7%)	1
Stomach pain	1/138 (0.7%)	1	0/142 (0%)	0
Upper gastrointestinal hemorrhage	0/138 (0%)	0	1/142 (0.7%)	1
Vomiting	5/138 (3.6%)	5	6/142 (4.2%)	6
General disorders
Chest pain	1/138 (0.7%)	1	2/142 (1.4%)	2
Chills	1/138 (0.7%)	1	2/142 (1.4%)	2
Edema limbs	3/138 (2.2%)	3	4/142 (2.8%)	4
Fatigue	13/138 (9.4%)	23	17/142 (12%)	23
Fever	6/138 (4.3%)	7	4/142 (2.8%)	4
Localized edema	2/138 (1.4%)	2	0/142 (0%)	0
Pain	1/138 (0.7%)	2	1/142 (0.7%)	1
Immune system disorders
Cytokine release syndrome	0/138 (0%)	0	2/142 (1.4%)	2
Infections and infestations
Bladder infection	1/138 (0.7%)	1	0/142 (0%)	0
Bronchitis	1/138 (0.7%)	1	0/142 (0%)	0
Infection	2/138 (1.4%)	2	3/142 (2.1%)	4
Peripheral nerve infection	0/138 (0%)	0	1/142 (0.7%)	1
Pharyngitis	0/138 (0%)	0	1/142 (0.7%)	1
Pneumonia	2/138 (1.4%)	2	4/142 (2.8%)	4
Skin infection	5/138 (3.6%)	5	2/142 (1.4%)	2
Soft tissue infection	1/138 (0.7%)	2	0/142 (0%)	0
Upper respiratory infection	0/138 (0%)	0	1/142 (0.7%)	1
Urinary tract infection	1/138 (0.7%)	1	2/142 (1.4%)	2
Wound infection	0/138 (0%)	0	1/142 (0.7%)	1
Injury, poisoning and procedural complications
Dermatitis radiation	1/138 (0.7%)	1	0/142 (0%)	0
Fracture	1/138 (0.7%)	2	2/142 (1.4%)	2
Thermal burn	0/138 (0%)	0	1/142 (0.7%)	1
Vascular access complication	1/138 (0.7%)	1	0/142 (0%)	0
Investigations
Alanine aminotransferase increased	4/138 (2.9%)	7	2/142 (1.4%)	2
Alkaline phosphatase increased	1/138 (0.7%)	1	0/142 (0%)	0
Aspartate aminotransferase increased	2/138 (1.4%)	4	3/142 (2.1%)	3
Creatinine increased	1/138 (0.7%)	1	0/142 (0%)	0
INR increased	0/138 (0%)	0	1/142 (0.7%)	1
Laboratory test abnormal	2/138 (1.4%)	2	1/142 (0.7%)	2
Leukocyte count decreased	3/138 (2.2%)	3	8/142 (5.6%)	12
Lymphocyte count decreased	1/138 (0.7%)	3	6/142 (4.2%)	11
Neutrophil count decreased	6/138 (4.3%)	7	13/142 (9.2%)	20
Platelet count decreased	1/138 (0.7%)	1	3/142 (2.1%)	3
Serum cholesterol increased	0/138 (0%)	0	1/142 (0.7%)	1
Weight gain	0/138 (0%)	0	3/142 (2.1%)	3
Weight loss	3/138 (2.2%)	4	2/142 (1.4%)	2
Metabolism and nutrition disorders
Alkalosis	1/138 (0.7%)	1	0/142 (0%)	0
Anorexia	3/138 (2.2%)	4	6/142 (4.2%)	6
Dehydration	3/138 (2.2%)	4	2/142 (1.4%)	2
Hyperglycemia	1/138 (0.7%)	1	3/142 (2.1%)	3
Hyperkalemia	1/138 (0.7%)	1	0/142 (0%)	0
Hypernatremia	1/138 (0.7%)	1	0/142 (0%)	0
Hypoalbuminemia	0/138 (0%)	0	2/142 (1.4%)	2
Hypocalcemia	1/138 (0.7%)	1	2/142 (1.4%)	2
Hypoglycemia	1/138 (0.7%)	1	0/142 (0%)	0
Hypokalemia	1/138 (0.7%)	2	3/142 (2.1%)	3
Hyponatremia	0/138 (0%)	0	2/142 (1.4%)	2
Musculoskeletal and connective tissue disorders
Back pain	2/138 (1.4%)	4	0/142 (0%)	0
Bone pain	1/138 (0.7%)	1	2/142 (1.4%)	2
Chest wall pain	1/138 (0.7%)	1	2/142 (1.4%)	4
Joint pain	3/138 (2.2%)	3	3/142 (2.1%)	3
Muscle weakness	1/138 (0.7%)	2	1/142 (0.7%)	2
Muscle weakness lower limb	1/138 (0.7%)	1	0/142 (0%)	0
Musculoskeletal disorder	1/138 (0.7%)	1	0/142 (0%)	0
Myalgia	1/138 (0.7%)	1	1/142 (0.7%)	1
Neck pain	1/138 (0.7%)	1	0/142 (0%)	0
Pain in extremity	2/138 (1.4%)	2	1/142 (0.7%)	4
Nervous system disorders
Dizziness	2/138 (1.4%)	2	3/142 (2.1%)	3
Encephalopathy	1/138 (0.7%)	2	0/142 (0%)	0
Headache	6/138 (4.3%)	7	9/142 (6.3%)	10
Neurological disorder NOS	1/138 (0.7%)	9	0/142 (0%)	0
Peripheral motor neuropathy	1/138 (0.7%)	1	1/142 (0.7%)	2
Peripheral sensory neuropathy	5/138 (3.6%)	6	8/142 (5.6%)	10
Syncope	2/138 (1.4%)	2	2/142 (1.4%)	2
Taste alteration	1/138 (0.7%)	4	1/142 (0.7%)	2
Tremor	0/138 (0%)	0	1/142 (0.7%)	1
Psychiatric disorders
Agitation	1/138 (0.7%)	1	0/142 (0%)	0
Anxiety	2/138 (1.4%)	4	2/142 (1.4%)	2
Confusion	1/138 (0.7%)	1	1/142 (0.7%)	1
Depression	2/138 (1.4%)	4	7/142 (4.9%)	8
Insomnia	1/138 (0.7%)	3	5/142 (3.5%)	5
Reproductive system and breast disorders
Breast pain	0/138 (0%)	0	2/142 (1.4%)	2
Irregular menstruation	0/138 (0%)	0	1/142 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/138 (0.7%)	1	0/142 (0%)	0
Bronchopulmonary hemorrhage	1/138 (0.7%)	1	0/142 (0%)	0
Bronchospasm	1/138 (0.7%)	1	0/142 (0%)	0
Cough	3/138 (2.2%)	3	4/142 (2.8%)	4
Dyspnea	7/138 (5.1%)	7	7/142 (4.9%)	7
Hemorrhage nasal	0/138 (0%)	0	2/142 (1.4%)	2
Pharyngolaryngeal pain	0/138 (0%)	0	1/142 (0.7%)	1
Pneumonitis	1/138 (0.7%)	1	2/142 (1.4%)	2
Respiratory disorder	2/138 (1.4%)	2	1/142 (0.7%)	1
Voice alteration	1/138 (0.7%)	3	1/142 (0.7%)	1
Skin and subcutaneous tissue disorders
Alopecia	9/138 (6.5%)	13	11/142 (7.7%)	14
Hand-and-foot syndrome	1/138 (0.7%)	1	0/142 (0%)	0
Nail disorder	4/138 (2.9%)	4	1/142 (0.7%)	1
Pain of skin	0/138 (0%)	0	1/142 (0.7%)	1
Rash acneiform	1/138 (0.7%)	1	0/142 (0%)	0
Rash desquamating	0/138 (0%)	0	2/142 (1.4%)	2
Skin disorder	1/138 (0.7%)	1	1/142 (0.7%)	1
Skin hyperpigmentation	1/138 (0.7%)	1	2/142 (1.4%)	2
Skin ulceration	1/138 (0.7%)	1	0/142 (0%)	0
Sweating	1/138 (0.7%)	1	1/142 (0.7%)	1
Vascular disorders
Hematoma	0/138 (0%)	0	1/142 (0.7%)	1
Hemorrhage	1/138 (0.7%)	1	0/142 (0%)	0
Hot flashes	2/138 (1.4%)	3	2/142 (1.4%)	2
Hypertension	2/138 (1.4%)	2	1/142 (0.7%)	1
Hypotension	2/138 (1.4%)	2	1/142 (0.7%)	2
Thrombosis	1/138 (0.7%)	1	3/142 (2.1%)	4
Other (Not Including Serious) Adverse Events
	Arm A		Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	136/138 (98.6%)		141/142 (99.3%)
Blood and lymphatic system disorders
Blood disorder	3/138 (2.2%)	6	5/142 (3.5%)	7
Febrile neutropenia	2/138 (1.4%)	3	3/142 (2.1%)	3
Hemoglobin decreased	53/138 (38.4%)	279	50/142 (35.2%)	269
Hemolysis	0/138 (0%)	0	2/142 (1.4%)	8
Lymph node pain	0/138 (0%)	0	1/142 (0.7%)	1
Lymphatic disorder	0/138 (0%)	0	2/142 (1.4%)	5
Thrombotic microangiopathy	2/138 (1.4%)	2	5/142 (3.5%)	8
Cardiac disorders
Arrhythmia	3/138 (2.2%)	4	1/142 (0.7%)	1
Cardiac disorder	1/138 (0.7%)	1	2/142 (1.4%)	2
Left ventricular dysfunction	0/138 (0%)	0	1/142 (0.7%)	1
Left ventricular failure	9/138 (6.5%)	14	18/142 (12.7%)	25
Myocardial ischemia	0/138 (0%)	0	1/142 (0.7%)	1
Palpitations	5/138 (3.6%)	7	4/142 (2.8%)	4
Pericardial effusion	1/138 (0.7%)	1	3/142 (2.1%)	4
Premature ventricular contractions	0/138 (0%)	0	1/142 (0.7%)	1
Sinus arrhythmia	1/138 (0.7%)	1	0/142 (0%)	0
Sinus bradycardia	1/138 (0.7%)	1	0/142 (0%)	0
Sinus tachycardia	9/138 (6.5%)	12	8/142 (5.6%)	14
Supraventricular tachycardia	0/138 (0%)	0	1/142 (0.7%)	1
Ventricular arrhythmia	1/138 (0.7%)	1	2/142 (1.4%)	14
Ventricular tachycardia	0/138 (0%)	0	1/142 (0.7%)	9
Ear and labyrinth disorders
Ear disorder	1/138 (0.7%)	3	2/142 (1.4%)	2
Ear pain	0/138 (0%)	0	2/142 (1.4%)	2
External ear inflammation	1/138 (0.7%)	1	0/142 (0%)	0
External ear pain	0/138 (0%)	0	2/142 (1.4%)	2
Hearing loss	0/138 (0%)	0	1/142 (0.7%)	2
Middle ear inflammation	0/138 (0%)	0	2/142 (1.4%)	2
Tinnitus	1/138 (0.7%)	1	0/142 (0%)	0
Endocrine disorders
Hypothyroidism	1/138 (0.7%)	1	0/142 (0%)	0
Eye disorders
Conjunctival disorder	0/138 (0%)	0	1/142 (0.7%)	1
Dry eye syndrome	2/138 (1.4%)	3	3/142 (2.1%)	5
Extraocular muscle paresis	2/138 (1.4%)	2	0/142 (0%)	0
Eye disorder	1/138 (0.7%)	5	9/142 (6.3%)	17
Eye pain	0/138 (0%)	0	2/142 (1.4%)	2
Eyelid function disorder	1/138 (0.7%)	1	1/142 (0.7%)	1
Vision blurred	11/138 (8%)	14	16/142 (11.3%)	37
Watering eyes	2/138 (1.4%)	4	3/142 (2.1%)	9
Gastrointestinal disorders
Abdominal distension	2/138 (1.4%)	2	4/142 (2.8%)	9
Abdominal pain	9/138 (6.5%)	12	16/142 (11.3%)	24
Anal hemorrhage	1/138 (0.7%)	1	0/142 (0%)	0
Anal mucositis	0/138 (0%)	0	1/142 (0.7%)	1
Colitis	0/138 (0%)	0	2/142 (1.4%)	2
Constipation	57/138 (41.3%)	142	51/142 (35.9%)	113
Diarrhea	72/138 (52.2%)	172	79/142 (55.6%)	210
Dry mouth	1/138 (0.7%)	1	3/142 (2.1%)	3
Dyspepsia	16/138 (11.6%)	48	24/142 (16.9%)	52
Dysphagia	4/138 (2.9%)	5	6/142 (4.2%)	9
Ear, nose and throat examination abnormal	46/138 (33.3%)	86	41/142 (28.9%)	78
Endoscopy large bowel abnormal	0/138 (0%)	0	1/142 (0.7%)	1
Enteritis	0/138 (0%)	0	1/142 (0.7%)	1
Esophageal mucositis	2/138 (1.4%)	4	1/142 (0.7%)	1
Esophagitis	1/138 (0.7%)	2	0/142 (0%)	0
Flatulence	1/138 (0.7%)	1	2/142 (1.4%)	2
Gastric mucositis	1/138 (0.7%)	1	1/142 (0.7%)	1
Gastritis	3/138 (2.2%)	3	8/142 (5.6%)	10
Gastrointestinal disorder	3/138 (2.2%)	4	9/142 (6.3%)	10
Gingival pain	0/138 (0%)	0	3/142 (2.1%)	3
Hemorrhoids	3/138 (2.2%)	6	7/142 (4.9%)	9
Ileus	2/138 (1.4%)	2	0/142 (0%)	0
Mucositis oral	21/138 (15.2%)	31	17/142 (12%)	31
Nausea	101/138 (73.2%)	325	108/142 (76.1%)	315
Oral hemorrhage	0/138 (0%)	0	1/142 (0.7%)	1
Oral pain	2/138 (1.4%)	2	1/142 (0.7%)	1
Pancreatitis	1/138 (0.7%)	1	0/142 (0%)	0
Proctitis	0/138 (0%)	0	1/142 (0.7%)	1
Rectal hemorrhage	2/138 (1.4%)	2	1/142 (0.7%)	1
Salivary gland disorder	1/138 (0.7%)	1	0/142 (0%)	0
Stomach pain	2/138 (1.4%)	2	5/142 (3.5%)	5
Tooth disorder	1/138 (0.7%)	1	2/142 (1.4%)	2
Toothache	0/138 (0%)	0	4/142 (2.8%)	4
Vomiting	54/138 (39.1%)	98	46/142 (32.4%)	89
General disorders
Chest pain	5/138 (3.6%)	5	9/142 (6.3%)	12
Chills	8/138 (5.8%)	14	7/142 (4.9%)	12
Edema limbs	28/138 (20.3%)	47	29/142 (20.4%)	85
Fatigue	124/138 (89.9%)	768	126/142 (88.7%)	711
Fever	10/138 (7.2%)	11	21/142 (14.8%)	28
Flu-like symptoms	2/138 (1.4%)	2	2/142 (1.4%)	2
General symptom	3/138 (2.2%)	4	3/142 (2.1%)	4
Ill-defined disorder	0/138 (0%)	0	2/142 (1.4%)	2
Localized edema	8/138 (5.8%)	9	4/142 (2.8%)	7
Pain	21/138 (15.2%)	44	28/142 (19.7%)	46
Visceral edema	1/138 (0.7%)	1	1/142 (0.7%)	1
Immune system disorders
Cytokine release syndrome	4/138 (2.9%)	5	4/142 (2.8%)	6
Hypersensitivity	2/138 (1.4%)	9	4/142 (2.8%)	6
Immune system disorder	1/138 (0.7%)	1	3/142 (2.1%)	8
Infections and infestations
Anal infection	1/138 (0.7%)	1	0/142 (0%)	0
Bladder infection	3/138 (2.2%)	3	3/142 (2.1%)	3
Bronchitis	1/138 (0.7%)	1	1/142 (0.7%)	1
Catheter related infection	1/138 (0.7%)	1	1/142 (0.7%)	2
Gingival infection	1/138 (0.7%)	1	0/142 (0%)	0
Infection	9/138 (6.5%)	11	12/142 (8.5%)	16
Infectious colitis	0/138 (0%)	0	1/142 (0.7%)	1
Laryngitis	1/138 (0.7%)	1	0/142 (0%)	0
Nail infection	0/138 (0%)	0	2/142 (1.4%)	2
Otitis externa	0/138 (0%)	0	1/142 (0.7%)	1
Peripheral nerve infection	3/138 (2.2%)	3	0/142 (0%)	0
Pharyngitis	3/138 (2.2%)	3	0/142 (0%)	0
Pneumonia	0/138 (0%)	0	4/142 (2.8%)	5
Rhinitis infective	0/138 (0%)	0	1/142 (0.7%)	1
Sepsis	0/138 (0%)	0	1/142 (0.7%)	1
Sinusitis	6/138 (4.3%)	9	10/142 (7%)	11
Skin infection	7/138 (5.1%)	10	3/142 (2.1%)	4
Tooth infection	1/138 (0.7%)	1	0/142 (0%)	0
Upper respiratory infection	14/138 (10.1%)	18	13/142 (9.2%)	14
Urinary tract infection	4/138 (2.9%)	5	7/142 (4.9%)	7
Vaginal infection	2/138 (1.4%)	2	3/142 (2.1%)	5
Wound infection	1/138 (0.7%)	1	2/142 (1.4%)	2
Injury, poisoning and procedural complications
Aortic injury	0/138 (0%)	0	1/142 (0.7%)	1
Bruising	2/138 (1.4%)	3	3/142 (2.1%)	10
Dermatitis radiation	8/138 (5.8%)	9	9/142 (6.3%)	9
Fracture	1/138 (0.7%)	6	1/142 (0.7%)	1
Intraoperative breast injury	0/138 (0%)	0	1/142 (0.7%)	1
Pharyngeal anastomotic leak	1/138 (0.7%)	1	0/142 (0%)	0
Radiation recall reaction (dermatologic)	3/138 (2.2%)	4	4/142 (2.8%)	4
Seroma	0/138 (0%)	0	6/142 (4.2%)	6
Thermal burn	2/138 (1.4%)	2	1/142 (0.7%)	2
Vascular access complication	3/138 (2.2%)	4	1/142 (0.7%)	1
Wound dehiscence	4/138 (2.9%)	4	4/142 (2.8%)	4
Investigations
Alanine aminotransferase increased	27/138 (19.6%)	104	35/142 (24.6%)	87
Alkaline phosphatase increased	14/138 (10.1%)	44	12/142 (8.5%)	41
Aspartate aminotransferase increased	26/138 (18.8%)	77	28/142 (19.7%)	78
Bilirubin increased	0/138 (0%)	0	3/142 (2.1%)	4
Creatinine increased	2/138 (1.4%)	2	3/142 (2.1%)	5
Gamma-glutamyltransferase increased	2/138 (1.4%)	5	2/142 (1.4%)	10
Laboratory test abnormal	3/138 (2.2%)	8	7/142 (4.9%)	22
Leukocyte count decreased	38/138 (27.5%)	129	35/142 (24.6%)	149
Lymphocyte count decreased	22/138 (15.9%)	99	21/142 (14.8%)	103
Neutrophil count decreased	70/138 (50.7%)	147	75/142 (52.8%)	202
Platelet count decreased	6/138 (4.3%)	6	13/142 (9.2%)	30
Weight gain	10/138 (7.2%)	20	14/142 (9.9%)	39
Weight loss	9/138 (6.5%)	17	8/142 (5.6%)	21
Metabolism and nutrition disorders
Alkalosis	1/138 (0.7%)	1	0/142 (0%)	0
Anorexia	27/138 (19.6%)	71	27/142 (19%)	78
Dehydration	4/138 (2.9%)	5	6/142 (4.2%)	6
Hypercalcemia	3/138 (2.2%)	14	4/142 (2.8%)	4
Hyperglycemia	16/138 (11.6%)	52	22/142 (15.5%)	89
Hyperkalemia	1/138 (0.7%)	1	5/142 (3.5%)	5
Hypertriglyceridemia	0/138 (0%)	0	1/142 (0.7%)	1
Hypoalbuminemia	2/138 (1.4%)	2	1/142 (0.7%)	3
Hypocalcemia	3/138 (2.2%)	3	9/142 (6.3%)	12
Hypoglycemia	0/138 (0%)	0	1/142 (0.7%)	2
Hypokalemia	14/138 (10.1%)	33	15/142 (10.6%)	32
Hypomagnesemia	1/138 (0.7%)	1	2/142 (1.4%)	6
Hyponatremia	7/138 (5.1%)	9	7/142 (4.9%)	14
Hypophosphatemia	0/138 (0%)	0	1/142 (0.7%)	1
Musculoskeletal and connective tissue disorders
Arthritis	0/138 (0%)	0	6/142 (4.2%)	11
Back pain	13/138 (9.4%)	21	21/142 (14.8%)	30
Bone pain	11/138 (8%)	23	16/142 (11.3%)	22
Chest wall pain	15/138 (10.9%)	17	14/142 (9.9%)	19
Fibrosis	3/138 (2.2%)	5	1/142 (0.7%)	1
Joint disorder	3/138 (2.2%)	5	3/142 (2.1%)	3
Joint effusion	1/138 (0.7%)	1	1/142 (0.7%)	1
Joint pain	38/138 (27.5%)	69	45/142 (31.7%)	103
Muscle weakness	5/138 (3.6%)	6	8/142 (5.6%)	8
Muscle weakness lower limb	1/138 (0.7%)	1	2/142 (1.4%)	2
Muscle weakness upper limb	0/138 (0%)	0	1/142 (0.7%)	1
Musculoskeletal deformity	1/138 (0.7%)	1	1/142 (0.7%)	1
Musculoskeletal disorder	2/138 (1.4%)	4	4/142 (2.8%)	4
Myalgia	39/138 (28.3%)	107	48/142 (33.8%)	132
Myositis	0/138 (0%)	0	1/142 (0.7%)	1
Neck pain	8/138 (5.8%)	8	5/142 (3.5%)	5
Neck soft tissue necrosis	0/138 (0%)	0	1/142 (0.7%)	3
Osteoporosis	1/138 (0.7%)	2	1/142 (0.7%)	1
Pain in extremity	23/138 (16.7%)	36	18/142 (12.7%)	34
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/138 (0%)	0	1/142 (0.7%)	1
Nervous system disorders
Ataxia	3/138 (2.2%)	3	1/142 (0.7%)	2
Cognitive disturbance	2/138 (1.4%)	2	1/142 (0.7%)	1
Dizziness	23/138 (16.7%)	34	23/142 (16.2%)	35
Facial nerve disorder	0/138 (0%)	0	1/142 (0.7%)	2
Headache	40/138 (29%)	72	38/142 (26.8%)	79
Hypoglossal nerve disorder	0/138 (0%)	0	1/142 (0.7%)	3
Intracranial hemorrhage	0/138 (0%)	0	1/142 (0.7%)	1
Leukoencephalopathy	0/138 (0%)	0	1/142 (0.7%)	3
Memory impairment	7/138 (5.1%)	13	5/142 (3.5%)	5
Mini mental status examination abnormal	1/138 (0.7%)	1	0/142 (0%)	0
Neuralgia	0/138 (0%)	0	2/142 (1.4%)	3
Neurological disorder NOS	2/138 (1.4%)	4	6/142 (4.2%)	10
Olfactory nerve disorder	1/138 (0.7%)	1	0/142 (0%)	0
Peripheral motor neuropathy	11/138 (8%)	22	15/142 (10.6%)	31
Peripheral sensory neuropathy	92/138 (66.7%)	352	104/142 (73.2%)	436
Seizure	0/138 (0%)	0	1/142 (0.7%)	1
Sinus pain	0/138 (0%)	0	1/142 (0.7%)	1
Syncope	1/138 (0.7%)	3	1/142 (0.7%)	1
Taste alteration	10/138 (7.2%)	37	20/142 (14.1%)	62
Tremor	0/138 (0%)	0	1/142 (0.7%)	1
Psychiatric disorders
Agitation	5/138 (3.6%)	6	2/142 (1.4%)	2
Anxiety	15/138 (10.9%)	62	23/142 (16.2%)	60
Confusion	2/138 (1.4%)	2	1/142 (0.7%)	1
Depression	15/138 (10.9%)	42	19/142 (13.4%)	50
Insomnia	30/138 (21.7%)	73	43/142 (30.3%)	76
Libido decreased	1/138 (0.7%)	1	1/142 (0.7%)	6
Psychosis	1/138 (0.7%)	1	0/142 (0%)	0
Renal and urinary disorders
Bladder pain	0/138 (0%)	0	2/142 (1.4%)	2
Cystitis	2/138 (1.4%)	2	0/142 (0%)	0
Hemoglobinuria	2/138 (1.4%)	2	0/142 (0%)	0
Hemorrhage urinary tract	0/138 (0%)	0	1/142 (0.7%)	1
Kidney pain	2/138 (1.4%)	2	0/142 (0%)	0
Proteinuria	2/138 (1.4%)	2	0/142 (0%)	0
Urinary frequency	1/138 (0.7%)	1	4/142 (2.8%)	4
Urinary incontinence	1/138 (0.7%)	1	2/142 (1.4%)	6
Urinary retention	2/138 (1.4%)	2	1/142 (0.7%)	2
Urine discoloration	0/138 (0%)	0	1/142 (0.7%)	1
Urogenital disorder	2/138 (1.4%)	2	3/142 (2.1%)	4
Reproductive system and breast disorders
Breast pain	28/138 (20.3%)	38	28/142 (19.7%)	46
Irregular menstruation	1/138 (0.7%)	1	6/142 (4.2%)	8
Lactation disorder	1/138 (0.7%)	1	0/142 (0%)	0
Ovulation pain	0/138 (0%)	0	1/142 (0.7%)	1
Pelvic pain	0/138 (0%)	0	5/142 (3.5%)	10
Reproductive tract disorder	1/138 (0.7%)	3	0/142 (0%)	0
Uterine hemorrhage	0/138 (0%)	0	2/142 (1.4%)	2
Vaginal discharge	2/138 (1.4%)	2	4/142 (2.8%)	5
Vaginal dryness	4/138 (2.9%)	7	4/142 (2.8%)	7
Vaginal hemorrhage	0/138 (0%)	0	3/142 (2.1%)	3
Vaginal inflammation	0/138 (0%)	0	1/142 (0.7%)	1
Vaginal mucositis	1/138 (0.7%)	1	0/142 (0%)	0
Vaginal pain	1/138 (0.7%)	1	2/142 (1.4%)	2
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	9/138 (6.5%)	9	16/142 (11.3%)	23
Atelectasis	0/138 (0%)	0	2/142 (1.4%)	2
Bronchial hemorrhage	0/138 (0%)	0	1/142 (0.7%)	1
Bronchopulmonary hemorrhage	0/138 (0%)	0	2/142 (1.4%)	3
Bronchospasm	4/138 (2.9%)	6	0/142 (0%)	0
Cough	27/138 (19.6%)	54	21/142 (14.8%)	40
Dyspnea	24/138 (17.4%)	40	25/142 (17.6%)	50
Hemorrhage nasal	8/138 (5.8%)	13	13/142 (9.2%)	21
Hiccough	0/138 (0%)	0	1/142 (0.7%)	1
Laryngeal edema	0/138 (0%)	0	1/142 (0.7%)	1
Laryngeal mucositis	1/138 (0.7%)	4	1/142 (0.7%)	1
Nasal congestion	7/138 (5.1%)	9	13/142 (9.2%)	24
Pharyngeal mucositis	1/138 (0.7%)	1	0/142 (0%)	0
Pharyngolaryngeal pain	5/138 (3.6%)	8	9/142 (6.3%)	11
Pleural effusion	1/138 (0.7%)	1	2/142 (1.4%)	2
Pneumonitis	0/138 (0%)	0	3/142 (2.1%)	3
Pulmonary fibrosis	0/138 (0%)	0	1/142 (0.7%)	1
Pulmonary hemorrhage	1/138 (0.7%)	1	0/142 (0%)	0
Respiratory disorder	11/138 (8%)	23	10/142 (7%)	11
Voice alteration	3/138 (2.2%)	6	2/142 (1.4%)	3
Skin and subcutaneous tissue disorders
Alopecia	93/138 (67.4%)	588	98/142 (69%)	579
Decubitus ulcer	2/138 (1.4%)	2	2/142 (1.4%)	2
Dry skin	7/138 (5.1%)	11	4/142 (2.8%)	6
Erythema multiforme	8/138 (5.8%)	11	5/142 (3.5%)	6
Hand-and-foot syndrome	17/138 (12.3%)	26	15/142 (10.6%)	28
Nail disorder	33/138 (23.9%)	71	42/142 (29.6%)	93
Pain of skin	4/138 (2.9%)	7	6/142 (4.2%)	7
Photosensitivity	1/138 (0.7%)	1	0/142 (0%)	0
Pruritus	11/138 (8%)	16	14/142 (9.9%)	14
Rash acneiform	15/138 (10.9%)	21	16/142 (11.3%)	29
Rash desquamating	24/138 (17.4%)	42	40/142 (28.2%)	59
Scalp pain	1/138 (0.7%)	1	1/142 (0.7%)	6
Skin disorder	12/138 (8.7%)	22	9/142 (6.3%)	15
Skin hyperpigmentation	9/138 (6.5%)	24	25/142 (17.6%)	60
Skin hypopigmentation	1/138 (0.7%)	1	2/142 (1.4%)	5
Skin induration	1/138 (0.7%)	1	1/142 (0.7%)	1
Skin ulceration	1/138 (0.7%)	1	2/142 (1.4%)	2
Sweating	7/138 (5.1%)	10	7/142 (4.9%)	13
Urticaria	1/138 (0.7%)	1	1/142 (0.7%)	1
Vascular disorders
Flushing	2/138 (1.4%)	5	8/142 (5.6%)	10
Hemorrhage	2/138 (1.4%)	2	4/142 (2.8%)	6
Hot flashes	40/138 (29%)	101	45/142 (31.7%)	101
Hypertension	25/138 (18.1%)	100	24/142 (16.9%)	83
Hypotension	3/138 (2.2%)	6	6/142 (4.2%)	10
Peripheral ischemia	1/138 (0.7%)	1	1/142 (0.7%)	1
Phlebitis	2/138 (1.4%)	3	0/142 (0%)	0
Thrombosis	4/138 (2.9%)	5	5/142 (3.5%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.