Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Positive Breast Cancer

Breast Cancer Clinical Trial

Official title:

A Phase III, Adjuvant Trial Comparing Three Chemotherapy Regimens in Women With Node-Positive Breast Cancer: Docetaxel/Doxorubicin/Cyclophosphamide (TAC); Dose-Dense (DD) Doxorubicin/Cyclophosphamide Followed By DD Paclitaxel (DD AC→P); DD AC Followed By DD Paclitaxel Plus Gemcitabine (DD AC→PG)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00093795
• Other study ID #: NSABP B-38
• Secondary ID: U10CA012027
• Status: Completed
• Phase: Phase 3
• First received: October 6, 2004
• Last updated: December 11, 2017
• Start date: October 2004
• Est. completion date: June 2016

Study information

• Verified date: December 2017
• Source: NSABP Foundation Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy, such as docetaxel, doxorubicin , cyclophosphamide, paclitaxel, and gemcitabine work in different ways to stop tumor cells from dividing so they stop growing or die. Giving combination chemotherapy after surgery may kill any remaining tumor cells.

PURPOSE: This randomized phase III trial is studying three different combination chemotherapy regimens and comparing how well they work in treating women who have undergone surgery for node-positive breast cancer.

Description:

OBJECTIVES:

Primary

• Compare disease-free survival in women with node-positive breast cancer treated with 3 different adjuvant chemotherapy regimens comprising dose-dense doxorubicin, cyclophosphamide, paclitaxel, and gemcitabine vs docetaxel, doxorubicin, and cyclophosphamide vs dose-dense doxorubicin, cyclophosphamide, and paclitaxel.

Secondary

• Compare overall survival, recurrence-free interval, and distant recurrence-free interval, in patients treated with these regimens.

• Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to number of positive lymph nodes (1-3 vs 4-9 vs ≥ 10), hormone receptor status (estrogen receptor [ER]- and progesterone receptor [PgR]- negative vs ER- and/or PgR-positive), type of prior surgery and planned radiotherapy (lumpectomy and local radiotherapy [RT] without regional RT vs lumpectomy and local RT with regional RT vs mastectomy without RT vs mastectomy with local or regional RT). Patients are randomized to 1 of 3 treatment arms.

• Group 1: Patients receive doxorubicin IV over 15 minutes, cyclophosphamide IV over 30 minutes, and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses.

• Group 2: Patients receive AC chemotherapy comprising doxorubicin IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 14 days for 4 courses. Beginning 14 days after the last dose of AC, patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 4 courses.

• Group 3: Patients receive AC chemotherapy as in Group 2. Beginning 14 days after the last dose of AC, patients receive paclitaxel as in Group 2 and gemcitabine IV over 30-60 minutes on day 1. Treatment repeats every 14 days for 4 courses.

In all arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Beginning 3-12 weeks after the last dose of chemotherapy, patients with ER-positive and/or PgR-positive tumors receive hormonal therapy.

Beginning no sooner than 3 weeks after the last dose of chemotherapy, patients treated with lumpectomy undergo whole-breast radiotherapy. Patients treated with mastectomy may undergo chest wall and/or regional nodal radiotherapy.

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

PROJECTED ACCRUAL: A total of 4,800 patients will be accrued for this study within 4 years.

Other known NCT identifiers

• NCT00191958

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4894
• Est. completion date: June 2016
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• The patient must consent to participate in the study and must have signed an approved consent form conforming with federal and institutional guidelines.

• The patient must have a life expectancy of at least 10 years and a Zubrod performance status of 0 or 1. (Comorbid conditions but not the diagnosis of breast cancer should be taken into consideration when determining life expectancy.)

• The interval between the last surgery for breast cancer staging or treatment and randomization must be no more than 84 days.

• The tumor must be invasive carcinoma of the breast on histologic examination.

• All of the following staging criteria must be met:

• By clinical and pathologic evaluation, primary tumor must be T1-3;

• By clinical evaluation, ipsilateral nodes must be cN0, cN1, or cN2a;

• By pathologic evaluation, ipsilateral nodes must be pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b (only if due to microscopic involvement of internal mammary node detected by sentinel lymph node dissection and with more than 3 positive axillary lymph nodes).

• Patients must have an estrogen receptor (ER) analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then progesterone receptor (PgR) analysis must be performed. If ER analysis is positive, PgR analysis is desired, but not mandatory. ("Marginal" or "borderline" results [i.e., those not definitely negative] will be considered positive regardless of the methodology used.)

• Patients must have had either a lumpectomy or a total mastectomy. Patients must have completed one of the following procedures for evaluation of pathologic nodal status.

• Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes (This approach is strongly recommended.)

• Sentinel lymphadenectomy alone if one of the following criteria is met:

• Pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1b

• Surgeon elects not to remove additional non-sentinel nodes (This approach is strongly discouraged, but will not preclude participation in B-38.)

• Axillary lymphadenectomy without sentinel node isolation procedure.

• Patients must have no clinical or radiologic evidence of metastatic disease.

• Patients with either skeletal pain or alkaline phosphatase that is greater than ULN but less than or equal to 2.5 x ULN are eligible for inclusion in the study if bone scans fail to demonstrate metastatic disease. Suspicious findings on bone scan must be confirmed as benign by x-ray, MRI, or biopsy.

• Patients with aspartate transaminase (AST) or alkaline phosphatase greater than ULN are eligible for inclusion in the study if liver imaging fails to demonstrate metastatic disease and the following requirements are met at the time of randomization.

• Postoperative absolute granulocyte count (AGC) must be greater than or equal to 1200/mm3.

• Postoperative platelet count must be greater than or equal to 100,000/mm3.

• The following criteria for postoperative evidence of adequate hepatic function must be met:

• total bilirubin must be less than or equal to ULN for the lab unless the patient has a grade 1 bilirubin elevation (greater than ULN to 1.5 x ULN) due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin; and

• alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and

• the AST must be less than or equal to 1.5 x ULN for the lab; and

• alkaline phosphatase and AST cannot both be greater than ULN.

• Postoperative serum creatinine must be less than or equal to ULN.

• At the time of randomization, the patient must have had the following: history and physical exam, EKG, and imaging of the chest within the past 3 months and bilateral mammogram within the past 6 months.

• Within 3 months prior to entry, the patient must have a baseline left ventricular ejection fraction (LVEF), measured by Multiple Gated Acquisition (MUGA) scan or echocardiogram, greater than or equal to lower limit of normal (LLN) for the facility performing the procedure and no evidence of regional wall abnormalities.

• Patients with a history of non-breast malignancies are eligible if they have been disease-free for 5 or more years prior to randomization and are deemed by their physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.

• Special conditions for eligibility of lumpectomy patients: radiation therapy and surgery. Patients treated by lumpectomy must meet all the eligibility criteria in addition to the following:

• Generally, lumpectomy should be reserved for tumors less than 5 cm. However, at the investigator's discretion, patients treated with lumpectomy for tumors greater than or equal to 5 cm are eligible if eligibility criteria for lumpectomy are met.

• The margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. In patients for whom pathologic examination demonstrates tumor present at the line of resection, additional operative procedures may be performed to obtain clear margins. This is permissible even if axillary evaluation has been completed. Patients in whom tumor is still present at the resected margin after re-excision(s) must undergo total mastectomy to be eligible. (Patients with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.)

• Irradiation of regional lymph nodes is optional, but plans for radiation therapy must be declared by the investigator prior to randomization for stratification purposes.

• Special conditions for eligibility of mastectomy patients: radiation therapy o Postmastectomy chest wall and/or regional nodal irradiation is optional. Plans for radiation in mastectomy patients must be declared by the investigator prior to randomization for stratification purposes.

Ineligibility Criteria

• Male patients are not eligible for this study. Women with one or more of the following conditions or prior therapies are also ineligible for this study:

• Tumor that has been determined to be human epidermal growth factor receptor 2 (HER2)-positive by immunohistochemistry (3+) or by fluorescent in situ hybridization (positive for gene amplification).

• Contralateral breast cancer (invasive or DCIS) or a mass or mammographic abnormality in the opposite breast suspicious for malignancy unless there is biopsy proof that the mass is not malignant.

• Primary tumor staged as T4 for any reason.

• Clinical nodal stages including cN2b and cN3 or pathologic nodal stages including pN0(i+), pN2b, pN3b with clinically apparent internal mammary nodes, or pN3c.

• Suspicious nodes in the contralateral axilla or suspicious supraclavicular nodes. Patients with these conditions are considered ineligible unless there is biopsy evidence that these are not involved with tumor.

• Prior history of breast cancer, including DCIS (patients with a history of LCIS are eligible).

• Treatment, including radiation therapy, chemotherapy, and/or hormonal therapy administered for the currently diagnosed breast cancer prior to randomization. One exception is hormonal therapy, which may have been given for up to a total of 28 days anytime after diagnosis and before study entry. In such a case, hormonal therapy must stop at or before randomization and be re-started, if indicated, following chemotherapy. A second exception is radiation therapy for patients enrolled in NSABP B-39 and assigned to partial breast irradiation (Group 2). These patients may have received RT prior to B-38 study entry.

• Prior therapy with anthracyclines or taxanes for any malignancy.

• Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible if this therapy is discontinued prior to randomization.)

• Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other selective estrogen-receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Patients are eligible only if these medications are discontinued prior to randomization.

• Cardiac disease that would preclude the use of anthracyclines. This includes:

• history of myocardial infarction documented by elevated cardiac enzymes or regional wall abnormalities on assessment of left ventricular (LV) function;

• angina pectoris that requires the use of anti-anginal medication;

• any history of documented congestive heart failure;

• serious cardiac arrhythmia requiring medication;

• severe conduction abnormality;

• valvular disease with documented cardiac function compromise; and

• uncontrolled hypertension defined as blood pressure greater than 160/100 on antihypertensive therapy.

• Conditions that would prohibit administration of corticosteroids.

• Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI's Common Terminology Criteria for Adverse Events Version 3.0.

• Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude a patient from receiving any of the treatment options or would prevent prolonged follow-up.

• History of hepatitis B or C.

• Pregnancy or lactation at the time of proposed randomization. Women of reproductive potential must agree to use an effective non-hormonal method of contraception.

• Concurrent treatment with other investigational agents for the treatment of breast cancer.

• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.

• Special conditions for ineligibility of lumpectomy patients: radiation therapy and surgery

• For patients treated by lumpectomy, whole breast irradiation is required.

• The following patients will be ineligible:

• Patients with diffuse tumors (as demonstrated on mammography) treated with lumpectomy. (These patients are eligible if they undergo mastectomy.)

• Patients treated with lumpectomy in whom there is another clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast remnant. Such a mass must be biopsied and demonstrated to be histologically benign prior to randomization or, if malignant, must be surgically removed with clear margins.

• Patients in whom the margins of the resected specimen are involved with invasive tumor or DCIS.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Cyclophosphamide
Group 1: cyclophosphamide 500 mg/m2 IV every 21 days for 6 cycles Group 2 and Group 3: cyclophosphamide 600 mg/m2 IV every 14 days for 4 cycles
• Docetaxel
75 mg/m2 IV every 21 days for 6 cycles
• Gemcitabine
2000 mg/m2 IV every 14 days for 4 cycles
• Paclitaxel
175 mg/m2 IV every 14 days for 4 cycles
• Doxorubicin
Group 1: 50 mg/m2 IV every 21 days for 6 cycles Group 2 and Group 3: 60 mg/m2 IV every 14 days for 4 cycles

Locations

Country	Name	City	State
United States	Providence Cancer Center	Anchorage	Alaska
United States	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Altru Cancer Center at Altru Hospital	Grand Forks	North Dakota
United States	CCOP - Northern New Jersey	Hackensack	New Jersey
United States	Community Oncology Group at Cleveland Clinic Cancer Center	Independence	Ohio
United States	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky
United States	Methodist Estabrook Cancer Center	Omaha	Nebraska
United States	Chestnut Hill Healthcare Cancer Center	Philadelphia	Pennsylvania
United States	South Shore Hospital	South Weymouth	Massachusetts
United States	Robert and Carol Weissman Cancer Center at Martin Memorial	Stuart	Florida
United States	Madigan Army Medical Center - Tacoma	Tacoma	Washington

Sponsors (2)

Lead Sponsor	Collaborator
NSABP Foundation Inc	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free Survival: Any Recurrence, Contralateral Breast Cancer, Second Primary Cancer, Death From Any Cause Prior to Recurrence or Second Primary Cancer	The percentage of patients alive and cancer-free.	5 years
Secondary	Overall Survival	Percentage of participants alive at 5 years	5 years
Secondary	Recurrence-free Interval: Time to First Local, Regional, or Distant Recurrence	Percentage of patients recurrence-free (no first local, regional, or distant recurrence)	5 years
Secondary	Distant Recurrence-free Interval: the Time to Distant Disease Recurrence Only	Percentage of patients distant recurrence-free (no distant disease recurrence only)	5 years
Secondary	Toxicity	Percentage of patients who ever experienced grade 2 or higher toxicities.	30 days after the last dose of study therapy (about 7 months after study entry)