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Four Versus Six Cycles of Cyclophosphamide/Doxorubicin or Paclitaxel in Adjuvant Breast Cancer

Cyclophosphamide And Doxorubicin (CA) (4 VS 6 Cycles) Versus Paclitaxel (4 VS 6 Cycles) As Adjuvant Therapy For Breast Cancer in Women With 0-3 Positive Axillary Lymph Nodes:A 2X2 Factorial Phase III Randomized Study

Status
Completed
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00041119
Enrollment
3871
Registered
2003-01-27
Start date
2002-05-31
Completion date
2014-06-30
Last updated
2017-05-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer

Keywords

stage IB breast cancer, stage II breast cancer

Brief summary

This randomized phase III trial studies cyclophosphamide and doxorubicin hydrochloride compared with paclitaxel as adjuvant therapy in treating breast cancer in women with 0-3 positive axillary lymph nodes. Giving additional cancer treatment after surgery may help to lower the risk that the cancer will come back (adjuvant therapy). Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether the standard adjuvant therapy of cyclophosphamide and doxorubicin hydrochloride is more effective than paclitaxel in treating women with breast cancer

Detailed description

PRIMARY OBJECTIVES: I. To determine the equivalence of paclitaxel given every two weeks with cyclophosphamide and doxorubicin hydrochloride (CA) given every two weeks as adjuvant therapy for women with 0-3 positive axillary lymph nodes, for disease-free survival. II. To determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either CA or paclitaxel for disease-free survival for women with primary breast cancer with 0-3 positive axillary lymph nodes. SECONDARY OBJECTIVES: I. To determine the equivalence of paclitaxel given every two weeks with CA given every two weeks, and the potential superiority of longer vs. shorter therapy, in relation to overall survival, local control (regardless of metastatic status) and time to distant metastases (regardless of local recurrence status). II. To compare toxicities of short and long course CA and paclitaxel as adjuvant therapy for women with 0-3 positive axillary lymph node breast cancer. III. To determine the effect of long and short course CA and paclitaxel on the induction of menopause for pre-menopausal patients. IV. To assess the discrepancy of myelosuppression among the common multidrug resistance protein 1 (MDR1) haplotypes in the CA treatment arm. V. To assess the effect of MDR1 haplotypes on disease-free survival (DFS) adjusted for treatment. VI. Exploratory analysis of the effect of cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5), cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), and cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6) polymorphisms on DFS and toxicity. VII. To identify genetic markers associated with the risk of developing neutropenia in adriamycin/ cyclophosphamide-treated breast cancer patients. VIII. To identify genetic markers associated with the risk of developing peripheral neuropathy in paclitaxel-treated breast cancer patients. IX. To identify genetic markers associated with differences in the efficacy of each chemotherapy regimen. X. To examine genetic associations with other response and toxicity phenotypes that become apparent during future analysis of Cancer and Leukemia Group B (CALGB) 40101 data. XI. To identify copy number variants associated with adriamycin/cyclophosphamide-induced neutropenia and paclitaxel-induced peripheral neuropathy. OUTLINE: Patients are randomized to 1 of 4 treatment arms. ARM I: Patients receive cyclophosphamide intravenously (IV) and doxorubicin hydrochloride IV on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. ARM III: Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. ARM IV: Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. Note: Randomization to Arms II and IV is no longer available, effective 12/15/2007. After completion of study treatment patients are followed up for 4-6 weeks, every 6 months for 2 years, and then annually for up to 13 years.

Interventions

Given IV

DRUGcyclophosphamide

Given IV

DRUGdoxorubicin hydrochloride

Given IV

DRUGpaclitaxel

Given IV

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Alliance for Clinical Trials in Oncology
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

Eligibility Criteria: * Patients must have histologically confirmed invasive carcinoma of the female breast, with 0-3 positive axillary lymph nodes * Patients must have 0-3 positive axillary lymph nodes to be eligible for this study; patients with node-negative breast cancer should have sufficiently high risk disease to warrant chemotherapy; as general guidelines, node-negative patients with tumors of \>= 1 cm or estrogen or progesterone receptor negative tumors of any size may be eligible; ultimately though, the definition of high risk may be determined by the treating physician, and if the treating physician feels the patient warrants chemotherapy, the patient is eligible; for patients with 1-3 positive axillary nodes, the patient is eligible regardless of primary breast tumor characteristics, if in the opinion of the treating physician, chemotherapy is deemed potentially beneficial to the patient * If the patient has had a negative sentinel node biopsy, then no further axillary dissection is required, and the patient is determined to be node-negative; if an axillary dissection, without a sentinel node biopsy, is performed to determine nodal status, at least six axillary lymph nodes must be removed and analyzed and negative for the patient to be considered node-negative; axillary nodes with single cells or tumor clusters =\< 0.2 mm by either hematoxylin and eosin stain (H&E) or immunohistochemistry (IHC), will be considered node-negative; lymph nodes positive for polymerase chain reaction (PCR) with tumor cells/clusters =\< 0.2 mm will be considered node-negative; any axillary lymph node with tumor clusters \> 0.2 mm will be considered positive * If the patient has a sentinel node biopsy and one of the sentinel nodes is positive, as defined by tumor clusters \> 0.2 mm, an axillary dissection must be performed; a total of at least 6 axillary lymph nodes, including sentinel nodes plus the subsequent dissection, must be removed for the patient to be eligible; of all the lymph nodes removed from both the sentinel node procedure and the axillary dissection, 1-3 must be positive for the patient to be eligible as a node-positive patient; if an axillary dissection is done without a sentinel node procedure, at least 6 lymph nodes must be removed and a 1-3 nodes must be positive for the patient to be considered node-positive and eligible for this study * Determination of involvement of axillary nodes with metastatic cancer will follow the revised tumor-node-metastasis (TNM) staging system: axillary nodes with single cells with tumor clusters =\< 0.2 mm, by either H&E or immunohistochemistry (IHC), will be considered negative axillary node; lymph nodes positive for PCR with tumor cells/clusters \< 0.2 mm will be considered negative axillary node; any axillary lymph node with clusters \> 0.2 mm will be considered to be positive * Patients with estrogen-receptor and/or progesterone receptor negative, positive, or unknown tumors are eligible; estrogen-receptor (ER) and progesterone receptor (PgR) assays should be performed by immunohistochemical methods according to the local institution's standard protocol * Patients with human epidermal growth factor receptor 2 (HER2) positive, negative or unknown disease are eligible for this trial; patients whose tumors are HER2 positive by either immunohistochemistry 3+ staining or demonstrate gene amplification by fluorescence in situ hybridization (FISH) may receive trastuzumab * There must be negative tumor margins for invasive cancer and ductal carcinoma in situ (DCIS) in the case of mastectomy or lumpectomy; lobular carcinoma in situ (LCIS) is acceptable at the margin * Patients with multi-centric breast cancer are eligible as long as all known disease is resected with negative margins, and have 0-3 positive axillary lymph nodes * Patients must be registered within 84 days of the last breast surgery; patients must have undergone either modified radical mastectomy or lumpectomy; for patients undergoing sentinel node sampling or axillary dissection a simple mastectomy is acceptable; lumpectomy patients must receive radiation therapy; for patients treated with radiation therapy prior to chemotherapy, the patients should be registered on this study after the conclusion of radiation, with chemotherapy administration beginning within 7 days of registration \* All primary breast and axillary node surgery must be completed prior to enrollment on study * No previous trastuzumab, chemotherapy or hormonal therapy for this malignancy, except for tamoxifen therapy * No previous anthracycline chemotherapy for any disease * Patients with locally advanced breast cancer, inflammatory breast cancer or metastatic breast cancer are not eligible; patients with involvement of dermal lymphatics on pathology are not eligible, even if there are no clinical signs of inflammatory cancer * Patients with bilateral, synchronous invasive breast cancer are eligible as long as both primary tumors; if a patient has an invasive cancer on one side that meets the eligibility criteria, and DCIS or LCIS on the contralateral side, the patient is eligible; DCIS or LCIS should be managed according to institutional guidelines * Patients must be disease free from prior malignancies for \> 5 years, except for curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix; patients with a history of invasive breast cancer, or DCIS are eligible if they have been disease free for \> 5 years; patients with a history of LCIS are eligible regardless of the interval from diagnosis * Common Toxicity Criteria (CTC) performance status 0-1 * Women must not be pregnant or nursing * Concomitant exogenous hormone therapy, including oral contraceptives, post-menopausal hormone replacement therapy, and raloxifene must be stopped before patients can be enrolled * Patients may have received up to 4 weeks of tamoxifen therapy for this malignancy and still be eligible for this study; patients who received tamoxifen or another selective estrogen receptor modulator (SERM) for prevention or for other indicators (e.g. osteoporosis) are eligible; tamoxifen therapy or other SERMs must be discontinued before the patient is enrolled on this study \* The use of bisphosphonates for the treatment of osteoporosis is permitted; the use of raloxifene is not permitted are enrollment on this study * Patients must have adequate organ function including no active congestive heart failure, and no myocardial infarction \< 6 months from time of registration * Absolute neutrophil count (ANC) \>= 1,000/mm\^3 * Platelet count \>= 100,00/mm\^3 * Creatinine =\< 2.0 mg/dl * Bilirubin =\< 1.5 x upper limits of institutional normal * Patients may be enrolled on adjuvant bisphosphonate studies; patients may be enrolled concurrently or sequentially on 40101 and bisphosphonate trials * Patients may be enrolled on adjuvant hormonal studies approved by CALGB or Cancer Trials Support Unit (CTSU), such as the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) trials

Design outcomes

Primary

MeasureTime frameDescription
Relapse Free Survival (RFS) 4 vs. 6 Cyclesfrom baseline up to 4 yearsTo determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either CA or paclitaxel for relapse-free survival for women with primary breast cancer with 0-3 positive axillary lymph nodes. An assessment of the superiority of 6 cycles over 4 cycles will be conducted. This analysis combines Arm I and Arm III together, and Arm II and Arm IV together.
Duration of Disease Free Survival (RFS)from baseline up to 6.4 yearsTo determine the equivalence of paclitaxel to CA as adjuvant therapy for women with 0-3 positive axillary lymph nodes, for disease-free survival. Objective progression is defined as the appearance of local (chest wall, axillary, supraclavicular nodes) or distant metastases. The trial is designed to show the equivalence of the experimental agent T with the standard agent combination CA, thus the 4 and 6 course arms of each drug will be combined to conduct this analysis.

Secondary

MeasureTime frameDescription
Time to Distant Metastasesfrom baseline up to 15 yearsLocal control and distant metastasis will be calculated as the cumulative incidence of first local relapse and first distant metastasis, respectively.
Overall Survival (OS)from baseline up to 5 yearsTo determine the equivalence of paclitaxel to CA as adjuvant therapy for women with 0-3 positive axillary lymph nodes, for overall survival. OS will be measured from study entry until death due to any cause. Survivors will be censored at the date of last follow-up.. The trial is designed to show the equivalence of the experimental agent T with the standard agent combination CA, thus the 4 and 6 course arms of each drug will be combined to conduct this analysis.
Overall Survival (OS) for 4 vs. 6 Cyclesfrom baseline up to 4 yearsTo determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either CA or paclitaxel for overall survival for women with primary breast cancer with 0-3 positive axillary lymph nodes. An assessment of the superiority of 6 cycles over 4 cycles will be conducted. This analysis combines Arm I and Arm III together, and Arm II and Arm IV together.
Local Controlfrom baseline up to 15 yearsLocal control will be calculated as the cumulative incidence of first local relapse.
Adverse Eventsfrom baseline up to 6 weeks post-treatmentTo compare toxicities of short course CA and paclitaxel with long course CA and paclitaxel as adjuvant therapy for women with 0-3 positive axillary lymph node breast cancer. The percentage of patients that received a grade 3 or higher hematologic event will be reported here. We will be combining arm I with arm III, as well as arm II with arm IV. For a complete list of adverse events, please refer to the adverse events section.

Countries

South Africa, United States

Participant flow

Participants by arm

ArmCount
Arm I (CA for 4 Courses)
Patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
1,142
Arm II (CA for 6 Courses [Closed to Accrual 12/15/2007])
Patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
789
Arm III (Paclitaxel for 4 Courses)
Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.
1,151
Arm IV (Paclitaxel for 6 Courses [Closed 12/15/2007])
Patients receive paclitaxel IV over 3 hours on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
789
Total3,871

Baseline characteristics

CharacteristicArm I (CA for 4 Courses)Arm II (CA for 6 Courses [Closed to Accrual 12/15/2007])Arm III (Paclitaxel for 4 Courses)Arm IV (Paclitaxel for 6 Courses [Closed 12/15/2007])Total
Age, Categorical
<=18 years
0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
>=65 years
164 Participants70 Participants164 Participants74 Participants472 Participants
Age, Categorical
Between 18 and 65 years
978 Participants719 Participants987 Participants715 Participants3399 Participants
Age, Continuous53.7 years
STANDARD_DEVIATION 9.9
52.6 years
STANDARD_DEVIATION 9.1
54.0 years
STANDARD_DEVIATION 9.9
52.7 years
STANDARD_DEVIATION 9.2
53.4 years
STANDARD_DEVIATION 9.6
Sex: Female, Male
Female
1142 Participants789 Participants1151 Participants789 Participants3871 Participants
Sex: Female, Male
Male
0 Participants0 Participants0 Participants0 Participants0 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
deaths
Total, all-cause mortality
— / —— / —— / —— / —
other
Total, other adverse events
940 / 1,110687 / 765975 / 1,118668 / 762
serious
Total, serious adverse events
113 / 1,142104 / 78959 / 1,15153 / 789

Outcome results

Primary

Duration of Disease Free Survival (RFS)

To determine the equivalence of paclitaxel to CA as adjuvant therapy for women with 0-3 positive axillary lymph nodes, for disease-free survival. Objective progression is defined as the appearance of local (chest wall, axillary, supraclavicular nodes) or distant metastases. The trial is designed to show the equivalence of the experimental agent T with the standard agent combination CA, thus the 4 and 6 course arms of each drug will be combined to conduct this analysis.

Time frame: from baseline up to 6.4 years

Population: All eligible patients were treated and analyzed.

ArmMeasureValue (MEDIAN)
4 Cycles (Arm I and Arm III Combined)Duration of Disease Free Survival (RFS)NA months
6 Cycles (Arm II and Arm IV Combined)Duration of Disease Free Survival (RFS)NA months
Primary

Relapse Free Survival (RFS) 4 vs. 6 Cycles

To determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either CA or paclitaxel for relapse-free survival for women with primary breast cancer with 0-3 positive axillary lymph nodes. An assessment of the superiority of 6 cycles over 4 cycles will be conducted. This analysis combines Arm I and Arm III together, and Arm II and Arm IV together.

Time frame: from baseline up to 4 years

Population: All patients that were eligible and received treatment were analyzed. 700 patients were not included due to the timing that the analysis was performed.

ArmMeasureValue (MEDIAN)
4 Cycles (Arm I and Arm III Combined)Relapse Free Survival (RFS) 4 vs. 6 CyclesNA years
6 Cycles (Arm II and Arm IV Combined)Relapse Free Survival (RFS) 4 vs. 6 CyclesNA years
Comparison: The null hypothesis is that the hazards of both 6 and 4 cycle regimens are equal. The alternative hypothesis is a hazard ratio of 0.77, corresponding to a decrease of 23% in hazard due to longer duration of chemotherapy.95% CI: [0.84, 1.28]
Secondary

Adverse Events

To compare toxicities of short course CA and paclitaxel with long course CA and paclitaxel as adjuvant therapy for women with 0-3 positive axillary lymph node breast cancer. The percentage of patients that received a grade 3 or higher hematologic event will be reported here. We will be combining arm I with arm III, as well as arm II with arm IV. For a complete list of adverse events, please refer to the adverse events section.

Time frame: from baseline up to 6 weeks post-treatment

Population: 3754 patients were considered evaluable for toxicity that occurred during treatment.

ArmMeasureValue (NUMBER)
4 Cycles (Arm I and Arm III Combined)Adverse Events38 percentage of patients
6 Cycles (Arm II and Arm IV Combined)Adverse Events29 percentage of patients
Secondary

Local Control

Local control will be calculated as the cumulative incidence of first local relapse.

Time frame: from baseline up to 15 years

Population: All patients that were eligible and received treatment were analyzed.

ArmMeasureValue (MEDIAN)
4 Cycles (Arm I and Arm III Combined)Local ControlNA years
6 Cycles (Arm II and Arm IV Combined)Local ControlNA years
Secondary

Overall Survival (OS)

To determine the equivalence of paclitaxel to CA as adjuvant therapy for women with 0-3 positive axillary lymph nodes, for overall survival. OS will be measured from study entry until death due to any cause. Survivors will be censored at the date of last follow-up.. The trial is designed to show the equivalence of the experimental agent T with the standard agent combination CA, thus the 4 and 6 course arms of each drug will be combined to conduct this analysis.

Time frame: from baseline up to 5 years

Population: All patients that were eligible and treated for the study were evaluated.

ArmMeasureValue (NUMBER)
4 Cycles (Arm I and Arm III Combined)Overall Survival (OS)95 percentage of participants at 5 years
6 Cycles (Arm II and Arm IV Combined)Overall Survival (OS)94 percentage of participants at 5 years
Secondary

Overall Survival (OS) for 4 vs. 6 Cycles

To determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either CA or paclitaxel for overall survival for women with primary breast cancer with 0-3 positive axillary lymph nodes. An assessment of the superiority of 6 cycles over 4 cycles will be conducted. This analysis combines Arm I and Arm III together, and Arm II and Arm IV together.

Time frame: from baseline up to 4 years

Population: All patients that were eligible and received treatment were analyzed.

ArmMeasureValue (NUMBER)
4 Cycles (Arm I and Arm III Combined)Overall Survival (OS) for 4 vs. 6 Cycles90.9 percentage of patients at 4 years
6 Cycles (Arm II and Arm IV Combined)Overall Survival (OS) for 4 vs. 6 Cycles91.8 percentage of patients at 4 years
95% CI: [0.84, 1.49]
Secondary

Time to Distant Metastases

Local control and distant metastasis will be calculated as the cumulative incidence of first local relapse and first distant metastasis, respectively.

Time frame: from baseline up to 15 years

Population: All patients that were eligible and received treatment were analyzed.

ArmMeasureValue (MEDIAN)
4 Cycles (Arm I and Arm III Combined)Time to Distant MetastasesNA years
6 Cycles (Arm II and Arm IV Combined)Time to Distant MetastasesNA years

Source: ClinicalTrials.gov · Data processed: Feb 23, 2026