Breast Cancer
Conditions
Keywords
stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer
Brief summary
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving them in different ways after surgery may kill more tumor cells. It is not yet known which chemotherapy regimen is more effective in treating older women with breast cancer. PURPOSE: This randomized phase III trial is studying different combination chemotherapy regimens to see how well they work in treating older women who have undergone surgery for breast cancer.
Detailed description
OBJECTIVES: * Compare the effectiveness of adjuvant chemotherapy comprising standard cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin and cyclophosphamide (AC) vs oral capecitabine, in terms of disease-free and overall survival, in elderly women with operable adenocarcinoma of the breast. * Compare the quality of life and physical functioning of patients treated with these regimens. * Compare the toxicity of these regimens in these patients. * Evaluate the adherence of older patients to an oral chemotherapy regimen. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (65 to 69 vs 70 to 80 vs over 80), performance status (0-1 vs 2), and HER2 status (positive vs negative vs unknown). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients with insufficient left ventricular ejection fraction (LVEF) are assigned to group A. Patients with normal LVEF are assigned to group A or B based on physician/patient choice. * Group A (CMF): Patients receive oral cyclophosphamide (CTX) daily on days 1-14 and methotrexate IV and fluorouracil IV on days 1 and 8. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. * Group B (AC): Patients receive doxorubicin IV and CTX IV on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. * Arm II: Patients receive oral capecitabine twice daily on days 1-14. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Beginning within 12 weeks after treatment in arm I or II, patients with estrogen or progesterone receptor-positive disease receive oral tamoxifen or an aromatase inhibitor daily for 5 years. Beginning 4-6 weeks after treatment in arm I or II, eligible patients who previously underwent breast conservation surgery undergo radiotherapy. Quality of life is assessed at baseline; at 6 weeks (group B), 9 weeks (arm II), or 12 weeks (group A); and then at 1, 12, 18, and 24 months after study. Drug adherence is assessed at 9 weeks during study (arm II). Patients are followed at 1 month, every 6 months for 2 years, and then annually for 15 years. PROJECTED ACCRUAL: A total of 600-1,800 patients (300-900 per treatment arm) will be accrued for this study within 2-6 years.
Interventions
DRUGStandard Treatment
Cyclophosphamide 100 mg/sq m PO d 1-14 + MTX 40 mg/sq m IV push d 1 & 8 and 5-FU 600 mg/sq m IV push d 1 & 8 q 28 days for 6 cycles OR doxorubicin 60 mg/sq m IV d 1 + cyclophosphamide 600 mg/sq m IV d 1 q 21 d for 4 cycles
DRUGcapecitabine
2000 mg/sq m PO d 1-14, 7 day rest then repeat for a total of 6 cycles
Sponsors
National Cancer Institute (NCI)
NCIC Clinical Trials Group
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with operable, histologically confirmed adenocarcinoma of the female breast. 2. TNM Stage per AJCC Cancer Staging Manual 6th edition: * T1-4 (Tumor size \> 1 cm), N0, M0 or T1-4, N1-3, M0 * Patients with bilateral, synchronous breast cancer are eligible as long as one primary tumor meets the criteria above. 3. Patients with HER2/neu 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 FISH will be eligible to receive trastuzumab, as outlined in the protocol. 4. Age 65 years or older 5. Performance status 0-2 (Common Toxicity Criteria). 6. Prior treatment: * Surgical resection - * All tumor should be removed by either a modified radical mastectomy or a lumpectomy. Patients must be registered ≤ 84 days from mastectomy or within 84 days of axillary dissection if patient's most extensive breast surgery was a breast sparing procedure. * Node dissection: Axillary node dissection is not required. Management of the axilla is at the discretion of the treating physician. There is no restriction on eligibility based on the number of nodes removed. * Mastectomy: There should be no evidence of gross or microscopic invasive tumor at the surgical resection margins noted in the final surgery or pathology reports for patients who have had a modified radical mastectomy. Patients with close margins (tumor \< 1 mm from margin) are eligible. * Segmental mastectomy (lumpectomy): Although clear margins are preferable, DCIS or LCIS at the surgical resection margin will not render a patient who has undergone a segmental mastectomy ineligible for this study. Invasive tumor at the final resection margin will render a patient ineligible. * No prior chemotherapy for this malignancy. * Patients with a history of hypersensitivity to 5-FU or known dihydropyrimidine dehydrogenase (DPD) deficiency are not eligible to participate. * Patients may receive up to four weeks of tamoxifen therapy for this malignancy and still be eligible for study entry. Patients who received tamoxifen or raloxifene for purposes of chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (including previous breast cancer) are eligible. Tamoxifen or raloxifene therapy should be discontinued before the patient is enrolled on this study. 7. Required Initial Laboratory Data: * Granulocytes \> 1,500/µl * Platelet count ≥100,000/µl * Calculated Creatinine Clearance \> 30 mL/min * Total bilirubin ≤ ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relapse-free Survival Rates at 2.4 Years | randomization until date of first event, or date last known to be event free if no event was reported (up to 5 years) | Percentage of participants who were alive and relapse-free at time of analysis were counted as Alive without relapse at 2.4 years. Participants who had a first local recurrence, first distant metastasis or death from any cause were counted as relapse, first occurrence. These rates were estimated using the Kaplan Meier method |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Rate at 2.4 Years | Time from registration to death (up to 15 years) | Percentage of patients who were alive at 2.4 years. This rate was estimated using the Kaplan Meier method. |
| Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. | Reported during protocol treatment after each cycle | The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0 was used to evaluate toxicity. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life Threatening; Grade 5: Death. |
Countries
Canada, Peru, United States
Participant flow
Recruitment details
This was an intergroup study led by the CALGB. Between September 2001 and December 2006, 633 participants were recruited.
Pre-assignment details
All participants recruited were randomized with equal probability to one of two treatment arms. Randomization was initially stratified by age and performance score. In 2006 tumoral HER2 status was added as a third stratification factor.
Participants by arm
| Arm | Count |
|---|---|
| Standard Chemotherapy Patient/Physician choice of:
CMF: cyclophosphamide (100 mg/m\^2 orally days 1-14)+ MTX (40 mg/m\^2 by IV days 1 and 8) + 5-FU (600 mg/m\^2 by IV days 1 and 8) repeated every 28 days for 6 cycles OR
AC: Cyclophosphamide (600 mg/m\^2 by IV on day 1)+ doxorubicin (60 mg/m\^2 by IV on day 1) repeated every 21 days for 4 cycles | 326 |
| Capecitabine Capecitabine (2000 mg/m\^2 in 2 doses days 1-14) repeated every 21 days for 6 cycles. | 307 |
| Total | 633 |
Baseline characteristics
| Characteristic | Standard Chemotherapy | Capecitabine | Total |
|---|---|---|---|
| Age, Customized 65-69 years | 112 participants | 110 participants | 222 participants |
| Age, Customized 70-79 years | 200 participants | 183 participants | 383 participants |
| Age, Customized >=80 years | 14 participants | 14 participants | 28 participants |
| ECOG Performance Status 0 or 1 (fully active or minimal symptoms) | 317 participants | 295 participants | 612 participants |
| ECOG Performance Status 2 (symptoms, but active > 50% of the time) | 9 participants | 12 participants | 21 participants |
| HER2 Status Negative | 246 participants | 232 participants | 478 participants |
| HER2 Status Positive | 35 participants | 30 participants | 65 participants |
| HER2 Status Unknown | 45 participants | 45 participants | 90 participants |
| Region of Enrollment Argentina | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Australia | 0 participants | 2 participants | 2 participants |
| Region of Enrollment United States | 326 participants | 302 participants | 628 participants |
| Sex: Female, Male Female | 326 Participants | 307 Participants | 633 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 121 / 131 | 168 / 181 | 279 / 299 |
| serious Total, serious adverse events | 15 / 131 | 17 / 181 | 26 / 299 |
Outcome results
Primary
Relapse-free Survival Rates at 2.4 Years
Percentage of participants who were alive and relapse-free at time of analysis were counted as Alive without relapse at 2.4 years. Participants who had a first local recurrence, first distant metastasis or death from any cause were counted as relapse, first occurrence. These rates were estimated using the Kaplan Meier method
Time frame: randomization until date of first event, or date last known to be event free if no event was reported (up to 5 years)
Population: RFS used the intent-to-treat approach
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Chemotherapy | Relapse-free Survival Rates at 2.4 Years | Relapse, first occurrence | 11 percentage of participants |
| Standard Chemotherapy | Relapse-free Survival Rates at 2.4 Years | Alive without relapse | 89 percentage of participants |
| Capecitabine | Relapse-free Survival Rates at 2.4 Years | Relapse, first occurrence | 20 percentage of participants |
| Capecitabine | Relapse-free Survival Rates at 2.4 Years | Alive without relapse | 80 percentage of participants |
p-value: <0.00195% CI: [1.38, 3.17]Regression, Cox
Secondary
Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment.
The National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 2.0 was used to evaluate toxicity. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life Threatening; Grade 5: Death.
Time frame: Reported during protocol treatment after each cycle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy | Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. | 92 participants |
| Capecitabine | Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. | 109 participants |
| Capecitabine | Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. | 101 participants |
Secondary
Overall Survival Rate at 2.4 Years
Percentage of patients who were alive at 2.4 years. This rate was estimated using the Kaplan Meier method.
Time frame: Time from registration to death (up to 15 years)
Population: OS used the intent-to-treat approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Chemotherapy | Overall Survival Rate at 2.4 Years | 93 percentage of participants |
| Capecitabine | Overall Survival Rate at 2.4 Years | 88 percentage of participants |
p-value: 0.0295% CI: [1.11, 3.08]Regression, Cox