Breast Cancer, Stage IV Breast Cancer
Conditions
Keywords
stage IV breast cancer, local therapy
Brief summary
RATIONALE: The primary tumor might be a source of re-seeding of distant sites and therefore elimination of this source of metastasizing cells by early local therapy may be of benefit. PURPOSE: This randomized phase III trial is studying early surgery to see how well it works compared to standard palliative therapy in treating patients with stage IV breast cancer.
Detailed description
OBJECTIVES: Primary * To evaluate whether early local therapy of intact primary disease in patients with Stage IV breast cancer whose disease does not progress during initial optimal systemic therapy, will result in prolonged survival, compared to patients who receive local therapy for palliation only. Secondary * To compare the time to uncontrolled chest wall disease between patients who receive early local therapy versus patients who receive palliative local therapy. * To determine whether there is a difference in health-related quality-of-life (HRQOL) between patients who receive early local therapy versus patients who receive palliative local therapy. * To determine whether the absolute value of circulating tumor cells (CTC) burden at 6 months following randomization (time +6) will be lower in the palliative therapy arm than in early local therapy arm, and whether this value is inversely related to survival (lower CTC, longer survival). Exploratory * To collect tumor and blood specimens for future exploration of the biological interactions between the primary tumor and metastatic lesions and the effect of primary tumor resection. OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor and treatment plan (ER+ or PR+, HER2-, endocrine therapy alone vs ER+ or PR+, and HER2-, chemotherapy and/or endocrine therapy vs ER- or PR-, and HER2- vs HER2+), and number of involved organ systems with distant disease (regional nodes in the axillary, supraclavicular, and internal mammary locations are not considered distant sites) (1 vs \> 1). Patients are randomized to 1 of 2 treatment arms in 1:1 ratio. * Arm I: Patients receive standard palliative therapy, if needed, to address symptoms such as tumor ulceration, pain, bulky adenopathy causing arm symptoms, and other similar situations. Therapy may consist of radiotherapy alone, surgery alone, or a combination of both. * Arm II: Patients undergo surgery comprising breast-conserving therapy (BCT) or total mastectomy according to patient and treating physician preference. Surgery is to occur no later than 10 weeks after completion of 32 weeks of systemic therapy. Free surgical margins must be achieved with re-excision or mastectomy for patients undergoing BCT. After completion of BCT, patients undergo radiotherapy once a day, 5 days per week. Patients who had mastectomy undergo radiotherapy at the discretion of treating physician. Patients may undergo blood and tumor tissue sample collection for circulating tumor cells (CTC) burden and future studies. Patients complete the Functional Assessment of Cancer Therapy - Breast Trial Outcome Index (FACT- TOI) and FACT - General (22) and the Breast Cancer Subscale (FACT-B) quality-of-life questionnaires at baseline and periodically during study. After completion of study therapy, patients are followed up periodically for 5 years.
Interventions
PROCEDUREpalliative surgery
Undergo standard palliative surgery
PROCEDUREtherapeutic conventional surgery
Undergo early surgery
RADIATIONpalliative radiation therapy
Undergo standard palliative radiotherapy
RADIATIONradiation therapy
Undergo radiotherapy
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of intact primary (not recurrent) invasive carcinoma of the breast * Stage IV disease * Confirmation of the primary tumor should be by needle biopsy (preferred) * Incisional surgical biopsy allowed as long as there is residual palpable or tumor image in the breast * Patients must be judged to be candidates for complete resection with free margins followed by radiation therapy (if radiation therapy is indicated) * For women not undergoing axillary dissection, sentinel node biopsy should document an axillary nodal burden of 1-2 involved lymph nodes (i.e., ACOSOG Z-11 criteria may be applied) * Prior non-invasive (Ductal Carcinoma In Situ) cancer allowed provided there has been no recurrence * Prior ipsilateral invasive cancer allowed if more than 5 years previous * Patients should have at least one organ system involved with distant metastatic disease * If patient has only one metastatic lesion/focus, this must be proven by biopsy and the pathology report confirming the diagnosis of primary breast cancer, as well as the metastatic site, must be available * Must have available radiologic reports documenting disease status within the past 6 weeks prior to initiating systemic therapy * CNS metastases allowed provided projected survival \> 6 months * Patients must have completed at least 16 weeks of optimal systemic therapy (appropriate to the tumor biological profile and the patient's age and menopausal status) * If systemic therapy is discontinued for toxicity, but there is no distant progression and at least 12 weeks of therapy have been delivered, then the patient remains eligible * Radiation therapy (if indicated) must begin within 12 weeks of final therapeutic surgical procedure (including re-excision for free margins and completion of axillary dissection) * Patients may register at any time from the time of diagnosis of stage IV breast cancer (if eligibility criteria met) to the time when a maximum of 30 weeks of induction systemic therapy has been completed * Patients must be randomized within 16-32 weeks after the start of systemic therapy * Patients must not have experienced disease progression since the start of systemic therapy, as evidenced by radiographic documentation of disease status before treatment and within 4 weeks +/- 2 weeks prior to randomization, including: * No new sites of disease * No enlargement of existing sites by 20% or more in longest diameter * No symptomatic deterioration * Patients who require radiotherapy to bone metastases during induction systemic therapy are eligible * Local disease at the primary site must be asymptomatic * Hormone receptor status known * Menopausal status not specified * Patients must have adequate organ function to undergo local therapy 4 weeks +/- 2 weeks prior to randomization per investigator discretion and institutional guidelines * More than 5 years since other primary cancers that were curatively treated * Negative pregnancy test * Fertile patients must use an accepted and effective contraception method
Exclusion criteria
* Synchronous contralateral breast cancer * Pregnant or nursing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 3-year Overall Survival Rate | Assessed at baseline, then every 3 months within 2 years and every 6 months between 2-5 years, up to 5 years | Overall survival (OS) was defined as time from randomization to death from any cause. All patients will be followed for survival through 5 years. Cases with incomplete follow-up or without record of vital status will be censored at the date of last contact. 3-year OS rate was estimated using Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 3-year Cumulative Incidence of Locoregional Recurrence/Progression | Assessed at baseline, then every 3 months within 2 years and every 6 months between 2-5 years, up to 5 years | For patients in arm II (early local therapy), time to locoregional recurrence was defined as time from randomization to date of locoregional recurrence; for patients in arm A (continued systemic therapy), time to locoregional progression was defined as time from randomization to date of locoregional progression. In this study, locoregional recurrence was defined as the new development or clinically significant increase in size of any supraclavicular, infraclavicular, internal mammary or axillary adenopathy or chest wall disease or invasive in-breast recurrence for patients on arm B; for patients on arm A, locoregional progression was defined as the development of symptoms leading to a decision for local therapy. Locoregional recurrence/progression and distant progression were followed separately in the study, and the occurrence of one did not preclude the other getting reported. 3-year cumulative incidence of locoregional recurrence/progression was estimated. |
| Health-related Quality of Life (HRQL) | Assessed at 18 months after randomization | The Functional Assessment of Cancer Therapy-Breast Trial Outcome Index (FACT-B TOI) was used as the primary HRQL endpoint, measured by the prorated aggregate score of the 24 items from the FACT-B (7 functional well-being, 7 physical well-being, 10 breast cancer specific items). The theoretical range of the prorated aggregate score was 0-96, higher scores indicate better quality of life. |
Countries
Canada, Israel, Saudi Arabia, South Africa, United States
Participant flow
Recruitment details
This study was activated on February 8, 2011, accrued its first patient on May 16, 2011, and accrual was terminated on July 23, 2015 with a final accrual of 390 patients on Step 1. Of the 390 patients enrolled, 256 of them were randomized to Step 2 to arm I and arm II.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Continued Systemic Therapy) Patients receive standard palliative therapy, if needed, to address symptoms such as tumor ulceration, pain, bulky adenopathy causing arm symptoms, and other similar situations. Therapy may consist of radiotherapy alone, surgery alone, or a combination of both.
palliative surgery: Undergo standard palliative surgery
palliative radiation therapy: Undergo standard palliative radiotherapy | 131 |
| Arm II (Early Local Therapy) Patients undergo surgery comprising breast-conserving therapy (BCT) or total mastectomy according to patient and treating physician preference. Surgery is to occur no later than 10 weeks after completion of 32 weeks of systemic therapy. Free surgical margins must be achieved with re-excision or mastectomy for patients undergoing BCT. After completion of BCT, patients undergo radiotherapy once a day, 5 days per week. Patients who had mastectomy undergo radiotherapy at the discretion of treating physician.
therapeutic conventional surgery: Undergo early surgery
radiation therapy: Undergo radiotherapy | 125 |
| Total | 256 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease progression | 0 | 3 |
| Overall Study | Lack of insurance coverage for surgery | 0 | 1 |
| Overall Study | Patient refusal | 0 | 10 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Reasons not reported | 0 | 4 |
Baseline characteristics
| Characteristic | Arm II (Early Local Therapy) | Total | Arm I (Continued Systemic Therapy) |
|---|---|---|---|
| Age, Continuous | 55 years | 56 years | 56 years |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 38 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 13 Participants | 7 Participants |
| Race (NIH/OMB) White | 98 Participants | 200 Participants | 102 Participants |
| Sex: Female, Male Female | 125 Participants | 256 Participants | 131 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 63 / 131 | 58 / 125 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
3-year Overall Survival Rate
Overall survival (OS) was defined as time from randomization to death from any cause. All patients will be followed for survival through 5 years. Cases with incomplete follow-up or without record of vital status will be censored at the date of last contact. 3-year OS rate was estimated using Kaplan-Meier method.
Time frame: Assessed at baseline, then every 3 months within 2 years and every 6 months between 2-5 years, up to 5 years
Population: All randomized patients at step 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Continued Systemic Therapy) | 3-year Overall Survival Rate | 67.9 percentage of participants |
| Arm II (Early Local Therapy) | 3-year Overall Survival Rate | 68.4 percentage of participants |
p-value: 0.32Log Rank
Secondary
3-year Cumulative Incidence of Locoregional Recurrence/Progression
For patients in arm II (early local therapy), time to locoregional recurrence was defined as time from randomization to date of locoregional recurrence; for patients in arm A (continued systemic therapy), time to locoregional progression was defined as time from randomization to date of locoregional progression. In this study, locoregional recurrence was defined as the new development or clinically significant increase in size of any supraclavicular, infraclavicular, internal mammary or axillary adenopathy or chest wall disease or invasive in-breast recurrence for patients on arm B; for patients on arm A, locoregional progression was defined as the development of symptoms leading to a decision for local therapy. Locoregional recurrence/progression and distant progression were followed separately in the study, and the occurrence of one did not preclude the other getting reported. 3-year cumulative incidence of locoregional recurrence/progression was estimated.
Time frame: Assessed at baseline, then every 3 months within 2 years and every 6 months between 2-5 years, up to 5 years
Population: All randomized patients at step 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Continued Systemic Therapy) | 3-year Cumulative Incidence of Locoregional Recurrence/Progression | 16.3 percentage of participants |
| Arm II (Early Local Therapy) | 3-year Cumulative Incidence of Locoregional Recurrence/Progression | 39.8 percentage of participants |
Secondary
Health-related Quality of Life (HRQL)
The Functional Assessment of Cancer Therapy-Breast Trial Outcome Index (FACT-B TOI) was used as the primary HRQL endpoint, measured by the prorated aggregate score of the 24 items from the FACT-B (7 functional well-being, 7 physical well-being, 10 breast cancer specific items). The theoretical range of the prorated aggregate score was 0-96, higher scores indicate better quality of life.
Time frame: Assessed at 18 months after randomization
Population: All randomized patients at step 2 who reported quality of life data at 18 months after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Continued Systemic Therapy) | Health-related Quality of Life (HRQL) | 74.2 score on a scale | Standard Deviation 11.5 |
| Arm II (Early Local Therapy) | Health-related Quality of Life (HRQL) | 68.0 score on a scale | Standard Deviation 13.7 |