Early Surgery or Standard Palliative Therapy in Treating Patients With Stage IV Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Phase III Trial of the Value of Early Local Therapy for the Intact Primary Tumor in Patients With Metastatic Breast Cancer

Conditions
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Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Procedure: palliative surgery
* Procedure: therapeutic conventional surgery
* Radiation: palliative radiation therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>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. | Procedure: palliative surgery<br>* Undergo standard palliative surgery<br>Radiation: palliative radiation therapy<br>* Undergo standard palliative radiotherapy<br>|
| Experimental: Arm II<br>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. | Procedure: therapeutic conventional surgery<br>* Undergo early surgery<br>Radiation: radiation therapy<br>* Undergo radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Assessed at baseline, then every 3 months within 2 years and every 6 months between 2-5 years, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Assessed at baseline, then every 3 months within 2 years and every 6 months between 2-5 years, up to 5 years | 
| 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. | Assessed at 18 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, local therapy