Testing Whether Treating Breast Cancer Metastases With Surgery or High-Dose Radiation Improves Survival

Study Overview
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Brief Summary
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This randomized phase II/III trial studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Standard of care therapy comprising chemotherapy, hormonal therapy, biological therapy, and others may help stop the spread of tumor cells. Radiation therapy and/or surgery is usually only given with standard of care therapy to relieve pain; however, in patients with limited metastatic breast cancer, stereotactic radiosurgery, also known as stereotactic body radiation therapy, may be able to send x-rays directly to the tumor and cause less damage to normal tissue and surgery may be able to effectively remove the metastatic tumor cells. It is not yet known whether standard of care therapy is more effective with stereotactic radiosurgery and/or surgery in treating limited metastatic breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Phase II: To determine whether ablation [through stereotactic body radiation therapy (SBRT) (stereotactic radiosurgery) and/or surgical resection of all known metastases] in oligometastatic breast cancer patients provides a sufficient signal for improved progression-free survival (PFS) to warrant full accrual to the Phase III portion of the trial. II. Phase III: To determine whether ablation (through SBRT and/or surgical resection of all known metastases) in oligometastatic breast cancer patients significantly improves overall survival (OS). SECONDARY OBJECTIVES: I. To evaluate treated metastasis control according to tumor receptor status [estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2)], use of chemotherapy, surgery versus (vs.) ablative therapy, and number of metastases. II. To evaluate whether the addition of ablative metastasis directed therapy significantly reduces the number of distant recurrences (new metastases) in patients who progress according to tumor receptor status (ER, PR, HER-2); use of chemotherapy, and number of metastases. III. To evaluate adverse events in patients who receive ablative metastasis-directed therapy to all known metastases in addition to standard medical therapy compared with those treated with standard medical therapy alone. EXPLORATORY OBJECTIVE: I. To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout the radiation therapy processes, including imaging, simulation, target and critical structure definition, treatment planning, image guidance, and delivery. TRANSLATIONAL RESEARCH OBJECTIVES: I. To determine whether < 5 circulating tumor cells (CTCs) (per 7.5 ml of blood) is an independent prognostic (outcome) marker for improved PFS and OS in oligometastatic breast cancer. II. To determine whether < 5 CTCs (per 7.5 ml of blood) is an independent predictive (response to therapy) marker for improved PFS and OS in oligometastatic breast cancer. III. To determine whether eliminating CTCs (0/7.5 ml of blood in patients with at least 2 CTCs at registration) is both a prognostic and predictive marker for improved PFS and OS. IV. To evaluate the prognostic and predictive properties of CTC count as a continuous measure of PFS and OS. V. To store material for retrospective analysis of circulating tumor deoxyribonucleic acid (ctDNA). VI. To store material for retrospective analysis of circulating micro-ribonucleic acid (RNA).

Official Title
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A Phase IIR/III Trial of Standard of Care Therapy With or Without Stereotactic Body Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer

Conditions
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Anatomic Stage IV Breast Cancer American Joint Committee on Cancer (AJCC) v8, Metastatic Breast Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Liver, Metastatic Malignant Neoplasm in the Lung, Metastatic Malignant Neoplasm in the Lymph Nodes, Metastatic Malignant Neoplasm in the Spine, Prognostic Stage IV Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8

Intervention / Treatment
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* Radiation: Stereotactic Body Radiotherapy
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient cannot be considered eligible for this study unless all of the following conditions are met. Pathologically confirmed metastatic breast cancer Known estrogen, progesterone, and HER2 status of either primary tumor or metastasis; Note: estrogen, progesterone and HER2 status of metastasis preferred for stratification Number of allowable metastases: =< 4 metastases seen on standard imaging within 60 days prior to registration when all metastatic disease is located within the following sites: Peripheral lung Osseous (bone) Spine Central lung Abdominal-pelvic metastases (lymph node/adrenal gland) Liver Mediastinal/cervical lymph node All known disease amenable to metastasis-directed therapy with either SBRT or resection Note: Symptomatic bone metastasis are allowed if ablative therapy can be delivered Note: Sites for possible surgical excision include lung, liver, adrenal gland, bone, small intestine, large intestine, ovary, and amenable nodal disease sites Note: Surgical stabilization is allowed for a metastasis if it is followed by conventionally fractionated external beam radiotherapy Maximum diameter of individual metastasis in any dimension =< 5 cm There are no restrictions on distance between the metastases Patients must be registered within 365 days of the initial metastatic breast cancer diagnosis; first-line standard systemic therapy (chemotherapy, anti-endocrine therapy, anti-HER2, or other standard targeted therapy) for metastatic breast cancer must be given or planned to be given; if given before study entry, it cannot have exceeded a duration of 12 months at the time of registration (Note: sequencing of ablative therapy [surgery or SBRT] relative to systemic therapy, for patients randomized to Arm 2, is at the discretion of the treating physician) The primary tumor site must be controlled prior to registration For those who present with synchronous primary and oligometastatic disease, primary must be controlled prior to registration The definition of control is definitive surgery by excision or mastectomy (+/- radiotherapy) per institution preference For those who present with local recurrence and oligometastatic disease, local recurrence must be controlled prior to registration The definition of control is definitive surgery by excision or mastectomy (+/- radiotherapy) per institution preference Appropriate stage for study entry based on the following diagnostic workup: History/physical examination within 60 days prior to registration Clinical grade computed tomography (CT) scans of the chest, abdomen, and pelvis with radionuclide bone scan OR whole body positron emission tomography (PET)/CT within 60 days prior to study registration Zubrod performance status =< 2 within 60 days prior to registration Blood cell count (CBC)/differential obtained within 60 days prior to registration on study Absolute neutrophil count (ANC) >= 500 cells/mm^3 Platelets >= 50,000 cells/mm^3 Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) For females of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to study registration The patient or a legally authorized representative must provide study-specific informed consent prior to study entry Exclusion Criteria: Patients with any of the following conditions are NOT eligible for this study. Pathologic evidence of active primary disease or local/regional breast tumor recurrence at the time of registration; Co-existing or prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a minimum of 3 years; previous RT dose, date, fraction size, must be reported Metastases with indistinct borders making targeting not feasible Note: A potential issue with bone metastases is that they often are not discrete; since many patients on this protocol will have bone metastases, this will be an important issue; theoretically, Houndsfield units might provide an appropriate measure; however, a sclerotic lesion against dense cortical bone will not have a sharp demarcation based on Houndsfield units (HU); therefore, we acknowledge that such determinations will pose a challenge and thus the physician's judgment will be required Prior palliative radiation treatment for metastatic disease to be treated on the protocol (including radiopharmaceuticals) Metastases located within 3 cm of the previously irradiated structures: Spinal cord previously irradiated to > 40 Gy (delivered in =< 3 Gy/fraction) Brachial plexus previously irradiated to > 50 Gy (delivered in =< 3 Gy/fraction) Small intestine, large intestine, or stomach previously irradiated to > 45 Gy (delivered in =< 3 Gy/fraction) Brainstem previously irradiated to > 50 Gy (delivered in =< 3 Gy/fraction) Whole lung previously irradiated with prior percent volume receiving greater than or equal to 20 Gy (V20Gy)> 30% (delivered in =< 3 Gy/fraction) Primary tumor irradiated with SBRT Metastasis irradiated with SBRT Brain metastases Exudative, bloody, or cytological proven malignant effusions Severe, active co-morbidity defined as follows: Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months Transmural myocardial infarction within the last 6 months Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration Pregnancy; lactating females must cease expression of milk prior to signing consent to be eligible Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a cluster of differentiation 4 (CD4) count >= 200 cells/microliter within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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 |
| --- | --- |
| No Intervention: Standard of Care (SOC)<br>Standard of care systemic therapy at the discretion of the treating physician. | |
| Experimental: Standard of Care + Ablation<br>Standard of care systemic therapy plus ablation of all metastases by stereotactic body radiotherapy or surgery at the discretion of the treating physician. | Radiation: Stereotactic Body Radiotherapy<br>* Patients receive 1, 3, or 5 fractions of radiation, beginning within 6 weeks of study entry. For metastases in the peripheral lung, patients receive a single fraction of 30 Gy or 3 fractions for a total of 45 Gy. For a single liver metastases, patients receive a single fraction of 30 Gy. For metastases in the abdominal-pelvic or liver (>1), patients receive 3 fractions for a total of 45 Gy. For metastases in the central lung or mediastinal/ cervical lymph nodes, patients receive 5 fractions for a total of 50 Gy. For spinal metastases, patients receive 1 fraction of 20 Gy. For non-spinal osseous metastases, patients receive 3 fractions for a total of 30 Gy. For thoracic/cervical spine metastases, patients receive 5 fractions for a total of 35 Gy.<br>* Other names: stereotactic ablative radiotherapy (SABR);Procedure: Surgery<br>* All surgical resections will be approached with intent of an R0 resection (rendering the patient with no evidence of measureable disease and pathologic negative margin) and must occur within 6 weeks of study entry. Approach to surgery will be based upon the treating surgeon. An open, laparoscopic, or thorascopic approach is acceptable.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Phase II) | Progression (failure) is defined as any of the following: progression of metastases, new metastases, or death. Progression-free survival (PFS) time is defined as time from randomization to the date of first progression, death, or last contact when participant had a documented clinical assessment (censored). PFS rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Median PFS is provided. | From randomization to last follow-up. Follow-up schedule: 3 mos after randomization and every 3 months to 24 months, then every six months to five years, then annually. Maximum follow-up at time of analysis was 63 months. | 
| Overall Survival (Phase III) | Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). | From randomization to last follow-up. Follow-up schedule: 3 mos after randomization and every 3 months to 24 months and then annually. Maximum follow-up at time of analysis was 63 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treated Metastasis Progression on the SOC + Ablation Arm | Metastasis progression (failure) is defined as the clearance and subsequent recurrence or the development of new metastases in the treated area. Failure time is defined as time from randomization to the date of first failure, last contact when participant had a documented clinical assessment (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method. Two-year failure rates are provided here. | From randomization to last follow-up. Follow-up schedule: 3 months after randomization, every 3 months up to 24 months, every six months up to five years, then annually. Maximum follow-up at time of analysis was 63 months. Two-year rates are provide here. | 
| Percentage of Participants With New Metastases | New metastases (failure) is defined as the appearance of any new metastases. Failure time is measured from randomization to the date of first failure, last contact when participant had a documented clinical assessment (censored), or death without failure (competing risk). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year failure rates are provided here | From randomization to last follow-up. Follow-up schedule: 3 months after randomization, every 3 months up to 24 months, every six months up to five years, then annually. Maximum follow-up at time of analysis was 63 months.Two-year rates are provided here. | 
| Number of Patients by Highest Grade Adverse Event Reported | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. | From randomization to last follow-up. Follow-up schedule: Arm 1: 3 mos. after randomization / Arm 2: weekly during SBRT and the last day of SBRT; both arms: then every 3 mos. to 24 mos., then annually. Maximum follow-up at time of analysis was 63 months. | 
| Progression-free Survival in the Presence or Absence of Circulating Tumor Cells (CTCs) | The presence of CTCs is defined as ≥ 5 CTCs (per 7.5ml of blood). Progression (failure) is defined as any of the following: progression of metastases, new metastases, or death. Progression-free survival (PFS) time is defined as time from randomization to the date of first progression, death, or last contact when participant had a documented clinical assessment (censored). PFS rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the groups, which is reported in the statistical analysis results. Two-year PFS rates are provided here | From randomization to last follow-up. Follow-up schedule: 3 months after randomization, every 3 months up to 24 months, every six months up to five years, then annually. Maximum follow-up at time of analysis was 63 months.Two-year rates are provided here. |