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Neoplasms, Second Primary

Breast Diseases

Skin Diseases

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Liver Extracts

Standard of care systemic therapy at the discretion of the treating physician.

Standard of care systemic therapy plus ablation of all metastases by stereotactic body radiotherapy or surgery at the discretion of the treating physician.

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.

Stereotactic Body Radiotherapy

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.

Surgery

Steven J Chmura

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.

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).

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

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

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.

Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored).

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.

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

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.

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

National Cancer Institute (NCI)

NRG Oncology

All-cause mortality was assessed in eligible participants. Adverse events were assessed in eligible participants who received systemic therapy and/or ablation.

Standard of Care (Arm 1)

Standard of care systemic therapy plus ablation of all metastases by stereotactic body radiotherapy or surgery at the discretion of the treating physician.

Stereotactic Body Radiotherapy: 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.

Surgery: 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.

Standard of Care + Ablation (Arm 2)

Standard of Care (SOC)

Standard of Care + Ablation

Total

Age, Continuous

≤ 49 years

50-59 years

60-69 years

70-79 years

≥ 80 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

0 - Asymptomatic; 1 - Symptomatic but completely ambulatory; 2 - Symptomatic, \<50% in bed during the day; 3 - Symptomatic, \>50% in bed, but not bedbound; 4 - Bedbound; 5 - Death

Zubrod Performance Status

Positive

Negative

Positive - breast cancer cells have a lot of HER2 protein. These cancers tend to grow and spread faster than breast cancers that are HER2-negative, but are much more likely to respond to treatment with drugs that target the HER2 protein.

Negative - breast cancer cells have little or no HER2 protein.

Human epidermal growth factor receptor 2 (HER2) status

Positive - breast cancer cells may need estrogen to grow, these cells may stop growing or die when treated with substances that block the binding and actions of estrogen.

Negative - breast cancer cells do not need estrogen to grow.

Estrogen Receptor (ER) Status

Positive - breast cancer cells may need progesterone to grow, these cells may stop growing or die when treated with substances that block the binding and actions of progesterone.

Negative - breast cancer cells do not need progesterone to grow.

Progesterone Receptor (PR) Status

ER+ and/or PR+

ER- and PR-

ER- and PR- = breast cancers have no estrogen or progesterone receptors. Treatment with hormone therapy drugs is not helpful for these cancers.

Hormone Receptor Status

Number of metastases seen on standard imaging prior to enrollment.

Patient Metastasis Count

First-line standard systemic chemotherapy

Synchronous

Not synchronous

Unknown

Synchronous = the diagnosis of oligometastatic breast disease is within 6 months of the primary breast cancer diagnosis.

Not synchronous = the diagnosis of oligometastatic breast disease is more than 6 months after the primary breast cancer diagnosis.

Timing of the diagnosis of the oligometastatic breast disease relative to the primary breast cancer

The trial completed accrual to the phase II portion and was temporarily closed to accrual on September 13, 2019, pending required follow-up for the full phase II analysis, per the protocol-specified statistical analysis plan. The full phase II primary endpoint analysis was done in December 2021 and did not support reopening accrual to address the phase III research question of overall survival.

Wendy Seiferheld

Assuming an increase in median PFS from 10.5 to 19 months (HR: 0.55), 69 events provide \>90% power to conclude superiority with 1-sided α = 0.15.

Standard of care systemic therapy plus ablation of all metastases by stereotactic body radiotherapy or surgery at the discretion of the treating physician.

Stereotactic Body Radiotherapy (SBRT): 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.

Surgery: 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.

Progression-free Survival (Phase II)

Standard of Care

It is pre-specified in the study protocol that analysis of Phase III data will not be performed as per the results of the Phase II analysis.

Overall Survival (Phase III)

Eligible participants on the SOC + Ablation arm

Percentage of Participants With Treated Metastasis Progression on the SOC + Ablation Arm

Percentage of Participants With New Metastases

Grade 1

Grade 2

Grade 3

Grade 4

Eligible participants who received systemic therapy and/or ablation.

Number of Patients by Highest Grade Adverse Event Reported

CTCs Absent

CTCs Present

Eligible with blood collection consent and baseline CTC data. The protocol specifies that participants from both treatment arms are combined for this analysis.

Spots Global Cancer Trial Database for anatomic stage iv breast cancer american joint committee on cancer (ajcc) v8