Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Standard of Care Therapy with or without Stereotactic Radiosurgery and/or Surgery in Treating Patients with Limited Metastatic Breast Cancer

Protocol: NRG-BR002

Full Title

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

Purpose

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.

Study Objective

PRIMARY OBJECTIVES:

I. 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. (Phase II-R)

II. To determine whether ablation (through SBRT and/or surgical resection of all known metastases) in oligometastatic breast cancer patients significantly improves overall survival (OS). (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate treated metastasis control according to tumor receptor status (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor [HER]-2), use of chemotherapy, surgery vs. ablative therapy, and solitary metastasis vs. 2 metastasis (may expand to >= 2 to =< 4 following completion of a Phase I trial).

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 solitary metastasis vs. 2 metastases (may expand to >= 2 to =< 4 following completion of the Phase I NRG-BR001 trial).

III. To evaluate adverse events in patients who receive ablative metastasis-directed therapy to all known metastases compared with those treated with standard systemic therapy and palliative local therapy as needed only to symptomatic areas.

IV. To evaluate patient reported quality of life in terms of symptoms (pain, nausea/vomiting, fatigue and shortness of breath) and functional status between treatment arms. In addition, the Patient Reported Outcome (PRO) Common Terminology Criteria for Adverse Events (CTCAE) will be compared against the physician reported toxicity.

V. 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.

TERTIARY 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).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM 1: Patients continue to receive their current planned systemic therapy at the discretion of the treating physician.

ARM 2: Patients continue to receive their current planned systemic therapy at the discretion of the treating physician. Patients also undergo stereotactic radiosurgery in 1, 3, or 5 fractions within 3 weeks and/or surgery at the discretion of the treating physician.

ARM 1: Patients are followed every 3 months from randomization to 2 years.

ARM 2: Patients are followed 25-35 days post-ablation, every 3 months from randomization to 2 years, and then yearly thereafter.

Are you eligible?

Inclusion Criteria:

Pathologically confirmed metastatic breast cancer

Known estrogen, progesterone, and HER2 status of either primary tumor or metastasis

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

=< 2 metastases seen on standard imaging within 60 days prior to registration when any one metastasis is located in one of the following sites:

  • liver
  • central lung
  • mediastinal/cervical lymph node
  • abdominal-pelvic metastases (lymph node/adrenal gland)

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

For patients who have ONLY peripheral lung, osseous, and/or spinal metastasis: there are no restrictions on distance between the metastases; for patients with any other combination of the seven allowable metastatic sites: metastases must be > 5 cm away from each other (defined as Edge to Edge of tumor)

NOTE: If metastases are =< 5 cm away from each other, consider enrollment in NRG-BR001

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 (+/- radiotherapy) for the primary tumor

Appropriate stage for study entry based on the following diagnostic workup:

History/physical examination within 60 days prior to registration

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

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 must provide study-specific informed consent prior to study entry

Exclusion Criteria:

Pathologic evidence of local/regional breast tumor recurrence

Co-existing or prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a minimum of 3 years

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 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 CD4 count >= 200 cells/microliter within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol

Breast Cancer