Description:
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.
Title
- Brief Title: Standard of Care Therapy With or Without Stereotactic Radiosurgery and/or Surgery in Treating Patients With Limited Metastatic Breast Cancer
- Official 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
Clinical Trial IDs
- ORG STUDY ID:
NRG-BR002
- SECONDARY ID:
NCI-2014-01810
- SECONDARY ID:
NRG-BR002
- SECONDARY ID:
NRG-BR002
- SECONDARY ID:
U10CA180868
- NCT ID:
NCT02364557
Conditions
- Dyspnea
- Fatigue
- Nausea and Vomiting
- Pain
- Stage IV 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.
Detailed Description
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 in addition to standard medical therapy alone.
IV. 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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Arm 1 (standard of care) | No Intervention | Patients continue to receive their current planned systemic therapy at the discretion of the treating physician. | |
| Arm 2 (stereotactic radiosurgery, surgery) | Experimental | 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. | |
Eligibility Criteria
Inclusion Criteria:
- Pathologically confirmed metastatic breast cancer
- Known estrogen, progesterone, and HER2 status of either primary tumor or metastasis
- ≤ 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(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
- 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
Exclusion Criteria:
- Pathologic evidence of 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 (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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Progression-free survival (failure: progression or death due to any cause) (Phase II-R) |
| Time Frame: | From the date of randomization to the date of first PFS failure or last follow-up; assessed up to 3 years |
| Safety Issue: | |
| Description: | Progression-free survival will be estimated by the Kaplan-Meier method, with progression defined as: progression of initial/treated metastases (using the revised Response Evaluation Criteria in Solid Tumors [RECIST] guideline), appearance of new metastases, or death due to any cause. The distribution of PFS estimates between the two arms will be compared using the log rank test. |
Secondary Outcome Measures
| Measure: | Appearance of new metastases |
| Time Frame: | From the date of randomization to the date of the first appearance of any new metastases; assessed up to 8 years |
| Safety Issue: | |
| Description: | Failure for this endpoint will be the appearance of any new metastases. The cumulative probability of new metastases in the presence of competing failure events will be estimated by the cumulative incidence method. The cumulative incidence distributions between the two arms will be compared using Gray's test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with the incidence of new metastases. |
| Measure: | Incidence of adverse events graded according to National Cancer Institute CTCAE version 4 |
| Time Frame: | From the date of randomization to the date of death or last follow-up; assessed up to 2 years |
| Safety Issue: | |
| Description: | The frequencies and severity of adverse events by treatment arm will be analyzed. |
| Measure: | Initial presence of CTCs in blood samples |
| Time Frame: | Baseline |
| Safety Issue: | |
| Description: | The prognostic effect of the initial presence of CTCs at baseline on PFS (OS) will be evaluated using the Cox proportional hazards model, controlling for treatment effect and stratification factors. The hypothesis tests will be two-sided and will use an alpha level of 0.05 to determine significance. |
| Measure: | Presence of CTCs after treatment in blood samples |
| Time Frame: | Up to 3 months |
| Safety Issue: | |
| Description: | The interaction between treatment effect and the initial presence of CTCs at baseline on PFS (OS) will be evaluated in the Cox model, which will include an indicator for treatment group, an indicator for presence of CTCs (>= 5 per 7.5 ml of blood), and their interaction term. The analysis will be adjusted for the stratification factors. |
| Measure: | Change in CTC count in blood samples |
| Time Frame: | Baseline to up to 3 months |
| Safety Issue: | |
| Description: | The effect of change in CTC count from CTC >= 2 per 7.5 ml of blood at baseline to CTC = 0 at follow-up after initial treatment on PFS (OS) will be evaluated using the Cox proportional hazards model, controlling for treatment effect and stratification factors. The analyses will be conditional on a patient's event-free survival up to post-treatment evaluation. The interaction between treatment effect and change in CTC count will be evaluated in the Cox model, which will include an indicator for treatment group, an indicator for change of CTCs, and their interaction term. |
| Measure: | Levels of ctDNA in plasma samples |
| Time Frame: | Up to 3 months |
| Safety Issue: | |
| Description: | The prognostic effect of dichotomized ctDNA on PFS (OS) will be evaluated using the Cox proportional hazards model, controlling for treatment effect and stratification factors. In addition, the presence of the interaction between treatment effect and dichotomized ctDNA will be evaluated (predictive effect). Spearman rank correlation coefficient will be used to correlate the levels of CTCs and ctDNA. |
Details
| Phase: | Phase 2/Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | NRG Oncology |
Last Updated
June 1, 2021
