Brain Metastases
Conditions
Keywords
brain metastases, Gamma Knife, Stereotactic Radiosurgery
Brief summary
This is a single-arm, single-center pilot study in which 10 patients with one to four brain metastases diagnosed on brain magnetic resonance imaging (MRI) within the past 30 days will be evaluated for study eligibility and enrolled as appropriate.
Detailed description
INTERVENTION: Enrolled patients will receive stereotactic radiosurgery (SRS) to all metastases followed by surgical resection of resectable metastases within one to 10 days following SRS. Pathologic specimens will be analyzed, and the patient will enter a standard pattern of surveillance (brain MRI every three months for two years). STUDY RATIONALE: Given the increased risk of leptomeningeal failure with surgery followed by SRS as well as the risk of radiation necrosis, new paradigms in therapy delivery and sequencing are being explored. Areas of investigation include optimization of target volume, marginal expansion, multi-fractionation, timeliness of SRS after surgery, and delivery of SRS prior to surgical resection. In theory, advantages of preoperative SRS include better target delineation, sterilization of tumor cells prior to surgical disruption of the tumor, vascular supply, and cerebrospinal fluid (CSF) spaces, and resection of tissue that would otherwise be at risk of radiation necrosis. In 2014, Asher, et al. reported that the use of neoadjuvant SRS prior to surgery was both safe and effective (even for metastases \>3 cm) with no reported leptomeningeal recurrences or radiation necrosis. More recently, Patel et al. performed a retrospective comparison of preoperative versus postoperative SRS and reported no difference in local control, distant brain failure, or overall survival. Furthermore, the authors reported significantly lower rates of leptomeningeal carcinomatosis and radiation necrosis with preoperative SRS. Huff, et al. recently published a protocol for a phase II prospective trial designed to compare outcomes using preoperative SRS versus historically cited outcomes for postoperative SRS. This pilot study mirrors this design and aims to confirm study feasibility and to assess local control, central nervous system (CNS) progression-free survival, overall survival, rates of leptomeningeal spread, rates of radiation necrosis, and quality of life measures with the use of preoperative SRS.
Interventions
DEVICEStereotactic Radiosurgery
Maximum Tumor Diameter ≤ 2 cm = 20-24 Gy; Maximum Tumor Diameter 2.1-3.0 cm = 18 Gy; Maximum Tumor Diameter 3.1-5.0 cm = 15 Gy
PROCEDURESurgical Resection
Enrolled patients will receive GK-SRS to all metastases followed by surgical resection of resectable metastases within one to10 days following GK-SRS.
DEVICEMagnetic Resonance Imaging
Following surgical resection, the patient will enter a standard pattern of surveillance (brain MRI every three months for two years).
Sponsors
Medical College of Wisconsin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntary written consent must be given before performance of any study related procedure that's is not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. 2. Female or Male subject's ≥ 18 years old at the time of informed consent. 3. Radiographically confirmed solid tumor brain metastases. 4. Criteria for surgical resection of at least one metastasis per neurosurgeon discretion. 5. Stereotactic radiosurgery candidate per radiation oncologist discretion. 6. A diagnostic MRI Brain or CT Head demonstrating the presence of 1-4 solid tumor brain metastases and lesion to be resected no more than 5 cm in any direction, performed within 30 days prior to stereotactic radiosurgery. 7. For known and unknown primary, diagnosis-specific graded prognostic assessment (ds-GPA) estimated median survival no less than 6 months. 8. Surgical resection able to be performed within 1-10 days after radiosurgery. 9. Patients currently on cytotoxic chemotherapy or immunotherapy are eligible, not including anti-vascular endothelial growth factor (anti-VEGF) therapy. 10. Female subjects who: 1. Are postmenopausal for at least 1 year before the screening visit, OR 2. Are surgically sterile, OR i. Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last study Intervention (female and male condoms should not be used together), OR ii. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.) 11. Male subjects, even if surgically sterilized (ie, status post-vasectomy), who: 1. Agree to practice effective barrier contraception during the entire study treatment period from the time of signing the informed consent through and through 4 months after the last study Intervention (female and male condoms should not be used together), OR 2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, post-ovulation methods for the female partner\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Exclusion criteria
1. Patients who received anti-VEGF therapy within 6 weeks prior to enrollment, as there is increased risk of fatal brain hemorrhage with surgical resection. 2. Major medical illnesses or psychiatric impairments, which in the investigator's opinion will prevent administration or completion of the protocol therapy and/or interfere with surveillance. 3. Patients with more than 4 brain metastases on MRI Brain. 4. Lesion to be resected is more than 5 cm in any dimension. 5. Patients with leptomeningeal metastases documented by MRI or cerebrospinal fluid (CSF) evaluation. 6. Previous whole brain radiation therapy. 7. Previous radiation therapy to the lesion to be resected. 8. Planned adjuvant focal therapy including additional radiation therapy to the brain. 9. Not a surgical candidate per neurosurgeon discretion. 10. Not a stereotactic radiosurgery candidate per radiation oncologist discretion. 11. Surgery unable to be performed between 1 - 10 days after radiosurgery. 12. Women who are pregnant or nursing as treatment involves unforeseeable risks to the fetus or child. 13. Patients who have a known or unknown primary and have an estimated median survival of less than 6 months per ds-GPA.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Subjects Undergoing Resection Following SRS. | 10 days following SRS | All subjects undergoing resection following SRS will be documented. |
| The Number of Subjects With no Identifiable Disease Following Resection. | 20 months | Identifiable disease will be determined by post-treatment MRI of the brain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Subjects Achieving CNS Progression-free Survival. | 6, 12 and 18 months | Progression/progressive disease for this outcome measure was assessed at the index lesion using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Lesions must be contrast-enhancing on T1-weighted MRI, with at least one dimension ≥ 10 mm and visible on ≥ 2 axial slices. Progression is defined as a ≥ 20% increase in the sum of diameters (with a ≥ 5 mm absolute increase) or new lesions. Subjects will be evaluated at six, 12 and 18 months. |
| The Number of Subjects Achieving Overall Survival. | 6, 12 and 18 months | The number of subjects alive at six, 12 and 18 months following surgical resection. |
| The Number of Subjects With Leptomeningeal Carcinomatosis Using Preoperative SRS. | Two years | The number of subjects with this diagnosis will be documented. |
| The Number of Subjects With Radiation Necrosis. | Two years | Radiation necrosis will be determined by radiographic appearance on posttreatment MRI. The number of patients with radiation necrosis will be documented. |
| The Number of Subjects Reporting a High Quality of Life. | Every 3 months until two years; 3, 6, 9, 12, 15, and 18 months reported | Quality of life will be measured by the MD Anderson Symptom Inventory for brain tumor (MDASI-BT). The MDASI assesses the severity of symptoms at their worst in the last. 24 hours on a 0-10 numeric rating scale (NRS), with 0 being "not present" and 10 being "as bad as you can imagine." Health-related quality of life was assessed using the EQ-5D-5L instrument. While not identical to the MDASI, the EQ-5D-5L has been shown to correlate strongly with symptom burden and overall quality-of-life measures commonly used in oncology populations and was used here as a pragmatic surrogate for global quality-of-life assessment. A High Quality of Life was defined a priori as an EQ-5D-5L visual analog scale (VAS) score ≥80, reflecting a high level of self-reported overall health status. This threshold was selected to represent preserved or favorable quality of life and to allow for consistent longitudinal reporting across study time points. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMichael Straza, MD
Medical College of Wisconsin
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 4 / 11 |
| other Total, other adverse events | 0 / 11 | 1 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
None listed