A Randomized Controlled Study Of Neurocognitive Outcomes In Patients With Five Or More Brain Metastases Treated With Radiosurgery Or Whole-Brain Radiotherapy
18 Years
N/A
Both
Brain Metastases
Trial Information
A Randomized Controlled Study Of Neurocognitive Outcomes In Patients With Five Or More Brain Metastases Treated With Radiosurgery Or Whole-Brain Radiotherapy
This is randomized controlled study of neurocognitive outcomes in patients with five or more
brain metastases treated with stereotactic radiosurgery (SRS), specifically the Gamma Knife
(GK) system, or whole-brain radiation therapy (WBRT). The goal of the study is to enroll 120
patients with at least five (≥5) newly-diagnosed brain metastases from non-melanoma, except
melanoma patients with BRAF V600E B-Raf protein mutation, primary cancers with the largest
intracranial tumor volume ≤10 cc, ≤15 cc total tumor volume, absence of leptomeningeal
disease on MRI, and Karnofsky performance status (KPS) score ≥70 (unless due to intracranial
disease), and KPS expected to improve to ≥70 with treatment.
All study participants will undergo standard, pre-treatment clinical evaluations that
include: complete clinical/neurologic exam, performance status assessment, systemic staging,
and diagnostic MRI of the brain. The baseline neurocognitive function (NCF) will be assessed
by a short (20-30 minute) online test battery that can be completed by patients at home. All
study participants will be randomized to receive radiosurgical or whole-brain radiation
treatment for their brain metastases. All patients will have treatment response assessments
every 10-12 weeks consisting of a clinical/neurologic exam, performance status evaluation,
disease re-staging (if indicated), and diagnostic MRI of the brain. If progressive disease
is identified (radiographic progression of treated lesions or new brain lesions), the
patients will be considered for "salvage" therapy which will primarily consiste of SRS,
WBRT, surgery±brachytherapy or best supportive care (e.g. steroids only). The preferred
salvage therapy will be SRS provided that the re-treatment criteria are met. The NCF
follow-up will start 2 weeks after completion of the initial SRS treatment and will repeat
at 2-week intervals, irrespective of any salvage therapy that may be indicated. All study
participants will be followed until death or withdrawal from the study.
The primary aim of this study is to compare the change in neurocognitive outcome between
baseline and 6 months for surviving patients in upfront WBRT versus SRS treatment groups.
The primary study endpoint is neurocognitive function as measured by a significant change in
online neurocognitive function (oNCF) z-score from baseline to 6 months. The outcomes will
be compared after initial treatment and then repeatedly in follow-up, and will include the
impact of salvage SRS treatments. This approach will allow us to assess the relative impact
on neurocognitive outcomes of repeat SRS treatments to sites of new brain metastases.
Since SRS and WBRT are two very different forms of treatment (single high-dose treatment vs.
multiple low-dose treatments) with markedly different target volumes, it is expected that
local control rates will also be markedly different. This, in turn, will impact salvage
therapies and associated costs. This study will evaluate local control rates and overall
intracranial disease control at 3, 6, 9, and 12 months as a function of initial treatment
cohort (SRS vs. WBRT). We also expect significant differences between the treatment groups
in patient and caregiver reported quality of life (QoL) measures.
It is also expected that the SRS cohort will require multiple SRS treatments over the course
of the study since, unlike WBRT, the treatments target only gross brain metastases and do
not address microscopic (clinically undetectable) disease. Conversely, WBRT is expected to
result in inferior control rates of gross metastatic disease, increasing the likelihood of
subsequent SRS or other salvage therapy. For these reasons, we will track the actual costs
of treatments over the course of the study, including the need for supportive care and the
ability of patients to continue to work in their previous occupation.
The structure of the current study provides a unique opportunity to explore various
dosimetric SRS parameters in the setting of multiple brain metastases. Dose-volume criteria
for SRS have been established in a prospective RTOG 90-05 dose-finding study and
subsequently validated in RTOG 95-08, a randomized controlled trial of WBRT±SRS in patients
with 1-3 brain metastases. Several single-institution series as well as multi-institutional
retrospective analyses support the use of single-dose SRS for treatment of brain metastases;
however, the dose-volume criteria and prescription guidelines are not known in the setting
of ≥5 brain metastases where dose interaction among different lesion targets are much more
likely. These interactions can potentially lead to increased rates of radiation necrosis,
and if the SRS doses are arbitrarily reduced because of such concerns, then to a potentially
decreased local control rates. These parameters will be closely tracked in this study with
the aim of establishing an evidence-based dosimetric guidelines for radiosurgical treatment
of multiple (≥5) brain metastases.
The data gained from this study could help define patient selection and treatment criteria
for SRS of multiple brain metastases as a potential alternative to WBRT in a select group of
patients. This will also be a first study of its kind to use online neurocognitive
assessments for its primary endpoints to demonstrate feasibility and cost-effectiveness of
such an approach in a multi-institutional setting.
Inclusion Criteria:
- Pathologically (histologically or cytologically) proven diagnosis of a
non-hematopoietic malignancy other than small cell lung cancer and germ cell
malignancy within 5 years of registration. If the original histologic proof of
malignancy is greater than 5 years, then pathological confirmation is required (e.g.
from extra- or intra-cranial disease).
- If an open biopsy is performed, the patient must be at least one week post biopsy.
This requirement does not apply to patients who undergo stereotactic biopsies.
- Patients with ≥5 measurable brain metastases on a diagnostic-quality
contrast-enhanced magnetic resonance imaging (MRI) obtained within 30 days prior to
registration.
- Patients with ≤10 cc largest tumor volume, and ≤15 cc total tumor volume.
- History/physical examination within 30 days prior to registration.
- Age ≥18 years.
- Karnofsky performance status ≥70 (RTOG recursive partitioning analysis (RPA) Class I
& II).
- Minimum pre-treatment oNCF score ≥70.
- Patients must provide study-specific informed consent prior to study entry.
- Women of child-bearing age must have a negative, quantitative serum pregnancy test
≤14 days prior to study entry, or have a documented reason why such a test is not
necessary (e.g. history of tubal ligation).
- Patients must be able to speak and read English fluently (required for the use of
online NCF testing).
- Patients must demonstrate basic computer literacy skills and have access to an
internet terminal (required for the use of online NCF testing).
Exclusion Criteria:
- Clinical (e.g. multiple new cranial nerve deficits in the absence of obvious
radiographic disease to explain symptoms) or radiographic evidence of leptomeningeal
disease.
- Patients with measurable brain metastasis(es) resulting from small cell lung cancer
and/or germ cell malignancy.
- No documentation of prior cytotoxic or other therapy for malignancy if such therapy
was previously received. Note: This does not apply to patients with synchronous
metastases at initial diagnosis.
- Contraindication to MR imaging, such as implanted metal devices or foreign bodies,
severe claustrophobia, or contraindications to contrast agent administration.
- Estimated glomerular filtration rate (eGFR) <60 within 6 weeks prior to registration.
• Prior radiation therapy to the brain. • 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.
- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization, or precluding study therapy at the time of
registration.
- Uncontrolled, clinically significant cardiac arrhythmias. - Radiologic or
clinical evidence of hydrocephalus, or history of previously treated
hydrocephalus.
- Women of childbearing potential and male participants who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the radiation treatment involved in this study is potentially
teratogenic
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
To compare the relative change in neurocognitive outcomes (change in oNCF z-score) between baseline and 6 months for surviving patients in upfront WBRT vs. SRS treatment groups.
Outcome Description:
All participants will be asked to complete: Online brain function testing: Complete a short 20-minute online brain function (cognitive) assessment every 2 weeks (twice per month, at least 10-14 days apart). Quality of Life Questionnaire: Complete a self-reported (if patient) and caregiver quality of life questionnaires every 10-12 weeks (2.5-3 months). These questionnaires take approximately 15-20 minutes to complete and can be done online or in clinic during follow-up visits.
Outcome Time Frame:
Every 3 months for 12 months
Safety Issue:
No
Principal Investigator
Igor J Barani, MD
Investigator Role:
Study Chair
Investigator Affiliation:
University of California, San Francisco
Authority:
United States: Institutional Review Board
Study ID:
121010/12-01
NCT ID:
NCT01731704
Start Date:
December 2012
Completion Date:
December 2018
Related Keywords:
- Brain Metastases
- 5 or more brain metastases
- proven diagnosis of a non-hematopoietic malignancy
- non-small cell lung cancer or germ cell malignancy
- Neoplasm Metastasis
- Neoplasms, Second Primary
- Brain Neoplasms
Name | Location |
|---|---|
| University of California, San Francisco | San Francisco, California 94143 |
