Clinical trial NCT00928226: Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases
Official title: A Phase I/II Study of Fractionated Stereotactic Radiosurgery to Treat Large Brain Metastases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Brain Cancer
Neoplasm Metastasis
Cancer of Brain and Nervous System
Metastatic Malignant Neoplasm to Brain
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2009-06-25
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The maximum tolerated dose of 3-session (ie, treatment) stereotactic radiosurgery (SRS) to treat brain metastases greater than 4.2 cm³ in size will be determined.

This study investigates if increasing radiation dose improves outcome for patients without greater toxicity (side effects).

Detailed description: Brain metastases are the most common intracranial tumors and occur in approximately 25% of patients with cancer. In the US, approximately 170,000 cancer patients a year are diagnosed with brain metastases.

The prognosis of patients with brain metastases is variable and depends on several factors, including performance status, age, control of the primary tumor, and extent of extracranial disease. Historically, patients with brain metastases who receive supportive care only have median survival of 1 to 2 months. However, a subgroup of patients with favorable prognosis who undergo treatment can enjoy an extended life expectancy with median survival of 10 to 16 months. Treatment options for brain metastases include medical management, surgery, and radiation therapy (radiotherapy). Both surgery and radiotherapy have an important role in management of brain metastases, and an optimized treatment plan may include both. It is well-established that surgery followed by conventional whole brain radiation (WBRT) decreases local recurrence and improves median survival compared to WBRT alone. Conventional WBRT is administered as radiotherapy to the whole cranium delivered in 10 to 20 daily treatments.

For this study, radiotherapy will be delivered using stereotactic radiosurgery (SRS) to treat individual metastases. SRS has the advantage of sparing normal brain tissue. In SRS, high energy radiation is precisely directed at the target lesion. Due to the steep fall-off of the radiation dose away from the target, the advantage of relative sparing of the normal brain may be realized. The present study is based on a rationale of treating brain metastases with surgical resection followed by adjuvant SRS to the resection cavity, while deferring conventional WBRT for salvage therapy.

WBRT is associated with a short-term decline in quality of life and long-term deficits in neurocognitive function ("late effects"). Late toxicity of WBRT, such as memory impairment and dementia, is usually irreversible and is likely due to demyelination, vascular damage, and necrosis. Following WBRT, the actuarial rate of neurocognitive toxicity at 2 years can be up to 49%. Recipients of WBRT may demonstrate a \> 2 standard deviation decline in their performance at 6 months. Compared to SRS alone, WBRT was reported to be associated with a marked decline in learning and memory function at 4 months (49% vs 23%, in favor of SRS).

To minimize the potential late effects of WBRT, investigators have explored the use of SRS alone, deferring the use of WBRT for salvage treatment if needed. Both retrospective analyses and a prospective randomized trial reported no apparent survival benefit to combining WBRT with SRS compared to SRS alone

Primary Objectives: Determine the maximum tolerated dose (MTD) of stereotactic radiosurgery (SRS).

Secondary Objectives:

1. Determine the local control rate as assessed on MRI and clinical exam.
2. Determine short- and long-term adverse effects.
3. Determine the distant intra-cranial control rate.
4. Determine the overall survival rate.
5. Assess the patient's health related quality of life.

Treatment Group assignment will be by SRS dose level. SRS will be administered as 3 fractions. Radiation dose is administered as "Greys" (or "Grays"; abbreviated Gy), a unit by which radiation is measured. Treatment Groups are as follows: Group 1 = 24 Gy (administered as 8 Gy x 3) Group 2 = 7 Gy (9 Gy x 3); Group 3 = 30 Gy (10 Gy x 3); Group 4 = 33 Gy (11 Gy x 3).

Within each Treatment Group, analysis may be stratified by tumor size and suitability for surgical resection, as below. For those participants eligible for surgical resection, the procedure will be conducted in advance of the SRS treatment.

* Strata A will be those with tumors 4.2 to 14.1 cm³, and suitable for resection.
* Strata B will be those with tumors 4.2 to 14.1 cm³, but not suitable for resection.
* Strata C will be those with tumors 14.2 to 33.5 cm³, and suitable for resection.
* Strata D will be those with tumors 14.2 to 33.5 cm³, but not suitable for resection.

Eligibility criteria: INCLUSION CRITERIA

* Age 18 years and older
* Pathologically-proven solid tumor malignancy
* 1 to 4 brain metastases, one of which is 4.2 to 33.5 cm³.
* Prior surgery or SRS is allowed as long as the target metastatic lesion in this study has not previously been treated with SRS.
* Prior cytotoxic systemic therapy must be completed ≥ 5 days prior to radiosurgery. No concurrent cytotoxic systemic therapy along with SRS. Cytotoxic systemic therapy to start ≥ 5 days after the completion of SRS.
* Life expectancy of ≥ 12 weeks.
* Ability to understand and the willingness to sign a written informed consent.

EXCLUSION CRITERIA

* Previously treated with whole brain irradiation
* Target metastatic lesion previously been treated with SRS.
* \> 4 total brain metastases at the time of initial evaluation.
* Pregnant
* Unable to give informed consent.

Primary outcomes:
measure: Stereotactic Radiosurgery (SRS) Maximum-tolerated Dose (MTD)
timeFrame: 60 days
Secondary outcomes:
measure: Local Disease Control
timeFrame: 12 months
measure: Distant Intra-cranial Disease Control
timeFrame: 12 months
measure: Adverse Effects Within 30 Days
timeFrame: 30 days
measure: Adverse Effects More Than 30 Days up to 1 Year
timeFrame: after 30 days and up to 1 year
measure: Overall Survival (OS)
timeFrame: 3 years
measure: Health-related Quality of Life (HR-QoL), as Measured by EORTC QLQ-C30
timeFrame: 6 months
measure: Health-related Quality of Life (HR-QoL), as Measured by EORTC Brain Cancer Module QLQ-BN20
timeFrame: 6 months
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
Study officials:
affiliation: Stanford University
name: Clara Choi
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Scott Soltys
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rahimy E, Dudley SA, von Eyben R, Pollom EL, Seiger K, Modlin L, Wynne J, Fujimoto D, Jacobs LR, Chang SD, Gibbs IC, Hancock SL, Adler JR, Li G, Choi CYH, Soltys SG. Phase I/II Dose-Escalation Trial of 3-Fraction Stereotactic Radiosurgery for Resection Cavities From Large Brain Metastases: Health-related Quality of Life Outcomes. Am J Clin Oncol. 2021 Nov 1;44(11):588-595. doi: 10.1097/COC.0000000000000868.